Sample records for tec kinases itk
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SH2-dependent autophosphorylation within the Tec family kinase Itk.
Joseph, Raji E; Severin, Andrew; Min, Lie; Fulton, D Bruce; Andreotti, Amy H
2009-08-07
The Tec family kinase, Itk (interleukin-2 tyrosine kinase), undergoes an in cis autophosphorylation on Y180 within its Src homology 3 (SH3) domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening Src homology 2 (SH2) domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full-length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the betaD strand. These results are extended into Btk (Bruton's tyrosine kinase), a Tec family kinase linked to the B-cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA-causing mutations might impair Btk phosphorylation.
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SH2 dependent autophosphorylation within the Tec family kinase Itk
Joseph, Raji E.; Severin, Andrew; Min, Lie; Fulton, D. Bruce; Andreotti, Amy H.
2009-01-01
The Tec family kinase, Itk, undergoes an in cis autophosphorylation on Y180 within its SH3 domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening SH2 domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the βD strand. These results are extended into Btk, a Tec family kinase linked to the B cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA causing mutations might impair Btk phosphorylation. PMID:19523959
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Bogin, Yaron; Ainey, Carmit; Beach, Dvora; Yablonski, Deborah
2007-04-17
ITK (IL-2-inducible T cell kinase), a Tec family protein tyrosine kinase (PTK), is one of three PTKs required for T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1). Like Src and Abl family PTKs, ITK adopts an inactive, "closed" conformation, and its conversion to the active conformation is not well understood, nor have its direct substrates been identified. In a side-by-side comparison of ITK and ZAP-70 (zeta chain-associated protein kinase of 70 kDa), ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not. SLP-76 (SH2-domain-containing leukocyte protein of 76 kDa), an adaptor required for TCR-induced activation of PLC-gamma1, was required for the phosphorylation of both PLC-gamma1 sites in intact cells. Furthermore, this event depended on the N-terminal tyrosines of SLP-76. Likewise, SLP-76, particularly its N-terminal tyrosines, was required for TCR-induced tyrosine phosphorylation and activation of ITK but was not required for the phosphorylation or activation of ZAP-70. Both ZAP-70 and ITK phosphorylated SLP-76 in vitro; thus, both PTKs are potential regulators of SLP-76, but only ITK is regulated by SLP-76. Upon TCR stimulation, a small fraction of ITK bound to SLP-76. This fraction, however, encompassed most of the catalytically active ITK. Catalytic activity was lost upon mild elution of ITK from the SLP-76-nucleated complex but was restored upon reconstitution of the complex. We propose that SLP-76 is required for ITK activation; furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation.
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Iyer, Archana S.; Morales, J. Luis; Huang, Weishan; Ojo, Folake; Ning, Gang; Wills, Elizabeth; Baines, Joel D.; August, Avery
2011-01-01
Mast cells are critical effector cells in the pathophysiology of allergic asthma and other IgE-mediated diseases. The Tec family of tyrosine kinases Itk and Btk serve as critical signal amplifiers downstream of antigen receptors. Although both kinases are expressed and activated in mast cells following FcϵRI stimulation, their individual contributions are not clear. To determine whether these kinases play unique and/or complementary roles in FcϵRI signaling and mast cell function, we generated Itk and Btk double knock-out mice. Analyses of these mice show decreased mast cell granularity and impaired passive systemic anaphylaxis responses. This impaired response is accompanied by a significant elevation in serum IgE in Itk/Btk double knock-out mice. In vitro analyses of bone marrow-derived mast cells (BMMCs) indicated that Itk/Btk double knock-out BMMCs are defective in degranulation and cytokine secretion responses downstream to FcϵRI activation. These responses were accompanied by a significant reduction in PLCγ2 phosphorylation and severely impaired calcium responses in these cells. This defect also results in altered NFAT1 nuclear localization in double knock-out BMMCs. Network analysis suggests that although they may share substrates, Itk plays both positive and negative roles, while Btk primarily plays a positive role in mast cell FcϵRI-induced cytokine secretion. PMID:21212279
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Joseph, Raji E.; Kleino, Iivari; Wales, Thomas E.; Xie, Qian; Fulton, D. Bruce; Engen, John R.; Berg, Leslie J.; Andreotti, Amy H.
2014-01-01
Itk and Btk are nonreceptor tyrosine kinases of the Tec family that signal downstream of the T cell receptor (TCR) and B cell receptor (BCR), respectively. Despite their high sequence similarity and related signaling roles, Btk is a substantially more active kinase than Itk. We showed that substitution of six of the 619 amino acid residues of Itk with those of Btk was sufficient to completely switch the activities of Itk and Btk. The substitutions responsible for the swap in activity are all localized to the activation segment of the kinase domain. Nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry analyses revealed that Itk and Btk had distinct protein dynamics in this region, which could explain the observed differences in catalytic efficiency between these kinases. Introducing Itk with enhanced activity into T cells led to enhanced and prolonged TCR signaling compared to that in cells with wild-type Itk. These findings imply that evolutionary pressures have led to Tec kinases having distinct enzymatic properties depending on the cellular context. We suggest that the weaker catalytic activities observed for T cell–specific kinases is one mechanism to regulate cellular activation and prevent aberrant immune responses. PMID:23982207
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Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLCgamma1.
Min, Lie; Joseph, Raji E; Fulton, D Bruce; Andreotti, Amy H
2009-12-15
Interleukin-2 tyrosine kinase (Itk) is a Tec family tyrosine kinase that mediates signaling processes after T cell receptor engagement. Activation of Itk requires recruitment to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. After activation, Itk phosphorylates and activates phospholipase C-gamma1 (PLC-gamma1), leading to production of two second messengers, DAG and IP(3). We have previously shown that phosphorylation of PLC-gamma1 by Itk requires a direct, phosphotyrosine-independent interaction between the Src homology 2 (SH2) domain of PLC-gamma1 and the kinase domain of Itk. We now define this docking interface using a combination of mutagenesis and NMR spectroscopy and show that disruption of the Itk/PLCgamma1 docking interaction attenuates T cell signaling. The binding surface on PLCgamma1 that mediates recognition by Itk highlights a nonclassical binding activity of the well-studied SH2 domain providing further evidence that SH2 domains participate in important signaling interactions beyond recognition of phosphotyrosine.
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Hussain, Alamdar; Mohammad, Dara K; Gustafsson, Manuela O; Uslu, Merve; Hamasy, Abdulrahman; Nore, Beston F; Mohamed, Abdalla J; Smith, C I Edvard
2013-03-08
The inducible T cell kinase-spleen tyrosine kinase (ITK-SYK) oncogene consists of the Tec homology-pleckstrin homology domain of ITK and the kinase domain of SYK, and it is believed to be the cause of peripheral T cell lymphoma. We and others have recently demonstrated that this fusion protein is constitutively tyrosine-phosphorylated and is transforming both in vitro and in vivo. To gain a deeper insight into the molecular mechanism(s) underlying its activation and signaling, we mutated a total of eight tyrosines located in the SYK portion of the chimera into either phenylalanine or to the negatively charged glutamic acid. Although mutations in the interdomain-B region affected ITK-SYK kinase activity, they only modestly altered downstream signaling events. In contrast, mutations that were introduced in the kinase domain triggered severe impairment of downstream signaling. Moreover, we show here that SLP-76 is critical for ITK-SYK activation and is particularly required for the ITK-SYK-dependent phosphorylation of SYK activation loop tyrosines. In Jurkat cell lines, we demonstrate that expression of ITK-SYK fusion requires an intact SLP-76 function and significantly induces IL-2 secretion and CD69 expression. Furthermore, the SLP-76-mediated induction of IL-2 and CD69 could be further enhanced by SYK or ZAP-70, but it was independent of their kinase activity. Notably, ITK-SYK expression in SYF cells phosphorylates SLP-76 in the absence of SRC family kinases. Altogether, our data suggest that ITK-SYK exists in the active conformation state and is therefore capable of signaling without SRC family kinases or stimulation of the T cell receptor.
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Hussain, Alamdar; Mohammad, Dara K.; Gustafsson, Manuela O.; Uslu, Merve; Hamasy, Abdulrahman; Nore, Beston F.; Mohamed, Abdalla J.; Smith, C. I. Edvard
2013-01-01
The inducible T cell kinase-spleen tyrosine kinase (ITK-SYK) oncogene consists of the Tec homology-pleckstrin homology domain of ITK and the kinase domain of SYK, and it is believed to be the cause of peripheral T cell lymphoma. We and others have recently demonstrated that this fusion protein is constitutively tyrosine-phosphorylated and is transforming both in vitro and in vivo. To gain a deeper insight into the molecular mechanism(s) underlying its activation and signaling, we mutated a total of eight tyrosines located in the SYK portion of the chimera into either phenylalanine or to the negatively charged glutamic acid. Although mutations in the interdomain-B region affected ITK-SYK kinase activity, they only modestly altered downstream signaling events. In contrast, mutations that were introduced in the kinase domain triggered severe impairment of downstream signaling. Moreover, we show here that SLP-76 is critical for ITK-SYK activation and is particularly required for the ITK-SYK-dependent phosphorylation of SYK activation loop tyrosines. In Jurkat cell lines, we demonstrate that expression of ITK-SYK fusion requires an intact SLP-76 function and significantly induces IL-2 secretion and CD69 expression. Furthermore, the SLP-76-mediated induction of IL-2 and CD69 could be further enhanced by SYK or ZAP-70, but it was independent of their kinase activity. Notably, ITK-SYK expression in SYF cells phosphorylates SLP-76 in the absence of SRC family kinases. Altogether, our data suggest that ITK-SYK exists in the active conformation state and is therefore capable of signaling without SRC family kinases or stimulation of the T cell receptor. PMID:23293025
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Marcotte, Douglas J.; Liu, Yu-Ting; Arduini, Robert M.
Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 {angstrom} resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 {angstrom} resolution. This data providesmore » information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Hussain, Alamdar, E-mail: alamdar.hussain@ki.se; Department of Biosciences, COMSATS Institute of Information Technology, Chak Shazad Campus, Islamabad; Faryal, Rani
Recurrent chromosomal translocations have long been implicated in various types of lymphomas and other malignancies. Novel recurrent t(5;9)(q33;q22) has been recently discovered in un-specified peripheral T-cell lymphoma. To elucidate the role of this translocation, the corresponding fusion construct encoding the N-terminal portion of the ITK kinase and the C-terminal catalytic region of the SYK kinase was generated. We herein show that the ITK-SYK fusion-protein is constitutively active. Moreover, we demonstrate that ITK-SYK is phosphorylated on key tyrosine residues and is capable of potently phosphorylating the related adapter proteins BLNK and SLP-76. In transiently transfected cells, SYK was phosphorylated at Y352more » but not detectably at the activation-loop tyrosines Y525/Y526. In contrast, ITK-SYK was phosphorylated both at Y212 and the activation-loop tyrosines Y385/Y386, corresponding to Y352 and Y525/Y526 in SYK, respectively. In resting primary lymphocytes, ITK-SYK predominantly localizes to the cell surface. In addition, we demonstrate that following stimulation, the ITK-SYK fusion-protein in cell lines translocates to the cell membrane and, moreover, that this phenomenon as well as SLP-76 phosphorylation are blocked upon phosphatidylinositol-3-kinase (PI3-kinase) inhibition.« less
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Scaffold Protein SLP-76 Primes PLCγ1 for Activation by ITK-Mediated Phosphorylation.
Devkota, Sujan; Joseph, Raji E; Min, Lie; Bruce Fulton, D; Andreotti, Amy H
2015-08-28
Activation of the phospholipase, PLCγ1, is critical for proper T cell signaling following antigen receptor engagement. In T cells, the Tec family kinase, interleukin-2-induced tyrosine kinase (ITK), phosphorylates PLCγ1 at tyrosine 783 (Y783) leading to activation of phospholipase function and subsequent production of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. In this work, we demonstrate that PLCγ1 can be primed for ITK-mediated phosphorylation on Y783 by a specific region of the adaptor protein, SLP-76. The SLP-76 phosphotyrosine-containing sequence, pY(173)IDR, does not conform to the canonical recognition motif for an SH2 domain yet binds with significant affinity to the C-terminal SH2 domain of PLCγ1 (SH2C). The SLP-76 pY(173) motif competes with the autoinhibited conformation surrounding the SH2C domain of PLCγ1 leading to exposure of the ITK recognition element on the PLCγ1 SH2 domain and release of the target tyrosine, Y783. These data contribute to the evolving model for the molecular events occurring early in the T cell activation process. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Devkota, Sujan; Joseph, Raji E; Boyken, Scott E; Fulton, D Bruce; Andreotti, Amy H
2017-06-13
Pleckstrin homology (PH) domains are well-known as phospholipid binding modules, yet evidence that PH domain function extends beyond lipid recognition is mounting. In this work, we characterize a protein binding function for the PH domain of interleukin-2-inducible tyrosine kinase (ITK), an immune cell specific signaling protein that belongs to the TEC family of nonreceptor tyrosine kinases. Its N-terminal PH domain is a well-characterized lipid binding module that localizes ITK to the membrane via phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) binding. Using a combination of nuclear magnetic resonance spectroscopy and mutagenesis, we have mapped an autoregulatory protein interaction site on the ITK PH domain that makes direct contact with the catalytic kinase domain of ITK, inhibiting the phospho-transfer reaction. Moreover, we have elucidated an important interplay between lipid binding by the ITK PH domain and the stability of the autoinhibitory complex formed by full length ITK. The ITK activation loop in the kinase domain becomes accessible to phosphorylation to the exogenous kinase LCK upon binding of the ITK PH domain to PIP 3 . By clarifying the allosteric role of the ITK PH domain in controlling ITK function, we have expanded the functional repertoire of the PH domain generally and opened the door to alternative strategies to target this specific kinase in the context of immune cell signaling.
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Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling.
de Bruijn, Marjolein J W; Rip, Jasper; van der Ploeg, Esmee K; van Greuningen, Lars W; Ta, Van T B; Kil, Laurens P; Langerak, Anton W; Rimmelzwaan, Guus F; Ellmeier, Wilfried; Hendriks, Rudi W; Corneth, Odilia B J
2017-04-15
The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca 2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase. Copyright © 2017 by The American Association of Immunologists, Inc.
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X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase
DOE Office of Scientific and Technical Information (OSTI.GOV)
Muckelbauer, Jodi; Sack, John S.; Ahmed, Nazia
Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 {angstrom} resolution and PP2 at 1.9 {angstrom} resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-orderedmore » protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.« less
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TEC protein tyrosine kinase is involved in the Erk signaling pathway induced by HGF
DOE Office of Scientific and Technical Information (OSTI.GOV)
Li, Feifei; Jiang, Yinan; Zheng, Qiping
Research highlights: {yields} TEC is rapidly tyrosine-phosphorylated and activated by HGF-stimulation in vivo or after partial hepatectomy in mice. {yields} TEC enhances the activity of Elk and serum response element (SRE) in HGF signaling pathway in hepatocyte. {yields} TEC promotes hepatocyte proliferation through the Erk-MAPK pathway. -- Abstract: Background/aims: TEC, a member of the TEC family of non-receptor type protein tyrosine kinases, has recently been suggested to play a role in hepatocyte proliferation and liver regeneration. This study aims to investigate the putative mechanisms of TEC kinase regulation of hepatocyte differentiation, i.e. to explore which signaling pathway TEC is involvedmore » in, and how TEC is activated in hepatocyte after hepatectomy and hepatocyte growth factor (HGF) stimulation. Methods: We performed immunoprecipitation (IP) and immunoblotting (IB) to examine TEC tyrosine phosphorylation after partial hepatectomy in mice and HGF stimulation in WB F-344 hepatic cells. The TEC kinase activity was determined by in vitro kinase assay. Reporter gene assay, antisense oligonucleotide and TEC dominant negative mutant (TEC{sup KM}) were used to examine the possible signaling pathways in which TEC is involved. The cell proliferation rate was evaluated by {sup 3}H-TdR incorporation. Results: TEC phosphorylation and kinase activity were increased in 1 h after hepatectomy or HGF treatment. TEC enhanced the activity of Elk and serum response element (SRE). Inhibition of MEK1 suppressed TEC phosphorylation. Blocking TEC activity dramatically decreased the activation of Erk. Reduced TEC kinase activity also suppressed the proliferation of WB F-344 cells. These results suggest TEC is involved in the Ras-MAPK pathway and acts between MEK1 and Erk. Conclusions: TEC promotes hepatocyte proliferation and regeneration and is involved in HGF-induced Erk signaling pathway.« less
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NASA Astrophysics Data System (ADS)
Raab, Monika; Cai, Yun-Cai; Bunnell, Stephen C.; Heyeck, Stephanie D.; Berg, Leslie J.; Rudd, Christopher E.
1995-09-01
T-cell activation requires cooperative signals generated by the T-cell antigen receptor ξ-chain complex (TCRξ-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, ξ-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.
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Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy
2013-01-01
Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays. PMID:24900590
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Ebert, Antje D; Laussmann, Mareike; Wegehingel, Sabine; Kaderali, Lars; Erfle, Holger; Reichert, Jürgen; Lechner, Johannes; Beer, Hans-Dietmar; Pepperkok, Rainer; Nickel, Walter
2010-06-01
Fibroblast growth factor 2 (FGF2) is a potent mitogen that is exported from cells by an endoplasmic reticulum (ER)/Golgi-independent mechanism. Unconventional secretion of FGF2 occurs by direct translocation across plasma membranes, a process that depends on the phosphoinositide phosphatidylinositol 4,5-biphosphate (PI(4,5)P(2)) at the inner leaflet as well as heparan sulfate proteoglycans at the outer leaflet of plasma membranes; however, additional core and regulatory components of the FGF2 export machinery have remained elusive. Here, using a highly effective RNAi screening approach, we discovered Tec kinase as a novel factor involved in unconventional secretion of FGF2. Tec kinase does not affect FGF2 secretion by an indirect mechanism, but rather forms a heterodimeric complex with FGF2 resulting in phosphorylation of FGF2 at tyrosine 82, a post-translational modification shown to be essential for FGF2 membrane translocation to cell surfaces. Our findings suggest a crucial role for Tec kinase in regulating FGF2 secretion under various physiological conditions and, therefore, provide a new perspective for the development of a novel class of antiangiogenic drugs targeting the formation of the FGF2/Tec complex.
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Harling, John D.; Deakin, Angela M.; Campos, Sébastien; Grimley, Rachel; Chaudry, Laiq; Nye, Catherine; Polyakova, Oxana; Bessant, Christina M.; Barton, Nick; Somers, Don; Barrett, John; Graves, Rebecca H.; Hanns, Laura; Kerr, William J.; Solari, Roberto
2013-01-01
IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models. PMID:23935099
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Dubovsky, Jason A; Beckwith, Kyle A; Natarajan, Gayathri; Woyach, Jennifer A; Jaglowski, Samantha; Zhong, Yiming; Hessler, Joshua D; Liu, Ta-Ming; Chang, Betty Y; Larkin, Karilyn M; Stefanovski, Matthew R; Chappell, Danielle L; Frissora, Frank W; Smith, Lisa L; Smucker, Kelly A; Flynn, Joseph M; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami; Lehman, Amy M; Furman, Richard; Sharman, Jeff; Mishra, Anjali; Caligiuri, Michael A; Satoskar, Abhay R; Buggy, Joseph J; Muthusamy, Natarajan; Johnson, Amy J; Byrd, John C
2013-10-10
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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Dubovsky, Jason A.; Beckwith, Kyle A.; Natarajan, Gayathri; Woyach, Jennifer A.; Jaglowski, Samantha; Zhong, Yiming; Hessler, Joshua D.; Liu, Ta-Ming; Chang, Betty Y.; Larkin, Karilyn M.; Stefanovski, Matthew R.; Chappell, Danielle L.; Frissora, Frank W.; Smith, Lisa L.; Smucker, Kelly A.; Flynn, Joseph M.; Jones, Jeffrey A.; Andritsos, Leslie A.; Maddocks, Kami; Lehman, Amy M.; Furman, Richard; Sharman, Jeff; Mishra, Anjali; Caligiuri, Michael A.; Satoskar, Abhay R.; Buggy, Joseph J.; Muthusamy, Natarajan; Johnson, Amy J.
2013-01-01
Given its critical role in T-cell signaling, interleukin-2–inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749. PMID:23886836
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In vivo significance of ITK-SLP-76 interaction in cytokine production.
Grasis, Juris A; Guimond, David M; Cam, Nicholas R; Herman, Krystal; Magotti, Paola; Lambris, John D; Tsoukas, Constantine D
2010-07-01
In vitro data have suggested that activation of the inducible T-cell kinase (ITK) requires an interaction with the adaptor protein SLP-76. One means for this interaction involves binding of the ITK SH3 domain to the polyproline-rich (PR) region of SLP-76. However, the biological significance of this association in live cells and the consequences of its disruption have not been demonstrated. Here, we utilized a polyarginine-rich, cell-permeable peptide that represents the portion of the SLP-76 PR region that interacts with the ITK SH3 domain as a competitive inhibitor to disrupt the association between ITK and SLP-76 in live cells. We demonstrate that treatment of cells with this peptide, by either in vitro incubation or intraperitoneal injection of the peptide in mice, inhibits the T-cell receptor (TCR)-induced association between ITK and SLP-76, recruitment and transphosphorylation of ITK, actin polarization at the T-cell contact site, and expression of Th2 cytokines. The inhibition is specific, as indicated by lack of effects by the polyarginine vehicle alone or a scrambled sequence of the cargo peptide. In view of the role of ITK as a regulator of Th2 cytokine expression, the data underscore the significance of ITK as a target for pharmacological intervention.
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SimITK: visual programming of the ITK image-processing library within Simulink.
Dickinson, Andrew W L; Abolmaesumi, Purang; Gobbi, David G; Mousavi, Parvin
2014-04-01
The Insight Segmentation and Registration Toolkit (ITK) is a software library used for image analysis, visualization, and image-guided surgery applications. ITK is a collection of C++ classes that poses the challenge of a steep learning curve should the user not have appropriate C++ programming experience. To remove the programming complexities and facilitate rapid prototyping, an implementation of ITK within a higher-level visual programming environment is presented: SimITK. ITK functionalities are automatically wrapped into "blocks" within Simulink, the visual programming environment of MATLAB, where these blocks can be connected to form workflows: visual schematics that closely represent the structure of a C++ program. The heavily templated C++ nature of ITK does not facilitate direct interaction between Simulink and ITK; an intermediary is required to convert respective data types and allow intercommunication. As such, a SimITK "Virtual Block" has been developed that serves as a wrapper around an ITK class which is capable of resolving the ITK data types to native Simulink data types. Part of the challenge surrounding this implementation involves automatically capturing and storing the pertinent class information that need to be refined from an initial state prior to being reflected within the final block representation. The primary result from the SimITK wrapping procedure is multiple Simulink block libraries. From these libraries, blocks are selected and interconnected to demonstrate two examples: a 3D segmentation workflow and a 3D multimodal registration workflow. Compared to their pure-code equivalents, the workflows highlight ITK usability through an alternative visual interpretation of the code that abstracts away potentially confusing technicalities.
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Lowekamp, Bradley C; Chen, David T; Ibáñez, Luis; Blezek, Daniel
2013-01-01
SimpleITK is a new interface to the Insight Segmentation and Registration Toolkit (ITK) designed to facilitate rapid prototyping, education and scientific activities via high level programming languages. ITK is a templated C++ library of image processing algorithms and frameworks for biomedical and other applications, and it was designed to be generic, flexible and extensible. Initially, ITK provided a direct wrapping interface to languages such as Python and Tcl through the WrapITK system. Unlike WrapITK, which exposed ITK's complex templated interface, SimpleITK was designed to provide an easy to use and simplified interface to ITK's algorithms. It includes procedural methods, hides ITK's demand driven pipeline, and provides a template-less layer. Also SimpleITK provides practical conveniences such as binary distribution packages and overloaded operators. Our user-friendly design goals dictated a departure from the direct interface wrapping approach of WrapITK, toward a new facade class structure that only exposes the required functionality, hiding ITK's extensive template use. Internally SimpleITK utilizes a manual description of each filter with code-generation and advanced C++ meta-programming to provide the higher-level interface, bringing the capabilities of ITK to a wider audience. SimpleITK is licensed as open source software library under the Apache License Version 2.0 and more information about downloading it can be found at http://www.simpleitk.org.
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Lowekamp, Bradley C.; Chen, David T.; Ibáñez, Luis; Blezek, Daniel
2013-01-01
SimpleITK is a new interface to the Insight Segmentation and Registration Toolkit (ITK) designed to facilitate rapid prototyping, education and scientific activities via high level programming languages. ITK is a templated C++ library of image processing algorithms and frameworks for biomedical and other applications, and it was designed to be generic, flexible and extensible. Initially, ITK provided a direct wrapping interface to languages such as Python and Tcl through the WrapITK system. Unlike WrapITK, which exposed ITK's complex templated interface, SimpleITK was designed to provide an easy to use and simplified interface to ITK's algorithms. It includes procedural methods, hides ITK's demand driven pipeline, and provides a template-less layer. Also SimpleITK provides practical conveniences such as binary distribution packages and overloaded operators. Our user-friendly design goals dictated a departure from the direct interface wrapping approach of WrapITK, toward a new facade class structure that only exposes the required functionality, hiding ITK's extensive template use. Internally SimpleITK utilizes a manual description of each filter with code-generation and advanced C++ meta-programming to provide the higher-level interface, bringing the capabilities of ITK to a wider audience. SimpleITK is licensed as open source software library under the Apache License Version 2.0 and more information about downloading it can be found at http://www.simpleitk.org. PMID:24416015
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Dynamics of the Tec‐family tyrosine kinase SH3 domains
Roberts, Justin M.; Tarafdar, Sreya; Joseph, Raji E.; Andreotti, Amy H.; Smithgall, Thomas E.; Engen, John R.
2016-01-01
Abstract The Src Homology 3 (SH3) domain is an important regulatory domain found in many signaling proteins. X‐ray crystallography and NMR structures of SH3 domains are generally conserved but other studies indicate that protein flexibility and dynamics are not. We previously reported that based on hydrogen exchange mass spectrometry (HX MS) studies, there is variable flexibility and dynamics among the SH3 domains of the Src‐family tyrosine kinases and related proteins. Here we have extended our studies to the SH3 domains of the Tec family tyrosine kinases (Itk, Btk, Tec, Txk, Bmx). The SH3 domains of members of this family augment the variety in dynamics observed in previous SH3 domains. Txk and Bmx SH3 were found to be highly dynamic in solution by HX MS and Bmx was unstructured by NMR. Itk and Btk SH3 underwent a clear EX1 cooperative unfolding event, which was localized using pepsin digestion and mass spectrometry after hydrogen exchange labeling. The unfolding was localized to peptide regions that had been previously identified in the Src‐family and related protein SH3 domains, yet the kinetics of unfolding were not. Sequence alignment does not provide an easy explanation for the observed dynamics behavior, yet the similarity of location of EX1 unfolding suggests that higher‐order structural properties may play a role. While the exact reason for such dynamics is not clear, such motions can be exploited in intra‐ and intermolecular binding assays of proteins containing the domains. PMID:26808198
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SimITK: rapid ITK prototyping using the Simulink visual programming environment
NASA Astrophysics Data System (ADS)
Dickinson, A. W. L.; Mousavi, P.; Gobbi, D. G.; Abolmaesumi, P.
2011-03-01
The Insight Segmentation and Registration Toolkit (ITK) is a long-established, software package used for image analysis, visualization, and image-guided surgery applications. This package is a collection of C++ libraries, that can pose usability problems for users without C++ programming experience. To bridge the gap between the programming complexities and the required learning curve of ITK, we present a higher-level visual programming environment that represents ITK methods and classes by wrapping them into "blocks" within MATLAB's visual programming environment, Simulink. These blocks can be connected to form workflows: visual schematics that closely represent the structure of a C++ program. Due to the heavily C++ templated nature of ITK, direct interaction between Simulink and ITK requires an intermediary to convert their respective datatypes and allow intercommunication. We have developed a "Virtual Block" that serves as an intermediate wrapper around the ITK class and is responsible for resolving the templated datatypes used by ITK to native types used by Simulink. Presently, the wrapping procedure for SimITK is semi-automatic in that it requires XML descriptions of the ITK classes as a starting point, as this data is used to create all other necessary integration files. The generation of all source code and object code from the XML is done automatically by a CMake build script that yields Simulink blocks as the final result. An example 3D segmentation workflow using cranial-CT data as well as a 3D MR-to-CT registration workflow are presented as a proof-of-concept.
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Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth.
Chen, Jun; Kinoshita, Taisei; Sukbuntherng, Juthamas; Chang, Betty Y; Elias, Laurence
2016-12-01
Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC 50 s were lower than that of lapatinib and dacomitinib. Inhibition of cell growth by ibrutinib coincided with downregulation of phosphorylation on HER2 and EGFR and their downstream targets, AKT and ERK. Irreversible inhibition of HER2 and EGFR in breast cancer cells was established after 30-minute incubation above 100 nmol/L or following 2-hour incubation at lower concentrations. Furthermore, ibrutinib inhibited recombinant HER2 and EGFR activity that was resistant to dialysis and rapid dilution, suggesting an irreversible interaction. The dual activity toward TEC family (BTK and ITK) and ERBB family kinases was unique to ibrutinib, as ERBB inhibitors do not inhibit or covalently bind BTK or ITK. Xenograft studies with HER2 + MDA-MB-453 and BT-474 cells in mice in conjunction with determination of pharmacokinetics demonstrated significant exposure-dependent inhibition of growth and key signaling molecules at levels that are clinically achievable. Ibrutinib's unique dual spectrum of activity against both TEC family and ERBB kinases suggests broader applications of ibrutinib in oncology. Mol Cancer Ther; 15(12); 2835-44. ©2016 AACR. ©2016 American Association for Cancer Research.
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Vargas, L; Hamasy, A; Nore, B F; Smith, C I E
2013-08-01
BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors. © 2013 John Wiley & Sons Ltd.
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Signaling network of the Btk family kinases.
Qiu, Y; Kung, H J
2000-11-20
The Btk family kinases represent new members of non-receptor tyrosine kinases, which include Btk/Atk, Itk/Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Src-family kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCgamma and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, differentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunodeficiency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the different modules of the kinases and the diverse signaling pathways in which they are involved.
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Huang, Weishan; Morales, J. Luis; Gozivoda, Victor P.; August, Avery
2015-01-01
Background Mast cells are indispensible for LPS-induced septic hypothermia, in which TNF-α plays an essential role to initiate septic responses. ITK and BTK regulate mast cell responses to allergen, but their roles in mast cell responses in LPS-induced sepsis are unclear. Objectives We sought to investigate the roles of ITK and BTK in mast cell responses during LPS-induced septic inflammation. Methods Mice (genetically modified or BMMC-reconstituted Sash) were given LPS to induce septic hypothermia, in the presence or absence of indicated inhibitors. Flow cytometry was used to determine LPS-induced cell influx and TNF-α production in peritoneal cells. Microarray was used for genome-wide gene expression analysis on BMMCs. Quantitative PCR and multiplex were used to determine transcribed and secreted pro-inflammatory cytokines. Microscopy and western blotting were used to determine activation of signal transduction pathways. Results The absence of ITK and BTK leads to exacerbation of LPS-induced septic hypothermia and neutrophil influx. Itk−/−Btk−/− mast cells exhibit hyperactive preformed and LPS-induced TNF-α production, and lead to more severe LPS-induced septic hypothermia when reconstituted into mast cell deficient Sash mice. LPS-induced NF-κB, Akt and p38 activation is enhanced in Itk−/−Btk−/− mast cells, and blockage of PI3K, Akt or p38 downstream MNK1 activation significantly suppresses TNF-α hyper-production and attenuates septic hypothermia. Conclusions ITK and BTK regulate thermal homeostasis during septic response through mast cell function in mice. They share regulatory function downstream of TLR4/LPS in mast cells, through regulating the activation of canonical NF-κB, PI3K/Akt and p38 signaling pathways. PMID:26581914
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Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells
Sela, Meirav; Bogin, Yaron; Beach, Dvora; Oellerich, Thomas; Lehne, Johanna; Smith-Garvin, Jennifer E; Okumura, Mariko; Starosvetsky, Elina; Kosoff, Rachelle; Libman, Evgeny; Koretzky, Gary; Kambayashi, Taku; Urlaub, Henning; Wienands, Jürgen; Chernoff, Jonathan; Yablonski, Deborah
2011-01-01
Cooperatively assembled signalling complexes, nucleated by adaptor proteins, integrate information from surface receptors to determine cellular outcomes. In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT. Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk. We identified a fourth, evolutionarily conserved SLP-76 phosphorylation site, Y173, which was phosphorylated upon T-cell receptor stimulation in primary murine and Jurkat T cells. Y173 was required for antigen receptor-induced phosphorylation of phospholipase C-γ1 (PLC-γ1) in both T and mast cells, and for consequent downstream events, including activation of the IL-2 promoter in T cells, and degranulation and IL-6 production in mast cells. In intact cells, Y173 phosphorylation depended on three, ZAP-70-targeted tyrosines at the N-terminus of SLP-76 that recruit and activate Itk, a kinase that selectively phosphorylated Y173 in vitro. These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to its substrate, PLC-γ1. PMID:21725281
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Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells.
Sela, Meirav; Bogin, Yaron; Beach, Dvora; Oellerich, Thomas; Lehne, Johanna; Smith-Garvin, Jennifer E; Okumura, Mariko; Starosvetsky, Elina; Kosoff, Rachelle; Libman, Evgeny; Koretzky, Gary; Kambayashi, Taku; Urlaub, Henning; Wienands, Jürgen; Chernoff, Jonathan; Yablonski, Deborah
2011-07-01
Cooperatively assembled signalling complexes, nucleated by adaptor proteins, integrate information from surface receptors to determine cellular outcomes. In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT. Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk. We identified a fourth, evolutionarily conserved SLP-76 phosphorylation site, Y173, which was phosphorylated upon T-cell receptor stimulation in primary murine and Jurkat T cells. Y173 was required for antigen receptor-induced phosphorylation of phospholipase C-γ1 (PLC-γ1) in both T and mast cells, and for consequent downstream events, including activation of the IL-2 promoter in T cells, and degranulation and IL-6 production in mast cells. In intact cells, Y173 phosphorylation depended on three, ZAP-70-targeted tyrosines at the N-terminus of SLP-76 that recruit and activate Itk, a kinase that selectively phosphorylated Y173 in vitro. These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to its substrate, PLC-γ1.
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Bruton's tyrosine kinase (BTK) as a promising target in solid tumors.
Molina-Cerrillo, J; Alonso-Gordoa, T; Gajate, P; Grande, E
2017-07-01
Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors. Copyright © 2017 Elsevier Ltd. All rights reserved.
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ITK Gene Mutation: Effect on Survival of Children with Severe Hemophagocytic Lymphohistiocytosis.
Zheng, Fang; Li, Juan; Zha, Hui; Zhang, Jue; Zhang, Zhiquan; Cheng, Fangjun
2016-11-01
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deadly hyperinflammatory syndrome, but data on severe HLH with multi-organ dysfunction in children are scant. The authors report a retrospective study of 8 cases with severe HLH from a pediatric intensive care unit (PICU) over a 1-y period and found that Epstein barr virus (EBV) -infection was the most common etiology. All patients had genetic analysis, which showed that four patients with EBV -infection had one homozygous mutation, c.985+75G>A (at position chr5:156667232) in exon10 of the ITK gene with poor survival rates. ITK + mutation group had higher percentages of CD3 + CD8 + T cells (36.0 ± 8.4 %) than those in ITK - mutation group (28.8 ± 5.5 %), while they had similar levels of CD3 + CD4 + T cells. ITK + mutation group had lower proportion of CD3 - CD19 + B cells (16.3 ± 2.9 %) and CD16 + CD56 + NK cells (8.4 ± 2.6 %) than ITK - mutation group (29.6 ± 5.1 % and 15.9 ± 9.0 % respectively). Most importantly, patients with EBV infection with c.985+75G>A mutation in ITK had lower survival rates than ITK - mutation group which it may be related with cellular immune dysfunction.
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Angioimmunoblastic T-cell lymphoma in Taiwan shows a frequent gain of ITK gene
Liang, Peir-In; Chang, Sheng-Tsung; Lin, Ming-Yen; Hsieh, Yen-Chuan; Chu, Pei-Yi; Chen, Chih-Jung; Lin, Kai-Jen; Jung, Yun-Chih; Hwang, Wei-Shou; Huang, Wen-Tsung; Chang, Wei-Chin; Ye, Hongtao; Chuang, Shih-Sung
2014-01-01
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma (PTCL) of follicular helper T-cell origin and is rare in Taiwan. There are overlapping features of AITL and peripheral T-cell lymphoma with a follicular growth pattern (PTCL-F). Around one fifth of PTCL-F exhibits t(5;9)(q33;q22)/ITK-SYK chromosomal translocation, which is essentially absent in AITL. We retrospectively investigated 35 cases of AITL from Taiwan with histopathology review, immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBV) and fluorescence in situ hybridization (FISH) for t(5;9)(q33;q22)/ITK-SYK and correlated the results with overall survival. Twenty-six cases of not otherwise specified PTCL (PTCL-NOS) were also examined by FISH for comparison. Most AITL patients were male (69%) and elderly (median age at 67 years) with frequent bone marrow involvement (53%), high Ann Arbor stages (77%), and elevated serum lactate dehydrogenase (68%). Most cases (80%) showed a typical CD4+/CD8- phenotype and in 90% cases there were scattered EBV-positive B-cells (less than 10% cells). None of these cases showed t(5;9)(q33;q22)/ITK-SYK translocation by FISH. Gain of ITK and SYK gene was identified in 38% and 14% tumors, respectively, but both were not associated with overall survival. Performance status < 2 was associated with a better outcome but not the other clinicopathological factors. All PTCL-NOS cases were negative for ITK-SYK translocation with similar rates (38% and 12%, respectively) of gains at ITK and SYK loci as that of AITL. In this so far the largest series of AITL from Taiwan, we reported the clinicopathological features and FISH findings on ITK and SYK genes. We confirmed the absence of t(5;9)(q33;q22)/ITK-SYK translocation, which may serve as an additional differential diagnostic tool from PTCL-F when present. PTCL-NOS shared a similar pattern of ITK and SYK gains with AITL. More studies are warranted to elucidate the roles of SYK and ITK and
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A new strips tracker for the upgraded ATLAS ITk detector
NASA Astrophysics Data System (ADS)
David, C.
2018-01-01
The ATLAS detector has been designed and developed to function in the environment of the present Large Hadron Collider (LHC). At the next-generation tracking detector proposed for the High Luminosity LHC (HL-LHC), the so-called ATLAS Phase-II Upgrade, the fluences and radiation levels will be higher by as much as a factor of ten. The new sub-detectors must thus be faster, of larger area, more segmented and more radiation hard while the amount of inactive material should be minimized and the power supply to the front-end systems should be increased. For those reasons, the current inner tracker of the ATLAS detector will be fully replaced by an all-silicon tracking system that consists of a pixel detector at small radius close to the beam line and a large area strip tracker surrounding it. This document gives an overview of the design of the strip inner tracker (Strip ITk) and summarises the intensive R&D activities performed over the last years by the numerous institutes within the Strips ITk collaboration. These studies are accompanied with a strong prototyping effort to contribute to the optimisation of the Strip ITk's structure and components. This effort culminated recently in the release of the ATLAS Strips ITk Technical Design Report (TDR).
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Module and electronics developments for the ATLAS ITk pixel system
NASA Astrophysics Data System (ADS)
Muñoz, F. J.
2018-03-01
The ATLAS experiment is preparing for an extensive modification of its detectors in the course of the planned HL-LHC accelerator upgrade around 2025. The ATLAS upgrade includes the replacement of the entire tracking system by an all-silicon detector (Inner Tracker, ITk). The five innermost layers of ITk will be a pixel detector built of new sensor and readout electronics technologies to improve the tracking performance and cope with the severe HL-LHC environment in terms of occupancy and radiation. The total area of the new pixel system could measure up to 14 m2, depending on the final layout choice, which is expected to take place in 2018. In this paper an overview of the ongoing R&D activities on modules and electronics for the ATLAS ITk is given including the main developments and achievements in silicon planar and 3D sensor technologies, readout and power challenges.
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Comparison with IRI-PLUS and IRI-2012-TEC values of GPS-TEC values
NASA Astrophysics Data System (ADS)
Atıcı, Ramazan; Saǧır, Selçuk
2016-07-01
This study presents a comparison with IRI-PLUS and IRI-2012 Total Electron Content (TEC) values of Total Electron Content (TEC) values obtained from Ankara station (39,7 N; 32,76 E) of Global Position System (GPS) of Turkey on equinox and solstice days of 2009 year. For all days, it is observed that GPS-TEC values are greater than IRI-2012-TEC values, while IRI-PLUS-TEC values are very close to GPS-TEC values. When GPS-TEC values for both equinoxes are compared, it is seen that TEC values on September equinox are greater than one on March equinox. However, it is observed that GPS-TEC values on June solstice are greater than one on December solstice. Also, the relationship between GPS-TEC values and geomagnetic indexes is investigated.
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An ITK framework for deterministic global optimization for medical image registration
NASA Astrophysics Data System (ADS)
Dru, Florence; Wachowiak, Mark P.; Peters, Terry M.
2006-03-01
Similarity metric optimization is an essential step in intensity-based rigid and nonrigid medical image registration. For clinical applications, such as image guidance of minimally invasive procedures, registration accuracy and efficiency are prime considerations. In addition, clinical utility is enhanced when registration is integrated into image analysis and visualization frameworks, such as the popular Insight Toolkit (ITK). ITK is an open source software environment increasingly used to aid the development, testing, and integration of new imaging algorithms. In this paper, we present a new ITK-based implementation of the DIRECT (Dividing Rectangles) deterministic global optimization algorithm for medical image registration. Previously, it has been shown that DIRECT improves the capture range and accuracy for rigid registration. Our ITK class also contains enhancements over the original DIRECT algorithm by improving stopping criteria, adaptively adjusting a locality parameter, and by incorporating Powell's method for local refinement. 3D-3D registration experiments with ground-truth brain volumes and clinical cardiac volumes show that combining DIRECT with Powell's method improves registration accuracy over Powell's method used alone, is less sensitive to initial misorientation errors, and, with the new stopping criteria, facilitates adequate exploration of the search space without expending expensive iterations on non-improving function evaluations. Finally, in this framework, a new parallel implementation for computing mutual information is presented, resulting in near-linear speedup with two processors.
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Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate
Wang, Qi; Vogan, Erik M; Nocka, Laura M; Rosen, Connor E; Zorn, Julie A; Harrison, Stephen C; Kuriyan, John
2015-01-01
Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk. DOI: http://dx.doi.org/10.7554/eLife.06074.001 PMID:25699547
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Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G.; Pidala, Joseph; Yu, Xue-Zhong
2015-01-01
Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically. PMID:26348529
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Schutt, Steven D; Fu, Jianing; Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G; Pidala, Joseph; Yu, Xue-Zhong
2015-01-01
Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.
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ITK: enabling reproducible research and open science
McCormick, Matthew; Liu, Xiaoxiao; Jomier, Julien; Marion, Charles; Ibanez, Luis
2014-01-01
Reproducibility verification is essential to the practice of the scientific method. Researchers report their findings, which are strengthened as other independent groups in the scientific community share similar outcomes. In the many scientific fields where software has become a fundamental tool for capturing and analyzing data, this requirement of reproducibility implies that reliable and comprehensive software platforms and tools should be made available to the scientific community. The tools will empower them and the public to verify, through practice, the reproducibility of observations that are reported in the scientific literature. Medical image analysis is one of the fields in which the use of computational resources, both software and hardware, are an essential platform for performing experimental work. In this arena, the introduction of the Insight Toolkit (ITK) in 1999 has transformed the field and facilitates its progress by accelerating the rate at which algorithmic implementations are developed, tested, disseminated and improved. By building on the efficiency and quality of open source methodologies, ITK has provided the medical image community with an effective platform on which to build a daily workflow that incorporates the true scientific practices of reproducibility verification. This article describes the multiple tools, methodologies, and practices that the ITK community has adopted, refined, and followed during the past decade, in order to become one of the research communities with the most modern reproducibility verification infrastructure. For example, 207 contributors have created over 2400 unit tests that provide over 84% code line test coverage. The Insight Journal, an open publication journal associated with the toolkit, has seen over 360,000 publication downloads. The median normalized closeness centrality, a measure of knowledge flow, resulting from the distributed peer code review system was high, 0.46. PMID:24600387
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ITK: enabling reproducible research and open science.
McCormick, Matthew; Liu, Xiaoxiao; Jomier, Julien; Marion, Charles; Ibanez, Luis
2014-01-01
Reproducibility verification is essential to the practice of the scientific method. Researchers report their findings, which are strengthened as other independent groups in the scientific community share similar outcomes. In the many scientific fields where software has become a fundamental tool for capturing and analyzing data, this requirement of reproducibility implies that reliable and comprehensive software platforms and tools should be made available to the scientific community. The tools will empower them and the public to verify, through practice, the reproducibility of observations that are reported in the scientific literature. Medical image analysis is one of the fields in which the use of computational resources, both software and hardware, are an essential platform for performing experimental work. In this arena, the introduction of the Insight Toolkit (ITK) in 1999 has transformed the field and facilitates its progress by accelerating the rate at which algorithmic implementations are developed, tested, disseminated and improved. By building on the efficiency and quality of open source methodologies, ITK has provided the medical image community with an effective platform on which to build a daily workflow that incorporates the true scientific practices of reproducibility verification. This article describes the multiple tools, methodologies, and practices that the ITK community has adopted, refined, and followed during the past decade, in order to become one of the research communities with the most modern reproducibility verification infrastructure. For example, 207 contributors have created over 2400 unit tests that provide over 84% code line test coverage. The Insight Journal, an open publication journal associated with the toolkit, has seen over 360,000 publication downloads. The median normalized closeness centrality, a measure of knowledge flow, resulting from the distributed peer code review system was high, 0.46.
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Joseph, Raji E; Ginder, Nathaniel D; Hoy, Julie A; Nix, Jay C; Honzatko, Richard B; Andreotti, Amy H
2011-02-01
Proline is a unique amino acid owing to the relatively small energy difference between the cis and trans conformations of its peptide bond. The X-Pro imide bond readily undergoes cis-trans isomerization in the context of short peptides as well as some proteins. However, the direct detection of cis-trans proline isomerization in folded proteins is technically challenging. NMR spectroscopy is well suited to the direct detection of proline isomerization in folded proteins. It is less clear how well X-ray crystallography can reveal this conformational exchange event in folded proteins. Conformational heterogeneity owing to cis-trans proline isomerization in the Src homology 2 (SH2) domain of the IL-2-inducible T-cell kinase (ITK) has been extensively characterized by NMR. Using the ITK SH2 domain as a test system, an attempt was made to determine whether proline isomerization could be detected in a crystal structure of the ITK SH2 domain. As a first step towards this goal, the purification, crystallization and preliminary characterization of the ITK SH2 domain are described.
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Wang, Tianjiao; Lu, Ye; Polk, Avery; Chowdhury, Pinki; Zamalloa, Carlos Murga; Fujiwara, Hiroshi; Suemori, Koichiro; Beyersdorf, Niklas; Hristov, Alexandra C.; Lim, Megan S.; Bailey, Nathanael G.; Wilcox, Ryan A.
2016-01-01
Purpose T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T-cell specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR’s role in mediating resistance to chemotherapy. Experimental Design Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following T-cell receptor (TCR) engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results Here we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3, and promotes chemotherapy resistance. Conclusions These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented activation of this signaling axis and overcame chemotherapy resistance. PMID:27780854
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Yaniv, Ziv; Lowekamp, Bradley C; Johnson, Hans J; Beare, Richard
2018-06-01
Modern scientific endeavors increasingly require team collaborations to construct and interpret complex computational workflows. This work describes an image-analysis environment that supports the use of computational tools that facilitate reproducible research and support scientists with varying levels of software development skills. The Jupyter notebook web application is the basis of an environment that enables flexible, well-documented, and reproducible workflows via literate programming. Image-analysis software development is made accessible to scientists with varying levels of programming experience via the use of the SimpleITK toolkit, a simplified interface to the Insight Segmentation and Registration Toolkit. Additional features of the development environment include user friendly data sharing using online data repositories and a testing framework that facilitates code maintenance. SimpleITK provides a large number of examples illustrating educational and research-oriented image analysis workflows for free download from GitHub under an Apache 2.0 license: github.com/InsightSoftwareConsortium/SimpleITK-Notebooks .
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NASA Astrophysics Data System (ADS)
Huang, Zhen; Roussel-Dupré, Robert
2005-12-01
Data collected from Fast On-Orbit Recording of Transient Events (FORTE) satellite-received Los Alamos Portable Pulser (LAPP) signals during 1997-2002 are used to derive the total electron content (TEC) at Los Alamos, New Mexico. The LAPP-derived TECs at Los Alamos are analyzed for diurnal, seasonal, interannual, and 27-day solar cycle variations. Several aspects in deriving TEC are analyzed, including slant to vertical TEC conversion, quartic effects on transionosperic signals, and geomagnetic storm effects on the TEC variance superimposed on the averaged TEC values.
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The Phase-II ATLAS ITk pixel upgrade
NASA Astrophysics Data System (ADS)
Terzo, S.
2017-07-01
The entire tracking system of the ATLAS experiment will be replaced during the LHC Phase-II shutdown (foreseen to take place around 2025) by an all-silicon detector called the ``ITk'' (Inner Tracker). The innermost portion of ITk will consist of a pixel detector with five layers in the barrel region and ring-shaped supports in the end-cap regions. It will be instrumented with new sensor and readout electronics technologies to improve the tracking performance and cope with the HL-LHC environment, which will be severe in terms of occupancy and radiation levels. The new pixel system could include up to 14 m2 of silicon, depending on the final layout, which is expected to be decided in 2017. Several layout options are being investigated at the moment, including some with novel inclined support structures in the barrel end-cap overlap region and others with very long innermost barrel layers. Forward coverage could be as high as |eta| <4. Supporting structures will be based on low mass, highly stable and highly thermally conductive carbon-based materials cooled by evaporative carbon dioxide circulated in thin-walled titanium pipes embedded in the structures. Planar, 3D, and CMOS sensors are being investigated to identify the optimal technology, which may be different for the various layers. The RD53 Collaboration is developing the new readout chip. The pixel off-detector readout electronics will be implemented in the framework of the general ATLAS trigger and DAQ system. A readout speed of up to 5 Gb/s per data link will be needed in the innermost layers going down to 640 Mb/s for the outermost. Because of the very high radiation level inside the detector, the first part of the transmission has to be implemented electrically, with signals converted for optical transmission at larger radii. Extensive tests are being carried out to prove the feasibility of implementing serial powering, which has been chosen as the baseline for the ITk pixel system due to the reduced
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Wang, Tianjiao; Lu, Ye; Polk, Avery; Chowdhury, Pinki; Zamalloa, Carlos Murga; Fujiwara, Hiroshi; Suemori, Koichiro; Beyersdorf, Niklas; Hristov, Alexandra C; Lim, Megan S; Bailey, Nathanael G; Wilcox, Ryan A
2017-05-15
Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy. Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance. Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506-15. ©2016 AACR . ©2016 American Association for Cancer Research.
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A single-station empirical model for TEC over the Antarctic Peninsula using GPS-TEC data
NASA Astrophysics Data System (ADS)
Feng, Jiandi; Wang, Zhengtao; Jiang, Weiping; Zhao, Zhenzhen; Zhang, Bingbing
2017-02-01
Compared with regional or global total electron content (TEC) empirical models, single-station TEC empirical models may exhibit higher accuracy in describing TEC spatial and temporal variations for a single station. In this paper, a new single-station empirical total electron content (TEC) model, called SSM-month, for the O'Higgins Station in the Antarctic Peninsula is proposed by using Global Positioning System (GPS)-TEC data from 01 January 2004 to 30 June 2015. The diurnal variation of TEC in the O'Higgins Station may have changing features in different months, sometimes even in opposite forms, because of ionospheric phenomena, such as the Mid-latitude Summer Nighttime Anomaly (MSNA). To avoid the influence of different diurnal variations, the concept of monthly modeling is proposed in this study. The SSM-month model, which is established by month (including 12 submodels that correspond to the 12 months), can effectively describe the diurnal variation of TEC in different months. Each submodel of the SSM-month model exhibits good agreement with GPS-TEC input data. Overall, the SSM-month model fits the input data with a bias of 0.03 TECU (total electron content unit, 1 TECU = 1016 el m-2) and a standard deviation of 2.78 TECU. This model, which benefits from the modeling method, can effectively describe the MSNA phenomenon without implementing any modeling correction. TEC data derived from Center for Orbit Determination in Europe global ionosphere maps (CODE GIMs), International Reference Ionosphere 2012 (IRI2012), and NeQuick are compared with the SSM-month model in the years of 2001 and 2015-2016. Result shows that the SSM-month model exhibits good consistency with CODE GIMs, which is better than that of IRI2012 and NeQuick, in the O'Higgins Station on the test days.
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Atrioventricular junction (AVJ) motion tracking: a software tool with ITK/VTK/Qt.
Pengdong Xiao; Shuang Leng; Xiaodan Zhao; Hua Zou; Ru San Tan; Wong, Philip; Liang Zhong
2016-08-01
The quantitative measurement of the Atrioventricular Junction (AVJ) motion is an important index for ventricular functions of one cardiac cycle including systole and diastole. In this paper, a software tool that can conduct AVJ motion tracking from cardiovascular magnetic resonance (CMR) images is presented by using Insight Segmentation and Registration Toolkit (ITK), The Visualization Toolkit (VTK) and Qt. The software tool is written in C++ by using Visual Studio Community 2013 integrated development environment (IDE) containing both an editor and a Microsoft complier. The software package has been successfully implemented. From the software engineering practice, it is concluded that ITK, VTK, and Qt are very handy software systems to implement automatic image analysis functions for CMR images such as quantitative measure of motion by visual tracking.
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Besson, Florent L; Henry, Théophraste; Meyer, Céline; Chevance, Virgile; Roblot, Victoire; Blanchet, Elise; Arnould, Victor; Grimon, Gilles; Chekroun, Malika; Mabille, Laurence; Parent, Florence; Seferian, Andrei; Bulifon, Sophie; Montani, David; Humbert, Marc; Chaumet-Riffaud, Philippe; Lebon, Vincent; Durand, Emmanuel
2018-04-03
Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK-SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI 41 ) and 50% VOI (VOI 50 ) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI 41 and VOI 50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth
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syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction
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
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NASA Astrophysics Data System (ADS)
Becker-Guedes, F.; Carmo, C. S.; Camargo, P. O.; Monico, J. F. G.; Nicoli Candido, C. M.
2017-12-01
Global Navigation Satellite System (GNSS) is becoming a reliable tool for use in air navigation systems. Its use as the main technology for determination of airplanes positioning has various economic and logistic benefits but it depends strongly on the ionospheric layer influences. The Brazilian sector ionosphere, mainly over the equatorial ionization anomaly (EIA), presents remarkable errors in the GNSS signal as compared to North America and Europe. In order to study the total electron content latitudinal variation of the Brazilian ionosphere we used a pair of GNSS receivers on the ground, one located in the equatorial region (Sao Luis) and other in the southern crest of the EIA (Cachoeira Paulista), to collect the GNSS observables and calculate the vertical TEC using different methods that has proven to work well to describe the ionospheric behavior in the North America and in Europe. We compared this results with a modified Nagoya TEC calculation method used by the EMBRACE (Estudo e Monitoramento BRAsileiro do Clima Espacial - Brazilian Study and Monitoring of Space Weather) program. This work intends to follow the performance of different TEC tuning methods to evaluate the spurious effects of the ionospheric EIA gradients in the TEC determination under typical conditions of the low-latitudes ionosphere in the Brazilian sector. The calculated TEC under different solar cycle conditions, geomagnetic activity, and seasonal variations show deviations in the performance of each method and stress the importance of well adjust the GNSS observations to local conditions in order to optimize the TEC evaluation. This study contributes to a better understanding of local GNSS signal errors in the global intent of offering conditions to improve the accuracy, integrity, availability, and continuity requirements for the use of GNSS for air navigation in South America.
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Tillman, Benjamin F; Pauff, James M; Satyanarayana, Gowri; Talbott, Mahsa; Warner, Jeremy L
2018-04-01
Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated. The published literature and conference abstracts of prospective clinical trials using ibrutinib in hematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc.org per PRISMA guidelines. Infectious events with a focus on pneumonia were collated per the Common Terminology Criteria for Adverse Events Version 4.03 grading. Infectious complications are common, occurring in 56% of patients taking single-agent ibrutinib and 52% of those on combination therapy. Approximately one in 5 patients developed pneumonia, which was the major contributor to a 2% rate of death from infections. Many of the cases of pneumonia were due to opportunistic pathogens. Ibrutinib use requires prudent consideration of the impacts on host immunity. We identified a high rate of serious adverse infectious events within prospective clinical trials. Data suggest a role of both BTK and ITK inhibition for the increased events. There was considerable variability in the reporting of adverse events between trials, journals, and conference reports. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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The NASA thermionic-conversion (TEC-ART) program
NASA Technical Reports Server (NTRS)
Morris, J. F.
1977-01-01
The current emphasis is on out-of-core thermionic conversion (TEC). The additional degrees of freedom offer new potentialities, but high-temperature material effects determine the level and lifetime of TEC performance: New electrodes not only raise power outputs but also maintain them regardless of emitter-vapor deposition on collectors. In addition, effective electrodes serve compatibly with hot-shell alloys. Space TEC withstands external and internal high-temperature vaporization problems, and terrestrial TEC tolerates hot corrosive atmospheres outside and near-vacuum inside. Finally, reduction of losses between converter electrodes is essential even though rather demanding geometries appear to be required for some modes of enhanced operation.
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NASA Astrophysics Data System (ADS)
Sulungu, Emmanuel D.; Uiso, Christian B. S.; Sibanda, Patrick
2018-04-01
We have compared the TEC obtained from the IRI-2012 model with the GPS derived TEC data recorded within southern crest of the EIA in the Eastern Africa region using the monthly means of the 5 international quiet days for equinoxes and solstices months for the period of 2012 - 2013. GPS-derived TEC data have been obtained from the Africa array and IGS network of ground based dual-frequency GPS receivers from four stations (Kigali (1.95°S, 30.09°E; Geom. Lat. 11.63°S), Malindi (2.99°S, 40.19°E; Geom. Lat. 12.42°S), Mbarara (0.60°S, 30.74°E; Geom. Lat. 10.22°S) and Nairobi (1.22°S, 36.89°E; Geom. Lat. 10.69°S)) located within the EIA crest in this region. All the three options for topside Ne of IRI-2012 model and ABT-2009 for bottomside thickness have been used to compute the IRI TEC. Also URSI coefficients were considered in this study. These results are compared with the TEC estimated from GPS measurements. Correlation Coefficients between the two sets of data, the Root-Mean Square Errors (RMSE) of the IRI-TEC from the GPS-TEC, and the percentage RMSE of the IRI-TEC from the GPS-TEC have been computed. Our general results show that IRI-2012 model with all three options overestimates the GPS-TEC for all seasons and at all stations, and IRI-2001 overestimates GPS-TEC more compared with other options. IRI-Neq and IRI-01-corr are closely matching in most of the time. The observation also shows that, GPS TEC are underestimated by TEC from IRI model during noon hours, especially during equinoctial months. Further, GPS-TEC values and IRI-TEC values using all the three topside Ne options show very good correlation (above 0.8). On the other hand, the TEC using IRI-Neq and IRI-01- corr had smaller deviations from the GPS-TEC compared to the IRI-2001.
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Space Weather Activities of IONOLAB Group: IONOLAB-TEC
NASA Astrophysics Data System (ADS)
Arikan, F.; Sezen, U.; Arikan, O.; Ugurlu, O.; Nayir, H.
2009-04-01
Space Weather (SW) is the concept of changing environmental conditions in outer space and affect Earth and its technological systems. SW is a consequence of the solar activities and the coupling of solar energy on Earth's atmosphere due to the Earth's magnetic field. The monitoring and prediction of SW has utmost importance for HF communication, Satellite communication, navigation and guidance systems, Low Earth Orbit (LEO) satellite systems, Space Craft exit and entry into the atmosphere. Ionosphere is the plasma layer of the atmosphere that is ionized by solar radiation and it is a key player of SW. Ionosphere is a temporally and spatially varying, dispersive, anisotropic and inhomogeneous medium that is characterized primarily by its electron density distribution. IONOLAB is a group of researchers of various disciplines, getting together to handle challenges of the Earth's ionosphere. The team has researchers from Hacettepe University and Bilkent University, Department of Electrical and Electronics Engineering and General Command of Mapping of Turkish Army. One of the most important contributions of IONOLAB group is the automated web-based computation service for Total Electron Content (TEC). TEC corresponds to the line integral of electron density distribution on a given path. TEC can also be expressed as the amount of free electrons within 1 m2 cross-sectional area of the cylinder on the ray path. Global Position System (GPS) provides a cost-effective medium for monitoring of ionosphere using the signals recorded by stationary GPS receivers in estimating TEC. IONOLAB group has developed IONOLAB-TEC for reliable and robust estimates for all latitudes and both calm and disturbed days by using RINEX, IONEX and satellite ephemeris data provided from the IGS centers. IONOLAB-TEC consists of a regularized signal estimation algorithm which combines signals from all GPS satellites for a given instant and a given receiver, for a desired time period or for 24 hours
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TEC Variations Over Korean Peninsula During Magnetic Storm
NASA Astrophysics Data System (ADS)
Ji, E.-Y.; Choi, B.-K.; Kim, K.-H.; Lee, D.-H.; Cho, J.-H.; Chung, J.-K.; Park, J.-U.
2008-03-01
By analyzing the observations from a number of ground- and space-based instruments, including ionosonde, magnetometers, and ACE interplanetary data, we examine the response of the ionospheric TEC over Korea during 2003 magnetic storms. We found that the variation of vertical TEC is correlated with the southward turning of the interplanetary magnetic field B_z. It is suggested that the electric fields produced by the dynamo process in the high-latitude region and the prompt penetration in the low-latitude region are responsible for TEC increases. During the June 16 event, dayside TEC values increase more than 15%. And the ionospheric F2-layer peak height (hmF2) was ˜300km higher and the vertical E×B drift (estimated from ground-based magnetometer equatorial electrojet delta H) showed downward drift, which may be due to the ionospheric disturbance dynamo electric field produced by the large amount of energy dissipation into high-latitude regions. In contr! ast, during November 20 event, the nightside TEC increases may be due to the prompt penetration westward electric field. The ionospheric F2-layer peak height was below 200km and the vertical E×B drift showed downward drift. Also, a strong correlation is observed between enhanced vertical TEC and enhanced interplanetary electric field. It is shown that, even though TEC increases are caused by the different processes, the electric field disturbances in the ionosphere play an important role in the variation of TEC over Korea.
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Thermionic Energy Conversion (TEC) topping thermoelectrics
NASA Technical Reports Server (NTRS)
Morris, J. F.
1981-01-01
Performance expectations for thermionic and thermoelectric energy conversion systems are reviewed. It is noted that internal radiation effects diminish thermoelectric figures of merit significantly at 1000 K and substantially at 2000 K; the effective thermal conductivity contribution of intrathermoelectric radiative dissipation increases with the third power of temperature. It is argued that a consideration of thermoelectric power generation with high temperature heat sources should include utilization of thermionic energy conversion (TEC) topping thermoelectrics. However TEC alone or TEC topping more efficient conversion systems like steam or gas turbines, combined cycles, or Stirling engines would be more desirable generally.
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Global empirical model of TEC response to geomagnetic activity
NASA Astrophysics Data System (ADS)
Mukhtarov, P.; Andonov, B.; Pancheva, D.
2013-10-01
global total electron content (TEC) model response to geomagnetic activity described by the Kp index is built by using the Center for Orbit Determination of Europe (CODE) TEC data for a full 13 years, January 1999 to December 2011. The model describes the most probable spatial distribution and temporal variability of the geomagnetically forced TEC anomalies assuming that these anomalies at a given modified dip latitude depend mainly on the Kp index, local time (LT), and longitude. The geomagnetic anomalies are expressed by the relative deviation of TEC from its 15 day median and are denoted as rTEC. The rTEC response to the geomagnetic activity is presented by a sum of two responses with different time delay constants and different signs of the cross-correlation function. It has been found that the mean dependence of rTEC on Kp index can be expressed by a cubic function. The LT dependence of rTEC is described by Fourier time series which includes the contribution of four diurnal components with periods 24, 12, 8, and 6 h. The rTEC dependence on longitude is presented by Fourier series which includes the contribution of zonal waves with zonal wave numbers up to 6. In order to demonstrate how the model is able to reproduce the rTEC response to geomagnetic activity, three geomagnetic storms at different seasons and solar activity conditions are presented. The model residuals clearly reveal two types of the model deviation from the data: some underestimation of the largest TEC response to the geomagnetic activity and randomly distributed errors which are the data noise or anomalies generated by other sources. The presented TEC model fits to the CODE TEC input data with small negative bias of -0.204, root mean squares error RMSE = 4.592, and standard deviation error STDE = 4.588. The model offers TEC maps which depend on geographic coordinates (5° × 5° in latitude and longitude) and universal time (UT) at given geomagnetic activity and day of the year. It could be
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The synthesis of ternary acetylides with tellurium: Li 2 TeC 2 and Na 2 TeC 2
DOE Office of Scientific and Technical Information (OSTI.GOV)
Németh, Károly; Unni, Aditya K.; Kalnmals, Christopher
The synthesis of ternary acetylides Li 2TeC 2 and Na 2TeC 2 is presented as the first example of ternary acetylides with metalloid elements instead of transition metals. The synthesis was carried out by the direct reaction of the corresponding bialkali acetylides with tellurium powder in liquid ammonia. Alternatively, the synthesis of Na 2TeC 2 was also carried out by the direct reaction of tellurium powder and two equivalents of NaC 2H in liquid ammonia leading to Na 2TeC 2 and acetylene gas through an equilibrium containing the assumed NaTeC 2H molecules besides the reactants and the products. The resultingmore » disordered crystalline materials were characterized by X-ray diffraction and Raman spectroscopy. Implications of these new syntheses on the synthesis of other ternary acetylides with metalloid elements and transition metals are also discussed.« less
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V-TECS Guide for Medical Assistant.
ERIC Educational Resources Information Center
South Carolina State Dept. of Education, Columbia. Office of Vocational Education.
This V-TECS (Vocational-Technical Consortium of States) Guide is an extension or continuation of the V-TECS catalog for the occupation of medical assistant. The guide is designed to help South Carolina teachers to promote the art of learning while teaching subject matter. The guide addresses the three domains of learning: psychomotor, cognitive,…
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Local TEC modelling and forecasting using neural networks
NASA Astrophysics Data System (ADS)
Tebabal, A.; Radicella, S. M.; Nigussie, M.; Damtie, B.; Nava, B.; Yizengaw, E.
2018-07-01
Modelling the Earth's ionospheric characteristics is the focal task for the ionospheric community to mitigate its effect on the radio communication, and satellite navigation. However, several aspects of modelling are still challenging, for example, the storm time characteristics. This paper presents modelling efforts of TEC taking into account solar and geomagnetic activity, time of the day and day of the year using neural networks (NNs) modelling technique. The NNs have been designed with GPS-TEC measured data from low and mid-latitude GPS stations. The training was conducted using the data obtained for the period from 2011 to 2014. The model prediction accuracy was evaluated using data of year 2015. The model results show that diurnal and seasonal trend of the GPS-TEC is well reproduced by the model for the two stations. The seasonal characteristics of GPS-TEC is compared with NN and NeQuick 2 models prediction when the latter one is driven by the monthly average value of solar flux. It is found that NN model performs better than the corresponding NeQuick 2 model for low latitude region. For the mid-latitude both NN and NeQuick 2 models reproduce the average characteristics of TEC variability quite successfully. An attempt of one day ahead forecast of TEC at the two locations has been made by introducing as drivers previous day solar flux and geomagnetic index values. The results show that a reasonable day ahead forecast of local TEC can be achieved.
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Local TEC Modelling and Forecasting using Neural Networks
NASA Astrophysics Data System (ADS)
Tebabal, A.; Radicella, S. M.; Nigussie, M.; Damtie, B.; Nava, B.; Yizengaw, E.
2017-12-01
Abstract Modelling the Earth's ionospheric characteristics is the focal task for the ionospheric community to mitigate its effect on the radio communication, satellite navigation and technologies. However, several aspects of modelling are still challenging, for example, the storm time characteristics. This paper presents modelling efforts of TEC taking into account solar and geomagnetic activity, time of the day and day of the year using neural networks (NNs) modelling technique. The NNs have been designed with GPS-TEC measured data from low and mid-latitude GPS stations. The training was conducted using the data obtained for the period from 2011 to 2014. The model prediction accuracy was evaluated using data of year 2015. The model results show that diurnal and seasonal trend of the GPS-TEC is well reproduced by the model for the two stations. The seasonal characteristics of GPS-TEC is compared with NN and NeQuick 2 models prediction when the latter one is driven by the monthly average value of solar flux. It is found that NN model performs better than the corresponding NeQuick 2 model for low latitude region. For the mid-latitude both NN and NeQuick 2 models reproduce the average characteristics of TEC variability quite successfully. An attempt of one day ahead forecast of TEC at the two locations has been made by introducing as driver previous day solar flux and geomagnetic index values. The results show that a reasonable day ahead forecast of local TEC can be achieved.
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Potentialities of TEC topping: A simplified view of parametric effects
NASA Technical Reports Server (NTRS)
Morris, J. F.
1980-01-01
An examination of the benefits of thermionic-energy-conversion (TEC)-topped power plants and methods of increasing conversion efficiency are discussed. Reductions in the cost of TEC modules yield direct decreases in the cost of electricity (COE) from TEC-topped central station power plants. Simplified COE, overall-efficiency charts presented illustrate this trend. Additional capital-cost diminution results from designing more compact furnaces with considerably increased heat transfer rates allowable and desirable for high temperature TEC and heat pipes. Such improvements can evolve of the protection from hot corrosion and slag as well as the thermal expansion compatibilities offered by silicon-carbide clads on TEC-heating surfaces. Greater efficiencies and far fewer modules are possible with high-temperature, high-power-density TEC: This decreases capital and fuel costs much more and substantially increases electric power outputs for fixed fuel inputs. In addition to more electricity, less pollution, and lower costs, TEC topping used directly in coal-combustion products contributes balance-of-payment gains.
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Preliminary study of TEC application in cooling system
NASA Astrophysics Data System (ADS)
Sulaiman, A. C.; Amin, N. A. M.; Saidon, M. S.; Majid, M. S. A.; Rahman, M. T. A.; Kazim, M. N. F. M.
2017-10-01
Integration of thermoelectric cooling (TEC) within a space cooling system in the lecturer room is studied. The studied area (air conditioned surrounding) is encapsulated with wall, floor, roof, and glass window. TEC module is placed on the glass window. The prototype of the studied compartment is designed using cabin container. The type and number of TEC module are studied and the effects on the cooling performance are analyzed as it is assumed to be tested within an air conditioned lecturer room. The experimental and mathematical modeling of the cooling system developed. It is expected that the mathematical modeling derived from this study will be used to estimate the use of the number of TEC module to be integrated with air conditioner unit where possible.
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Pollmann, Katrin; Beil, Stefan; Pieper, Dietmar H.
2001-01-01
The tecB gene, located downstream of tecA and encoding tetrachlorobenzene dioxygenase, in Ralstonia sp. strain PS12 was cloned into Escherichia coli DH5α together with the tecA gene. The identity of the tecB gene product as a chlorobenzene dihydrodiol dehydrogenase was verified by transformation into the respective catechols of chlorobenzene, the three isomeric dichlorobenzenes, as well as 1,2,3- and 1,2,4-trichlorobenzenes, all of which are transformed by TecA into the respective dihydrodihydroxy derivatives. Di- and trichlorotoluenes were either subject to TecA-mediated dioxygenation (the major or sole reaction observed for the 1,2,4-substituted 2,4-, 2,5-, and 3,4-dichlorotoluenes), resulting in the formation of the dihydrodihydroxy derivatives, or to monooxygenation of the methyl substituent (the major or sole reaction observed for 2,3-, 2,6-, and 3,5-dichloro- and 2,4,5-trichlorotoluenes), resulting in formation of the respective benzyl alcohols. All of the chlorotoluenes subject to dioxygenation by TecA were transformed, without intermediate accumulation of dihydrodihydroxy derivatives, into the respective catechols by TecAB, indicating that dehydrogenation is no bottleneck for chlorobenzene or chlorotoluene degradation. However, only those chlorotoluenes subject to a predominant dioxygenation were growth substrates for PS12, confirming that monooxygenation is an unproductive pathway in PS12. PMID:11526005
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A role for the Swe1 checkpoint kinase during filamentous growth of Saccharomyces cerevisiae.
La Valle, R; Wittenberg, C
2001-01-01
In this study we show that inactivation of Hsl1 or Hsl7, negative regulators of the Swe1 kinase, enhances the invasive behavior of haploid and diploid cells. The enhancement of filamentous growth caused by inactivation of both genes is mediated via the Swe1 protein kinase. Whereas Swe1 contributes noticeably to the effectiveness of haploid invasive growth under all conditions tested, its contribution to pseudohyphal growth is limited to the morphological response under standard assay conditions. However, Swe1 is essential for pseudohyphal differentiation under a number of nonstandard assay conditions including altered temperature and increased nitrogen. Swe1 is also required for pseudohyphal growth in the absence of Tec1 and for the induction of filamentation by butanol, a related phenomenon. Although inactivation of Hsl1 is sufficient to suppress the defect in filamentous growth caused by inactivation of Tec1 or Flo8, it is insufficient to promote filamentous growth in the absence of both factors. Moreover, inactivation of Hsl1 will not bypass the requirement for nitrogen starvation or growth on solid medium for pseudohyphal differentiation. We conclude that the Swe1 kinase modulates filamentous development under a broad spectrum of conditions and that its role is partially redundant with the Tec1 and Flo8 transcription factors. PMID:11404321
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Latitudinal and Seasonal Investigations of Storm-Time TEC Variation
NASA Astrophysics Data System (ADS)
Adimula, I. A.; Oladipo, O. A.; Adebiyi, S. J.
2016-07-01
The ionosphere responds markedly and unpredictably to varying magnetospheric energy inputs caused by solar disturbances on the geospace. Knowledge of the impact of the space weather events on the ionosphere is important to assess the environmental effect on the operations of ground- and space-based technologies. Thus, global positioning system (GPS) measurements from the international GNSS service (IGS) database were used to investigate the ionospheric response to 56 geomagnetic storm events at six different latitudes comprising the northern and southern hemispheres in the Afro-European sector. Statistical distributions of total electron content (TEC) response show that during the main phase of the storms, enhancement of TEC is more pronounced in most of the seasons, regardless of the latitude and hemisphere. However, a strong seasonal dependence appears in the TEC response during the recovery phase. Depletion of TEC is majorly observed at the high latitude stations, and its appearance at lower latitudes is seasonally dependent. In summer hemisphere, the depletion of TEC is more pronounced in nearly all the latitudinal bands. In winter hemisphere, enhancement as well as depletion of TEC is observed over the high latitude, while enhancement is majorly observed over the mid and low latitudes. In equinoxes, the storm-time TEC distribution shows a fairly consistent characteristic with the summer distribution, particularly in the northern hemisphere.
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Observing Traveling Ionospheric Disturbances Caused by Tsunamis Using GPS TEC Measurements
NASA Technical Reports Server (NTRS)
Galvan, David A.; Komjathy, Attila; Hickey, Michael; Foster, James; Mannucci, Anthony J.
2010-01-01
Ground-based Global Positioning System (GPS) measurements of ionospheric Total Electron Content (TEC) show variations consistent with atmospheric internal gravity waves caused by ocean tsunamis following two recent seismic events: the American Samoa earthquake of September 29, 2009, and the Chile earthquake of February 27, 2010. Fluctuations in TEC correlated in time, space, and wave properties with these tsunamis were observed in TEC estimates processed using JPL's Global Ionospheric Mapping Software. These TEC estimates were band-pass filtered to remove ionospheric TEC variations with wavelengths and periods outside the typical range of internal gravity waves caused by tsunamis. Observable variations in TEC appear correlated with the tsunamis in certain locations, but not in others. Where variations are observed, the typical amplitude tends to be on the order of 1% of the background TEC value. Variations with amplitudes 0.1 - 0.2 TECU are observable with periods and timing affiliated with the tsunami. These observations are compared to estimates of expected tsunami-driven TEC variations produced by Embry Riddle Aeronautical University's Spectral Full Wave Model, an atmosphere-ionosphere coupling model, and found to be in good agreement in some locations, though there are cases when the model predicts an observable tsunami-driven signature and none is observed. These TEC variations are not always seen when a tsunami is present, but in these two events the regions where a strong ocean tsunami was observed did coincide with clear TEC observations, while a lack of clear TEC observations coincided with smaller tsunami amplitudes. There exists the potential to apply these detection techniques to real-time GPS TEC data, providing estimates of tsunami speed and amplitude that may be useful for early warning systems.
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Long-term trends in the total electron content (TEC)
NASA Astrophysics Data System (ADS)
Laštovička, Jan
2017-04-01
The long-term trends in the total electron content (TEC) have very little been studied. Lean et al. (2011; J. Geophys. Res., 116, A00H04, doi:10.1029/2010JA016378) studied trends in TEC globally based on JPL maps for 1995-2010. However, their trends appear to be too positive, which is not plausible taking into account the trends in other ionospheric parameters. Therefore they prefer the less positive trends calculated under the assumption of the same level of solar activity in solar cycle minima 22/23 and 23/24. However, as it is now clear, this is not a correct assumption. Lastovicka (2013; J. Geophys. Res. Space Phys., 118, 3831-3835, doi:10.1002/jgra.50261) selected a region around Florence, Italy, as a region with available historical TEC data based on Faraday rotation measurements and remarkably larger than average trends in TEC by Lean et al. (2011). Historical data from Florence provide no trend in TEC. However, foF2 from Juliusruh provide slight negative trends for 1976-1996 but no trends for 1995-2010. Thus the question of reality of trends by Lean et al. (2011) remained open. Here we use TEC from GIM and JPL data for two European regions with high Lean's trends, regions around Florence and around Prague, using 10-14 LT medians, 1998-2015, yearly average values. A classical approach is applied. First a model of solar activity dependence of TEC is constructed separately for each region from all data. Then model data are subtracted from experimental data and analysis is made with residuals. This analysis shows that early data (1998-2001) are by several TECU lower than they should be according to solar activity, the year 2002 is intermediate and in 2003-2015 the data fit well a weak or rather no trend of TEC. The change in TEC data does not seem to be jump-like, it lasted at least a year, if not longer. Thus the positive TEC trends reported by Lean et al. (2011) appear to be affected by data problem; real trends are evidently less positive if any.
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Assessment of Modeling Capability for Reproducing Storm Impacts on TEC
NASA Astrophysics Data System (ADS)
Shim, J. S.; Kuznetsova, M. M.; Rastaetter, L.; Bilitza, D.; Codrescu, M.; Coster, A. J.; Emery, B. A.; Foerster, M.; Foster, B.; Fuller-Rowell, T. J.; Huba, J. D.; Goncharenko, L. P.; Mannucci, A. J.; Namgaladze, A. A.; Pi, X.; Prokhorov, B. E.; Ridley, A. J.; Scherliess, L.; Schunk, R. W.; Sojka, J. J.; Zhu, L.
2014-12-01
During geomagnetic storm, the energy transfer from solar wind to magnetosphere-ionosphere system adversely affects the communication and navigation systems. Quantifying storm impacts on TEC (Total Electron Content) and assessment of modeling capability of reproducing storm impacts on TEC are of importance to specifying and forecasting space weather. In order to quantify storm impacts on TEC, we considered several parameters: TEC changes compared to quiet time (the day before storm), TEC difference between 24-hour intervals, and maximum increase/decrease during the storm. We investigated the spatial and temporal variations of the parameters during the 2006 AGU storm event (14-15 Dec. 2006) using ground-based GPS TEC measurements in the selected 5 degree eight longitude sectors. The latitudinal variations were also studied in two longitude sectors among the eight sectors where data coverage is relatively better. We obtained modeled TEC from various ionosphere/thermosphere (IT) models. The parameters from the models were compared with each other and with the observed values. We quantified performance of the models in reproducing the TEC variations during the storm using skill scores. This study has been supported by the Community Coordinated Modeling Center (CCMC) at the Goddard Space Flight Center. Model outputs and observational data used for the study will be permanently posted at the CCMC website (http://ccmc.gsfc.nasa.gov) for the space science communities to use.
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A dual-stage sodium thermal electrochemical converter (Na-TEC)
NASA Astrophysics Data System (ADS)
Limia, Alexander; Ha, Jong Min; Kottke, Peter; Gunawan, Andrey; Fedorov, Andrei G.; Lee, Seung Woo; Yee, Shannon K.
2017-12-01
The sodium thermal electrochemical converter (Na-TEC) is a heat engine that generates electricity through the isothermal expansion of sodium ions. The Na-TEC is a closed system that can theoretically achieve conversion efficiencies above 45% when operating between thermal reservoirs at 1150 K and 550 K. However, thermal designs have confined previous single-stage devices to thermal efficiencies below 20%. To mitigate some of these limitations, we consider dividing the isothermal expansion into two stages; one at the evaporator temperature (1150 K) and another at an intermediate temperature (650 K-1050 K). This dual-stage Na-TEC takes advantage of regeneration and reheating, and could be amenable to better thermal management. Herein, we demonstrate how the dual-stage device can improve the efficiency by up to 8% points over the best performing single-stage device. We also establish an application regime map for the single- and dual-stage Na-TEC in terms of the power density and the total thermal parasitic loss. Generally, a single-stage Na-TEC should be used for applications requiring high power densities, whereas a dual-stage Na-TEC should be used for applications requiring high efficiency.
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CFD Extraction Tool for TecPlot From DPLR Solutions
NASA Technical Reports Server (NTRS)
Norman, David
2013-01-01
This invention is a TecPlot macro of a computer program in the TecPlot programming language that processes data from DPLR solutions in TecPlot format. DPLR (Data-Parallel Line Relaxation) is a NASA computational fluid dynamics (CFD) code, and TecPlot is a commercial CFD post-processing tool. The Tec- Plot data is in SI units (same as DPLR output). The invention converts the SI units into British units. The macro modifies the TecPlot data with unit conversions, and adds some extra calculations. After unit conversions, the macro cuts a slice, and adds vectors on the current plot for output format. The macro can also process surface solutions. Existing solutions use manual conversion and superposition. The conversion is complicated because it must be applied to a range of inter-related scalars and vectors to describe a 2D or 3D flow field. It processes the CFD solution to create superposition/comparison of scalars and vectors. The existing manual solution is cumbersome, open to errors, slow, and cannot be inserted into an automated process. This invention is quick and easy to use, and can be inserted into an automated data-processing algorithm.
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Operation and Maintenance Manual, TECS 18.
1978-11-01
width modulated variable output voltage and frequency using a three-phase transistor bridge circuit . Reduced power line electromagnetic interference...Description 3-1 Section II. Circuit Fundamentals 3-1 Section III. System Description 3-2 CHAPTER 4. Protection and Maintenance 4-1 Section I. Internal...Number I-la TECS 18 Electronic Module Location-Evaporator Side 1-3 1-lb TECS 18 Electronic Module Location-Condenser Side 1-4 1-2 Remote Control Panel 1-5
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CoLiTec software - detection of the near-zero apparent motion
NASA Astrophysics Data System (ADS)
Khlamov, Sergii V.; Savanevych, Vadym E.; Briukhovetskyi, Olexandr B.; Pohorelov, Artem V.
2017-06-01
In this article we described CoLiTec software for full automated frames processing. CoLiTec software allows processing the Big Data of observation results as well as processing of data that is continuously formed during observation. The scope of solving tasks includes frames brightness equalization, moving objects detection, astrometry, photometry, etc. Along with the high efficiency of Big Data processing CoLiTec software also ensures high accuracy of data measurements. A comparative analysis of the functional characteristics and positional accuracy was performed between CoLiTec and Astrometrica software. The benefits of CoLiTec used with wide field and low quality frames were observed. The efficiency of the CoLiTec software was proved by about 700.000 observations and over 1.500 preliminary discoveries.
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Space Weather Activities of IONOLAB Group: TEC Mapping
NASA Astrophysics Data System (ADS)
Arikan, F.; Yilmaz, A.; Arikan, O.; Sayin, I.; Gurun, M.; Akdogan, K. E.; Yildirim, S. A.
2009-04-01
Being a key player in Space Weather, ionospheric variability affects the performance of both communication and navigation systems. To improve the performance of these systems, ionosphere has to be monitored. Total Electron Content (TEC), line integral of the electron density along a ray path, is an important parameter to investigate the ionospheric variability. A cost-effective way of obtaining TEC is by using dual-frequency GPS receivers. Since these measurements are sparse in space, accurate and robust interpolation techniques are needed to interpolate (or map) the TEC distribution for a given region in space. However, the TEC data derived from GPS measurements contain measurement noise, model and computational errors. Thus, it is necessary to analyze the interpolation performance of the techniques on synthetic data sets that can represent various ionospheric states. By this way, interpolation performance of the techniques can be compared over many parameters that can be controlled to represent the desired ionospheric states. In this study, Multiquadrics, Inverse Distance Weighting (IDW), Cubic Splines, Ordinary and Universal Kriging, Random Field Priors (RFP), Multi-Layer Perceptron Neural Network (MLP-NN), and Radial Basis Function Neural Network (RBF-NN) are employed as the spatial interpolation algorithms. These mapping techniques are initially tried on synthetic TEC surfaces for parameter and coefficient optimization and determination of error bounds. Interpolation performance of these methods are compared on synthetic TEC surfaces over the parameters of sampling pattern, number of samples, the variability of the surface and the trend type in the TEC surfaces. By examining the performance of the interpolation methods, it is observed that both Kriging, RFP and NN have important advantages and possible disadvantages depending on the given constraints. It is also observed that the determining parameter in the error performance is the trend in the Ionosphere
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Short Term Single Station GNSS TEC Prediction Using Radial Basis Function Neural Network
NASA Astrophysics Data System (ADS)
Muslim, Buldan; Husin, Asnawi; Efendy, Joni
2018-04-01
TEC prediction models for 24 hours ahead have been developed from JOG2 GPS TEC data during 2016. Eleven month of TEC data were used as a training model of the radial basis function neural network (RBFNN) and 1 month of last data (December 2016) is used for the RBFNN model testing. The RBFNN inputs are the previous 24 hour TEC data and the minimum of Dst index during the previous 24 hours. Outputs of the model are 24 ahead TEC prediction. Comparison of model prediction show that the RBFNN model is able to predict the next 24 hours TEC is more accurate than the TEC GIM model.
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The Response of Mid-Latitude Ionospheric TEC to Geomagnetic Storms and Solar Flares
NASA Astrophysics Data System (ADS)
Huang, Z.; Roussel-Dupre, R.
2004-12-01
The effects of geomagnetic storms and solar flares on the ionosphere are manifested as large magnitude sudden fluctuations in the Total Electron Content (TEC). In this study, the broadband VHF signal (30-100MHz) data from the Los Alamos Portable Pulser (LAPP) received by the FORTE (Fast Onboard Recording of Transient Events) satellite during the period of 1997-2002 are used to investigate the mean TEC variation response to geomagnetic storm. A total of 14 geomagnetic storms are selected where FORTE-LAPP data are available to derive average TECs during extended storm-time and non-storm time for a given storm. The variations in the ionospheric TECs at Los Alamos, New Mexico are investigated for the 14 selected geomagnetic storms. In most cases (12 out of 14), we see overall enhancements in TEC as a result of geomagnetic storm impact at Los Alamos. The relative enhancements in TEC at Los Alamos due to a geomagnetic storm can reach as high as 3-fold of the normal TEC values. The overall absolute enhancements in TEC at Los Alamos are up to about 30 TECU. The magnitude of TEC enhancements is diversified over all storm categories without a clean-cut relationship between the storm intensity and the TEC enhancement. The mean TEC variation response to geomagnetic storm can be complicated when several consecutive storms occurred in a row and a net TEC reduction may be seen. Data of continuous GPS TEC measurements are collected at a 1-minute time resolution during July 2004 when 5 X-class solar flares occurred from two Allen Osborne Associates ICS-4000Z GPS receivers mounted at the Physics Building at Los Alamos National Laboratory. In detecting effects of solar flares on the ionospheric TEC, we apply appropriate filtering to remove the linear trend of TEC and a coherent processing of TEC variations simultaneously for all the visible GPS satellites in a given time interval. The responses of ionospheric TEC at minute time scale to these powerful impulsive solar flares are
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Quantitative Evaluation of Ionosphere Models for Reproducing Regional TEC During Geomagnetic Storms
NASA Astrophysics Data System (ADS)
Shim, J. S.; Kuznetsova, M.; Rastaetter, L.; Bilitza, D.; Codrescu, M.; Coster, A. J.; Emery, B.; Foster, B.; Fuller-Rowell, T. J.; Goncharenko, L. P.; Huba, J.; Mitchell, C. N.; Ridley, A. J.; Fedrizzi, M.; Scherliess, L.; Schunk, R. W.; Sojka, J. J.; Zhu, L.
2015-12-01
TEC (Total Electron Content) is one of the key parameters in description of the ionospheric variability that has influence on the accuracy of navigation and communication systems. To assess current TEC modeling capability of ionospheric models during geomagnetic storms and to establish a baseline against which future improvement can be compared, we quantified the ionospheric models' performance by comparing modeled vertical TEC values with ground-based GPS TEC measurements and Multi-Instrument Data Analysis System (MIDAS) TEC. The comparison focused on North America and Europe sectors during selected two storm events: 2006 AGU storm (14-15 Dec. 2006) and 2013 March storm (17-19 Mar. 2013). The ionospheric models used for this study range from empirical to physics-based, and physics-based data assimilation models. We investigated spatial and temporal variations of TEC during the storms. In addition, we considered several parameters to quantify storm impacts on TEC: TEC changes compared to quiet time, rate of TEC change, and maximum increase/decrease during the storms. In this presentation, we focus on preliminary results of the comparison of the models performance in reproducing the storm-time TEC variations using the parameters and skill scores. This study has been supported by the Community Coordinated Modeling Center (CCMC) at the Goddard Space Flight Center. Model outputs and observational data used for the study will be permanently posted at the CCMC website (http://ccmc.gsfc.nasa.gov) for the space science communities to use.
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78 FR 64207 - Application To Export Electric Energy; TEC Energy Inc.
Federal Register 2010, 2011, 2012, 2013, 2014
2013-10-28
... DEPARTMENT OF ENERGY [OE Docket No. EA-388] Application To Export Electric Energy; TEC Energy Inc. AGENCY: Office of Electricity Delivery and Energy Reliability, DOE. ACTION: Notice of Application. SUMMARY: TEC Energy Inc. (TEC) has applied for authority to transmit electric energy from the United...
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TEC variability near northern EIA crest and comparison with IRI model
NASA Astrophysics Data System (ADS)
Aggarwal, Malini
2011-10-01
Monthly median values of hourly total electron content (TEC) is obtained with GPS at a station near northern anomaly crest, Rajkot (geog. 22.29°N, 70.74°E; geomag. 14.21°N, 144.9°E) to study the variability of low latitude ionospheric behavior during low solar activity period (April 2005 to March 2006). The TEC exhibit characteristic features like day-to-day variability, semiannual anomaly and noon bite out. The observed TEC is compared with latest International Reference Ionosphere (IRI) - 2007 model using options of topside electron density, NeQuick, IRI01-corr and IRI-2001 by using both URSI and CCIR coefficients. A good agreement of observed and predicted TEC is found during the daytime with underestimation at other times. The predicted TEC by NeQuick and IRI01-corr is closer to the observed TEC during the daytime whereas during nighttime and morning hours, IRI-2001 shows lesser discrepancy in all seasons by both URSI and CCIR coefficients.
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StarTEC: A Technology Project in Education Reform.
ERIC Educational Resources Information Center
Hawley, Helen; Benavides, Otto; Duffy, Sharon; Georgi, David; Guay, Diane; Redmond, Pamela; Richmond, James
StarTEC (Staff, Teacher, and Restructured Technology Education Consortium) was a 3-year technology catalyst program funded by the U.S. Department of Education, and continued for a third year to complete its activities. The goal of StarTEC was to ensure that all teachers prepared by partners in the Consortium would meet the new California standard…
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Bani, MariaRosa; Decio, Alessandra; Giavazzi, Raffaella; Ghilardi, Carmen
2017-05-01
Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.
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Comparison of Two IRI plasmasphere Extensions with GPS-TEC Observations
NASA Technical Reports Server (NTRS)
Gulyaeva, T. L.; Gallagher, Dennis L.
2006-01-01
Comparisons of two model results with Global Positioning System GPS-TEC measurements have been carried out for different latitudinal, solar activity, magnetic activity, diurnal and seasonal conditions. The models evaluated are the Global Core Plasma Model (GCPM-2000) and the IRI extension with Russian plasmasphere model (IRI*).Data of 23 observatories providing GPS-TEC and ionosonde data have been used. It is shown that IRI* plasmasphere electron density is greater than GCPM results by an order of magnitude at 6370 km altitude (one Earth's radius) with this excess growing to 2-3 orders of magnitude towards the GPS satellite altitude of 20000 km. Another source of model and GPS-TEC differences is a way of selection of the F2 layer peak parameters driving the models either with ITU-R (former CCIR) maps or ionosonde observations. Plasmasphere amendment to IRI improves accuracy of TEC model predictions because the plasmasphere contribution to the total TEC varies from 10% by daytime under quiet magnetic conditions to more than 50% by night under stormy conditions.
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Derivation of GPS TEC and receiver bias for Langkawi station in Malaysia
NASA Astrophysics Data System (ADS)
Teh, W. L.; Chen, W. S.; Abdullah, M.
2017-05-01
This paper presents the polynomial-type TEC model to derive total electron content (TEC) and receiver bias for Langkawi (LGKW) station in Malaysia at geographic latitude of 6.32° and longitude of 99.85°. The model uses a polynomial function of coordinates of the ionospheric piercing point to describe the TEC distribution in space. In the model, six polynomial coefficients and a receiver bias are unknown which can be solved by the least squares method. A reasonable agreement is achieved for the derivation of TEC and receiver bias for IENG station in Italy, as compared with that derived by the IGS analysis center, CODE. We process one year of LGKW data in 2010 and show the monthly receiver bias and the seasonal TEC variation. The monthly receiver bias varies between -48 and -24 TECu (1016 electrons/m2), with the mean value at -37 TECu. Large variations happen in the monthly receiver biases due to the low data coverage of high satellite elevation angle (60° < α ≤ 90°). Post-processing TEC approach is implemented which can resolve the wavy pattern of the monthly TEC baseline resulted from the large variation of the receiver bias. The seasonal TEC variation at LGKW exhibits a semi-annual variation, where the peak occurs during equinoctial months, and the trough during summer and winter months.
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Ionospheric earthquake effects detection based on Total Electron Content (TEC) GPS Correlation
NASA Astrophysics Data System (ADS)
Sunardi, Bambang; Muslim, Buldan; Eka Sakya, Andi; Rohadi, Supriyanto; Sulastri; Murjaya, Jaya
2018-03-01
Advances in science and technology showed that ground-based GPS receiver was able to detect ionospheric Total Electron Content (TEC) disturbances caused by various natural phenomena such as earthquakes. One study of Tohoku (Japan) earthquake, March 11, 2011, magnitude M 9.0 showed TEC fluctuations observed from GPS observation network spread around the disaster area. This paper discussed the ionospheric earthquake effects detection using TEC GPS data. The case studies taken were Kebumen earthquake, January 25, 2014, magnitude M 6.2, Sumba earthquake, February 12, 2016, M 6.2 and Halmahera earthquake, February 17, 2016, M 6.1. TEC-GIM (Global Ionosphere Map) correlation methods for 31 days were used to monitor TEC anomaly in ionosphere. To ensure the geomagnetic disturbances due to solar activity, we also compare with Dst index in the same time window. The results showed anomalous ratio of correlation coefficient deviation to its standard deviation upon occurrences of Kebumen and Sumba earthquake, but not detected a similar anomaly for the Halmahera earthquake. It was needed a continous monitoring of TEC GPS data to detect the earthquake effects in ionosphere. This study giving hope in strengthening the earthquake effect early warning system using TEC GPS data. The method development of continuous TEC GPS observation derived from GPS observation network that already exists in Indonesia is needed to support earthquake effects early warning systems.
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Long-Term Prediction of the Arctic Ionospheric TEC Based on Time-Varying Periodograms
Liu, Jingbin; Chen, Ruizhi; Wang, Zemin; An, Jiachun; Hyyppä, Juha
2014-01-01
Knowledge of the polar ionospheric total electron content (TEC) and its future variations is of scientific and engineering relevance. In this study, a new method is developed to predict Arctic mean TEC on the scale of a solar cycle using previous data covering 14 years. The Arctic TEC is derived from global positioning system measurements using the spherical cap harmonic analysis mapping method. The study indicates that the variability of the Arctic TEC results in highly time-varying periodograms, which are utilized for prediction in the proposed method. The TEC time series is divided into two components of periodic oscillations and the average TEC. The newly developed method of TEC prediction is based on an extrapolation method that requires no input of physical observations of the time interval of prediction, and it is performed in both temporally backward and forward directions by summing the extrapolation of the two components. The backward prediction indicates that the Arctic TEC variability includes a 9 years period for the study duration, in addition to the well-established periods. The long-term prediction has an uncertainty of 4.8–5.6 TECU for different period sets. PMID:25369066
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Te/C nanocomposites for Li-Te Secondary Batteries
NASA Astrophysics Data System (ADS)
Seo, Jeong-Uk; Seong, Gun-Kyu; Park, Cheol-Min
2015-01-01
New battery systems having high energy density are actively being researched in order to satisfy the rapidly developing market for longer-lasting mobile electronics and hybrid electric vehicles. Here, we report a new Li-Te secondary battery system with a redox potential of ~1.7 V (vs. Li+/Li) adapted on a Li metal anode and an advanced Te/C nanocomposite cathode. Using a simple concept of transforming TeO2 into nanocrystalline Te by mechanical reduction, we designed an advanced, mechanically reduced Te/C nanocomposite electrode material with high energy density (initial discharge/charge: 1088/740 mA h cm-3), excellent cyclability (ca. 705 mA h cm-3 over 100 cycles), and fast rate capability (ca. 550 mA h cm-3 at 5C rate). The mechanically reduced Te/C nanocomposite electrodes were found to be suitable for use as either the cathode in Li-Te secondary batteries or a high-potential anode in rechargeable Li-ion batteries. We firmly believe that the mechanically reduced Te/C nanocomposite constitutes a breakthrough for the realization and mass production of excellent energy storage systems.
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Detection of Seismic Precursors Using Distance Metrics Between GPS-TEC and IRI-Plas
NASA Astrophysics Data System (ADS)
Necat Deviren, M.; Gulyaeva, Tamara; Sezen, Umut; Arikan, Feza; Arikan, Orhan
Ionosphere is an important layer of atmosphere that varies under solar, geomagnetic, gravitational and seismic activities. Total Electron Content (TEC) is one of the main observables of ionosphere. International Reference Ionosphere Extended to Plasmasphere (IRI-Plas) is accepted by International Organization for Standardization (ISO) as the standard climatic model. IRI-Plas provides TEC up to GPS satellite height. TEC can be estimated using Global Positioning System (GPS) Networks. In this study, TEC is computed using both IRI-Plas and Turkish National Permanent GPS Network as IONOLAB-TEC. In order to detect seismic precursors, three different distance metrics, namely Symmetric Kullback-Liebler Distance (SKLD), Cross-Correlation Coefficient (CC), and L2-Norm (L2N), are implemented between IONOLAB-TEC and IRI-Plas-TEC values. SKLD is also computed between IONOLAB-TEC Maps and IRI-Plas-TEC Maps over Turkey. Between May 2009 and September 2012, it is observed that SKLD metric indicates a disturbance within the period prior to 10 days of earthquake day. The disturbance in SKLD increases for the range of stations in the neighborhood of the epicenter. For strong earthquakes all of the three distance metrics indicate a disturbance before the earthquake, yet SKLD behaves as a more sensitive precursor for earthquakes larger than magnitude 4. This study is supported by the joint grant of TUBITAK 112E568 and RFBR 13-02-91370-CT_a.
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NASA Astrophysics Data System (ADS)
Patel, N. C.; Karia, S. P.; Pathak, K. N.
2017-07-01
This paper presents a comparison of GPS-derived TEC with IRI-2012 and IRI-2007 TEC Predictions at Surat (21.16°N Geographic latitude, 72.78°E Geographic longitude, 12.90°N Geomagnetic latitude) a location around the Equatorial Ionisation Anomaly (EIA) crest in the Indian sector, during the Ascending Phase of Solar Cycle 24, for a period of three years (January 2010-December 2012). In this comparison, plasmaspheric electron content (PEC) contribution to the GPS-TEC has been removed. It is observed that percentage PEC contribution to the GPS-TEC varies from about ∼15% (at the noon local time) to about ∼30% (at the morning local time). From the monthly comparison of GPS-TEC with IRI-TEC, it is observed that, TEC predicted by both the models overestimates in June-2012 and underestimates TEC in November-2011, December-2011 and March-2011. For all other months IRI estimates the TEC well. From the seasonal comparison, it is observed that the peak time appears ∼1-h later than the actual peak time in Winter 2010, Summer 2011, and Equinox 2010 and 2012 (the result suggest that it may be due to discrepancies/disagreement of both the versions of the IRI model in estimating the peak density as well as the thickness and shape parameters of the electron density profiles). For the Summer season, the IRI-TEC estimates the TEC well for all the years. Further, the seasonal variation of the GPS-TEC for all the three years matches well with IRI-2012 model compared to IRI-2007 model. Also, the mean annual TEC is predicted well by both the versions of the IRI model.
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The Visible Human Data Sets (VHD) and Insight Toolkit (ITk): Experiments in Open Source Software
Ackerman, Michael J.; Yoo, Terry S.
2003-01-01
From its inception in 1989, the Visible Human Project was designed as an experiment in open source software. In 1994 and 1995 the male and female Visible Human data sets were released by the National Library of Medicine (NLM) as open source data sets. In 2002 the NLM released the first version of the Insight Toolkit (ITk) as open source software. PMID:14728278
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NASA Astrophysics Data System (ADS)
ćepni, Murat S.; Potts, Laramie V.; Miima, John B.
2013-09-01
electron content (TEC) estimates derived from Global Navigation Satellite System (GNSS) signal delays provide a rich source of information about the Earth's ionosphere. Networks of Global Positioning System (GPS) receivers data can be used to represent the ionosphere by a Global Ionospheric Map (GIM). Data input for GIMs is dual-frequency GNSS-only or a mixture of GNSS and altimetry observations. Parameterization of GNSS-only GIMs approaches the ionosphere as a single-layer model (SLM) to determine GPS TEC models over a region. Limitations in GNSS-only GIM TEC are due largely to the nonhomogenous global distribution of GPS tracking stations with large data gaps over the oceans. The utility of slant GPS ionospheric-induced path delays for high temporal resolution from a single-station data rate offers better representation of TEC over a small region. A station-based vertical TEC (TECV) approach modifies the traditional single-layer model (SLM) GPS TEC method by introducing a zenith angle weighting (ZAW) filter to capture signal delays from mostly near-zenith satellite passes. Comparison with GIMs shows the station-dependent TEC (SD-TEC) model exhibits robust performance under variable space weather conditions. The SD-TEC model was applied to investigate ionospheric TEC variability during the geomagnetic storm event of 9 March 2012 at midlatitude station NJJJ located in New Jersey, USA. The high temporal resolution TEC results suggest TEC production and loss rate differences before, during, and after the storm.
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GIM-TEC adaptive ionospheric weather assessment and forecast system
NASA Astrophysics Data System (ADS)
Gulyaeva, T. L.; Arikan, F.; Hernandez-Pajares, M.; Stanislawska, I.
2013-09-01
The Ionospheric Weather Assessment and Forecast (IWAF) system is a computer software package designed to assess and predict the world-wide representation of 3-D electron density profiles from the Global Ionospheric Maps of Total Electron Content (GIM-TEC). The unique system products include daily-hourly numerical global maps of the F2 layer critical frequency (foF2) and the peak height (hmF2) generated with the International Reference Ionosphere extended to the plasmasphere, IRI-Plas, upgraded by importing the daily-hourly GIM-TEC as a new model driving parameter. Since GIM-TEC maps are provided with 1- or 2-days latency, the global maps forecast for 1 day and 2 days ahead are derived using an harmonic analysis applied to the temporal changes of TEC, foF2 and hmF2 at 5112 grid points of a map encapsulated in IONEX format (-87.5°:2.5°:87.5°N in latitude, -180°:5°:180°E in longitude). The system provides online the ionospheric disturbance warnings in the global W-index map establishing categories of the ionospheric weather from the quiet state (W=±1) to intense storm (W=±4) according to the thresholds set for instant TEC perturbations regarding quiet reference median for the preceding 7 days. The accuracy of IWAF system predictions of TEC, foF2 and hmF2 maps is superior to the standard persistence model with prediction equal to the most recent ‘true’ map. The paper presents outcomes of the new service expressed by the global ionospheric foF2, hmF2 and W-index maps demonstrating the process of origin and propagation of positive and negative ionosphere disturbances in space and time and their forecast under different scenarios.
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Regional And Seasonal Aspects Of Within-The-Hour Tec Statistics
NASA Astrophysics Data System (ADS)
Koroglu, Ozan; Arikan, Feza; Koroglu, Meltem
2015-04-01
Ionosphere is one of the atmosphere layers which has a plasma structure. Several mechanisms originating from both space and earth itself governs this plasma layer such as solar radiation and geomagnetic effects. Ionosphere plays important role for HF and satellite communication, and space based positioning systems. Therefore, the determination of statistical behavior of ionosphere has utmost importance. The variability of the ionosphere has complex spatio-temporal characteristics, which depends on solar, geomagnetic, gravitational and seismic activities. Total Electron Content (TEC) is one of the major observables for investigating and determining this variability. In this study, spatio-temporal within-the-hour statistical behavior of TEC is determined for Turkey, which is located in mid-latitude, using the TEC estimates from Turkish National Permanent GPS Network (TNPGN)-Active between the years 2009 and 2012. TEC estimates are obtained as IONOLAB-TEC which is developed by IONOLAB group (www.ionolab.org) from Hacettepe University. IONOLAB-TEC for each station in TNPGN-Active is organized in a database and grouped with respect to years, ionospheric seasons, hours and regions 2 degree by 3 degree, in latitude and longitude, respectively. The data sets are used to calculate within-the-hour parametric Probability Density Functions (PDF). For every year, every region and every hour, a representative PDF is determined. It is observed that TEC values have a strong hourly, seasonal and positional dependence on east-west direction, and the growing trend shifts according to sunrise and sunset times. It is observed that the data are distributed predominantly as Lognormal and Weibull. The averages and standard deviations of the chosen distributions follow the trends in 24 hour diurnal and 11 year solar cycle periods. The regional and seasonal behavior of PDFs are investigated using a representative GPS station within each region. Within-the-hour PDF estimates are grouped into
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Joint Analysis of the Full AzTEC Sub-Millimeter Galaxy Data Set
NASA Astrophysics Data System (ADS)
Wilson, Grant; Ade, P.; Aretxaga, I.; Austermann, J.; Bock, J.; Hughes, D.; Kang, Y.; Kim, S.; Lowenthal, J.; Mauskopf, P.; Perera, T.; Scott, K.; Yun, M.
2006-12-01
Using the new AzTEC millimeter-wave camera on the James Clerk Maxwell Telescope (JCMT) in winter 2005/06, we conducted several surveys of the submm galaxy (SMG) population. The AzTEC 1.1 millimeter surveys include both blank-fields (no significant bias or foreground contamination) and regions of known over-densities, and are both large (100-1000 sq. arcmin.) and sensitive ( 1 mJy rms). The unique power of the AzTEC data set lies not only in the size and depth of the individual fields, but in the combined surveyed area that totals over 1 square degree. Hundreds of new sub-millimeter sources have been detected. A joint analysis of all AzTEC surveys will provide important new constraints on many characteristics of the SMG population, including number counts, clustering, and variance. In particular, the large area of the full AzTEC data set provides the first significant measurement of the brightest and most rare of the SMG population. Herein we present the initial combined results and explore the future potential of a complete joint analysis of the full AzTEC SMG data set.
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Short-Term TEC Perturbations Associated With Planetary Waves Occurrence in the Ionosphere
NASA Astrophysics Data System (ADS)
Shagimuratov, I. I.; Karpov, I.; Krankowski, A.
2008-12-01
Analysis of TEC response to storm showed short-term perturbations which were observed after initial phase of geomagnetic storms. The perturbations demonstrated very well expressed latitudinal structure and were recognized on diurnal variations as surges of TEC enhancement of TEC. Ordinary such storm-time positive effect was associated with TAD. Duration of the perturbations was about 2-4 hours and their amplitude increased toward low latitudes. Such TEC perturbations have the longitudinal dependence. It is important that time location of surges have week dependence on latitude. The observed structure appeared to arrive from high latitudes, but at middle latitudes it was represented as a standing wave. It is assumed that such TEC perturbations can be produced due to superposition of the eastward and westward propagating planetary Poincare waves. The periods of these waves are usually several hours. Poincare waves can be excited at the atmosphere in storm time. At middle latitudes their superposition is as standing wave that forms observing TEC perturbations. In the report, the possibilities of application Poincare waves to the ionosphere dynamics studies are discussed and an explanation of the observed ionospheric effects is given.
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NASA Astrophysics Data System (ADS)
Jhuang, Hau-Kun; Ho, Yi-Ying; Lee, Lou-Chuang
2016-04-01
The northern ionosphere is coupled to the conjugate southern ionosphere through the highly conducting geomagenetic field lines. The coupling is very strong or "perfect" if the geomagnetic field lines are equipotential (the parallel electric field E||=0) and hence the perpendicular electric field (E⊥) at the conjugate sites of both ionospheres are equal. The coupling is "imperfect" if some of the geomagnetic field lines are non-equipotential (E||≠0). The field-aligned electric field E|| can be associated with electron inertia, pressure gradient and collisions appearing in the form of double layer, kinetic Alfvén waves and finite field-aligned conductivity σ||. We use the Global Ionospheric Maps (GIM) data to examine the conjugate effect of total electron content (TEC) for six significant earthquakes. The anomalous (ΔTEC)source in the source ionosphere and (ΔTEC)conjugate in the conjugate ionosphere are obtained for 85 events before the six earthquakes. The ΔTEC ratio β = (ΔTEC)conjugate / (ΔTEC)source is calculated for each anomaly. For a "perfect" coupling, β=1. There are 85 anomalous events before the six significant earthquakes, with 62 events occurring in the daytime (07-18 LT) and 23 events in the nighttime (19-06 LT). The average value of daytime (07-18 LT) TEC variations in the source ionosphere is |ΔTEC|source =20.13 TECu, while the average value in the nighttime (19-06 LT) ionosphere is |ΔTEC|source=14.43 TECu. The value of ΔTEC ratio β ranges from 0.05 (very weak coupling) to 0.98 (nearly perfect coupling) with an average of 0.52. There are 14 strong coupling cases with β ≥0.8, which take place from 11 LT to 19 LT. The daytime (07-18 LT) β average value is 0.57 and the nighttime (19-06 LT) β average is 0.37. The south-north ionosphere coupling is stronger (weaker) in the daytime (nighttime).
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NMobTec-EnvEdu: M-Learning System for Environmental Education
ERIC Educational Resources Information Center
Cavus, Nadire
2008-01-01
This paper introduced the implementation of a New Mobile Technologies and Environmental Education System (NMobTec-EnvEdu) designed for m-learning environments. The NMobTec-EnvEdu system has been developed to provide environmental education in a collaborative framework to undergraduate students through the Internet using mobile phones. The study…
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NASA Astrophysics Data System (ADS)
Sur, D.; Paul, A.
2017-12-01
The equatorial ionosphere shows sharp diurnal and latitudinal Total Electron Content (TEC) variations over a major part of the day. Equatorial ionosphere also exhibits intense post-sunset ionospheric irregularities. Accurate prediction of TEC in these low latitudes is not possible from standard ionospheric models. An Artificial Neural Network (ANN) based Vertical TEC (VTEC) model has been designed using TEC data in low latitude Indian longitude sector for accurate prediction of VTEC. GPS TEC data from the stations Calcutta (22.58°N, 88.38°E geographic, magnetic dip 32°), Baharampore (24.09°N, 88.25°E geographic, magnetic dip 35°) and Siliguri (26.72°N, 88.39°E geographic; magnetic dip 40°) are used as training dataset for the duration of January 2007-September 2011. Poleward VTEC gradients from northern EIA crest to region beyond EIA crest have been calculated from measured VTEC and compared with that obtained from ANN based VTEC model. TEC data from Calcutta and Siliguri are used to compute VTEC gradients during April 2013 and August-September 2013. It has been observed that poleward VTEC gradient computed from ANN based TEC model has shown good correlation with measured values during vernal and autumnal equinoxes of high solar activity periods of 2013. Possible correlation between measured poleward TEC gradients and post-sunset scintillations (S4 ≥ 0.4) from northern crest of EIA has been observed in this paper. From the observation, a suitable threshold poleward VTEC gradient has been proposed for possible occurrence of post-sunset scintillations at northern crest of EIA along 88°E longitude. Poleward VTEC gradients obtained from ANN based VTEC model are used to forecast possible ionospheric scintillation after post-sunset period using the threshold value. It has been observed that these predicted VTEC gradients obtained from ANN based VTEC model can forecast post-sunset L-band scintillation with an accuracy of 67% to 82% in this dynamic low latitude
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Linear time series modeling of GPS-derived TEC observations over the Indo-Thailand region
NASA Astrophysics Data System (ADS)
Suraj, Puram Sai; Kumar Dabbakuti, J. R. K.; Chowdhary, V. Rajesh; Tripathi, Nitin K.; Ratnam, D. Venkata
2017-12-01
This paper proposes a linear time series model to represent the climatology of the ionosphere and to investigate the characteristics of hourly averaged total electron content (TEC). The GPS-TEC observation data at the Bengaluru international global navigation satellite system (GNSS) service (IGS) station (geographic 13.02°N , 77.57°E ; geomagnetic latitude 4.4°N ) have been utilized for processing the TEC data during an extended period (2009-2016) in the 24{th} solar cycle. Solar flux F10.7p index, geomagnetic Ap index, and periodic oscillation factors have been considered to construct a linear TEC model. It is evident from the results that solar activity effect on TEC is high. It reaches the maximum value (˜ 40 TECU) during the high solar activity (HSA) year (2014) and minimum value (˜ 15 TECU) during the low solar activity (LSA) year (2009). The larger magnitudes of semiannual variations are observed during the HSA periods. The geomagnetic effect on TEC is relatively low, with the highest being ˜ 4 TECU (March 2015). The magnitude of periodic variations can be seen more significantly during HSA periods (2013-2015) and less during LSA periods (2009-2011). The correlation coefficient of 0.89 between the observations and model-based estimations has been found. The RMSE between the observed TEC and model TEC values is 4.0 TECU (linear model) and 4.21 TECU (IRI2016 Model). Further, the linear TEC model has been validated at different latitudes over the northern low-latitude region. The solar component (F10.7p index) value decreases with an increase in latitude. The magnitudes of the periodic component become less significant with the increase in latitude. The influence of geomagnetic component becomes less significant at Lucknow GNSS station (26.76°N, 80.88°E) when compared to other GNSS stations. The hourly averaged TEC values have been considered and ionospheric features are well recovered with linear TEC model.
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NASA Astrophysics Data System (ADS)
Marlia, Dessi; Wu, Falin
2016-07-01
This paper investigates the variations of vertical Total Electron Content (VTEC) at Manado, Indonesia (geographic coordinates : lat 1.34 ° S and long 124.82 ° E) for period 2013. The GPS measured TEC is compared with the TEC derived from the IRI (International Reference Ionosphere) 2012 model. Vertical TEC measurements obtained from dual frequency GPS receiver that is GISTM (GPS Ionospheric Scintillations and TEC monitor). Variation of TEC validate to IRI 2012 model at Manado station has been compared with the model for three different topside of electron density namely NeQuick, IRI-01-Corr and IRI2001.There is a need to investigation on diurnal, seasonal variations, solar activity dependence of TEC and including effects of space weather related events to TEC and modeling of TEC. In this paper, diurnal and seasonal variations of VTEC and the effect of VTEC due to space weather events like Geomagnetic storms are analyzed. The result show that the TEC prediction using IRI-2001 model overestimated the GPS TEC measurements, while IRI-NeQuick and IRI-01-corr show a tendency to underestimates the observed TEC during the day time particularly in low latitude region in the maximum solar activity period (2013). The variations of VTEC during 17th March, 2013, 29th June, 2013 storms are analyzed. During 17th March,2013 storm enhancement in VTEC with Kp value 6 and Disturbance storm index (DST) -132 nT. During 29th June, 2013 storm VTEC depletion with value 7 and DST -98 nT. Significant deviations in VTEC during the main phase of the storms are observed. It is found that the response of ionospheric TEC consist of effects of both enhancement and depletions in ionospheric structures (positive and negative storm). Keywords: TEC ionosphere, GPS, GISTM, IRI 2012 model, solar activity, geomagnetic storm
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Anamolous ionospheric TEC variations prior to the Indonesian earthquake (M 7.1) of November 15, 2014
NASA Astrophysics Data System (ADS)
Alcay, Salih
2017-05-01
This paper investigates preearthquake ionospheric variations with the use of TEC of Global Ionospheric Maps (GIMs) and regional maps based on Precise Point Positioning (PPP) during the 7.1-M Indonesian earthquake that occurred on November 15, 2014. TEC maps corresponding to 10 days before to 4 days after the event were examined. In addition, a time series of TEC values according to the PPP maps were also evaluated. In addition to GIMs, it was possible to detect TEC variations with PPP maps. The results showed that ionospheric TEC decreased strikingly 4 days prior to the earthquake. This TEC variation was highly likely related to seismic activity.
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Empirical model of TEC response to geomagnetic and solar forcing over Balkan Peninsula
NASA Astrophysics Data System (ADS)
Mukhtarov, P.; Andonov, B.; Pancheva, D.
2018-01-01
An empirical total electron content (TEC) model response to external forcing over Balkan Peninsula (35°N-50°N; 15°E-30°E) is built by using the Center for Orbit Determination of Europe (CODE) TEC data for full 17 years, January 1999 - December 2015. The external forcing includes geomagnetic activity described by the Kp-index and solar activity described by the solar radio flux F10.7. The model describes the most probable spatial distribution and temporal variability of the externally forced TEC anomalies assuming that they depend mainly on latitude, Kp-index, F10.7 and LT. The anomalies are expressed by the relative deviation of the TEC from its 15-day mean, rTEC, as the mean value is calculated from the 15 preceding days. The approach for building this regional model is similar to that of the global TEC model reported by Mukhtarov et al. (2013a) however it includes two important improvements related to short-term variability of the solar activity and amended geomagnetic forcing by using a "modified" Kp index. The quality assessment of the new constructing model procedure in terms of modeling error calculated for the period of 1999-2015 indicates significant improvement in accordance with the global TEC model (Mukhtarov et al., 2013a). The short-term prediction capabilities of the model based on the error calculations for 2016 are improved as well. In order to demonstrate how the model is able to reproduce the rTEC response to external forcing three geomagnetic storms, accompanied also with short-term solar activity variations, which occur at different seasons and solar activity conditions are presented.
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Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation.
Kaneshiro, Shoichi; Ebina, Kosuke; Shi, Kenrin; Yoshida, Kiyoshi; Otsuki, Dai; Yoshikawa, Hideki; Higuchi, Chikahisa
2015-09-01
The Tec family of nonreceptor tyrosine kinases has been shown to play a key role in inflammation and bone destruction. Bruton tyrosine kinase (Btk) has been the most widely studied because of its critical role in B cells. Furthermore, recent evidence has demonstrated that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. The role of Btk in osteoblastic differentiation has not been well elucidated. In this study, we demonstrated the role of Btk in osteoblastic differentiation and investigated the effects of a Btk inhibitor on osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells, primary calvarial osteoblasts, and bone marrow stromal ST2 cells. Btk expression was detected in all three cell lines. Btk inhibition stimulated mRNA expression of osteoblastic markers (alkaline phosphatase, osteocalcin, and osterix) and promoted mineralization of the extracellular matrix. In addition, Btk knockdown caused increased mRNA expression of osteoblastic markers. Furthermore, Btk inhibition suppressed the phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NFκB), and protein kinase Cα (PKCα). Our results indicate that Btk may regulate osteoblastic differentiation through the MAPK, NFκB, and PKCα signaling pathways.
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Thermodynamic Analysis of TEG-TEC Device Including Influence of Thomson Effect
NASA Astrophysics Data System (ADS)
Feng, Yuanli; Chen, Lingen; Meng, Fankai; Sun, Fengrui
2018-01-01
A thermodynamic model of a thermoelectric cooler driven by thermoelectric generator (TEG-TEC) device is established considering Thomson effect. The performance is analyzed and optimized using numerical calculation based on non-equilibrium thermodynamic theory. The influence characteristics of Thomson effect on the optimal performance and variable selection are investigated by comparing the condition with and without Thomson effect. The results show that Thomson effect degrades the performance of TEG-TEC device, it decreases the cooling capacity by 27 %, decreases the coefficient of performance (COP) by 19 %, decreases the maximum cooling temperature difference by 11 % when the ratio of thermoelectric elements number is 0.6, the cold junction temperature of thermoelectric cooler (TEC) is 285 K and the hot junction temperature of thermoelectric generator (TEG) is 450 K. Thomson effect degrades the optimal performance of TEG-TEC device, it decreases the maximum cooling capacity by 28 % and decreases the maximum COP by 28 % under the same junction temperatures. Thomson effect narrows the optimal variable range and optimal working range. In the design of the devices, limited-number thermoelectric elements should be more allocated appropriately to TEG when consider Thomson effect. The results may provide some guidelines for the design of TEG-TEC devices.
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A Year-Long Comparison of GPS TEC and Global Ionosphere-Thermosphere Models
NASA Astrophysics Data System (ADS)
Perlongo, N. J.; Ridley, A. J.; Cnossen, I.; Wu, C.
2018-02-01
The prevalence of GPS total electron content (TEC) observations has provided an opportunity for extensive global ionosphere-thermosphere model validation efforts. This study presents a year-long data-model comparison using the Global Ionosphere-Thermosphere Model (GITM) and the Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIE-GCM). For the entire year of 2010, each model was run and compared to GPS TEC observations. The results were binned according to season, latitude, local time, and magnetic local time. GITM was found to overestimate the TEC everywhere, except on the midlatitude nightside, due to high O/N2 ratios. TIE-GCM produced much less TEC and had lower O/N2 ratios and neutral wind speeds. Seasonal and regional biases in the models are discussed along with ideas for model improvements and further validation efforts.
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South Carolina TEC Student Code.
ERIC Educational Resources Information Center
Edwards, C. A., Ed.; Kiser, J. A., Ed.
This student code has statewide application to South Carolina Technical Colleges and Technical Education Centers (TEC). Provisions are divided into eight articles: (1) General Provisions, including the purpose of a student code, the precept of internal solution of problems, and definitions; (2) Student Rights, including Bill of Rights protections;…
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Statistical Analysis of TEC Anomalies Prior to M6.0+ Earthquakes During 2003-2014
NASA Astrophysics Data System (ADS)
Zhu, Fuying; Su, Fanfan; Lin, Jian
2018-04-01
There are many studies on the anomalous variations of the ionospheric TEC prior to large earthquakes. However, whether or not the morphological characteristics of the TEC anomalies in the daytime and at night are different is rarely studied. In the present paper, based on the total electron content (TEC) data from the global ionosphere map (GIM), we carry out a statistical survey on the spatial-temporal distribution of TEC anomalies before 1339 global M6.0+ earthquakes during 2003-2014. After excluding the interference of geomagnetic disturbance, the temporal and spatial distributions of ionospheric TEC anomalies prior to the earthquakes in the daytime and at night are investigated and compared. Except that the nighttime occurrence rates of the pre-earthquake ionospheric anomalies (PEIAs) are higher than those in the daytime, our analysis has not found any statistically significant difference in the spatial-temporal distribution of PEIAs in the daytime and at night. Moreover, the occurrence rates of pre-earthquake ionospheric TEC both positive anomalies and negative anomalies at night tend to increase slightly with the earthquake magnitude. Thus, we suggest that monitoring the ionospheric TEC changes at night might be a clue to reveal the relation between ionospheric disturbances and seismic activities.
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Probability Distribution Extraction from TEC Estimates based on Kernel Density Estimation
NASA Astrophysics Data System (ADS)
Demir, Uygar; Toker, Cenk; Çenet, Duygu
2016-07-01
Statistical analysis of the ionosphere, specifically the Total Electron Content (TEC), may reveal important information about its temporal and spatial characteristics. One of the core metrics that express the statistical properties of a stochastic process is its Probability Density Function (pdf). Furthermore, statistical parameters such as mean, variance and kurtosis, which can be derived from the pdf, may provide information about the spatial uniformity or clustering of the electron content. For example, the variance differentiates between a quiet ionosphere and a disturbed one, whereas kurtosis differentiates between a geomagnetic storm and an earthquake. Therefore, valuable information about the state of the ionosphere (and the natural phenomena that cause the disturbance) can be obtained by looking at the statistical parameters. In the literature, there are publications which try to fit the histogram of TEC estimates to some well-known pdf.s such as Gaussian, Exponential, etc. However, constraining a histogram to fit to a function with a fixed shape will increase estimation error, and all the information extracted from such pdf will continue to contain this error. In such techniques, it is highly likely to observe some artificial characteristics in the estimated pdf which is not present in the original data. In the present study, we use the Kernel Density Estimation (KDE) technique to estimate the pdf of the TEC. KDE is a non-parametric approach which does not impose a specific form on the TEC. As a result, better pdf estimates that almost perfectly fit to the observed TEC values can be obtained as compared to the techniques mentioned above. KDE is particularly good at representing the tail probabilities, and outliers. We also calculate the mean, variance and kurtosis of the measured TEC values. The technique is applied to the ionosphere over Turkey where the TEC values are estimated from the GNSS measurement from the TNPGN-Active (Turkish National Permanent
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LISN: Measurement of TEC values, and TID characteristics over South and Central America (Invited)
NASA Astrophysics Data System (ADS)
Valladares, C. E.
2013-12-01
The Low-latitude Ionospheric Sensor Network (LISN) is a distributed observatory designed to provide the climatology and weather of the low latitude ionosphere over the South American continent. Presently, the LISN observatory consists of 47 GPS receivers able to transmit TEC and scintillation values to a central server in a real-time basis. Historical TEC values from these receivers and from about 300 other GPSs that operated in South and Central America between 2008 and 2012 were used to derive regional maps of TEC and TIDs. A prominent feature of the TEC maps is the intense day-to-day variability that is observed during all seasons and under quiet and active magnetic conditions. To assess the TEC dependencies a non-linear least-square fit was conducted to simultaneously extract the solar flux, magnetic and seasonal variability for each square cell of the TEC maps and for each 30-min local time sector. It was found that TEC values and the anomaly intensity increase as a function of the solar flux. The latitudinal separation increases with magnetic activity, and TEC values in Central America become the largest when Kp is equal to 5o or more. TIDs are seen quite frequently over the Caribbean region and in the northern part of South America. To calculate the TIDs travel velocities, their propagation direction, and the scale-size of the disturbances a multi-site multi-dimension cross-correlation method was applied to the TEC database. Phase velocities of order 150 m/s and scale sizes between 100 and 400 km were typically observed. This paper will present the morphology and statistics of TIDs as a function of latitude, longitude, local time and season. It is also introduced the results of an investigation to correlate the appearance, phase velocity and angle of propagation of TIDs and tropospheric phenomena observed with the TRMM satellite.
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Development of TEC fluctuations in northern and southern hemispheres on the base of GPS observations
NASA Astrophysics Data System (ADS)
Shagimuratov, Irk; Krankowski, Andrzej; Sieradzki, Rafal; Ephishov, I. I.
GPS technique is widely used to study the global structure and dynamics of the ionosphere. In this paper GPS observations carried out at Arctic and Antarctic stations belonging to the IGS network were used to study TEC fluctuations in the high-latitude ionosphere during the ionospheric storms. Dual-frequency GPS phase measurements along individual satellite passes served as raw data. It was shown that ionospheric irregularities of a different scale were devel-oped in the auroral and polar ionosphere. It is a common phenomenon caused phase fluctuations of GPS signals. In November 2009, West Department of IZMIRAN in Kaliningrad (Russia) and University of Warmia and Mazury in Olsztyn (Poland) established computer server for automatic monitoring of these irregularities. The rate of TEC index (ROTI) expressed in TECU/min was used as a measure of TEC fluctuations. During its operation TEC variations related to ionospheric structures of a spatial scale more than 200-300 km were detected. Large-scale ionospheric structures cause an increase in horizontal gradients and difficulties with the carrier phase ambiguity resolution in GPS positioning. In turn, the phase fluctuations can cause cycle-slip effects. At the polar stations, ionospheric structures with TEC enhanced by a factor of 3-5 relative to the background were detected, whereas TEC increased to 5-8 TECU in about 10-15 min. These structures were observed during a storm, as well as during a moderate geomagnetic activity. It can be probably attributed to the polar cap patches. In this study are presented the extended and more detailed analyses of TEC fluctuations in both the northern and southern hemispheres and compare the winter and summer events (November and July 2004 storms). A special attention is given to the features related to TEC fluctuations occur-rence in both hemispheres for conjugated GPS stations. The temporal development of both storms was rather similar. During storms the intensity of irregularities
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Detection of Geomagnetic Pulsations of the Earth Using GPS-TEC Data
NASA Astrophysics Data System (ADS)
Koroglu, Ozan; Arikan, Feza; Köroǧlu, Meltem; Sabri Ozkazanc, Yakup
2016-07-01
The magnetosphere of the Earth is made up of both magnetic fields and plasma. In this layer, plasma waves propagate as Ultra Low Frequency (ULF) waves having mHz scale frequencies. ULF waves are produced due to complicated solar-geomagnetic interactions. In the literature, these ULF waves are defined as pulsations. The geomagnetic pulsations are classified into main two groups as continuous pulsations (Pc) and irregular pulsations (Pi). These pulsations can be determined by ionospheric parameters due to the complex lithosphere-ionosphere-magnetosphere coupling processes. Total Electron Content (TEC) is one of the most important parameters for investigating the variability of ionosphere. Global Positioning System (GPS) provides a cost-effective means for estimating TEC from GPS satellite orbital height of 20,000 km to the ground based receivers. Therefore, the time series of GPS-TEC inherently contains the above mentioned ULF waves. In this study, time series analysis of GPS-TEC is carried out by applying periodogram method to the mid-latitude annual TEC data. After the analysis of GPS-TEC data obtained for GPS stations located in Central Europe and Turkey for 2011, it is observed that some of the fundamental frequencies that are indicators of Pc waves, diurnal and semi-diurnal periodicity and earth-free oscillations can be identified. These results will be used in determination of low frequency trend structure of magnetosphere and ionosphere. Further investigation of remaining relatively low magnitude frequencies, all Pi and Pc can be identified by using time and frequency domain techniques such as wavelet analysis. This study is supported by the joint TUBITAK 115E915 and joint TUBITAK114E092 and AS CR 14/001 projects.
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V-TECS Career Cluster Frameworks.
ERIC Educational Resources Information Center
Vocational Technical Education Consortium of States, Decatur, GA.
This document includes 16 vocational-technical crosswalk wheels relating the 14 Vocational Technical Education Consortium of States (V-TECS) Career Families to the 16 Career Clusters developed by the U.S. Department of Education. The career clusters are based on the common academic, workplace, and technical knowledge and skills that cut across all…
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Epizootic rabbit enteropathy inoculum (TEC4): antibiograms and antibiotic fractionation.
Huybens, Nathalie; Houeix, Julien; Licois, Dominique; Mainil, Jacques; Marlier, Didier
2011-01-01
Epizootic rabbit enteropathy (ERE) emerged and spread in Europe within the last 13 years causing major economical loss. The aims of the study was to evaluate antibiograms of TEC4, an inoculum composed of an extract of intestinal content of affected rabbits, and to test the potential of different antibiotic-based TEC4 fractions to reproduce the disease. Twenty nine different antibiotic discs were incubated for determining bacteria resistance. In a complementary study, nine tubes of liquid medium were inoculated with TEC4, incubated and added individually with amoxicillin/clavulanic acid, bacitracin, ceftiofur, doxycycline, novobiocin, streptomycyin, tylosin, vancomycin and 0.9% saline solution as control. The content of each tube was washed by centrifugation and suspended in saline. The three most effective antibiotics are florfenicol, amoxycillin/clavulanic acid and tylosin. A high concentration of Clostridium sordelli and Bacillus firmus were isolated in all fractions. Species never cultured from TEC4 were identified as Fusobacterium necrogenes (in vancomycin fraction), Cellulomonas sp (in novobiocin fraction) and Bacteroides distasonis (in doxycycline fraction). The ERE was reproduced when bacitracin, doxycycline and 0.9% fractions were inoculated. Rabbits showed ERE clinical signs with the specific drop in daily weight gain.
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Investigation of TEC Variations over Mid-Latitude during Quit and Disturbed Days of March 2015
NASA Astrophysics Data System (ADS)
Atıcı, Ramazan; Saǧır, Selçuk; Güzel, Esat
2016-07-01
The variations during 09-14-March-2015 quit days and 15-20 March 2015 disturbed days of Total Electron Content (TEC) values (provided by IONOLAB group) obtained by analysis the data from Ankara Global Position System (GPS) station of Turkey located at mid-latitude, IRI -2012 model the and IRI-PLUS model are investigated. Also, the variations of the geomagnetic, interplanetary and solar wind parameters are examined. As a result of investigations, TEC values from all three models are not change too much at quit days. Unlike, at the disturbed days, although IRI-2012 and IRI-PLUS TEC values are not change too much, a noticeable change in GPS-TEC values is occurred. GPS-TEC values are rapidly increased on 17-March 2015 to be severe magnetic storm (Dst = -124 nT). Then, on following days it was observed to significantly decrease. Thus, it is said that GPS-TEC values are more sensitive than IRI-2012 and IRI-PLUS models to variations occurred on disturbed days.
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Near-Real Time Monitoring of TEC Over Japan at NICT (RWC Tokyo OF ISES)
NASA Astrophysics Data System (ADS)
Miyake, W.; Jin, H.
2010-05-01
The world wide use of global navigation satellite systems such as GPS offers unique opportunities for a permanent monitoring of the total electron content (TEC) of the ionosphere. We have developed a system of the rapid derivation of TEC from GEONET (a dense GPS receiver network in Japan). In addition to a previous plot of TEC temporal variation over Japan, we have recently developed a near-real-time two-dimensional TEC map and have used it for the daily operation of Space Weather Forecast Center at NICT (Regional Warning Center Tokyo of International Space Environment Service). The TEC map can be used to continuously monitor the ionospheric disturbances over Japan, including spatial and temporal development of ionospheric storms, large-amplitude traveling ionospheric disturbances, and plasma bubbles intruding over Japan, with high time resolution. The development of the real-time monitoring system of TEC enables us to monitor large ionospheric disturbances, ranging from global- to small-scale disturbances, expected in the next solar maximum. The plot and maps are open to the public and are available on http://wdc.nict.go.jp/IONO/index_E.html.
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NASA Astrophysics Data System (ADS)
Feng, Jiandi; Jiang, Weiping; Wang, Zhengtao; Zhao, Zhenzhen; Nie, Linjuan
2017-08-01
Global empirical total electron content (TEC) models based on TEC maps effectively describe the average behavior of the ionosphere. However, the accuracy of these global models for a certain region may not be ideal. Due to the number and distribution of the International GNSS Service (IGS) stations, the accuracy of TEC maps is geographically different. The modeling database derived from the global TEC maps with different accuracy is likely one of the main reasons that limits the accuracy of the new models. Moreover, many anomalies in the ionosphere are geographic or geomagnetic dependent, and as such the accuracy of global models can deteriorate if these anomalies are not fully incorporated into the modeling approach. For regional models built in small areas, these influences on modeling are immensely weakened. Thus, the regional TEC models may better reflect the temporal and spatial variations of TEC. In our previous work (Feng et al., 2016), a regional TEC model TECM-NEC is proposed for northeast China. However, this model is only directed against the typical region of Mid-latitude Summer Nighttime Anomaly (MSNA) occurrence, which is meaningless in other regions without MSNA. Following the technique of TECM-NEC model, this study proposes another regional empirical TEC model for other regions in mid-latitudes. Taking a small area BeiJing-TianJin-Tangshan (JJT) region (37.5°-42.5° N, 115°-120° E) in China as an example, a regional empirical TEC model (TECM-JJT) is proposed using the TEC grid data from January 1, 1999 to June 30, 2015 provided by the Center for Orbit Determination in Europe (CODE) under quiet geomagnetic conditions. The TECM-JJT model fits the input CODE TEC data with a bias of 0.11TECU and a root mean square error of 3.26TECU. Result shows that the regional model TECM-JJT is consistent with CODE TEC data and GPS-TEC data.
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Interactive deformation registration of endorectal prostate MRI using ITK thin plate splines.
Cheung, M Rex; Krishnan, Karthik
2009-03-01
Magnetic resonance imaging with an endorectal coil allows high-resolution imaging of prostate cancer and the surrounding normal organs. These anatomic details can be used to direct radiotherapy. However, organ deformation introduced by the endorectal coil makes it difficult to register magnetic resonance images for treatment planning. In this study, plug-ins for the volume visualization software VolView were implemented on the basis of algorithms from the National Library of Medicine's Insight Segmentation and Registration Toolkit (ITK). Magnetic resonance images of a phantom simulating human pelvic structures were obtained with and without the endorectal coil balloon inflated. The prostate not deformed by the endorectal balloon was registered to the deformed prostate using an ITK thin plate spline (TPS). This plug-in allows the use of crop planes to limit the deformable registration in the region of interest around the prostate. These crop planes restricted the support of the TPS to the area around the prostate, where most of the deformation occurred. The region outside the crop planes was anchored by grid points. The TPS was more accurate in registering the local deformation of the prostate compared with a TPS variant, the elastic body spline. The TPS was also applied to register an in vivo T(2)-weighted endorectal magnetic resonance image. The intraprostatic tumor was accurately registered. This could potentially guide the boosting of intraprostatic targets. The source and target landmarks were placed graphically. This TPS plug-in allows the registration to be undone. The landmarks could be added, removed, and adjusted in real time and in three dimensions between repeated registrations. This interactive TPS plug-in allows a user to obtain a high level of accuracy satisfactory to a specific application efficiently. Because it is open-source software, the imaging community will be able to validate and improve the algorithm.
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Comparison of Plateletpheresis on the Fenwal Amicus and Fresenius Com.Tec Cell Separators.
Altuntas, Fevzi; Sari, Ismail; Kocyigit, Ismail; Kaynar, Leylagul; Hacioglu, Sibel; Ozturk, Ahmet; Oztekin, Mehmet; Solmaz, Musa; Eser, Bulent; Cetin, Mustafa; Unal, Ali
2008-01-01
SUMMARY: BACKGROUND: A variety of apheresis devices are now available on the market for plateletapheresis. We compared two apheresis instruments (Fenwal Amicus and Fresenius COM.TEC) with regard to processing time, platelet (PLT) yield and efficiency, and white blood cell (WBC) content. MATERIAL AND METHODS: Donors undergoing plateletpheresis were randomly separated into two groups (either the Amicus or the COM.TEC cell separator). RESULTS: In the pre-apheresis setting, 32 plateletpheresis procedures performed with each instrument revealed no significant differences in donors' sex, age, weight, height and total blood volume between the two groups. However, the pre-apheresis PLT count was higher with the COM.TEC than with the Amicus (198 × 10(3)/μl vs. 223 × 10(3)/μl; p = 0.035). The blood volume processed to reach a target PLT yield of ≥3.3 × 10(11) was higher in the COM.TEC compared to the Amicus (3,481 vs. 2,850 ml; p < 0.001). The median separation time was also significantly longer in the COM.TEC than in the Amicus (61 vs. 44 min; p < 0.001). 91 and 88% of the PLT products collected with the Amicus and the COM.TEC, respectively, had a PLT count of >3.3 × 10(11) (p = 0.325). All products obtained with both instruments had WBC counts lower than 5 ↔ 10(6), as required. There was no statistical difference with regard to collection efficiency between the devices (55 ± 15 vs. 57 ± 15%; p = 0.477). However, the collection rate was significantly higher with the Amicus compared to the COM.TEC instrument (0.077 ± 0.012 × 10(11) vs. 0.057 ± 0.008 × 10(11) PLT/min; p < 0.001). CONCLUSION: Both instruments collected platelets efficiently. Additionally, consistent leukoreduction was obtained with both instruments; however, compared with the COM.TEC instrument, the Amicus reached the PLT target yield more quickly.
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Observations of the Weddell Sea Anomaly in the ground-based and space-borne TEC measurements
NASA Astrophysics Data System (ADS)
Zakharenkova, Irina; Cherniak, Iurii; Shagimuratov, Irk
2017-08-01
The Weddell Sea Anomaly (WSA) is a summer ionospheric anomaly, which is characterized by a greater nighttime ionospheric density than that in daytime in the region near the Weddell Sea. We investigate the WSA signatures in the ground-based TEC (vertical total electron content) by using GPS and GLONASS measurements of the dense regional GNSS networks in South America. We constructed the high-resolution regional TEC maps for December 2014-January 2015. The WSA effects of the TEC exceed the noontime values are registered starting from 17 LT, it reaches its maximum at 01-05 LT and starts to disappear after 09 LT. Maximal TEC enhancements were as large as a factor of 2.5-3.5 and were registered at 03-04 LT. This effect was mainly localized in the geographical region of 55°S-75°S latitude and 80°W-30°W longitude, close to the Antarctic Peninsula. Further, we examined the WSA occurrence in the topside ionosphere by using GPS measurements from a zenith-looking GPS antenna on board three Swarm satellites to determine topside TEC (above ∼500 km altitude) at the topside ionosphere-plasmasphere system. Global maps of the topside TEC indicated that the zone with significant WSA effect in the topside TEC (TEC increase ∼2-4 times the noontime level) had a large spatial extent over southern Pacific and Atlantic Ocean. It was observed around 150°W-20°W and between 40°S and 70°S during 23 LT - 06 LT. For the first time, the WSA signatures were shown in the topside TEC data derived from the GPS measurements onboard the Swarm constellation. Independently, two other instruments - FORMOSAT-3/COSMIC radio occultation electron density profiles and in situ measurements by the Langmuir Probe instrument onboard Swarm satellites - were able to confirm: (1) the same location of the WSA zone as revealed in Swarm TEC; (2) the most-pronounced WSA effect, as a maximal electron density exceed over the noontime values, corresponds to altitudes above 400-500 km.
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NASA Astrophysics Data System (ADS)
Rit, S.; Vila Oliva, M.; Brousmiche, S.; Labarbe, R.; Sarrut, D.; Sharp, G. C.
2014-03-01
We propose the Reconstruction Toolkit (RTK, http://www.openrtk.org), an open-source toolkit for fast cone-beam CT reconstruction, based on the Insight Toolkit (ITK) and using GPU code extracted from Plastimatch. RTK is developed by an open consortium (see affiliations) under the non-contaminating Apache 2.0 license. The quality of the platform is daily checked with regression tests in partnership with Kitware, the company supporting ITK. Several features are already available: Elekta, Varian and IBA inputs, multi-threaded Feldkamp-David-Kress reconstruction on CPU and GPU, Parker short scan weighting, multi-threaded CPU and GPU forward projectors, etc. Each feature is either accessible through command line tools or C++ classes that can be included in independent software. A MIDAS community has been opened to share CatPhan datasets of several vendors (Elekta, Varian and IBA). RTK will be used in the upcoming cone-beam CT scanner developed by IBA for proton therapy rooms. Many features are under development: new input format support, iterative reconstruction, hybrid Monte Carlo / deterministic CBCT simulation, etc. RTK has been built to freely share tomographic reconstruction developments between researchers and is open for new contributions.
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NASA Astrophysics Data System (ADS)
Padokhin, A. M.; Kurbatov, G. A.; Yasyukevich, Y.; Yasyukevich, A.
2017-12-01
With the development of GNSS and SBAS constellations, the coherent multi-frequency L band transmissions are now available from a number of geostationary satellites. These signals can be used for ionospheric TEC estimations in the same way as widely used GPS/GLONASS signals. In this work, we compare noise patterns in TEC estimations based on different geostationary satellites data: augmentation systems (Indian GAGAN, European EGNOS and American WAAS), and Chinese COMPASS/Beidou navigation system. We show that noise level in geostationary COMPASS/Beidou TEC estimations is times smaller than noise in SBAS TEC estimation and corresponds to those of GPS/GLONASS at the same elevation angles. We discuss the capabilities of geostationary TEC data for studying ionospheric variability driven by space weather and meteorological sources at different time scales. Analyzing data from IGS/MGEX receivers we present geostationary TEC response on X-class Solar flares of current cycle, moderate and strong geomagnetic storms, including G4 St. Patrick's day Storm 2015 and recent G3 storm of the end of May 2017. We also discuss geostationary TEC disturbances in near equatorial ionosphere caused by two SSW events (minor and major final warming of 2015-2016 winter season) as well as geostationary TEC response on typhoons activity near Taiwan in autumn 2016. Our results show large potential of geostationary TEC estimations with GNSS and SBAS signals for continuous ionospheric monitoring.
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Receiver DCB estimation and GPS vTEC study at a low latitude station in the South Pacific
NASA Astrophysics Data System (ADS)
Prasad, Ramendra; Kumar, Sushil; Jayachandran, P. T.
2016-11-01
The statistical estimation of receiver differential code bias (DCB) of the GSV4004B receiver at a low latitude station, Suva (lat. 18.15°S, long. 178.45°E, Geomag. Lat. 21.07°S), Fiji, and the subsequent behaviour of vTEC, are presented. By means of least squares linear regression fitting technique, the receiver DCB was determined using the GPS vTEC data recorded during the year 2010, CODE TEC and IRI-2012 model for 2010. To substantiate the results, minimization of the standard deviation (SD) method was also used for GPS vTEC data. The overall monthly DCB was estimated to be in the range of 62.6 TECU. The vTEC after removing the resultant monthly DCB was consistent with other low latitude observations. The GPS vTEC 2010 data after eliminating the resultant DCB were lower in comparison to Faraday rotation vTEC measurements at Suva during 1984 primarily due to higher solar activity during 1984 as compared to 2010. Seasonally, vTEC was maximum during summer and minimum during winter. The winter showed least vTEC variability whereas equinox showed the largest daytime variability. The geomagnetic disturbances effect showed that both vTEC and its variability were higher on magnetically disturbed days as compared to quiet days with maximum variability in the daytime. Two geomagnetic storms of moderate strengths with main phases in the local daytime showed long duration (∼52 h) increase in vTEC by 33-67% which can be accounted by changes in E×B drifts due to prompt penetration of storm-time auroral electric field in the daytime and disturbance dynamo electric field in the nighttime to low latitudes.
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Regional ionospheric TEC data assimilation and now-casting service
NASA Astrophysics Data System (ADS)
Aa, E.; Liu, S.; Wengeng, H.
2017-12-01
Ionospheric data assimilation is a now-casting technique to incorporate irregular ionospheric measurements into certain background model, which is an effective and efficient way to overcome the limitation of the unbalanced data distribution and to improve the accuracy of the model, so that the model and the data can be optimally combined with each other to produce a more reliable and reasonable system specification. In this study, a regional total electron content (TEC) now-casting system over China and adjacent areas (70E-140E and 15N-55N) is developed on the basis of data assimilation technique. The International Reference Ionosphere (IRI) is used here as background model, and the GNSS data are derived from both the Space Environment Monitoring Network of Chinese Academy of Sciences (SEMnet) and International GNSS Service (IGS) data. A Three-dimensional variation algorithm (3DVAR) combined with Gauss-Markov Kalman filter technique is used to implement the data assimilation. The regional gridded TEC maps and the position errors of single-frequency GPS receivers can be generated and publicized online (http://sepc.ac.cn/TEC_chn.php) in quasi-real time, which is updated for every 15 min. It is one of the ionospheric now-casting systems in China based on data assimilation algorithm, which can be used not only for real-time monitoring of ionosphere environment over China and adjacent areas, but also in providing accurate and effective specification of regional ionospheric TEC and error correction for satellite navigation, radar imaging, shortwave communication, and other relevant applications.
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Short-term estimation of GNSS TEC using a neural network model in Brazil
NASA Astrophysics Data System (ADS)
Ferreira, Arthur Amaral; Borges, Renato Alves; Paparini, Claudia; Ciraolo, Luigi; Radicella, Sandro M.
2017-10-01
This work presents a novel Neural Network (NN) model to estimate Total Electron Content (TEC) from Global Navigation Satellite Systems (GNSS) measurements in three distinct sectors in Brazil. The purpose of this work is to start the investigations on the development of a regional model that can be used to determine the vertical TEC over Brazil, aiming future applications on a near real-time frame estimations and short-term forecasting. The NN is used to estimate the GNSS TEC values at void locations, where no dual-frequency GNSS receiver that may be used as a source of data to GNSS TEC estimation is available. This approach is particularly useful for GNSS single-frequency users that rely on corrections of ionospheric range errors by TEC models. GNSS data from the first GLONASS network for research and development (GLONASS R&D network) installed in Latin America, and from the Brazilian Network for Continuous Monitoring of the GNSS (RMBC) were used on TEC calibration. The input parameters of the NN model are based on features known to influence TEC values, such as geographic location of the GNSS receiver, magnetic activity, seasonal and diurnal variations, and solar activity. Data from two ten-days periods (from DoY 154 to 163 and from 282 to 291) are used to train the network. Three distinct analyses have been carried out in order to assess time-varying and spatial performance of the model. At the spatial performance analysis, for each region, a set of stations is chosen to provide training data to the NN, and after the training procedure, the NN is used to estimate vTEC behavior for the test station which data were not presented to the NN in training process. An analysis is done by comparing, for each testing station, the estimated NN vTEC delivered by the NN and reference calibrated vTEC. Also, as a second analysis, the network ability to forecast one day after the time interval (DoY 292) based on information of the second period of investigation is also assessed
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NASA Astrophysics Data System (ADS)
Shim, J. S.; Rastätter, L.; Kuznetsova, M.; Bilitza, D.; Codrescu, M.; Coster, A. J.; Emery, B. A.; Fedrizzi, M.; Förster, M.; Fuller-Rowell, T. J.; Gardner, L. C.; Goncharenko, L.; Huba, J.; McDonald, S. E.; Mannucci, A. J.; Namgaladze, A. A.; Pi, X.; Prokhorov, B. E.; Ridley, A. J.; Scherliess, L.; Schunk, R. W.; Sojka, J. J.; Zhu, L.
2017-10-01
In order to assess current modeling capability of reproducing storm impacts on total electron content (TEC), we considered quantities such as TEC, TEC changes compared to quiet time values, and the maximum value of the TEC and TEC changes during a storm. We compared the quantities obtained from ionospheric models against ground-based GPS TEC measurements during the 2006 AGU storm event (14-15 December 2006) in the selected eight longitude sectors. We used 15 simulations obtained from eight ionospheric models, including empirical, physics-based, coupled ionosphere-thermosphere, and data assimilation models. To quantitatively evaluate performance of the models in TEC prediction during the storm, we calculated skill scores such as RMS error, Normalized RMS error (NRMSE), ratio of the modeled to observed maximum increase (Yield), and the difference between the modeled peak time and observed peak time. Furthermore, to investigate latitudinal dependence of the performance of the models, the skill scores were calculated for five latitude regions. Our study shows that RMSE of TEC and TEC changes of the model simulations range from about 3 TECU (total electron content unit, 1 TECU = 1016 el m-2) (in high latitudes) to about 13 TECU (in low latitudes), which is larger than latitudinal average GPS TEC error of about 2 TECU. Most model simulations predict TEC better than TEC changes in terms of NRMSE and the difference in peak time, while the opposite holds true in terms of Yield. Model performance strongly depends on the quantities considered, the type of metrics used, and the latitude considered.
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Ionospheric TEC Weather Map Over South America
NASA Astrophysics Data System (ADS)
Takahashi, H.; Wrasse, C. M.; Denardini, C. M.; Pádua, M. B.; de Paula, E. R.; Costa, S. M. A.; Otsuka, Y.; Shiokawa, K.; Monico, J. F. Galera; Ivo, A.; Sant'Anna, N.
2016-11-01
Ionospheric weather maps using the total electron content (TEC) monitored by ground-based Global Navigation Satellite Systems (GNSS) receivers over South American continent, TECMAP, have been operationally produced by Instituto Nacional de Pesquisas Espaciais's Space Weather Study and Monitoring Program (Estudo e Monitoramento Brasileiro de Clima Especial) since 2013. In order to cover the whole continent, four GNSS receiver networks, (Rede Brasileiro de Monitoramento Contínuo) RBMC/Brazilian Institute for Geography and Statistics, Low-latitude Ionospheric Sensor Network, International GNSS Service, and Red Argentina de Monitoreo Satelital Continuo, in total 140 sites, have been used. TECMAPs with a time resolution of 10 min are produced in 12 h time delay. Spatial resolution of the map is rather low, varying between 50 and 500 km depending on the density of the observation points. Large day-to-day variabilities of the equatorial ionization anomaly have been observed. Spatial gradient of TEC from the anomaly trough (total electron content unit, 1 TECU = 1016 el m-2 (TECU) <10) to the crest region (TECU > 80) causes a large ionospheric range delay in the GNSS positioning system. Ionospheric plasma bubbles, their seeding and development, could be monitored. This plasma density (spatial and temporal) variability causes not only the GNSS-based positioning error but also radio wave scintillations. Monitoring of these phenomena by TEC mapping becomes an important issue for space weather concern for high-technology positioning system and telecommunication.
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Session Overview and AzTEC Instrument Performance
NASA Astrophysics Data System (ADS)
Wilson, Grant; Ade, P. A.; Aretxaga, I.; Austermann, J.; Bock, J. J.; Hughes, D.; Kang, Y.; Kim, S.; Lowenthal, J.; Mauskopf, P.; Scott, K.; Yun, M.
2006-12-01
AzTEC is a new 144 element bolometer receiver destined as a first-generation instrument for the Large Millimeter Telescope. >From November 2005 and through January 2006, AzTEC made science observations at the 15m James Clerk Maxwell Telescope (JCMT). Approximately 1/2 of the available time was spent mapping the submillimeter galaxy population in blank and biased fields. Overall, over 1 square degree of sky was mapped with uniform coverage in each of five primary fields making this the largest set of surveys of the submillimeter galaxy population ever performed. Hundreds of new submillimeter galaxies have been detected. Here we discuss the instrument, our mapping technique, and a brief summary of the data reduction process. We conclude with a brief summary of the overall impact of these surveys on our understanding of the submillimeter galaxy population.
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Comparison of GPS TEC variations with Holt-Winter method and IRI-2012 over Langkawi, Malaysia
NASA Astrophysics Data System (ADS)
Elmunim, N. A.; Abdullah, M.; Hasbi, A. M.; Bahari, S. A.
2017-07-01
The Total Electron Content (TEC) is the ionospheric parameter that has the main effect on radio wave propagation. Therefore, it is crucial to evaluate the performance of the TEC models for the further improvement of the ionospheric modelling in equatorial regions. This work presents an analysis of the TEC, derived from the GPS Ionospheric Scintillation and TEC Monitor (GISTM) receiver at the Langkawi station, Malaysia, located at the geographic coordinates of 6.19°N, 99.51°E and the geomagnetic coordinates of 3.39°S, 172.42°E. The diurnal, monthly and seasonal variations in 2014 of the observed GPS-TEC were compared with the statistical Holt-Winter method and a recent version of the International Reference Ionosphere model (IRI-2012), using three different topside options of an electron density, which are the IRI-2001, IRI01-corr and NeQuick. The maximum peaks of the GPS-TEC were observed in the post-noon time and the minimum was observed during the early morning time. In addition, in monthly variations the Holt-Winter and the IRI-2012 topside options showed an underestimation that was in agreement with the GPS-TEC, except for the IRI-2001 model which showed an overestimation in June, July and August. Regarding the seasonal variation of the GPS-TEC, the lowest values were observed during summer and it reached its maximum value during the equinox season. The IRI-2001 showed the highest value of percentage deviation compared to the IRI01-corr, NeQuick and Holt-Winter method. Therefore, the accuracy of the models was found to be approximately 95% in the Holt-Winter method, 75% in the IRI01-corr, 73% in the NeQuick and 66% in the IRI-2001 model. Hence, it can be inferred that the Holt-Winter method showed a higher performance and better estimates of the TEC compared to the IRI01-corr and NeQuick, while the IRI-2001 showed a poor predictive performance in the equatorial region over Malaysia.
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Imaging the topside ionosphere and plasmasphere with ionospheric tomography using COSMIC GPS TEC
NASA Astrophysics Data System (ADS)
Pinto Jayawardena, Talini S.; Chartier, Alex T.; Spencer, Paul; Mitchell, Cathryn N.
2016-01-01
GPS-based ionospheric tomography is a well-known technique for imaging the total electron content (TEC) between GPS satellites and receivers. However, as an integral measurement of electron concentration, TEC typically encompasses both the ionosphere and plasmasphere, masking signatures from the topside ionosphere-plasmasphere due to the dominant ionosphere. Imaging these regions requires a technique that isolates TEC in the topside ionosphere-plasmasphere. Multi-Instrument Data Analysis System (MIDAS) employs tomography to image the electron distribution in the ionosphere. Its implementation for regions beyond is yet to be seen due to the different dynamics present above the ionosphere. This paper discusses the extension of MIDAS to image these altitudes using GPS phase-based TEC measurements and follows the work by Spencer and Mitchell (2011). Plasma is constrained to dipole field lines described by Euler potentials, resulting in a distribution symmetrical about the geomagnetic equator. A simulation of an empirical plasmaspheric model by Gallagher et al. (1988) is used to verify the technique by comparing reconstructions of the simulation with the empirical model. The Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) is used as GPS receiver locations. The verification is followed by a validation of the modified MIDAS algorithm, where the regions' TEC is reconstructed from COSMIC GPS phase measurements and qualitatively compared with previous studies using Jason-1 and COSMIC data. Results show that MIDAS can successfully image features/trends of the topside ionosphere-plasmasphere observed in other studies, with deviations in absolute TEC attributed to differences in data set properties and the resolution of the images.
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The 1980 V-TECS Marketing Study.
ERIC Educational Resources Information Center
Hattwick, Richard E.; And Others
The Vocational-Technical Education Consortium of States (V-TECS) conducted a marketing study that considered the implications of six options for the organization's future. The first option is continuation of the status quo, which is dangerous because existing members may leave the consortium. The second option is the status quo combined with an…
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NASA Astrophysics Data System (ADS)
Hajra, Rajkumar; Chakraborty, Shyamal Kumar; Tsurutani, Bruce T.; DasGupta, Ashish; Echer, Ezequiel; Brum, Christiano G. M.; Gonzalez, Walter D.; Sobral, José Humberto Andrade
2016-07-01
We present a geomagnetic quiet time (Dst > -50 nT) empirical model of ionospheric total electron content (TEC) for the northern equatorial ionization anomaly (EIA) crest over Calcutta, India. The model is based on the 1980-1990 TEC measurements from the geostationary Engineering Test Satellite-2 (ETS-2) at the Haringhata (University of Calcutta, India: 22.58° N, 88.38° E geographic; 12.09° N, 160.46° E geomagnetic) ionospheric field station using the technique of Faraday rotation of plane polarized VHF (136.11 MHz) signals. The ground station is situated virtually underneath the northern EIA crest. The monthly mean TEC increases linearly with F10.7 solar ionizing flux, with a significantly high correlation coefficient (r = 0.89-0.99) between the two. For the same solar flux level, the TEC values are found to be significantly different between the descending and ascending phases of the solar cycle. This ionospheric hysteresis effect depends on the local time as well as on the solar flux level. On an annual scale, TEC exhibits semiannual variations with maximum TEC values occurring during the two equinoxes and minimum at summer solstice. The semiannual variation is strongest during local noon with a summer-to-equinox variability of ~50-100 TEC units. The diurnal pattern of TEC is characterized by a pre-sunrise (0400-0500 LT) minimum and near-noon (1300-1400 LT) maximum. Equatorial electrodynamics is dominated by the equatorial electrojet which in turn controls the daytime TEC variation and its maximum. We combine these long-term analyses to develop an empirical model of monthly mean TEC. The model is validated using both ETS-2 measurements and recent GNSS measurements. It is found that the present model efficiently estimates the TEC values within a 1-σ range from the observed mean values.
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NASA Astrophysics Data System (ADS)
Lee, Han-Byul; Kim, Yong Ha; Kim, Eunsol; Hong, Junseok; Kwak, Young-Sil
2016-10-01
Topside ionospheric profiles have been measured by Alouette 1 and ISIS 1/2 in the periods of 1962-1972 and 1972-1979, respectively. The profiles cover from the orbital altitude of 1000 km to the F2 peak and show large variations over local time, latitude, and seasons. We here analyze these variations in comparison with plasmaspheric total electron contents (pTECs) that were measured by Jason-1 satellite from the altitude of 1336 km to 20,200 km (GPS orbit). The scale heights of the profiles are generally smaller in the daytime than nighttime but show large day-to-day variations, implying that the ionospheric profiles at 1000 km are changing dynamically, rather than being in diffusive equilibrium. We also derived transition heights between O+ and H+, which show a clear minimum at dawn for low-latitude profiles due to decreasing O+ density at night. To compare with pTEC, we compute topside ionospheric total electron content (tiTEC) by integrating over 800-1336 km using the slope of the profiles. The tiTEC varies in a clear diurnal pattern from 0.3 to 1 and 3 total electron content unit (TECU, 1 TECU = 1016 el m-2) for low and high solar activity, respectively, whereas Jason-1 pTEC values are distributed over 2-6 TECU and 4-8 TECU for low and high solar activity, respectively, with no apparent diurnal modulation. Latitudinal variations of tiTEC show distinctive hemispheric asymmetry while that of Jason-1 pTEC is closely symmetric about the magnetic equator. The local time and latitudinal variations of tiTEC basically resemble those of the ionosphere but are characteristically different from those of Jason-1 pTEC. Based on the difference between tiTEC and pTEC variations, we propose that the region above 1300 km should be considered as the plasmasphere. Lower altitudes for the base of "plasmaspheric TEC," as used in some studies, would cause contamination of ionospheric influence.
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Simultaneous response of NmF2 and GPS-TEC to storm events at Ilorin
NASA Astrophysics Data System (ADS)
Joshua, B. W.; Adeniyi, J. O.; Oladipo, O. A.; Doherty, P. H.; Adimula, I. A.; Olawepo, A. O.; Adebiyi, S. J.
2018-06-01
A comparative study of both TEC and NmF2 variations during quiet and disturbed conditions has been investigated using simultaneous measurements from dual frequency Global Positioning System (GPS) receiver and a DPS-4 Digisonde co-located at Ilorin (Geog. Lat. 8.50°N, Long. 4.50°E, dip. - 7.9°). The results of the quiet time variations of the two parameters show some similarities as well as differences in their structures. The values of both parameters generally increase during the sunrise period attaining a peak around the noon and then decaying towards the night time. The onset time of the sunrise growth is observed to be earlier in TEC than in NmF2. The rate of decay of TEC was observed to be faster than that of the NmF2 in most cases. Also, the noon 'bite-outs', leading to the formation of pre-noon and post-noon peaks, are prominent in the NmF2 structure and was hardly noticed in TEC. Results of the variations of both TEC and NmF2 during the 5 April, 10 May and 3 August 2010 geomagnetic storm events showed a simultaneous deviations of both parameters from the quiet time behavior. The magnitude of the deviations is however most pronounced in NmF2 structure than in TEC. We also found that the enhancement observed in the two parameters during the storm events generally corresponds to decrease in hmF2.
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ERIC Educational Resources Information Center
Business and Technician Education Council, London (England).
This package contains a paper summarizing the aims and services provided by the Business and Technician Education Council (B/TEC). Established to advance the quality and availability of a wide range of employment-related education to persons in the United Kingdom who are studying at or beyond the equivalent of the American associate-degree level,…
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Industrial Maintenance Technology (IM-TEC). Student Manual.
ERIC Educational Resources Information Center
Fusch, Gene E.
This student manual explains an innovative strategy through which Bellingham Technical College's (Washington) evening Industrial Electrician and Millwright Apprenticeships were aggregated with workforce upgrade course offerings to form the college's first evening degree program in Industrial Maintenance Technology (IM-TEC). Section 1 contains a…
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Maa, April Y; Wojciechowski, Barbara; Hunt, Kelly J; Dismuke, Clara; Shyu, Jason; Janjua, Rabeea; Lu, Xiaoqin; Medert, Charles M; Lynch, Mary G
2017-04-01
The aging population is at risk of common eye diseases, and routine eye examinations are recommended to prevent visual impairment. Unfortunately, patients are less likely to seek care as they age, which may be the result of significant travel and time burdens associated with going to an eye clinic in person. A new method of eye-care delivery that mitigates distance barriers and improves access was developed to improve screening for potentially blinding conditions. We present the quality data from the early experience (first 13 months) of Technology-Based Eye Care Services (TECS), a novel ophthalmologic telemedicine program. With TECS, a trained ophthalmology technician is stationed in a primary care clinic away from the main hospital. The ophthalmology technician follows a detailed protocol that collects information about the patient's eyes. The information then is interpreted remotely. Patients with possible abnormal findings are scheduled for a face-to-face examination in the eye clinic. Any patient with no known ocular disease who desires a routine eye screening examination is eligible. Technology-Based Eye Care Services was established in 5 primary care clinics in Georgia surrounding the Atlanta Veterans Affairs hospital. Four program operation metrics (patient satisfaction, eyeglass remakes, disease detection, and visit length) and 2 access-to-care metrics (appointment wait time and no-show rate) were tracked. Care was rendered to 2690 patients over the first 13 months of TECS. The program has been met with high patient satisfaction (4.95 of 5). Eyeglass remake rate was 0.59%. Abnormal findings were noted in 36.8% of patients and there was >90% agreement between the TECS reading and the face-to-face findings of the physician. TECS saved both patient (25% less) and physician time (50% less), and access to care substantially improved with 99% of patients seen within 14 days of contacting the eye clinic, with a TECS no-show rate of 5.2%. The early experience with
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Equatorial late-afternoon periodic TEC fluctuations observed by multiple GPS receivers
NASA Astrophysics Data System (ADS)
Tsugawa, T.; Maruyama, T.; Saito, S.; Ishii, M.
2009-12-01
We report, for the first time, equatorial periodic total electron content (TEC) fluctuations observed in the late afternoon by multiple GPS receivers. As a part of Southeast Asia low-latitude ionospheric network (SEALION), GPS receivers at Chiang Mai and Chumphon, Thailand, have been operated since 2005. We found that periodic TEC fluctuations (PTF) with the periods of 15-30 minutes are often observed at these two sites in the spring (Apr-May) late afternoon. Further investigations using multiple GPS receivers in Southeast Asia revealed that the PTFs propagate at 150-200 m/s away from the equator and their amplitudes depend on the satellite azimuth angle. Statistical study of the PTF activity at different latitudes and longitudes clarified that the PTFs are not observed at mid-latitudes, and their seasonal variations are different at different longitudes and at geomagnetically conjugate regions. These observational results indicate that the PTFs are caused by the atmospheric gravity waves (AGW) which are generated in the equatorial lower atmosphere and propagate away from the equator. Simultaneous GPS-TEC and ionosonde observations at Chumphon revealed that the day-to-day variations of PTF activities are well correlated with those of the rate of TEC change index (ROTI) and the occurrence of equatorial spread F (ESF) after the sunset, indicating the PTFs may be related with the onset of the ESF and plasma bubbles.
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Keklik, Muzaffer; Eser, Bulent; Kaynar, Leylagul; Sivgin, Serdar; Keklik, Ertugrul; Solmaz, Musa; Ozturk, Ahmet; Buyukoglan, Ruksan; Yay, Mehmet; Cetin, Mustafa; Unal, Ali
2015-06-01
Blood component donations by apheresis have become more common in modern blood transfusion practices. We compared three apheresis instruments (Fenwal Amicus, Fresenius COM.TEC, and Trima Accel) with regard to platelet (PLT) yield, collection efficiency (CE), and collection rate (CR). The single-needle or double-needle plateletpheresis procedures of the three instruments were compared in a retrospective, randomized study in 270 donors. The blood volume processed was higher in the COM.TEC compared with the Amicus and Trima. Also there was a significantly higher median volume of ACD used in collections on the COM.TEC compared with the Amicus and Trima. The PLT yield was significantly lower with the COM.TEC compared with the Amicus and Trima. Additionally, the CE was significantly lower with the COM.TEC compared with the Amicus and Trima. There was no significant difference in median separation time and CR between the three groups. When procedures were compared regarding CE by using Amicus device, it was significantly higher in single-needle than double-needle plateletpheresis. When double-needle Amicus system was compared with double-needle COM.TEC system, CE and PLT yield were significantly higher with Amicus system. When single-needle Amicus system was compared with single-needle Trima system, CE and PLT yield were significantly higher with Trima system. All instruments collected PLTs efficiently. However, the CE was lower with the COM.TEC compared with the Amicus and Trima. Also, we found Amicus single-needle system collected PLTs more efficiently compared with the double-needle system. CE and PLT yields were significantly higher with the single-needle Trima instrument compared with the single-needle Amicus device. © 2014 Wiley Periodicals, Inc.
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Investigation of the TEC Changes in the vicinity of the Earthquake Preparation Zone
NASA Astrophysics Data System (ADS)
Ulukavak, Mustafa; Yalcinkaya, Mualla
2016-04-01
Recently, investigation of the anomalies in the ionosphere before the earthquake has taken too much attention. The Total Electron Content (TEC) data has been used to monitor the changes in the ionosphere. Hence, researchers use the TEC changes before the strong earthquakes to monitor the anomalies in the ionosphere. In this study, the GPS-TEC variations, obtained from the GNSS stations in the vicinity of the earthquake preparation zone, was investigated. Nidra earthquake (M6.5), which was occurred on the north-west of Greece on November 17th, 2015 (38.755°N, 20.552°E), was selected for this study. First, the equation proposed by Dobrovolsky et al. (1979) was used to calculate the radius of the earthquake preparation zone. International GNSS Service (IGS) stations in the region were classified with respect to the radius of the earthquake preparation zone. The observation data of each station was obtained from the Crustal Dynamics Data and Information System (CDDIS) archive to estimate GPS-TEC variations between 16 October 2015 and 16 December 2015. Global Ionosphere Maps (GIM) products, obtained from the IGS, was used to check the robustness of the GPS-TEC variations. Possible anomalies were analyzed for each GNSS station by using the 15-day moving median method. In order to analyze these pre-earthquake ionospheric anomalies, we investigated three indices (Kp, F10.7 and Dst) related to the space weather conditions between 16 October 2015 and 16 December 2015. Solar and geomagnetic indices were obtained from The Oceanic and Atmospheric Administration (NOAA), The Canadian Space Weather Forecast Centre (CSWFC), and the Data Analysis Center for Geomagnetism and Space Magnetism Graduate School of Science, Kyoto University (WDC). This study aims at investigating the possible effects of the earthquake on the TEC variations.
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Osada, Masako; Jardine, Logan; Misir, Ruth; Andl, Thomas; Millar, Sarah E; Pezzano, Mark
2010-02-08
Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated
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Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury.
Yaomura, Takaaki; Tsuboi, Naotake; Urahama, Yoshinori; Hobo, Akinori; Sugimoto, Kenji; Miyoshi, Jun; Matsuguchi, Tetsuya; Reiji, Kannagi; Matsuo, Seiichi; Yuzawa, Yukio
2008-10-01
Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-alpha and apoptosis are the major pathogenetic factors was studied. IRI was induced in wild type (Cot/Tpl2(+/+)) mice and in Cot/Tpl2-deficient (Cot/Tpl2(-/-)) mice. The extent of tubular injury and renal function were studied. TNF-alpha production, neutrophil infiltration and apoptosis were also compared between the two groups. Cot/Tpl2(-/-) mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-alpha production, neutrophil infiltration or MAPK activation between Cot/Tpl2(+/+) and Cot/Tpl2(-/-) mice. In contrast, Cot/Tpl2(-/-) mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. Cot/Tpl2 did not function as a member of MAPK family, but as a promoter of apoptosis in IRI. These results suggest that Cot/Tpl2 could be a possible therapeutic target in IRI.
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Seismo-Ionospheric Precursor in the GIM TEC of the 24 August 2014 M6 Napa Earthquake
NASA Astrophysics Data System (ADS)
Wu, T. Y.; Liu, T. J. Y.; Liu, J. Y.
2015-12-01
This study examines seismo-ionospheric precursors (SIPs) in the global ionosphere map (GIM) of the total electron content (TEC) associated with the 24 August 2014 M6 South Napa earthquake and statistical evidence of SIPs of the GPS TEC in western USA during 2000-2014. The temporal SIP in the GIM TEC around the epicenter significantly decreasing (negative anomaly) on 22 August. To discriminate the global effect, such as solar flares, magnetic storms, etc., and the local effect, such as earthquakes, 5183 lattices on the GIM are employed to conduct a global search of the SIP distribution. Anomalies of both GIM TEC and associated gradients specifically and continuously appearing over the epicenter suggest that the SIP relate to the 2014 South Napa earthquake. A simulation is further carried out to produce the SIP in GIM TEC before the earthquake. Results indicate that the eastward electric field generated over the epicenter area during the earthquake preparation period to be essential.
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Curriculum Change. An Evaluation of TEC Programme Development in Colleges. The Main Findings.
ERIC Educational Resources Information Center
Parkin, Christopher; And Others
An evaluation was made of the adoption of curriculum changes mandated by the Technician Education Council (TEC) by 78 colleges in England. The study concentrated on the processes of adaptation that occurred in the colleges in order to cope with the degree of change required by TEC. Data were collected via questionnaires, interviews, case studies,…
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NASA Astrophysics Data System (ADS)
Yildirim, Omer; Inyurt, Samed; Mekik, Cetin
2016-02-01
Turkey is a country located in the middle latitude zone, where tectonic activity is intensive. Recently, an earthquake of magnitude 6.5 Mw occurred offshore in the Aegean Sea on 24 May 2014 at 09:25 UTC, which lasted about 40 s. The earthquake was also felt in Greece, Romania, and Bulgaria in addition to Turkey. In recent years, ionospheric anomaly detection studies have been carried out because of seismicity with total electron content (TEC) computed from the global navigation satellite system's (GNSS) signal delays and several interesting findings have been published. In this study, both TEC and positional variations have been examined separately following a moderate size earthquake in the Aegean Sea. The correlation of the aforementioned ionospheric variation with the positional variation has also been investigated. For this purpose, a total of 15 stations was used, including four continuously operating reference stations in Turkey (CORS-TR) and stations in the seismic zone (AYVL, CANA, IPSA, and YENC), as well as international GNSS service (IGS) and European reference frame permanent network (EPN) stations. The ionospheric and positional variations of the AYVL, CANA, IPSA, and YENC stations were examined using Bernese v5.0 software. When the precise point positioning TEC (PPP-TEC) values were examined, it was observed that the TEC values were approximately 4 TECU (total electron content unit) above the upper-limit TEC value at four stations located in Turkey, 3 days before the earthquake at 08:00 and 10:00 UTC. At the same stations, on the day before the earthquake at 06:00, 08:00, and 10:00 UTC, the TEC values were approximately 5 TECU below the lower-limit TEC value. The global ionosphere model TEC (GIM-TEC) values published by the Centre for Orbit Determination in Europe (CODE) were also examined. Three days before the earthquake, at all stations, it was observed that the TEC values in the time period between 08:00 and 10:00 UTC were approximately 2 TECU
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C-TEC: Ohio's First All-Green School
ERIC Educational Resources Information Center
Krall, Angie
2009-01-01
In Ohio's Licking County, the Career and Technology Education Centers (C-TEC) is a leader in the green movement. This eco-friendly school incorporates environmental sustainability in all aspects of its programming and is the first Leadership in Energy and Environmental Design (LEED)-certified public building in the state. While eco-friendly…
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SynTec Final Technical Report: Synthetic biology for Tailored Enzyme cocktails
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lin, Janine; Teter, Sarah
Using a novel enzyme screening method inspired by synthetic biology, Novozymes developed new technology under SynTec which allows for more rapidly tailoring of enzyme cocktails. The methodology can be applied to specific feedstocks, and or coupled to address a specific hydrolytic conversion process context. Using combinatorial high throughput screening of libraries of enzyme domains, we can quickly assess which combination of catalytic modules delivers the best performance for a specific condition. To demonstrate the effectiveness of the screening process, we measured performance of the output catalytic cocktail compared to CTec3/HTec3. SynTec benchmark cocktail - blend of Cellic® CTec3 and HTec3.more » The test substrate was - ammonia fiber expansion pretreated corn stover (AFEX™ PCS).CTec3/HTec3 was assayed at the optimal pH and temperature, and also in the absence of any pH adjustment. The new enzyme cocktail discovered under SynTec was assayed in the absence of any pH adjustment and at the optimal temperature. Conversion is delivered by SynTec enzyme at significant dose reduction relative to CTec3/HTec3 at the controlled pH optimum, and without titrant required to maintain pH, which delivers additional cost savings relative to current state of the art process. In this 2.5 year $4M project, the team delivered an experimental cocktail that significantly outperformed CTec3/HTec3 for a specific substrate, and for specific hydrolysis conditions. As a means of comparing performance improvement delivered per research dollar spent, we note that SynTec delivered a similar performance improvement to the previous award, in a shorter time and with fewer resources than for the previously successful DOE project DECREASE, a 3.5 year, $25M project, though this project focused on a different substrate and used different hydrolysis conditions. The newly implemented technology for rapid sourcing of new cellulases and hemicellulases from nature is an example of Novozymes
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NASA Astrophysics Data System (ADS)
Yan, Xiangxiang; Yu, Tao; Shan, Xinjian; Liu, Zhan; Wang, Zhenjie
2016-04-01
Recently, there are growing interests in studying the seismo-ionospheric disturbance prior to earthquakes, mainly including the anomalies in the electric field, magnetic field and plasma parameters. However, there are still some controversies over this topic, mainly because of strong day-to-day variability of the ionosphere itself. It is hard to determine whether the different forms of ionospheric disturbances are associated with earthquakes or not. Using data of Crustal Movement Observation Network of China (CMONC) and IGS (International GNSS Service), we attempt to give a statistical investigation about the total electron content (TEC) perturbation before 30 Mw6.0+ earthquakes during January 2000 to December 2010 in China. To determine the abnormal TEC signals, a quartile-based process is performed. At each time point we calculated the median M using the TEC values at the same local time for the preceding 15 days. In addition, we calculated the maps of differential TEC from global ionosphere maps (GIM) in the above period. It is shown that TEC anomalies were detected before 20 earthquakes, nearly 67%. The anomalies represent positive before most events and occurred mostly within 2-6 days before the shocks, significantly during the afternoon period, 1200-2000LT. Part of perturbations appeared more than one time. Moreover, the affected area of TEC is not coincide with the vertical projection of the epicenter but shifts equatorward and is controlled by equatorial ionization anomaly (EIA) crest. On the other hand, we analyzed variations of TEC over southwest China during a period of low solar and geomagnetic activity in April-October 2008, based on the data of CMONC. During that time, six large earthquakes with magnitude M≧6.0 occurred around the southwest region of China. The method to detect abnormal TEC signals is same with above statistical study. Known that the decisive role in the ionosphere state is performed by space weather effects, we compared the TEC
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ERIC Educational Resources Information Center
Dodd, S.; And Others
A study examined the day-to-day work activities of teachers of Technician Education Council (TEC) certificate programs in Great Britain. During the study, a detailed questionnaire dealing with the tasks performed by TEC teachers, the amount of time spent on TEC teachers on individual activities, and the impact of the TEC programs on teacher…
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Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer
2007-09-01
Recurrence. Lont, A.P. et al. J. Uro 2006;176:580. 5. 2006 Cambio AJ, Evans CP. Outcomes and quality of life issues in the pharmacological...epithelial cells. BMC Cancer 1, 19. [104] Flowers LO , Subramaniam PS, and Johnson HM (2005). A SOCS-1 peptide mimetic inhibits both constitutive and...the BTK/ITK/TEC/TXK family lo - cated in chromosome Xp22.2. Oncogene 9, 3683–3688. [119] Qiu Y, Robinson D, Pretlow TG, and Kung HJ (1998). Etk/Bmx, a
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The TolTEC Camera for the LMT Telescope
NASA Astrophysics Data System (ADS)
Bryan, Sean
2018-01-01
TolTEC is a new camera being built for the 50-meter Large Millimeter-wave Telescope (LMT) on Sierra Negra in Puebla, Mexico. The instrument will discover and characterize distant galaxies by detecting the thermal emission of dust heated by starlight. The polarimetric capabilities of the camera will measure magnetic fields in star-forming regions in the Milky Way. The optical design of the camera uses mirrors, lenses, and dichroics to simultaneously couple a 4 arcminute diameter field of view onto three single-band focal planes at 150, 220, and 280 GHz. The 7000 polarization-selective detectors are single-band horn-coupled LEKID detectors fabricated at NIST. A rotating half wave plate operates at ambient temperature to modulate the polarized signal. In addition to the galactic and extragalactic surveys already planned, TolTEC installed at the LMT will provide open observing time to the community.
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Molecular Mechanisms of Hormone-Refractory Prostate Cancer
2006-02-01
FIN-00014 Helsinki, Finland Bmx/Etk, a member of the Tec/ Btk family of nonrecep- tor kinases, has recently been shown to mediate cell motility in...Bmx, which is a member of the Tec/ Btk family of tyrosine kinases (37). In addition to the SH2, SH3, and kinase domains, the Tec family of tyrosine...divided and resuspended in 18 l of kinase buffer with or without 1 M Src inhibitor SU6656 in the presence of either 2 g of GST or 2 g of GST-CasSD
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Reconstruction of missed critical frequency of F2-layer over Mexico using TEC
NASA Astrophysics Data System (ADS)
Sergeeva, M. A.; Maltseva, O. A.; Gonzalez-Esparza, A.; Romero Hernandez, E.; De la Luz, V.; Rodriguez-Martinez, M. R.
2016-12-01
The study of the Earth's ionosphere's state is one of the key issues within the Space Weather monitoring task. It is hard to overestimate the importance of diagnostics of its current state and forecasts of Space Weather conditions. There are different methods of short-time predictions for the ionosphere state change. The real-time monitoring of the ionospheric Total Electron Content (TEC) provides the opportunity to choose an appropriate technique for the particular observation point on the Earth. From September 2015 the continuous monitoring of TEC variations over the territory of Mexico is performed by the Mexican Space Weather Service (SCiESMEX). Regular patterns of the diurnal and seasonal TEC variations were revealed in base of past statistics and real-time observations which can be used to test the prediction method. Some specific features of the ionosphere behaviour are discussed. However, with all the merits of TEC as an ionospheric parameter, for the full picture of the processes in the ionosphere and for practical applications it is needed to identify the behaviour of other principal ionospheric parameters provided by ionosondes. Currently, SCiESMEX works on the project of the ionosonde installation in Mexico. This study was focused on the reconstruction of the critical frequency of F2-layer of the ionosphere (foF2) when this data is missing. For this purpose measurements of TEC and the median value of the equivalent slab thickness of the ionosphere were used. First, the foF2 values reconstruction was made for the case of the ionosonde data being absent during some hours or days. Second, the possibility of foF2 reconstruction was estimated for the Mexican region having no ionosonde using local TEC data and foF2 data obtained in the regions close to Mexico. Calculations were performed for quiet and disturbed periods. The results of reconstruction were compared to the foF2 obtained from the International Reference Model and to median foF2 values. Comparison
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Lamoral-Theys, Delphine; Wauthoz, Nathalie; Heffeter, Petra; Mathieu, Véronique; Jungwirth, Utte; Lefranc, Florence; Nève, Jean; Dubois, Jacques; Dufrasne, François; Amighi, Karim; Berger, Walter; Gailly, Philippe; Kiss, Robert
2012-01-01
Abstract Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC50in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs. PMID:21810170
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Quantifications of Geomagnetic Storm Impact on TEC and NmF2 during 2013 Mar. event
NASA Astrophysics Data System (ADS)
Shim, J. S.; Tsagouri, I.; Goncharenko, L. P.; Mays, M. L.; Taktakishvili, A.; Rastaetter, L.; Kuznetsova, M. M.
2016-12-01
We investigate the ionospheric response to 2013 Mar. geomagnetic storm event using GPS TEC, ISR and ionosonde observations in North American sector. In order to quantify variations of TEC and NmF2 (or foF2) due to the storm, we remove the background quiet-time values (e.g., TEC of one day prior to the storm, NmF2 median and average of five quietest days for 30 days prior to the storm). In addition, in order to assess modeling capability of reproducing storm impacts on TEC and NmF2, we compare the observations with various model simulations, which are obtained from empirical, physics-based, and data assimilation models. Further, we investigate how uncertainty in the interplanetary magnetic field (IMF) impacts on TEC and NmF2 during the geomagnetic storm event. For this uncertainty study, we use a physics-based coupled ionosphere-thermosphere model, CTIPe, and solar wind parameters obtained from ensemble of WSA-ENLIL+Cone model simulations. This study has been supported by the Community Coordinated Modeling Center (CCMC) at the Goddard Space Flight Center. Model outputs and observational data used for the study will be permanently posted at the CCMC website (http://ccmc.gsfc.nasa.gov) for the space science communities to use.
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Support vector machines for TEC seismo-ionospheric anomalies detection
NASA Astrophysics Data System (ADS)
Akhoondzadeh, M.
2013-02-01
Using time series prediction methods, it is possible to pursue the behaviors of earthquake precursors in the future and to announce early warnings when the differences between the predicted value and the observed value exceed the predefined threshold value. Support Vector Machines (SVMs) are widely used due to their many advantages for classification and regression tasks. This study is concerned with investigating the Total Electron Content (TEC) time series by using a SVM to detect seismo-ionospheric anomalous variations induced by the three powerful earthquakes of Tohoku (11 March 2011), Haiti (12 January 2010) and Samoa (29 September 2009). The duration of TEC time series dataset is 49, 46 and 71 days, for Tohoku, Haiti and Samoa earthquakes, respectively, with each at time resolution of 2 h. In the case of Tohoku earthquake, the results show that the difference between the predicted value obtained from the SVM method and the observed value reaches the maximum value (i.e., 129.31 TECU) at earthquake time in a period of high geomagnetic activities. The SVM method detected a considerable number of anomalous occurrences 1 and 2 days prior to the Haiti earthquake and also 1 and 5 days before the Samoa earthquake in a period of low geomagnetic activities. In order to show that the method is acting sensibly with regard to the results extracted during nonevent and event TEC data, i.e., to perform some null-hypothesis tests in which the methods would also be calibrated, the same period of data from the previous year of the Samoa earthquake date has been taken into the account. Further to this, in this study, the detected TEC anomalies using the SVM method were compared to the previous results (Akhoondzadeh and Saradjian, 2011; Akhoondzadeh, 2012) obtained from the mean, median, wavelet and Kalman filter methods. The SVM detected anomalies are similar to those detected using the previous methods. It can be concluded that SVM can be a suitable learning method to detect
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Inverting Coseismic TEC Disturbances for Neutral Atmosphere Pressure Wave
NASA Astrophysics Data System (ADS)
Lee, R. F.; Mikesell, D.; Rolland, L.
2017-12-01
Research from the past 20 years has shown that we can detect coseismic disturbances in the total electron content (TEC) using global navigation space systems (GNSS). In the near field, TEC disturbances are created by the direct wave from rupture on the surface. This pressure wave travels through the neutral atmosphere to the ionosphere within about 10 minutes. This provides the opportunity to almost immediately characterize the source of the acoustic disturbance on the surface using methods from seismology. In populated areas, this could provide valuable information to first responders. To retrieve the surface motion amplitude information we must account for changes in the waveform caused by the geomagnetic field, motion of the satellites and the geometry of the satellites and receivers. One method is to use a transfer function to invert for the neutral atmosphere pressure wave. Gómez et al (2015) first employed an analytical model to invert for acoustic waves produced by Rayleigh waves propagating along the Earth's surface. Here, we examine the same model in the near field using the TEC disturbances from the direct wave produced by rupture at the surface. We compare results from the forward model against a numerical model that has been shown to be in good agreement with observations from the 2011 Van (Turkey) earthquake. We show the forward model predictions using both methods for the Van earthquake. We then analyze results for hypothetical events at different latitudes and discuss the reliability of the analytical model in each scenario. Gómez, D., R. Jr. Smalley, C. A. Langston, T. J. Wilson, M. Bevis, I. W. D. Dalziel, E. C. Kendrick, S. A. Konfal, M. J. Willis, D. A. Piñón, et al. (2015), Virtual array beamforming of GPS TEC observations of coseismic ionospheric disturbances near the Geomagnetic South Pole triggered by teleseismic megathrusts, J. Geophys. Res. Space Physics, 120, 9087-9101, doi:10.1002/2015JA021725.
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V-TECS Guide for Bookkeeping/Accounting/Payroll Clerk.
ERIC Educational Resources Information Center
Gregory, Margaret R.; Benson, Robert T.
This guide, an extension of the Vocational-Technical Education Consortium of States (V-TECS) catalog, includes such considerations as background information, decision-making skills, attitudes, and learning methods surrounding the occupations of bookkeeper/accountant/payroll clerk. The guide provides job-relevant task, performance objectives,…
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NASA Astrophysics Data System (ADS)
Ansari, Kutubuddin; Corumluoglu, Ozsen; Panda, Sampad Kumar
2017-04-01
The present study investigates the ionospheric Total Electron Content (TEC) variations in the lower mid-latitude Turkish region from the Turkish Permanent GNSS Network (TPGN) and International GNSS Services (IGS) observations during the period from January 2015 to December 2015. The corresponding TEC predicted by the International Reference Ionosphere (IRI 2012) and Standard Plasmasphere-Ionosphere Model (SPIM), and interpolated from Global Ionosphere Maps (GIMs) are evaluated to realize their reliability over the region. We studied the diurnal and monthly behavior of TEC and the relative TEC deviations along with the upper and lower quartiles to represent its spatio-temporal variability. The diurnal variation of GNSS-derived TEC indicates its maximum peak value around 10.00 UT which decreases gradually to attain minimum value after midnight. The monthly maximum value of TEC is observed in March followed by May and August, and the lowest value is seen during September. Studies show that the monthly relative deviation of TEC variability lies in the range of -1 to 4 units for all stations with the maximum difference between positive and negative variability remaining around 5. The studies also cover seasonal variation, grand-mean of ionospheric TEC and TEC intensity from the TPGN. The seasonal ionospheric VTEC pattern over all stations depicts slight increment in VTEC distribution during March equinox compared to September equinox. The December solstice perceived relatively higher VTEC than June solstice. The overall of VTEC values enhanced at all stations towards end of the year 2015 compare to mid of year due the high solar activity. The maximum grand-mean of VTEC is registered in March equinox while the lowest value is seen in September irrespective of all stations. The measured grand-mean intensity variations of VTEC values are in ascending phase during March, May, August and November months, but in descending phase during February, April, June and September
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Keklik, Muzaffer; Eser, Bulent; Kaynar, Leylagul; Solmaz, Musa; Ozturk, Ahmet; Yay, Mehmet; Birekul, Ayse; Oztekin, Mehmet; Sivgin, Serdar; Cetin, Mustafa; Unal, Ali
2014-10-01
A variety of apheresis instruments are now available on the market for double dose plateletpheresis. We compared three apheresis devices (Fenwal Amicus, Fresenius COM.TEC and Trima Accel) with regard to processing time, platelet (PLT) yield, collection efficiency (CE) and collection rate (CR). The single-needle or double-needle double plateletpheresis procedures of the three instruments were compared in a retrospective, randomized study in 135 donors. In the pre-apheresis setting, 45 double plateletpheresis procedures performed with each instrument revealed no significant differences in donor's age, sex, weight, hemoglobin, white blood cell and PLT count between three groups. The blood volume processed to reach a target PLT yield of ≥ 6 × 10(11) was higher in the COM.TEC compared with the Amicus and Trima (4394 vs. 3780 and 3340 ml, respectively; p < 0.001). Also there was a significantly higher median volume of ACD used in collections on the COM.TEC compared with the Amicus and Trima (426 vs. 387 and 329 ml, respectively; p < 0.001). There was a significantly higher median time needed for the procedures on the COM.TEC compared with the Amicus and Trima (66 vs. 62 and 63 min, respectively; p = 0.024). The CE was significantly higher with the Trima compared with the Amicus and COM.TEC (83.57 ± 17.19 vs. 66.71 ± 3.47 and 58.79 ± 5.14%, respectively; p < 0.001). Also, there was a significantly higher product volume on the Trima compared with the Amicus and COM.TEC (395.56 vs. 363.11 and 386.4 ml, respectively; p = 0.008). Additionally, the CR was significantly lower with the COM.TEC compared with the Amicus and Trima (0.092 ± 0.011 vs. 0.099 ± 0.013 and 0.097 ± 0.013 plt × 10(11)/min, respectively; p = 0.039). There was no significant differences in PLT yield between the three groups (p = 0.636). Trima single-needle device collected double dose platelets more efficiently than Amicus and
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AzTEC/ASTE 1.1 mm Deep Surveys: Number Counts and Clustering of Millimeter-bright Galaxies
NASA Astrophysics Data System (ADS)
Hatsukade, B.
2011-11-01
We present results of a 1.1 mm deep survey of the AKARI Deep Field South (ADF-S) with AzTEC mounted on the Atacama Submillimetre Telescope Experiment (ASTE). We obtained a map of 0.25 deg2 area with an rms noise level of 0.32-0.71 mJy. This is one of the deepest and widest maps thus far at millimetre and submillimetre wavelengths. We uncovered 198 sources with a significance of 3.5-15.6σ, providing the largest catalog of 1.1 mm sources in a contiguous region. Most of the sources are not detected in the far-infrared bands of the AKARI satellite, suggesting that they are mostly at z ≥ 1.5 given the detection limits. We construct differential and cumulative number counts of the ADF-S, the Subaru/XMM Newton Deep Field (SXDF), and the SSA 22 field surveyed by AzTEC/ASTE, which provide currently the tightest constraints on the faint end. The integration of the differential number counts of the ADF-S find that the contribution of 1.1 mm sources with ≥1 mJy to the cosmic infrared background (CIB) at 1.1 mm is 12-16%, suggesting that the large fraction of the CIB originates from faint sources of which number counts are not yet constrained. We estimate the cosmic star-formation rate density contributed by 1.1 mm sources with ≥1 mJy using the differential number counts and find that it is lower by about a factor of 5-10 compared to those derived from UV/optically-selected galaxies at z ~ 2-3. Clustering analyses of AzTEC sources in the ADF-S and the SXDF find that bright (>3 mJy) AzTEC sources are more strongly clustered than faint (< 3 mJy) AzTEC sources and the average mass of dark halos hosting bright AzTEC sources was calculated to be 1013-1014M⊙. Comparison of correlation length of AzTEC sources with other populations and with a bias evolution model suggests that dark halos hosting bright AzTEC sources evolve into systems of clusters at present universe and the AzTEC sources residing the dark halos evolve into massive elliptical galaxies located in the center of
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NASA Astrophysics Data System (ADS)
Toker, C.; Gokdag, Y. E.; Arikan, F.; Arikan, O.
2012-04-01
Ionosphere is a very important part of Space Weather. Modeling and monitoring of ionospheric variability is a major part of satellite communication, navigation and positioning systems. Total Electron Content (TEC), which is defined as the line integral of the electron density along a ray path, is one of the parameters to investigate the ionospheric variability. Dual-frequency GPS receivers, with their world wide availability and efficiency in TEC estimation, have become a major source of global and regional TEC modeling. When Global Ionospheric Maps (GIM) of International GPS Service (IGS) centers (http://iono.jpl.nasa.gov/gim.html) are investigated, it can be observed that regional ionosphere along the midlatitude regions can be modeled as a constant, linear or a quadratic surface. Globally, especially around the magnetic equator, the TEC surfaces resemble twisted and dispersed single centered or double centered Gaussian functions. Particle Swarm Optimization (PSO) proved itself as a fast converging and an effective optimization tool in various diverse fields. Yet, in order to apply this optimization technique into TEC modeling, the method has to be modified for higher efficiency and accuracy in extraction of geophysical parameters such as model parameters of TEC surfaces. In this study, a modified PSO (mPSO) method is applied to regional and global synthetic TEC surfaces. The synthetic surfaces that represent the trend and small scale variability of various ionospheric states are necessary to compare the performance of mPSO over number of iterations, accuracy in parameter estimation and overall surface reconstruction. The Cramer-Rao bounds for each surface type and model are also investigated and performance of mPSO are tested with respect to these bounds. For global models, the sample points that are used in optimization are obtained using IGS receiver network. For regional TEC models, regional networks such as Turkish National Permanent GPS Network (TNPGN
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1991-04-04
AIR. j NO ABSOLUTE TEC. C: NEW SATELITE WINDOWS INSERTED. j - IAPEDRIVE PROBLEM. D: SOME DATA ON CHART NOT RECORDED ON TAPE. H = NPIB INTERFASE...PROBLEM. E: SOME DATA BROKEN UP. V 2 FLOPPY DISK/DRIVE PROBLEM. F: TAPE CHANGE. W - WRONG SATELITE WINDOWS. TOTAL HOURS OF ACTIVITY LEVEL 1:300 P - POWER...0 1 0 31 1 COMMENT’S: ADDITIONAL COMMENT’S. A: TAPE STOP * L1/L2 SCINTILLATION. B: GPS SYSTEM OFF THE AIR. O= N ABSOLUTE TEC. C: NEW SATELITE WINDOWS
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NASA Astrophysics Data System (ADS)
Aa, Ercha; Huang, Wengeng; Yu, Shimei; Liu, Siqing; Shi, Liqin; Gong, Jiancun; Chen, Yanhong; Shen, Hua
2015-06-01
In this paper, a regional total electron content (TEC) mapping technique over China and adjacent areas (70°E-140°E and 15°N-55°N) is developed on the basis of a Kalman filter data assimilation scheme driven by Global Navigation Satellite Systems (GNSS) data from the Crustal Movement Observation Network of China and International GNSS Service. The regional TEC maps can be generated accordingly with the spatial and temporal resolution being 1°×1° and 5 min, respectively. The accuracy and quality of the TEC mapping technique have been validated through the comparison with GNSS observations, the International Reference Ionosphere model values, the global ionosphere maps from Center for Orbit Determination of Europe, and the Massachusetts Institute of Technology Automated Processing of GPS TEC data from Madrigal database. The verification results indicate that great systematic improvements can be obtained when data are assimilated into the background model, which demonstrates the effectiveness of this technique in providing accurate regional specification of the ionospheric TEC over China and adjacent areas.
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Millimeter-Wave Polarimeters Using Kinetic Inductance Detectors for TolTEC and Beyond
NASA Astrophysics Data System (ADS)
Austermann, J. E.; Beall, J. A.; Bryan, S. A.; Dober, B.; Gao, J.; Hilton, G.; Hubmayr, J.; Mauskopf, P.; McKenney, C. M.; Simon, S. M.; Ullom, J. N.; Vissers, M. R.; Wilson, G. W.
2018-05-01
Microwave kinetic inductance detectors (MKIDs) provide a compelling path forward to the large-format polarimeter, imaging, and spectrometer arrays needed for next-generation experiments in millimeter-wave cosmology and astronomy. We describe the development of feedhorn-coupled MKID detectors for the TolTEC millimeter-wave imaging polarimeter being constructed for the 50-m Large Millimeter Telescope (LMT). Observations with TolTEC are planned to begin in early 2019. TolTEC will comprise ˜ 7000 polarization-sensitive MKIDs and will represent the first MKID arrays fabricated and deployed on monolithic 150 mm diameter silicon wafers—a critical step toward future large-scale experiments with over 10^5 detectors. TolTEC will operate in observational bands at 1.1, 1.4, and 2.0 mm and will use dichroic filters to define a physically independent focal plane for each passband, thus allowing the polarimeters to use simple, direct-absorption inductive structures that are impedance matched to incident radiation. This work is part of a larger program at NIST-Boulder to develop MKID-based detector technologies for use over a wide range of photon energies spanning millimeter-waves to X-rays. We present the detailed pixel layout and describe the methods, tools, and flexible design parameters that allow this solution to be optimized for use anywhere in the millimeter and sub-millimeter bands. We also present measurements of prototype devices operating in the 1.1 mm band and compare the observed optical performance to that predicted from models and simulations.
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SubTec-7 Gives New Technologies a Flight Test
2017-12-08
NASA successfully launched the SubTec-7 payload on a Black Brant IX suborbital sounding rocket at 5:45 a.m. EDT, May 16, from the NASA's Wallops Flight Facility. The payload flew to an altitude of about 154 miles before descending by parachute and landing in the Atlantic Ocean. SubTec-7 provided a flight test for more than 20 technologies to improve sounding rocket and spacecraft capabilities. Good data was received during the flight. The payload has been recovered. Credit: NASA/Wallops NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram
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Evaluation of long term solar activity effects on GPS derived TEC
NASA Astrophysics Data System (ADS)
Mansoori, Azad A.; Khan, Parvaiz A.; Ahmad, Rafi; Atulkar, Roshni; M, Aslam A.; Bhardwaj, Shivangi; Malvi, Bhupendra; Purohit, P. K.; Gwal, A. K.
2016-10-01
The solar activity hence the solar radiance follows a long term periodic variability with eleven years periodicity, known as solar cycle. This drives the long term variability of the ionosphere. In the present problem we investigate the long term behaviour of the ionosphere with the eleven year cyclic solar activity. Under the present study we characterize the ionospheric variability by Total Electron Content (TEC) using measurements made by Global Positioning System (GPS) and solar cycle variability by various solar activity indices. We make use of five solar activity indices viz. sunspot number (Rz), solar radio Flux (F10.7 cm), EUV Flux (26-34 nm), flare index and CME occurrences. The long term variability of these solar activity indices were then compared and correlated with the variability of ionospheric TEC, at a mid latitude station, Usuda (36.13N, 138.36E), of Japan, during the solar cycle 23 and ascending phase of cycle 24. From our study, we found that long term changes in the ionospheric TEC vary synchronously with corresponding changes in the solar activity indices. The correlation analysis shows that all the solar activity indices exhibit a very strong correlation with TEC (R =0.76 -0.99). Moreover the correlation between the two is stronger in the descending phase of the solar cycle. The correlation is found to be remarkably strongest during the deep minimum of the solar cycle 24 i.e. between 2007- 2009. Also we noticed a hysteresis effect exists with solar radio flux (F10.7 cm) and solar EUV flux (26-34 nm). This effect is absent with other parameters.
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NASA Astrophysics Data System (ADS)
Liu, Wenjing; Xu, Liang
2017-07-01
Based on Center of Orbit Determination in Europe (CODE) global ionospheric map (GIM) data, a statistical analysis of local total electron content (TEC) anomalies before 121 low-depth ( D ≤ 100 km) strong ( M w ≥ 7.0) earthquakes has been made using the sliding median differential calculation method combining with a new approach of image processing technique. The results show that significant local TEC anomalies could be observed 0-6 days before 80 earthquakes, about 66.1% out of the total. The positive anomalies occur more often than negative ones. For 26 cases, both positive and negative anomalies are observed before the shock. The pre-earthquake TEC anomalies show local time recurrence for 38 earthquakes, which occur around the same local time on different days. The local time distribution of the pre-earthquake TEC anomalies mainly concentrates between 19 and 06 LT, roughly from the sunset to sunrise. Most of the pre-earthquake TEC anomalies do not locate above the epicenter but shift to the south. The pre-earthquake TEC anomalies could be extracted near the magnetic conjugate point of the epicenter for 40 events, which is 50% out of the total 80 cases with significant local TEC anomalies. In general, the signs of the anomalies around epicenter and its conjugate point are the same, but the abnormal magnitude and lasting time are not.
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Anomalous variation in GPS based TEC measurements prior to the 30 September 2009 Sumatra Earthquake
NASA Astrophysics Data System (ADS)
Karia, Sheetal; Pathak, Kamlesh
This paper investigates the features of pre-earthquake ionospheric anomalies in the total elec-tron content (TEC) data obtained on the basis of regular GPS observations from the GPS receiver at SVNIT Surat (21.16 N, 72.78 E Geog) located at the northern crest of equatorial anomaly region. The data has been analysed for 5 different earthquakes that occurred during 2009 in India and its neighbouring regions. Our observation shows that for the cases of the earthquake, in which the preparation area lies between the crests of the equatorial anomaly close to the geomagnetic equator the enhancement in TEC was followed by a depletion in TEC on the day of earthquake, which may be connected to the equatorial anomaly shape distortions. For the analysis of the ionospheric effects of one of such case-the 30 September 2009 Sumatra earthquake, Global Ionospheric Maps of TEC were used. The possible influence of the earth-quake preparation processes on the main low-latitude ionosphere peculiarity—the equatorial anomaly—is discussed.
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TEC Longitude Difference Using GIMS and the IRI Model
NASA Astrophysics Data System (ADS)
Natali, Maria Paula; Meza, Amalia Margarita; Mendoza, Gastón
2016-07-01
The main geomagnetic field declination has a global distribution with positive and negative values showing maximum east-west differences over North America and Oceania and minimum differences over America and Asia. Several authors study one or more of these regions using TEC data derived from GNSS observations to describe variations in TEC. They reported a pronounced longitudinal variation respect to zero magnetic declination. One of the important factors that cause the longitude difference at mid-latitude is a combined effect of the longitude variations of magnetic declination and the variations of the zonal thermospheric winds with local time. We propose to study this effect using Global Ionospheric Maps (GIMs) and the respective TEC values generated from the International Reference Ionospheric (IRI) model, during a solar cycle, applying Principal Component Analysis (PCA). Our works is focused over different local times and regions at mid-latitude. PCA involves a mathematical procedure that transforms a number of correlated variables into a number of uncorrelated variables using the data itself. The spatial structure of the ionosphere variability and its temporal evolution, together are called modes, and there are ordered according to their percentage of the variability of data from highest to lowest. In this analysis the first mode has more than the 90 % of the variability, representing the nominal behavior of the ionosphere, and the second and third modes are the more important for our analysis, because they show the strong longitudinal variation in the different regions using either GIMs or the IRI model.
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Anomalous Variation in GPS TEC, Land and Ocean Parameters Prior to 3 Earthquakes
NASA Astrophysics Data System (ADS)
Yadav, Kunvar; Karia, Sheetal P.; Pathak, Kamlesh N.
2016-02-01
The present study reports the analysis of GPS TEC prior to 3 earthquakes ( M > 6.0). The earthquakes are: (1) Loyalty Island (22°36'S, 170°54'E) on 19 January 2009 ( M = 6.6), (2) Samoa Island (15°29'S, 172°5'W) on 30 August 2009 ( M = 6.6), and (3) Tohoku (38°19'N, 142°22'E) on 11 March 2011 ( M = 9.0). In an effort to search for a precursory signature we analysed the land and ocean parameters prior to the earthquakes, namely SLHF (Land) and SST (Ocean). The GPS TEC data indicate an anomalous behaviour from 1-13 days prior to earthquakes. The main purpose of this study was to explore and demonstrate the possibility of any changes in TEC, SST, and SLHF before, during and after the earthquakes which occurred near or beneath an ocean. This study may lead to better understanding of response of land, ocean, and ionosphere parameters prior to seismic activities.
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Regional TEC dynamic modeling based on Slepian functions
NASA Astrophysics Data System (ADS)
Sharifi, Mohammad Ali; Farzaneh, Saeed
2015-09-01
In this work, the three-dimensional state of the ionosphere has been estimated by integrating the spherical Slepian harmonic function and Kalman filter. The spherical Slepian harmonic functions have been used to establish the observation equations because of their properties in local modeling. Spherical harmonics are poor choices to represent or analyze geophysical processes without perfect global coverage but the Slepian functions afford spatial and spectral selectivity. The Kalman filter has been utilized to perform the parameter estimation due to its suitable properties in processing the GPS measurements in the real-time mode. The proposed model has been applied to the real data obtained from the ground-based GPS observations across some portion of the IGS network in Europe. Results have been compared with the estimated TECs by the CODE, ESA, IGS centers and IRI-2012 model. The results indicated that the proposed model which takes advantage of the Slepian basis and Kalman filter is efficient and allows for the generation of the near-real-time regional TEC map.
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AzTEC millimetre survey of the COSMOS field - I. Data reduction and source catalogue
NASA Astrophysics Data System (ADS)
Scott, K. S.; Austermann, J. E.; Perera, T. A.; Wilson, G. W.; Aretxaga, I.; Bock, J. J.; Hughes, D. H.; Kang, Y.; Kim, S.; Mauskopf, P. D.; Sanders, D. B.; Scoville, N.; Yun, M. S.
2008-04-01
We present a 1.1 mm wavelength imaging survey covering 0.3 deg2 in the COSMOS field. These data, obtained with the AzTEC continuum camera on the James Clerk Maxwell Telescope, were centred on a prominent large-scale structure overdensity which includes a rich X-ray cluster at z ~ 0.73. A total of 50 mm-galaxy candidates, with a significance ranging from 3.5 to 8.5σ, are extracted from the central 0.15 deg2 area which has a uniform sensitivity of ~1.3 mJybeam-1. 16 sources are detected with S/N >= 4.5, where the expected false-detection rate is zero, of which a surprisingly large number (9) have intrinsic (deboosted) fluxes >=5 mJy at 1.1 mm. Assuming the emission is dominated by radiation from dust, heated by a massive population of young, optically obscured stars, then these bright AzTEC sources have far-infrared luminosities >6 × 1012Lsolar and star formation rates >1100Msolaryr-1. Two of these nine bright AzTEC sources are found towards the extreme peripheral region of the X-ray cluster, whilst the remainder are distributed across the larger scale overdensity. We describe the AzTEC data reduction pipeline, the source-extraction algorithm, and the characterization of the source catalogue, including the completeness, flux deboosting correction, false-detection rate and the source positional uncertainty, through an extensive set of Monte Carlo simulations. We conclude with a preliminary comparison, via a stacked analysis, of the overlapping MIPS 24-μm data and radio data with this AzTEC map of the COSMOS field.
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NASA Astrophysics Data System (ADS)
Yildirim, O.; Inyurt, S.; Mekik, C.
2015-10-01
Turkey is a country located in Middle Latitude zone and in which tectonic activity is intensive. Lastly, an earthquake of magnitude 6.5Mw occurred at Aegean Sea offshore on date 24 May 2014 at 12:25 UTC and it lasted approximately 40 s. The said earthquake was felt also in Greece, Romania and Bulgaria in addition to Turkey. In recent years seismic origin ionospheric anomaly detection studies have been done with TEC (Total Electron Contents) generated from GNSS (Global Navigation Satellite System) signals and the findings obtained have been revealed. In this study, TEC and positional variations have been examined seperately regarding the earthquake which occurred in the Aegean Sea. Then The correlation of the said ionospheric variation with the positional variation has been investigated. For this purpose, total fifteen stations have been used among which the data of four numbers of CORS-TR stations in the seismic zone (AYVL, CANA, IPSA, YENC) and IGS and EUREF stations are used. The ionospheric and positional variations of AYVL, CANA, IPSA and YENC stations have been examined by Bernese 5.0v software. When the (PPP-TEC) values produced as result of the analysis are examined, it has been understood that in the four stations located in Turkey, three days before the earthquake at 08:00 and 10:00 UTC, the TEC values were approximately 4 TECU above the upper limit TEC value. Still in the same stations, one day before the earthquake at 06:00, 08:00 and 10:00 UTC, it is being shown that the TEC values were approximately 5 TECU below the lower limit TEC value. On the other hand, the GIM-TEC values published by the CODE center have been examined. Still in all stations, it has been observed that three days before the earthquake the TEC values in the time portions of 08:00 and 10:00 UTC were approximately 2 TECU above, one day before the earthquake at 06:00, 08:00 and 10:00 UTC, the TEC values were approximately 4 TECU below the lower limit TEC value. Again, by using the same
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NASA Astrophysics Data System (ADS)
Huang, Z.; Roussel-Dupre, R.
2003-12-01
The total electron content (TEC) of ionosphere and its electron density irregularities (scintillation) have effects of degradation and disruption on radio signals passed between ground stations and orbiting man-made satellites. With the rapid increase in operational reliance on UHF/VHF satellite communication, it is desirable to obtain understandings of ionosphere TEC variability and scintillation characteristics to improve our ability of predicting satellite communication outages. In this work, data collected from FORTE satellite received LAPP (Los Alamos Portable Pulser) signals during 1998-2002 are used to derive TEC and ionospheric scintillation index at Los Alamos, New Mexico. To characterize in-situ TEC variability at Los Alamos, the FORTE-LAPP derived TECs are analyzed against diurnal, seasonal, solar activity, magnetic storm, and stratospheric warming. The results are also compared with the TEC estimates from the Los Alamos ionospheric transfer function (ITF) implemented with the global ionospheric models (IRI, PIM), and GPS -derived TEC maps. The FORTE-LAPP signals are also analyzed against two important measures of the effect of scintillation on broadband signals, the mean time delay and the time delay jitter. The results are used to examine coherence frequency bandwidth and compared with the predictions from a global scintillation model (WBMOD). The FORTE-LAPP analyzed and WBMOD predicted scintillation characteristics are used to investigate temporal and seasonal behavior of scintillation at Los Alamos.
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Observed TEC Anomalies by GNSS Sites Preceding the Aegean Sea Earthquake of 2014
NASA Astrophysics Data System (ADS)
Ulukavak, Mustafa; Yal&ccedul; ınkaya, Mualla
2016-11-01
In recent years, Total Electron Content (TEC) data, obtained from Global Navigation Satellites Systems (GNSS) receivers, has been widely used to detect seismo-ionospheric anomalies. In this study, Global Positioning System - Total Electron Content (GPS-TEC) data were used to investigate ionospheric abnormal behaviors prior to the 2014 Aegean Sea earthquake (40.305°N 25.453°E, 24 May 2014, 09:25:03 UT, Mw:6.9). The data obtained from three Continuously Operating Reference Stations in Turkey (CORS-TR) and two International GNSS Service (IGS) sites near the epicenter of the earthquake is used to detect ionospheric anomalies before the earthquake. Solar activity index (F10.7) and geomagnetic activity index (Dst), which are both related to space weather conditions, were used to analyze these pre-earthquake ionospheric anomalies. An examination of these indices indicated high solar activity between May 8 and 15, 2014. The first significant increase (positive anomalies) in Vertical Total Electron Content (VTEC) was detected on May 14, 2014 or 10 days before the earthquake. This positive anomaly can be attributed to the high solar activity. The indices do not imply high solar or geomagnetic activity after May 15, 2014. Abnormal ionospheric TEC changes (negative anomaly) were observed at all stations one day before the earthquake. These changes were lower than the lower bound by approximately 10-20 TEC unit (TECU), and may be considered as the ionospheric precursor of the 2014 Aegean Sea earthquake
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NASA Astrophysics Data System (ADS)
Abe, O. E.; Otero Villamide, X.; Paparini, C.; Radicella, S. M.; Nava, B.; Rodríguez-Bouza, M.
2017-04-01
Global Navigation Satellite Systems (GNSS) have become a powerful tool use in surveying and mapping, air and maritime navigation, ionospheric/space weather research and other applications. However, in some cases, its maximum efficiency could not be attained due to some uncorrelated errors associated with the system measurements, which is caused mainly by the dispersive nature of the ionosphere. Ionosphere has been represented using the total number of electrons along the signal path at a particular height known as Total Electron Content (TEC). However, there are many methods to estimate TEC but the outputs are not uniform, which could be due to the peculiarity in characterizing the biases inside the observables (measurements), and sometimes could be associated to the influence of mapping function. The errors in TEC estimation could lead to wrong conclusion and this could be more critical in case of safety-of-life application. This work investigated the performance of Ciraolo's and Gopi's GNSS-TEC calibration techniques, during 5 geomagnetic quiet and disturbed conditions in the month of October 2013, at the grid points located in low and middle latitudes. The data used are obtained from the GNSS ground-based receivers located at Borriana in Spain (40°N, 0°E; mid latitude) and Accra in Ghana (5.50°N, -0.20°E; low latitude). The results of the calibrated TEC are compared with the TEC obtained from European Geostationary Navigation Overlay System Processing Set (EGNOS PS) TEC algorithm, which is considered as a reference data. The TEC derived from Global Ionospheric Maps (GIM) through International GNSS service (IGS) was also examined at the same grid points. The results obtained in this work showed that Ciraolo's calibration technique (a calibration technique based on carrier-phase measurements only) estimates TEC better at middle latitude in comparison to Gopi's technique (a calibration technique based on code and carrier-phase measurements). At the same time
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NASA Astrophysics Data System (ADS)
Habarulema, J. B.; McKinnell, L.-A.
2012-05-01
In this work, results obtained by investigating the application of different neural network backpropagation training algorithms are presented. This was done to assess the performance accuracy of each training algorithm in total electron content (TEC) estimations using identical datasets in models development and verification processes. Investigated training algorithms are standard backpropagation (SBP), backpropagation with weight delay (BPWD), backpropagation with momentum (BPM) term, backpropagation with chunkwise weight update (BPC) and backpropagation for batch (BPB) training. These five algorithms are inbuilt functions within the Stuttgart Neural Network Simulator (SNNS) and the main objective was to find out the training algorithm that generates the minimum error between the TEC derived from Global Positioning System (GPS) observations and the modelled TEC data. Another investigated algorithm is the MatLab based Levenberg-Marquardt backpropagation (L-MBP), which achieves convergence after the least number of iterations during training. In this paper, neural network (NN) models were developed using hourly TEC data (for 8 years: 2000-2007) derived from GPS observations over a receiver station located at Sutherland (SUTH) (32.38° S, 20.81° E), South Africa. Verification of the NN models for all algorithms considered was performed on both "seen" and "unseen" data. Hourly TEC values over SUTH for 2003 formed the "seen" dataset. The "unseen" dataset consisted of hourly TEC data for 2002 and 2008 over Cape Town (CPTN) (33.95° S, 18.47° E) and SUTH, respectively. The models' verification showed that all algorithms investigated provide comparable results statistically, but differ significantly in terms of time required to achieve convergence during input-output data training/learning. This paper therefore provides a guide to neural network users for choosing appropriate algorithms based on the availability of computation capabilities used for research.
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NASA Astrophysics Data System (ADS)
Allen, Kathleen
2003-03-01
N2TEC, the National Network for Technology Entrepreneurship and Commercialization, is a National Science Foundation "Partnerships for Innovation" initiative designed to raise the level of innovation and technology commercialization in colleges, universities, and communities across the nation. N2TEC is creating a network of people and institutions, and a set of technology tools that will facilitate the pooling of resources and knowledge and enable faculty and students to share those resources and collaborate without regard to geographic boundaries. N2TEC will become the backbone by which educational institutions across the nation can move their technologies into new venture startups. The ultimate goal is to create new wealth and strengthen local, regional and national economies.
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High Temporal and Spatial Resolution Global GPS TEC Observations of the 2015 St. Patrick Day Storm
NASA Astrophysics Data System (ADS)
Vierinen, J.
2015-12-01
High spatiotemperal resolution global GPS TEC measurements of the 2015 St. Patrick's day storm are presented. The high resolution data is useful, as it clearly shows the high latitude convection patterns, the equatorward progression of the auroral region, the tongue of ionization, as well as the increased electron density in the equatorial anomaly region. The measurements are compared with high power large aperture radar and passive radar measurements of coherent and incoherent scatter at Millstone Hill. Regions of fast convection identified in the GPS TEC data are found to coincide with coherent scatter in both radar data. Convection velocities determined from GPS TEC are compared with those obtained from incoherent scatter radar measurements.
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Altuntas, Fevzi; Kocyigit, Ismail; Ozturk, Ahmet; Kaynar, Leylagul; Sari, Ismail; Oztekin, Mehmet; Solmaz, Musa; Eser, Bulent; Cetin, Mustafa; Unal, Ali
2007-04-01
Peripheral blood progenitor cells (PBPC) are commonly used as a stem cell source for autologous transplantation. This study was undertaken to evaluate blood cell separators with respect to separation results and content of the harvest. Forty autologous PBPC collections in patients with hematological malignancies were performed with either the Amicus or the COM.TEC cell separators. The median product volume was lower with the Amicus compared to the COM.TEC (125 mL vs. 300 mL; p < 0.001). There was no statistically significant difference in the median number of CD34+ cell/kg in product between the Amicus and the COM.TEC (3.0 x 10(6) vs. 4.1 x 10(6); p = 0.129). There was a statistically higher mean volume of ACD used in collections on the Amicus compared to the COM.TEC (1040 +/- 241 mL vs. 868 +/- 176 mL; p = 0.019). There was a statistical difference in platelet (PLT) contamination of the products between the Amicus and the COM.TEC (0.3 x 10(11) vs. 1.1 x 10(11); p < 0.001). The median % decrease in PB PLT count was statistically higher in the COM.TEC compared to the Amicus instruments (18.5% vs. 9.5%; p = 0.028). In conclusion, both instruments collected PBPCs efficiently. However, Amicus has the advantage of lower PLT contamination in the product, and less decrease in PB platelet count with lower product volume in autologous setting.
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Galaxy evolution at high-redshift: Millimeter-wavelength surveys with the AzTEC camera
NASA Astrophysics Data System (ADS)
Scott, Kimberly S.
Galaxies detected by their thermal dust emission at submillimeter (submm) and millimeter (mm) wavelengths comprise a population of massive, intensely star-forming systems in the early Universe. These "submm/mm- galaxies", or SMGs, likely represent an important phase in the assembly and/or evolution of massive galaxies and are thought to be the progenitors of massive elliptical galaxies. While their projected number density as a function of source brightness provides key constraints on models of galaxy evolution, SMG surveys carried out over the past twelve years with the first generation of submm/mm-wavelength cameras have not imaged a large enough area to sufficient depths to provide the statistical power needed to discriminate between competing galaxy evolution scenarios. In this dissertation, we present the results from SMG surveys carried out over the past four years using the new sensitive mm-wavelength camera AzTEC. With the improved mapping speed of the AzTEC camera combined with dedicated telescope time devoted to deep, large-area extragalactic surveys, we have tripled both the area surveyed towards blank- fields (that is, regions with no known galaxy over-densities) at submm/mm wavelengths and the total number of detected SMGs. Here, we describe the properties and performance of the AzTEC instrument while operating on the James Clerk Maxwell Telescope (JCMT) and the Atacama Submillimeter Telescope Experiment (ASTE). We then present the results from two of the blank-field regions imaged with AzTEC: the JCMT/COSMOS field, which we discovered is over- dense in the number of very bright SMGs, and the ASTE survey of the Great Observatories Origins Deep-South field, which represents one of the deepest surveys ever carried out at submm/mm wavelengths. Finally, we combine the results from all of the blank-fields imaged with AzTEC while operating on the JCMT and the ASTE to calculate the most accurate measurements to date of the SMG number counts.
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Variation of GPS-TEC in a low latitude Indian region during the year 2012 and 2013
NASA Astrophysics Data System (ADS)
Patel, Nilesh C.; Karia, Sheetal P.; Pathak, Kamlesh N.
2018-05-01
The paper is based on the ionospheric variations in terms of vertical total electron content (VTEC) for the period from January 2012 to December 2013 based on the analysis of dual frequency signals from the Global Positioning System (GPS) satellites recorded at ground stations Surat (21.16°N, 72.78°E Geog.), situated under the northern crest of the equatorial ionization anomaly region (EIA) and other three International GNSS Service (IGS) stations Bangalore (13.02°N, 77.57°E Geog.), Hyderabad (17.25°N, 78.30°E Geog.), and Lucknow (26.91°N, 80.95°E Geog.) in India. We describe the diurnal and seasonal characteristics. It was observed that GPS-TEC reaches its maximum value between 12:00 and 16:00 IST. Further, Seasonal variations of GPS-TEC is categorized into four seasons, i.e., March equinox (February, March, and April), June solstice (May, June, and July), September equinox (August, September, and October) and December solstice (November, December and January). The forenoon rate of production in Lucknow (beyond EIA crest) is faster than Bangalore, Hyderabad and Surat station. It is found that September equinox shows GPS-TEC slightly higher than the March equinox, followed by June solstice and the lowest GPS-TEC are in winter solstice at four stations. The equinoctial asymmetry clearly observed in the current study. Also GPS-TEC shows a semiannual variation.
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NASA Astrophysics Data System (ADS)
Shagimuratov, Irk; Cherniak, Iurii; Zakharenkova, Irina; Ephishov, Ivan; Krankowski, Andrzej; Radievsky, Alexander
2014-05-01
The total electron content (TEC) is a key parameter not only for space radio communication but also for addressing the fundamental problems of the ionosphere physics and near Earth space. Currently, the main sources of information on the TEC in the global scale are GNSS signals measurements. The spatial-temporal behavior of the ionosphere can be most effectively analyzed using TEC maps. To date, global IGS global ionospheric maps with a resolution of 2.5 degree in latitude and 5 in longitude and a time resolution of 2 h are most widely used. To study the detailed structure of the ionospheric gradients and rapid process as well as for precise positioning task it is necessary to use more precise regional TEC maps. The Regional TEC maps are currently constructed by different research groups for different regions: USA, Europe, Japan etc. The West Department of IZMIRAN research group is a one in Russia who works on the task of regional ionosphere mapping since 2000. It was developed the methodology for obtaining information on the spatial TEC distribution, TEC maps of the ionosphere on the basis of the algorithm for multi-station processing of GNSS observations. Using a set of algorithms and programs, regional TEC maps with a spatial resolution of 1° and a time resolution up to 15 min can be produced. Here is developed the approach to establish the regular online internet service for regional ionosphere mapping of the Western Russia and Eastern Europe. Nowadays the development of GLONASS navigation system is completely finished and it consists of a constellation of more than 24 satellites. It is good perspective for investigations of the ionosphere structure and dynamics on the base of the simultaneous observations of GPS and GLONASS systems. The GLONASS satellites have the inclination about 64 degrees as against GPS satellites with 56. So the GLONASS provides opportunity to study the high latitude ionosphere. The different scale electron density irregularities
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NASA Astrophysics Data System (ADS)
Sands, Sandra S.; Meek, William D.; Hayashi, Jun; Ketchum, Robert J.
2005-08-01
Isolation and culture of thymic epithelial cells (TECs) using conventional primary tissue culture techniques under conditions employing supplemented low calcium medium yielded an immortalized cell line derived from the LDA rat (Lewis [Rt1l] cross DA [Rt1a]) that could be manipulated in vitro. Thymi were harvested from 4 5-day-old neonates, enzymically digested using collagenase (1 mg/ml, 37°C, 1 h) and cultured in low calcium WAJC404A medium containing cholera toxin (20 ng/ml), dexamethasone (10 nM), epidermal growth factor (10 ng/ml), insulin (10 [mu]g/ml), transferrin (10 [mu]g/ml), 2% calf serum, 2.5% Dulbecco's Modified Eagle's Medium (DMEM), and 1% antibiotic/antimycotic. TECs cultured in low calcium displayed round to spindle-shaped morphology, distinct intercellular spaces (even at confluence), and dense reticular-like keratin patterns. In high calcium (0.188 mM), TECs formed cobblestone-like confluent monolayers that were resistant to trypsinization (0.05%) and displayed keratin intermediate filaments concentrated at desmosomal junctions between contiguous cells. Changes in cultured TEC morphology were quantified by an analysis of desmosome/membrane relationships in high and low calcium media. Desmosomes were significantly increased in the high calcium medium. These studies may have value when considering the growth conditions of cultured primary cell lines like TECs.
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NASA Astrophysics Data System (ADS)
Shim, J. S.; Tsagouri, I.; Goncharenko, L. P.; Kuznetsova, M. M.
2017-12-01
To address challenges of assessment of space weather modeling capabilities, the CCMC (Community Coordinated Modeling Center) is leading the newly established "International Forum for Space Weather Modeling Capabilities Assessment." This presentation will focus on preliminary outcomes of the International Forum on validation of modeled foF2 and TEC during geomagnetic storms. We investigate the ionospheric response to 2013 Mar. geomagnetic storm event using ionosonde and GPS TEC observations in North American and European sectors. To quantify storm impacts on foF2 and TEC, we first quantify quiet-time variations of foF2 and TEC (e.g., the median and the average of the five quietest days for the 30 days during quiet conditions). It appears that the quiet time variation of foF2 and TEC are about 10% and 20-30%, respectively. Therefore, to quantify storm impact, we focus on foF2 and TEC changes during the storm main phase larger than 20% and 50%, respectively, compared to 30-day median. We find that in European sector, both foF2 and TEC response to the storm are mainly positive phase with foF2 increase of up to 100% and TEC increase of 150%. In North America sector, however, foF2 shows negative effects (up to about 50% decrease), while TEC shows positive response (the largest increase is about 200%). To assess modeling capability of reproducing the changes of foF2 and TEC due to the storm, we use various model simulations, which are obtained from empirical, physics-based, and data assimilation models. The performance of each model depends on the selected metrics, therefore, only one metrics is not enough to evaluate the models' predictive capabilities in capturing the storm impact. The performance of the model also varies with latitude and longitude.
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AzTEC 1.1 mm OBSERVATIONS OF THE MBM12 MOLECULAR CLOUD
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kim, M. J.; Kim, S.; Youn, S.
2012-02-10
We present 1.1 mm observations of the dust continuum emission from the MBM12 high-latitude molecular cloud observed with the Astronomical Thermal Emission Camera (AzTEC) mounted on the James Clerk Maxwell Telescope on Mauna Kea, Hawaii. We surveyed 6.34 deg{sup 2} centered on MBM12, making this the largest area that has ever been surveyed in this region with submillimeter and millimeter telescopes. Eight secure individual sources were detected with a signal-to-noise ratio of over 4.4. These eight AzTEC sources can be considered to be real astronomical objects compared to the other candidates based on calculations of the false detection rate. Themore » distribution of the detected 1.1 mm sources or compact 1.1 mm peaks is spatially anti-correlated with that of the 100 {mu}m emission and the {sup 12}CO emission. We detected the 1.1 mm dust continuum emitting sources associated with two classical T Tauri stars, LkH{alpha}262 and LkH{alpha}264. Observations of spectral energy distributions (SEDs) indicate that LkH{alpha}262 is likely to be Class II (pre-main-sequence star), but there are also indications that it could be a late Class I (protostar). A flared disk and a bipolar cavity in the models of Class I sources lead to more complicated SEDs. From the present AzTEC observations of the MBM12 region, it appears that other sources detected with AzTEC are likely to be extragalactic and located behind MBM12. Some of these have radio counterparts and their star formation rates are derived from a fit of the SEDs to the photometric evolution of galaxies in which the effects of a dusty interstellar medium have been included.« less
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The Role of ESA TEC-QTE in the ISS Safety Process
NASA Astrophysics Data System (ADS)
Orlandi, M.; Rohr, T.; Stienstra, M. H.; Semprimoschnig, C.
2013-09-01
On the 17th of July 2000, the Materials and Processes Reciprocal Agreement was signed between NASA and ESA to define the process for selection and certification of materials used in the Space Shuttle and the International Space Station. Consecutively, on the 20th of June 2003 this agreement was extended to the Automated Transport Vehicle (ATV). It is therefore the responsibility of ESA TEC-QTE, the Materials Space Evaluation and Radiation Effects section, part of the Product Assurance and Safety Department, to ensure that all materials, parts and processes of each of the ISS payloads not only function as required but also do not pose a risk to the safety of the crew members. In this context, TEC-QTE provides qualified expertise to support the ESA Flight Safety Review and assesses safety aspects related to manned projects (materials properties, fluid system compatibility, fungus resistance). This is supported by the Materials Space Evaluation and Radiation Effects section's Materials and Electrical Components laboratory having at its disposition a range of facilities designed to perform environmental effects testing of which off-gassing tests according to ECSS-Q-ST-70-29C (equivalent to NASA STD 6001 test 7) and outgassing tests according to ECSS-Q-ST-70-02C (equivalent to ASTM-E-595). The ESA facility to perform flammability tests according to ECSS-Q-ST-70-21A (equivalent to NASA STD 6001 test1) was moved to Astrium Bremen.TEC-QTE is in charge of reviewing and approving, via RFA or MUA , all materials that do not meet safety requirements as well as COTS or CAM (black boxes) equipment.The safety process ends with the issue of the Materials Certification of the reviewed payload hardware that shows compliance with the relevant materials and processes requirements and standards.In addition to the safety related activities for the ISS, specialised TEC-QTE personnel provide measurements of the air quality inside the ATV and assess whether the toxicity index is within
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Ramírez-Zavala, Bernardo; Weyler, Michael; Gildor, Tsvia; Schmauch, Christian; Kornitzer, Daniel; Arkowitz, Robert; Morschhäuser, Joachim
2013-01-01
Depending on the environmental conditions, the pathogenic yeast Candida albicans can undergo different developmental programs, which are controlled by dedicated transcription factors and upstream signaling pathways. C. albicans strains that are homozygous at the mating type locus can switch from the normal yeast form (white) to an elongated cell type (opaque), which is the mating-competent form of this fungus. Both white and opaque cells use the Ste11-Hst7-Cek1/Cek2 MAP kinase signaling pathway to react to the presence of mating pheromone. However, while opaque cells employ the transcription factor Cph1 to induce the mating response, white cells recruit a different downstream transcription factor, Tec1, to promote the formation of a biofilm that facilitates mating of opaque cells in the population. The switch from the white to the opaque cell form is itself induced by environmental signals that result in the upregulation of the transcription factor Wor1, the master regulator of white-opaque switching. To get insight into the upstream signaling pathways controlling the switch, we expressed all C. albicans protein kinases from a tetracycline-inducible promoter in a switching-competent strain. Screening of this library of strains showed that a hyperactive form of Ste11 lacking its N-terminal domain (Ste11ΔN467) efficiently stimulated white cells to switch to the opaque phase, a behavior that did not occur in response to pheromone. Ste11ΔN467-induced switching specifically required the downstream MAP kinase Cek1 and its target transcription factor Cph1, but not Cek2 and Tec1, and forced expression of Cph1 also promoted white-opaque switching in a Wor1-dependent manner. Therefore, depending on the activation mechanism, components of the pheromone-responsive MAP kinase pathway can be reconnected to stimulate an alternative developmental program, switching of white cells to the mating-competent opaque phase. PMID:24130492
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NASA Astrophysics Data System (ADS)
Li, Wang; Yue, Jianping; Guo, Jinyun; Yang, Yang; Zou, Bin; Shen, Yi; Zhang, Kefei
2018-03-01
The Circum-Pacific seismic belt is the region heavily affected by earthquakes in the world. The relationship between earthquake (e.g., the geographic location, occurrence time, magnitude, and focal depth) and ionospheric anomalies in the belt was investigated using 100 M7.0+ earthquakes during 2006-2015. The ground-based GPS measurements and global ionosphere map (GIM) data were used for the analyses of the ionospheric variations preceding the earthquakes. The results indicated that the occurrence rate of total electron content (TEC) anomalies was proportional to the magnitude and inversely proportional to the focal depth to a certain degree, and the occurrence frequency of anomalies had a rising trend with the days getting close to the main shock. The occurrence rate of TEC anomalies in the Southern hemisphere was larger than that in the Northern hemisphere. Besides, the spatial characteristics of TEC anomalies showed that the anomalies in low-middle latitudes did not coincide with the epicenter, sometimes the anomalies were also observed in the corresponding conjugated region. However, the TEC anomalies in the high latitude usually appeared around the epicenter and within the seismogenic zone while no TEC anomalies appeared in the conjugated area. These results may have potential applications to the earthquake prediction in the Circum-Pacific seismic belt.
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PCA and vTEC climatology at midnight over mid-latitude regions
NASA Astrophysics Data System (ADS)
Natali, M. P.; Meza, A.
2017-12-01
The effect of the thermospheric vertical neutral wind on vertical total electron content (vTEC) variations including longitudinal anomaly, remaining winter anomaly, mid-latitude summer night anomaly, and semiannual anomaly is studied at mid-latitude regions around zero magnetic declination at midnight during high solar activity. By using the principal component analysis (PCA) numerical technique, this work studies the spatial and temporal variations of the ionosphere at midnight over mid-latitude regions during 2000-2002. PCA is applied to a time series of global vTEC maps produced by the International Global Navigation Satellite System (GNSS) Service. Four regions were studied in particular, each located at mid-latitude and approximately centered at zero magnetic declination, with two in the northern hemisphere and two in southern hemisphere, and all are located near and far from geomagnetic poles in each case. This technique provides an effective method to analyze the main ionospheric variabilities at mid-latitudes. PCA is also applied to the vTEC computed using the International Reference Ionosphere (IRI) 2012 model, to analyze the capability of this model to represent ionospheric variabilities at mid-latitude. Also, the Horizontal Wind Model 2007 (HWM07) is used to improve our climatology interpretation, by analyzing the relationship between vTEC and thermospheric wind, both quantitatively and qualitatively. At midnight, the behavior of mean vTEC values strongly responds to vertical wind variation, experiencing a decrease of about 10-15% with the action of the positive vertical component of the field-aligned neutral wind lasting for 2 h in all regions except for Oceania. Notable results include: a significant increase toward higher latitudes during summer in the South America and Asia regions, associated with the mid-latitude summer night anomaly, and an increase toward higher latitudes in winter in the North America and Oceania regions, highlighting the
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NASA Astrophysics Data System (ADS)
Kubota, M.; Nishioka, M.; Tsugawa, T.; Ishii, M.
2014-12-01
We observed clear concentric waves and short-period oscillations in the ionosphere after the EF5 tornado hit Moore, Oklahoma, USA, on 20 May 2013 using a dense wide-coverage ionospheric total electron content (TEC) observation in North America. These concentric waves were non-dispersive waves with a horizontal wavelength of ~120 km and a period of ~13 minutes. They were observed for more than seven hours throughout North America. TEC oscillations with a period of ~4 minutes were also observed in the south of Moore for more than eight hours. Comparison between the TEC observation and the infrared cloud image from the GOES satellite indicates that the concentric waves were caused by supercells rather than the tornados themselves. Backward ray-tracing analysis suggests that the leaking of atmospheric waves in a thermal duct excited AGWs in the ionosphere. The short-period TEC oscillation could be explained by the acoustic resonance triggered by strong long-lasting supercells. This observational result provides the first clear evidence of a severe meteorological event causing atmospheric waves propagating upward in the upper atmosphere and reaching the ionosphere.
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NASA Astrophysics Data System (ADS)
Yun, Min S.; Aretxaga, I.; Gurwell, M. A.; Hughes, D. H.; Montaña, A.; Narayanan, G.; Rosa-González, D.; Sánchez-Argüelles, D.; Schloerb, F. P.; Snell, R. L.; Vega, O.; Wilson, G. W.; Zeballos, M.; Chavez, M.; Cybulski, R.; Díaz-Santos, T.; De La Luz, V.; Erickson, N.; Ferrusca, D.; Gim, H. B.; Heyer, M. H.; Iono, D.; Pope, A.; Rogstad, S. M.; Scott, K. S.; Souccar, K.; Terlevich, E.; Terlevich, R.; Wilner, D.; Zavala, J. A.
2015-12-01
Measuring redshifted CO line emission is an unambiguous method for obtaining an accurate redshift and total cold gas content of optically faint, dusty starburst systems. Here, we report the first successful spectroscopic redshift determination of AzTEC J095942.9+022938 (`COSMOS AzTEC-1'), the brightest 1.1 mm continuum source found in the AzTEC/James Clerk Maxwell Telescope survey (Scott et al.), through a clear detection of the redshifted CO (4-3) and CO (5-4) lines using the Redshift Search Receiver on the Large Millimeter Telescope. The CO redshift of z = 4.3420 ± 0.0004 is confirmed by the detection of the redshifted 158 μm [C II] line using the Submillimeter Array. The new redshift and Herschel photometry yield LFIR = (1.1 ± 0.1) × 1013 L⊙ and SFR ≈ 1300 M⊙ yr-1. Its molecular gas mass derived using the ultraluminous infrared galaxy conversion factor is 1.4 ± 0.2 × 1011M⊙ while the total interstellar medium mass derived from the 1.1 mm dust continuum is 3.7 ± 0.7 × 1011M⊙ assuming Td = 35 K. Our dynamical mass analysis suggests that the compact gas disc (r ≈ 1.1 kpc, inferred from dust continuum and spectral energy distribution analysis) has to be nearly face-on, providing a natural explanation for the uncommonly bright, compact stellar light seen by the HST. The [C II] line luminosity L_[C II]= 7.8± 1.1 × 10^9 L_{⊙} is remarkably high, but it is only 0.04 per cent of the total IR luminosity. AzTEC COSMOS-1 and other high redshift sources with a spatially resolved size extend the tight trend seen between [C II]/FIR ratio and ΣFIR among IR-bright galaxies reported by Díaz-Santos et al. by more than an order of magnitude, supporting the explanation that the higher intensity of the IR radiation field is responsible for the `[C II] deficiency' seen among luminous starburst galaxies.
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NASA Astrophysics Data System (ADS)
Kassa, Tsegaye; Tilahun, Samson; Damtie, Baylie
2017-09-01
This paper was aimed at investigating the solar variations of vTEC as a function of solar activity parameters, EUV and F10.7 radio flux. The daily values of ionospheric vertical Total Electron Content (vTEC) were observed using a dual frequency GPS receiver deployed at Bahir Dar (11.6°N and 37.36°E), Ethiopia. Measurements were taken during the period of 2010-2014 for successive five years and analysis was done on only quiet day observations. A quadratic fit was used as a model to describe the daily variation of vTEC in relation to solar parameters. Linear and non-linear coefficients of the vTEC variations were calculated in order to capture the trend of the variation. The variation of vTEC have showed good agreement with the trend of solar parameters in almost all of the days we consider during the period of our observations. We have explicitly observed days with insignificant TECU deviation (eg. modeling with respect to EUV, DOY = 49 in 2010 and modeling with respect to F10.7, DOY = 125 in 2012 and the like) and days with maximum deviation (about 50 TECU). A maximum deviation were observed, on average, during months of equinox whereas minimum during solstice months. This implies that there is a need to consider more parameters, including EUV and F10.7, that can affect the variation of vTEC during equinox seasons. Relatively, small deviations was observed in modeling vTEC as a function of EUV compared to that of the variation due to F10.7 cm flux. This may also tell us that EUV can be more suitable in modeling the solar variation of vTEC especially for longterm trends. Even though, the linear trend of solar variations of vTEC was frequently observed, significant saturation and amplification trends of the solar variations of vTEC were also observed to some extent across the months of the years we have analyzed. This mixed trend of the solar variation of vTEC implies the need for thorough investigation on the effect of solar parameters on TEC. However, based on
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NASA Astrophysics Data System (ADS)
Kutiev, Ivan; Marinov, Pencho; Fidanova, Stefka; Belehaki, Anna; Tsagouri, Ioanna
2012-12-01
Validation results on the latest version of TaD model (TaDv2) show realistic reconstruction of the electron density profiles (EDPs) with an average error of 3 TECU, similar to the error obtained from GNSS-TEC calculated paremeters. The work presented here has the aim to further improve the accuracy of the TaD topside reconstruction, adjusting the TEC parameter calculated from TaD model with the TEC parameter calculated by GNSS transmitting RINEX files provided by receivers co-located with the Digisondes. The performance of the new version is tested during a storm period demonstrating further improvements in respect to the previous version. Statistical comparison of modeled and observed TEC confirms the validity of the proposed adjustment. A significant benefit of the proposed upgrade is that it facilitates the real-time implementation of TaD. The model needs a reliable measure of the scale height at the peak height, which is supposed to be provided by Digisondes. Oftenly, the automatic scaling software fails to correctly calculate the scale height at the peak, Hm, due to interferences in the receiving signal. Consequently the model estimated topside scale height is wrongly calculated leading to unrealistic results for the modeled EDP. The proposed TEC adjustment forces the model to correctly reproduce the topside scale height, despite the inaccurate values of Hm. This adjustment is very important for the application of TaD in an operational environment.
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NASA Astrophysics Data System (ADS)
Alothman, A. O.; Alsubaie, M. A.; Ayhan, M. E.
2011-09-01
The ionosphere is a dispersive medium for radio waves with the refractive index which is a function of frequency and total electron content (TEC). TEC has a strong diurnal variation in addition to monthly, seasonal and solar cycle variations and small and large scale irregularities. Dual frequency GPS observations can be utilized to obtain TEC and investigate its spatial and temporal variations. We here studied short term TEC variations over the Kingdom of Saudi Arabia (KSA). A regional GPS network is formed consisting of 16 sites in and around KSA. GPS observations, acquired between 1st and 11th February 2009, were processed on a daily basis by using the Bernese v5.0 software and IGS final products. The geometry-free zero difference smoothed code observables were used to obtain two hour interval snapshots of TEC and their RMS errors at 0.5 × 0.5 degree grid nodes and regional ionosphere models in a spherical harmonics expansion to degree and order six. The equatorial ionized anomaly (EIA) is recovered in the south of 20°N from 08:00 to 12:00 UT. We found that day-by-day TEC variation is more stable than the night time variation.
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NASA Astrophysics Data System (ADS)
Fuller-Rowell, Tim; Araujo-Pradere, Eduardo; Minter, Cliff; Codrescu, Mihail; Spencer, Paul; Robertson, Doug; Jacobson, Abram R.
2006-12-01
The potential of data assimilation for operational numerical weather forecasting has been appreciated for many years. For space weather it is a new path that we are just beginning to explore. With the emergence of satellite constellations and the networks of ground-based observations, sufficient data sources are now available to make the application of data assimilation techniques a viable option. The first space weather product at Space Environment Center (SEC) utilizing data assimilation techniques, US-TEC, was launched as a test operational product in November 2004. US-TEC characterizes the ionospheric total electron content (TEC) over the continental United States (CONUS) every 15 min with about a 15-min latency. US-TEC is based on a Kalman filter data assimilation scheme driven by a ground-based network of real-time GPS stations. The product includes a map of the vertical TEC, an estimate of the uncertainty in the map, and the departure of the TEC from a 10-day average at that particular universal time. In addition, data files are provided for vertical TEC and the line-of-sight electron content to all GPS satellites in view over the CONUS at that time. The information can be used to improve single-frequency GPS positioning by providing more accurate corrections for the ionospheric signal delay, or it can be used to initialize rapid integer ambiguity resolution schemes for dual-frequency GPS systems. Validation of US-TEC indicates an accuracy of the line-of-sight electron content of between 2 and 3 TEC units (1 TECU = 1016 el m-2), equivalent to less than 50 cm signal delay at L1 frequencies, which promises value for GPS users. This is the first step along a path that will likely lead to major improvement in space weather forecasting, paralleling the advances achieved in meteorological weather forecasting.
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Modeling of Heat and Mass Transfer in a TEC-Driven Lyophilizer
NASA Technical Reports Server (NTRS)
Yuan, Zeng-Guang; Hegde, Uday; Litwiller, Eric; Flynn, Michael; Fisher, John
2006-01-01
Dewatering of wet waste during space exploration missions is important for crew safety as it stabilizes the waste. It may also be used to recover water and serve as a preconditioning step for waste compaction. A thermoelectric cooler (TEC)-driven lyophilizer is under development at NASA Ames Research Center for this purpose. It has three major components: (i) an evaporator section where water vapor sublimes from the frozen waste, (ii) a condenser section where this water vapor deposits as ice, and (iii) a TEC section which serves as a heat pump to transfer heat from the condenser to the evaporator. This paper analyses the heat and mass transfer processes in the lyophilizer in an effort to understand the ice formation behavior in the condenser. The analysis is supported by experimental observations of ice formation patterns in two different condenser units.
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Molecular Mechanisms of Hormone-Refractory Prostate Cancer
2005-02-01
Helsinki, Finland Bmx/Etk, a member of the Tec/ Btk family of nonrecep- signals that lead to the regulation of cell motility (reviewed in tor kinases...member of the with anti-Cas antibodies. Tec/ Btk family of tyrosine kinases (37). In addition to the SH2, In vitro immunocomplex kinase assays were...which corre- MgC12). The immunoprecipitates were equally divided and resuspendedon in 18 g1 of kinase buffer with or without 1 tM Src inhibitor SU6656
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NASA Astrophysics Data System (ADS)
Miettinen, O.; Smolčić, V.; Novak, M.; Aravena, M.; Karim, A.; Masters, D.; Riechers, D. A.; Bussmann, R. S.; McCracken, H. J.; Ilbert, O.; Bertoldi, F.; Capak, P.; Feruglio, C.; Halliday, C.; Kartaltepe, J. S.; Navarrete, F.; Salvato, M.; Sanders, D.; Schinnerer, E.; Sheth, K.
2015-05-01
We used the Plateau de Bure Interferometer (PdBI) to map a sample of 15 submillimetre galaxies (SMGs) in the COSMOS field at the wavelength of 1.3 mm. The target SMGs were originally discovered in the James Clerk Maxwell Telescope (JCMT)/AzTEC 1.1 mm continuum survey at S/N1.1 mm = 4-4.5. This paper presents, for the first time, interferometric millimetre-wavelength observations of these sources. The angular resolution of our observations, 1''&dotbelow;8, allowed us to accurately determine the positions of the target SMGs. Using a detection threshold of S/N1.3 mm> 4.5 regardless of multiwavelength counterpart association, and 4
TEC19. Three of our detected SMGs (AzTEC21, 27, and 28; which corresponds to 20%) are marginally resolved at our angular resolution, and these sources are found to have elongated or clumpy morphologies and/or multiple components. Using optical to near-infrared photometric redshifts, available spectroscopic redshifts, and redshifts estimated from the radio-to-submm spectral index we infer a median redshift of tilde{z}= 3.20 ± 0.25 for our sample. To study the overall multiplicity and redshift distribution of flux-limited samples of SMGs we combined these sources with the 15 brightest JCMT/AzTEC SMGs detected at 1.1 mm, AzTEC1-15, and studied previously. This constitutes a complete, flux- and S/N-limited 1.1-mm selected sample. We find that the median redshift for the 15 brightest JCMT/AzTEC SMGs (tilde{z}= 3.05 ± 0.44) is consistent with that for AzTEC16-30. This conforms to recent observational findings that SMGs do not exhibit any significant trend between the redshift and (sub)mm flux density. For the combined AzTEC1-30 sample we derive a median redshift of tilde{z}= 3.17 ± 0.27, consistent with previous results based on mm -
NASA Astrophysics Data System (ADS)
Bhuyan, Pradip Kumar; Hazarika, Rumajyoti
2013-10-01
Total electron content (TEC) data obtained from GPS dual frequency measurements during the ascending half of the solar cycle 24 from 2009 to 2012 over Dibrugarh (27.5°N, 94.9°E; 17.6°N MLAT) have been used to study the diurnal, seasonal, annual and solar cycle variation of TEC. The measurements reported here are for the first time from the location situated at the poleward edge of the northern equatorial ionization anomaly (EIA) and within the peak region of the longitudinal wave number 4 (WN4) structure in EIA crest TEC. TEC exhibits a minimum around 0600 LT and diurnal maximum around 1300-1600 LT. In the low and moderate solar activity years 2009-2010 and 2010-2011, average daytime (1000-1600 LT) TEC in summer was higher (25.4 and 36.6 TECU) compared to that in winter (21.5 and 26.1 TECU). However, at the peak of the solar cycle in 2011-2012, reversal in the level of ionization between winter and summer takes place and winter TEC becomes higher (50.6 TECU) than that in summer (45.0 TECU). Further, TEC in spring (34.1, 49.9 and 63.3 TECU respectively in 2009-10, 2010-11 and 2011-12) is higher than that in autumn (24.2, 32.3 and 51.9 TECU respectively) thus showing equinoctial asymmetry in all the years of observation. The winter anomaly in high solar activity years and equinoctial asymmetry all throughout may be largely attributed to changes in the thermospheric O/N2 density ratio. A winter to summer delay of ˜1 h in the time of occurrence of the diurnal maximum has also been observed. Daytime maximum TEC bears a nonlinear relationship with F10.7 cm solar flux. TEC increases linearly with F10.7 cm solar flux initially up to about 140 sfu (1 sfu = 10-22 W m-2 Hz-1) after which it tends to saturate. On the contrary, TEC increases linearly with solar EUV flux (photons cm-2 s-1, 0.5-50 nm) during the same period. TEC predicted by the IRI 2012 are lower than the measured TEC for nearly 90% of the time.
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NASA Astrophysics Data System (ADS)
Shah, Munawar; Jin, Shuanggen
2015-12-01
Pre-earthquake ionospheric anomalies are still challenging and unclear to obtain and understand, particularly for different earthquake magnitudes and focal depths as well as types of fault. In this paper, the seismo-ionospheric disturbances (SID) related to global earthquakes with 1492 Mw ≥ 5.0 from 1998 to 2014 are investigated using the total electron content (TEC) of GPS global ionosphere maps (GIM). Statistical analysis of 10-day TEC data before global Mw ≥ 5.0 earthquakes shows significant enhancement 5 days before an earthquake of Mw ≥ 6.0 at a 95% confidence level. Earthquakes with a focal depth of less than 60 km and Mw ≥ 6.0 are presumably the root of deviation in the ionospheric TEC because earthquake breeding zones have gigantic quantities of energy at shallower focal depths. Increased anomalous TEC is recorded in cumulative percentages beyond Mw = 5.5. Sharpness in cumulative percentages is evident in seismo-ionospheric disturbance prior to Mw ≥ 6.0 earthquakes. Seismo-ionospheric disturbances related to strike slip and thrust earthquakes are noticeable for magnitude Mw6.0-7.0 earthquakes. The relative values reveal high ratios (up to 2) and low ratios (up to -0.5) within 5 days prior to global earthquakes for positive and negative anomalies. The anomalous patterns in TEC related to earthquakes are possibly due to the coupling of high amounts of energy from earthquake breeding zones of higher magnitude and shallower focal depth.
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Effect of geomagnetic storms of different solar origin on the ionospheric TEC
NASA Astrophysics Data System (ADS)
Mansoori, Azad A.; Khan, Parvaiz A.; Purohit, P. K.
2018-05-01
We have studied the behaviour of ionospheric Total Electron Content (TEC) at a mid latitude station Usuda (36.130N, 138.360E), Japan during intense geomagnetic storms which were observed during 23 solar cycle (1998-2006). For the present study we have selected 47 intense geomagnetic storms (Dst≤-100nT), for the given period, which were then categorised into four categories depending upon their solar and interplanetary sources like Magnetic Cloud (MC), Co-rotating Interaction Region (CIR), Sheath driven Interplanetary Coronal Mass Ejection (SH+ICME) and Sheath driven Magnetic cloud (SH+MC). From our study we found that the geomagnetic storms significantly affect the ionosphere having any of the solar origin. However the geomagnetic storms which are either caused by SH+MC or SH+ICME produced maximum effect in TEC.
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Global features of ionospheric slab thickness derived from JPL TEC and COSMIC observations
NASA Astrophysics Data System (ADS)
Huang, He; Liu, Libo
2016-04-01
The ionospheric equivalent slab thickness (EST) is the ratio of total electron content (TEC) to F2-layer peak electron density (NmF2), describing the thickness of the ionospheric profile. In this study, we retrieve EST from Jet Propulsion Laboratory (JPL) TEC data and NmF2 retrieved from Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC) ionospheric radio occultation data. The diurnal, seasonal and solar activity variations of global EST are analyzed as the excellent spatial coverage of JPL TEC and COSMIC data. During solstices, daytime EST in the summer hemisphere is larger than that in the winter hemisphere, except in some high-latitude regions; and the reverse is true for the nighttime EST. The peaks of EST often appear at 0400 local time. The pre-sunrise enhancement in EST appears in all seasons, while the post-sunset enhancement in EST is not readily observed in equinox. The dependence of EST on solar activity is very complicated. Furthermore, an interesting phenomenon is found that EST is enhanced from 0° to 120° E in longitude and 30° to 75° S in latitude during nighttime, just to the east of Weddell Sea Anomaly, during equinox and southern hemisphere summer.
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V-TECS Criterion-Referenced Test Item Bank for Radiologic Technology Occupations.
ERIC Educational Resources Information Center
Reneau, Fred; And Others
This Vocational-Technical Education Consortium of States (V-TECS) criterion-referenced test item bank provides 696 multiple-choice items and 33 matching items for radiologic technology occupations. These job titles are included: radiologic technologist, chief; radiologic technologist; nuclear medicine technologist; radiation therapy technologist;…
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Comparison of plateletpheresis on the Fresenius AS.TEC 204 and Haemonetics MCS 3p.
Ranganathan, Sudha
2007-02-01
This is an attempt at comparing two cell separators for plateletpheresis, namely the Fresenius AS.TEC 204 and Haemonetics MCS 3p, at a tertiary care center in India. Donors who weighed between 55-75 kg, who had a hematocrit of 41-43%, and platelet counts of 250x10(3)-400x10(3)/microl were selected for the study. The comparability of the donors who donated on the two cell separators were analysed by t-test independent samples and no significant differences were found (P>0.05). The features compared were time taken for the procedure, volume processed on the separators, adverse reactions of the donors, quality control of the product, separation efficiency of the separators, platelet loss in the donors after the procedure, and the predictor versus the actual yield of platelets given by the cell separator. The volume processed to get a target yield of >3x10(11) was equal to 2.8-3.2 l and equal in both the cell separators. Symptoms of citrate toxicity were seen in 4 and 2.5% of donors who donated on the MCS 3p and the AS.TEC 204, respectively, and 3 and 1% of donors, respectively, had vasovagal reactions. All the platelet products collected had a platelet count of >3x10(11); 90% of the platelet products collected on the AS.TEC 204 attained the predicted yield that was set on the cell separator where as 75% of the platelet products collected on the MCS 3p attained the target yield. Quality control of the platelets collected on both the cell separators complied with the standards except that 3% of the platelets collected on the MCS 3p had a visible red cell contamination. The separation efficiency of the MCS 3p was higher, 50-52% as compared to the 40-45% on the AS.TEC 204. A provision of double venous access, less adverse reactions, negligible RBC contamination with a better predictor yield of platelets makes the AS.TEC 204 a safer and more reliable alternative than the widely used Haemonetics MCS 3p. Copyright (c) 2006 Wiley-Liss, Inc.
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Estimation of total electron content (TEC) using spaceborne GPS measurements
NASA Astrophysics Data System (ADS)
Choi, Key-Rok; Lightsey, E. Glenn
2008-09-01
TerraSAR-X (TSX), a high-resolution interferometric Synthetic Aperture Radar (SAR) mission from DLR (German Aerospace Center, Deutsches Zentrum für Luft-und Raumfahrt), was successfully launched into orbit on June 15, 2007. It includes a dual-frequency GPS receiver called IGOR (Integrated GPS Occultation Receiver), which is a heritage NASA/JPL BlackJack receiver. The software for the TSX IGOR receiver was specially-modified software developed at UT/CSR. This software was upgraded to provide enhanced occultation capabilities. This paper describes total electron content (TEC) estimation using simulation data and onboard GPS data of TerraSAR-X. The simulated GPS data were collected using the IGOR Engineering Model (EM) in the laboratory and the onboard GPS data were collected from the IGOR Flight Model (FM) on TSX. To estimate vertical total electron content (vTEC) for the simulation data, inter-frequency biases (IFB) were estimated using the "carrier to code leveling process." For the onboard GPS data, IFBs of GPS satellites were retrieved from the navigation message and applied to the measurements.
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NASA Astrophysics Data System (ADS)
Rakoto, V.; Lognonne, P. H.; Rolland, L. M.
2015-12-01
Large earthquakes (i.eM>6) and tsunamis associated are responsible for ionospheric perturbations. These perturbations can be observed in the total electron content (TEC) measured from multi- frequency Global Navigation Satellite systems (GNSS) data (e.g GPS). We will focus on the studies of the Haïda Gwaii earthquake and tsunami case. It happened the 28 october 2012 along the Queen Charlotte fault of the Canada Western Coast. First, we compare GPS data of perturbation TEC to our model. We model the TEC perturbation in several steps. (1) First, we compute tsunami normal modes modes in atmosphere in using PREM model with 4.7km of oceanic layer. (2) We sum all the tsunami modes to obtain the neutral displacement. (3) We couple the ionosphere with the neutral atmosphere. (4) We integrate the perturbed electron density along each satellite station line of sight. At last, we present first results of TEC inversion in order to retrieve the waveform of the tsunami. This inversion has been done on synthetics data assuming Queen Charlotte Earthquake and Tsunami can be considered as a point source in far field.
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Wide extragalactic (sub-)millimeter surveys with SCUBA and AzTEC
NASA Astrophysics Data System (ADS)
Aretxaga, I.; Hughes, D. H.; SHADES Collaboration; AzTEC Collaboration
2009-05-01
We summarize the present status of our knowledge of the millimeter galaxy population derived from extensive (sub-) millimeter extragalactic surveys like the SCUBA HAlf Degree Survey (SHADES), and the current status of the next generation of surveys traced with the AzTEC camera, that has, so far, surveyed more than 2 degrees at 1.1wavelengths.
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NASA Astrophysics Data System (ADS)
Barros, Diego; Takahashi, Hisao; Wrasse, Cristiano M.; Figueiredo, Cosme Alexandre O. B.
2018-01-01
A ground-based network of GNSS receivers has been used to monitor equatorial plasma bubbles (EPBs) by mapping the total electron content (TEC map). The large coverage of the TEC map allowed us to monitor several EPBs simultaneously and get characteristics of the dynamics, extension and longitudinal distributions of the EPBs from the onset time until their disappearance. These characteristics were obtained by using TEC map analysis and the keogram technique. TEC map databases analyzed were for the period between November 2012 and January 2016. The zonal drift velocities of the EPBs showed a clear latitudinal gradient varying from 123 m s-1 at the Equator to 65 m s-1 for 35° S latitude. Consequently, observed EPBs are inclined against the geomagnetic field lines. Both zonal drift velocity and the inclination of the EPBs were compared to the thermospheric neutral wind, which showed good agreement. Moreover, the large two-dimensional coverage of TEC maps allowed us to study periodic EPBs with a wide longitudinal distance. The averaged values observed for the inter-bubble distances also presented a clear latitudinal gradient varying from 920 km at the Equator to 640 km at 30° S. The latitudinal gradient in the inter-bubble distances seems to be related to the difference in the zonal drift velocity of the EPB from the Equator to middle latitudes and to the difference in the westward movement of the terminator. On several occasions, the distances reached more than 2000 km. Inter-bubble distances greater than 1000 km have not been reported in the literature.
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Momin, Mohamed; Xin, Yao; Hamelberg, Donald
2017-06-29
Although the regulation of function of proteins by allosteric interactions has been identified in many subcellular processes, molecular switches are also known to induce long-range conformational changes in proteins. A less well understood molecular switch involving cis-trans isomerization of a peptidyl-prolyl bond could induce a conformational change directly to the backbone that is propagated to other parts of the protein. However, these switches are elusive and hard to identify because they are intrinsic to biomolecules that are inherently dynamic. Here, we explore the conformational dynamics and free energy landscape of the SH2 domain of interleukin-2-inducible T-cell or tyrosine kinase (ITK) to fully understand the conformational coupling between the distal cis-trans molecular switch and its binding pocket of the phosphotyrosine motif. We use multiple microsecond-long all-atom molecular dynamics simulations in explicit water for over a total of 60 μs. We show that cis-trans isomerization of the Asn286-Pro287 peptidyl-prolyl bond is directly coupled to the dynamics of the binding pocket of the phosphotyrosine motif, in agreement with previous NMR experiments. Unlike the cis state that is localized and less dynamic in a single free energy basin, the trans state samples two distinct conformations of the binding pocket-one that recognizes the phosphotyrosine motif and the other that is somewhat similar to that of the cis state. The results provide an atomic-level description of a less well understood allosteric regulation by a peptidyl-prolyl cis-trans molecular switch that could aid in the understanding of normal and aberrant subcellular processes and the identification of these elusive molecular switches in other proteins.
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NASA Astrophysics Data System (ADS)
Kakoti, Geetashree; Bhuyan, Pradip Kumar; Hazarika, Rumajyoti
2017-07-01
TEC measured at Dibrugarh (27.5°N, 94.9°E, 17.5°N Geomag.) from 2009 to 2014 is used to study its temporal characteristics during the ascending half of solar cycle 24. The measurements provide an opportunity to assess the diurnal, seasonal and longterm predictability of the IRI 2012 (with IRI Nequick, IRI01-corr, IRI 2001topside options) during this solar cycle which is distinctively low in magnitude compared to the previous cycles. The low latitude station Dibrugarh is normally located at the poleward edge of the northern EIA. A semi-annual variation in GPS TEC is observed with the peaks occurring in the equinoxes. The peak in spring (March, April) is higher than that in autumn (September, October) irrespective of the year of observation. The spring autumn asymmetry is also observed in IRI TEC. In contrast, the winter (November, December, January, February) anomaly is evident only in high activity years. TEC bears a distinct nonlinear relationship with 10.7 cm solar flux (F10.7). TEC increases linearly with F10.7 up to about 125 sfu beyond which it tends to saturate. The correlation between TEC and solar flux is found to be a function of local time and peaks at 10:00 LT. TEC varies nonlinearly with solar EUV flux similar to its variation with F10.7. The nonlinearity is well captured by the IRI. The saturation of TEC at high solar activity is attributed to the inability of the ionosphere to accommodate more ionization after it reaches the level of saturation ion pressure. Annual mean TEC increased from the minimum in 2009 almost linearly till 2012, remains at the same level in 2013 and then increased again in 2014. IRI TEC shows a linear increase from 2009 to 2014. IRI01-corr and IRI-NeQuick TEC are nearly equal at all local times, season and year of observation while IRI-2001 simulated TEC are always higher than that simulated by the other two versions. The IRI 2012 underestimates the TEC at about all local times except for a few hours in the midday in all
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Study of TEC and foF2 with the Help of GPS and Ionosonde Data over Maitri, Antarctica
NASA Astrophysics Data System (ADS)
Khatarkar, Prakash; Gwal, Ashok Kumar
Prakash Khatarkar, Purusottam Bhaware, Azad Ahmad Mansoori, Varsha Kachneria, Shweta Thakur, and A. K. Gwal Abstract The behavior of ionosphere can be diagnosed by a number of techniques. The common techniques used are the space based Global Positioning System and the ground based Ionosonde. We have compared the variability of ionospheric parameters by using two different techniques GPS and Ionosonde, during December 2009 to November 2010 at the Indian base station Maitri (11.45E, 70.45S). The comparison between the measurements of two techniques was realized through the Total Electron Content (TEC) parameters derived by using different methods. The comparison was made diurnally, seasonally, polar day and polar night variations and the annually. From our analysis we found that a strong correlation exists between the GPS derived TEC and Ionosonde derived foF2 during the day period while during the night time the correlation is insignificant. At the same time we found that a strong correlation exists between the Ionosonde and GPS derived TEC. The pattern of variation of ionospheric parameters derived from two techniques is strikingly similar indicating that the high degree of synchronization between them. This has a practical applicability by allowing calculating the error in one technique by comparing with other. Keywords: Ionosphere, Ionosonde, GPS, foF2, TEC.
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Radio Identification of Millimeter-Bright Galaxies Detected in the AzTEC/ASTE Blank Field Survey
NASA Astrophysics Data System (ADS)
Hatsukade, Bunyo; Kohno, Kotaro; White, Glenn; Matsuura, Shuji; Hanami, Hitoshi; Shirahata, Mai; Nakanishi, Kouichiro; Hughes, David; Tamura, Yoichi; Iono, Daisuke; Wilson, Grant; Yun, Min
2008-10-01
We propose a deep 1.4-GHz imaging of millimeter-bright sources in the AzTEC/ASTE 1.1-mm blank field survey of AKARI Deep Field-South. The AzTEC/ASTE uncovered 37 sources, which are possibly at z > 2. We have obtained multi-wavelength data in this field, but the large beam size of AzTEC/ASTE (30 arcsec) prevents us from identifying counterparts. The aim of this proposal is to identify radio counterparts with higher-angular resolution. This enables us (i) To identifying optical/IR counterparts. It enables optical spectroscopy to determine precise redshifts, allowing us to derive SFRs, luminosity functions, clustering properties, mass of dark matter halos, etc. (ii) To constrain luminosity evolutions of SMGs by comparing of 1.4-GHz number counts (and luminosity functions) with luminosity evolution models. (iii) To estimate photometric redshifts from 1.4-GHz and 1.1-mm data using the radio-FIR flux correlation. In case of non-detection, we can put deep lower limits (3 sigma limit of z > 3). These information lead to the study of evolutionary history of SMGs, their relationship with other galaxy populations, contribution to the cosmic star formation history and the infrared background.
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NASA Astrophysics Data System (ADS)
Ahmed Ismail, Nouf Abd Emunim; Abdullah, Mardina; Hasbi, Alina Marie
2016-07-01
Total Electron Content (TEC) is the main parameter in the ionosphere that has significant effects on radio wave; it changes the speed and direction of the signal propagation, causing the delay of the Global Positioning System (GPS) signals. Therefore, it is crucial to validate the performance of the ionospheric model to reveal the variety of ionospheric behaviour during quiet and disturbed period. This research presents the performance evaluation of the statistical Holt-Winter method and IRI-2012 model using three topside electron density options: IRI-2001, IRI01-corr and NeQuick with the observed GPS-TEC during quiet and disturbed period. The GPS-TEC data were derived from the dual frequency GPS receiver at JUPEM (Department of Survey and Mapping Malaysia), from the UUMK station (north Peninsular Malaysia) at geographic coordinates of 6.46°N-100.50°E and geomagnetic coordinates of 3.32°S-172.99°E and TGPG station (south Peninsular Malaysia) at geographic coordinates of 1.36°N-104.10°E and geomagnetic coordinates of 8.43°S -176.53°E, during March of 2013. The maximum value of the GPS-TEC was at the post noon time at 17:00 LT and the minimum was in the early morning from 6:00-7:00 LT. During the quiet period, the maximum GPS-TEC at the UUMK station was 52 TECU while at the TGPG station, it was 60 TECU. During the disturbed period, when intense geomagnetic storm occurred on 17 March 2013, the maximum GPS-TEC recorded was 58 TECU and 65 TECU in UUMK and TGPG station, respectively. The diurnal hourly variation during the quiet period indicated that IRI-2001, IRI01-corr, and NeQuick had overestimation agreement during the day hours except for the time between 11:00-19:00 LT when IRI01-corr and NeQuick showed underestimation, while during 13:00-20:00 LT, IRI-2001 showed slight underestimation whereas the Holt-Winter method showed good agreement with GPS-TEC. During the disturbed period, IRI-2001 showed overestimation agreement for all hours, while the IRI01-corr
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Cao, Lulu; Ding, Yiyuan; Hung, Norris; Yu, Kebing; Ritz, Anna; Raphael, Benjamin J.; Salomon, Arthur R.
2012-01-01
The SH2-domain-containing leukocyte protein of 76 kDa (SLP-76) plays a critical scaffolding role in T cell receptor (TCR) signaling. As an adaptor protein that contains multiple protein-binding domains, SLP-76 interacts with many signaling molecules and links proximal receptor stimulation to downstream effectors. The function of SLP-76 in TCR signaling has been widely studied using the Jurkat human leukaemic T cell line through protein disruption or site-directed mutagenesis. However, a wide-scale characterization of SLP-76-dependant phosphorylation events is still lacking. Quantitative profiling of over a hundred tyrosine phosphorylation sites revealed new modes of regulation of phosphorylation of PAG, PI3K, and WASP while reconfirming previously established regulation of Itk, PLCγ, and Erk phosphorylation by SLP-76. The absence of SLP-76 also perturbed the phosphorylation of Src family kinases (SFKs) Lck and Fyn, and subsequently a large number of SFK-regulated signaling molecules. Altogether our data suggests unique modes of regulation of positive and negative feedback pathways in T cells by SLP-76, reconfirming its central role in the pathway. PMID:23071622
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Cao, Lulu; Ding, Yiyuan; Hung, Norris; Yu, Kebing; Ritz, Anna; Raphael, Benjamin J; Salomon, Arthur R
2012-01-01
The SH2-domain-containing leukocyte protein of 76 kDa (SLP-76) plays a critical scaffolding role in T cell receptor (TCR) signaling. As an adaptor protein that contains multiple protein-binding domains, SLP-76 interacts with many signaling molecules and links proximal receptor stimulation to downstream effectors. The function of SLP-76 in TCR signaling has been widely studied using the Jurkat human leukaemic T cell line through protein disruption or site-directed mutagenesis. However, a wide-scale characterization of SLP-76-dependant phosphorylation events is still lacking. Quantitative profiling of over a hundred tyrosine phosphorylation sites revealed new modes of regulation of phosphorylation of PAG, PI3K, and WASP while reconfirming previously established regulation of Itk, PLCγ, and Erk phosphorylation by SLP-76. The absence of SLP-76 also perturbed the phosphorylation of Src family kinases (SFKs) Lck and Fyn, and subsequently a large number of SFK-regulated signaling molecules. Altogether our data suggests unique modes of regulation of positive and negative feedback pathways in T cells by SLP-76, reconfirming its central role in the pathway.
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Yoo, Terry S; Ackerman, Michael J; Lorensen, William E; Schroeder, Will; Chalana, Vikram; Aylward, Stephen; Metaxas, Dimitris; Whitaker, Ross
2002-01-01
We present the detailed planning and execution of the Insight Toolkit (ITK), an application programmers interface (API) for the segmentation and registration of medical image data. This public resource has been developed through the NLM Visible Human Project, and is in beta test as an open-source software offering under cost-free licensing. The toolkit concentrates on 3D medical data segmentation and registration algorithms, multimodal and multiresolution capabilities, and portable platform independent support for Windows, Linux/Unix systems. This toolkit was built using current practices in software engineering. Specifically, we embraced the concept of generic programming during the development of these tools, working extensively with C++ templates and the freedom and flexibility they allow. Software development tools for distributed consortium-based code development have been created and are also publicly available. We discuss our assumptions, design decisions, and some lessons learned.
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THE REDSHIFT AND NATURE OF AzTEC/COSMOS 1: A STARBURST GALAXY AT z = 4.6
DOE Office of Scientific and Technical Information (OSTI.GOV)
Smolcic, V.; Capak, P.; Blain, A. W.
2011-04-20
Based on broadband/narrowband photometry and Keck DEIMOS spectroscopy, we report a redshift of z = 4.64{sup +0.06}{sub -0.08} for AzTEC/COSMOS 1, the brightest submillimeter galaxy (SMG) in the AzTEC/COSMOS field. In addition to the COSMOS-survey X-ray to radio data, we report observations of the source with Herschel/PACS (100, 160 {mu}m), CSO/SHARC II (350 {mu}m), and CARMA and PdBI (3 mm). We do not detect CO(5 {yields} 4) line emission in the covered redshift ranges, 4.56-4.76 (PdBI/CARMA) and 4.94-5.02 (CARMA). If the line is within this bandwidth, this sets 3{sigma} upper limits on the gas mass to {approx}<8 x 10{sup 9}more » M{sub sun} and {approx}<5 x 10{sup 10} M{sub sun}, respectively (assuming similar conditions as observed in z {approx} 2 SMGs). This could be explained by a low CO-excitation in the source. Our analysis of the UV-IR spectral energy distribution of AzTEC 1 shows that it is an extremely young ({approx}<50 Myr), massive (M{sub *} {approx} 10{sup 11} M{sub sun}), but compact ({approx}<2 kpc) galaxy, forming stars at a rate of {approx}1300 M{sub sun} yr{sup -1}. Our results imply that AzTEC 1 is forming stars in a 'gravitationally bound' regime in which gravity prohibits the formation of a superwind, leading to matter accumulation within the galaxy and further generations of star formation.« less
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NASA Astrophysics Data System (ADS)
Arikan, Feza; Gulyaeva, Tamara; Sezen, Umut; Arikan, Orhan; Toker, Cenk; Hakan Tuna, MR.; Erdem, Esra
2016-07-01
International Reference Ionosphere is the most acknowledged climatic model of ionosphere that provides electron density profile and hourly, monthly median values of critical layer parameters of the ionosphere for a desired location, date and time between 60 to 2,000 km altitude. IRI is also accepted as the International Standard Ionosphere model. Recently, the IRI model is extended to the Global Positioning System (GPS) satellite orbital range of 20,000 km. The new version is called IRI-Plas and it can be obtained from http://ftp.izmiran.ru/pub/izmiran /SPIM/. A user-friendly online version is also provided at www.ionolab.org as a space weather service. Total Electron Content (TEC), which is defined as the line integral of electron density on a given ray path, is an observable parameter that can be estimated from earth based GPS receivers in a cost-effective manner as GPS-TEC. One of the most important advantages of IRI-Plas is the possible input of GPS-TEC to update the background deterministic ionospheric model to the current ionospheric state. This option is highly useful in regional and global tomography studies and HF link assessments. IONOLAB group currently implements IRI-Plas as a background model and updates the ionospheric state using GPS-TEC in IONOLAB-CIT and IONOLAB-RAY algorithms. The improved state of ionosphere allows the most reliable 4-D imaging of electron density profiles and HF and satellite communication link simulations.This study is supported by TUBITAK 115E915 and joint TUBITAK 114E092 and AS CR 14/001.
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Real time validation of GPS TEC precursor mask for Greece
NASA Astrophysics Data System (ADS)
Pulinets, Sergey; Davidenko, Dmitry
2013-04-01
It was established by earlier studies of pre-earthquake ionospheric variations that for every specific site these variations manifest definite stability in their temporal behavior within the time interval few days before the seismic shock. This self-similarity (characteristic to phenomena registered for processes observed close to critical point of the system) permits us to consider these variations as a good candidate to short-term precursor. Physical mechanism of GPS TEC variations before earthquakes is developed within the framework of Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) model. Taking into account the different tectonic structure and different source mechanisms of earthquakes in different regions of the globe, every site has its individual behavior in pre-earthquake activity what creates individual "imprint" on the ionosphere behavior at every given point. Just this so called "mask" of the ionosphere variability before earthquake in the given point creates opportunity to detect anomalous behavior of electron concentration in ionosphere basing not only on statistical processing procedure but applying the pattern recognition technique what facilitates the automatic recognition of short-term ionospheric precursors of earthquakes. Such kind of precursor mask was created using the GPS TEC variation around the time of 9 earthquakes with magnitude from M6.0 till M6.9 which took place in Greece within the time interval 2006-2011. The major anomaly revealed in the relative deviation of the vertical TEC was the positive anomaly appearing at ~04PM UT one day before the seismic shock and lasting nearly 12 hours till ~04AM UT. To validate this approach it was decided to check the mask in real-time monitoring of earthquakes in Greece starting from the 1 of December 2012 for the earthquakes with magnitude more than 4.5. During this period (till 9 of January 2013) 4 cases of seismic shocks were registered, including the largest one M5.7 on 8 of January. For all of
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Ibrutinib treatment improves T cell number and function in CLL patients
Long, Meixiao; Do, Priscilla; Mundy, Bethany L.; Gordon, Amber; Lehman, Amy M.; Maddocks, Kami J.; Cheney, Carolyn; Jones, Jeffrey A.; Flynn, Joseph M.; Andritsos, Leslie A.; Fraietta, Joseph A.; June, Carl H.; Maus, Marcela V.; Woyach, Jennifer A.; Caligiuri, Michael A.; Johnson, Amy J.
2017-01-01
BACKGROUND. Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton’s tyrosine kinase (BTK) and IL-2–inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. FUNDING. The National Cancer Institute. PMID:28714866
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Ibrutinib treatment improves T cell number and function in CLL patients.
Long, Meixiao; Beckwith, Kyle; Do, Priscilla; Mundy, Bethany L; Gordon, Amber; Lehman, Amy M; Maddocks, Kami J; Cheney, Carolyn; Jones, Jeffrey A; Flynn, Joseph M; Andritsos, Leslie A; Awan, Farrukh; Fraietta, Joseph A; June, Carl H; Maus, Marcela V; Woyach, Jennifer A; Caligiuri, Michael A; Johnson, Amy J; Muthusamy, Natarajan; Byrd, John C
2017-08-01
Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. The National Cancer Institute.
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NASA Astrophysics Data System (ADS)
Adebiyi, S. J.; Adebesin, B. O.; Ikubanni, S. O.; Joshua, B. W.
2017-05-01
Empirical models of the ionosphere, such as the International Reference Ionosphere (IRI) model, play a vital role in evaluating the environmental effect on the operation of space-based communication and navigation technologies. The IRI extended to Plasmasphere (IRI-Plas) model can be adjusted with external data to update its electron density profile while still maintaining the overall integrity of the model representations. In this paper, the performance of the total electron content (TEC) assimilation option of the IRI-Plas at two equatorial stations, Jicamarca, Peru (geographic: 12°S, 77°W, dip angle 0.8°) and Cachoeira Paulista, Brazil (Geographic: 22.7°S, 45°W, dip angle -26°), is examined during quiet and disturbed conditions. TEC, F2 layer critical frequency (foF2), and peak height (hmF2) predicted when the model is operated without external input were used as a baseline in our model evaluation. Results indicate that TEC predicted by the assimilation option generally produced smaller estimation errors compared to the "no extra input" option during quiet and disturbed conditions. Generally, the error is smaller at the equatorial trough than near the crest for both quiet and disturbed days. With assimilation option, there is a substantial improvement of storm time estimations when compared with quiet time predictions. The improvement is, however, independent on storm's severity. Furthermore, the modeled foF2 and hmF2 are generally poor with TEC assimilation, particularly the hmF2 prediction, at the two locations during both quiet and disturbed conditions. Consequently, IRI-Plas model assimilated with TEC value only may not be sufficient where more realistic instantaneous values of peak parameters are required.
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NASA Astrophysics Data System (ADS)
Contadakis, M. E.; Arabelos, D. N.; Vergos, G.
2012-04-01
In this paper the Total Electron Content (TEC) data of 8 Global Positioning System (GPS) stations of the EUREF network, 4 close and 4 remote to EQ epicentre stations, which are being provided by IONOLAB (Turkey), were analysed using wavelet analysis and Discrete Fourier Analysis in order to investigate the TEC variations over North-western Balkan Peninsula before and during the seismic activity of 24th of May, 2009. The main conclusions of this analysis are the following. (a) TEC oscillations in a broad range of frequencies occur randomly over a broad area of several hundred km from the earthquake and (b) high frequency oscillations (f ≥ 0.0003Hz, periods T ≤ 60m) seems to point to the location of the earthquake with a questionable accuracy but the fractal characteristics of the frequencies distribution, points to the locus of the earthquake with a rather higher accuracy. We conclude that the LAIC mechanism through acoustic or gravity wave could explain this phenomenology.
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Measuring Ionospheric Irregularities Globally by the Rate of TEC Index and GNSS Networks
NASA Technical Reports Server (NTRS)
Pi, Xiaoqing
2012-01-01
Outline of presentation: Why do we use the rate of TEC index (ROTI) instead of the standard s4 and sigma-phi indices? What are the differences between S4, sigma-phi and ROTI? Examples of ROTI measurements and Development status and plan.
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NASA Astrophysics Data System (ADS)
Pattisahusiwa, Asis; Houw Liong, The; Purqon, Acep
2016-08-01
In this study, we compare two learning mechanisms: outliers and novelty detection in order to detect ionospheric TEC disturbance by November 2004 geomagnetic storm and January 2005 substorm. The mechanisms are applied by using v-SVR learning algorithm which is a regression version of SVM. Our results show that both mechanisms are quiet accurate in learning TEC data. However, novelty detection is more accurate than outliers detection in extracting anomalies related to geomagnetic events. The detected anomalies by outliers detection are mostly related to trend of data, while novelty detection are associated to geomagnetic events. Novelty detection also shows evidence of LSTID during geomagnetic events.
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NASA Astrophysics Data System (ADS)
Tsagouri, Ioanna; Belehaki, Anna; Elias, Panagiotis
2017-04-01
This paper builts the discussion on the comparative analysis of the variations in the peak electron density at F2 layer and the TEC parameter during a significant number of geomagnetic storm events that occurred in the present solar cycle 24. The ionospheric disturbances are determined through the comparison of actual observations of the foF2 critical frequency and GPS-TEC estimates obtained over European locations with the corresponding median estimates, and they are analysed in conjunction to the solar wind conditions at L1 point that are monitored by the ACE spacecraft. The quantification of the storm impact on the TEC parameter in terms of possible limitations introduced by different TEC derivation methods is carefully addressed.The results reveal similarities and differences in the response of the two parameters with respect to the solar wind drivers of the storms, as well as the local time and the latitude of the observation point. The aforementioned dependences drive the storm-time forecasts of the SWIF model (Solar Wind driven autorgressive model for Ionospheric short-term Forecast), which is operationally implemented in the DIAS system (http://dias.space.noa.gr) and extensively tested in performance at several occassions. In its present version, the model provides alerts and warnings for upcoming ionospheric disturbances, as well as single site and regional forecasts of the foF2 characteristic over Europe up to 24 hours ahead based on the assesment of the solar wind conditions at ACE location. In that respect, the results obtained above support the upgrade of the SWIF's modeling technique in forecasting the storm-time TEC variation within an operational environment several hours in advance. Preliminary results on the evaluation of the model's efficiency in TEC prediction are also discussed, giving special attention in the assesment of the capabilities through the TEC-derivation uncertanties for future discussions.
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NASA Astrophysics Data System (ADS)
Sur, D.; Haldar, S.; Ray, S.; Paul, A.
2017-07-01
The perturbations imposed on transionospheric signals by the ionosphere are a major concern for navigation. The dynamic nature of the ionosphere in the low-latitude equatorial region and the Indian longitude sector has some specific characteristics such as sharp temporal and latitudinal variation of total electron content (TEC). TEC in the Indian longitude sector also undergoes seasonal variations. The large magnitude and sharp variation of TEC cause large and variable range errors for satellite-based navigation system such as Global Positioning System (GPS) throughout the day. For accurate navigation using satellite-based augmentation systems, proper prediction of TEC under certain geophysical conditions is necessary in the equatorial region. It has been reported in the literature that prediction accuracy of TEC has been improved using measured data-driven artificial neural network (ANN)-based vertical TEC (VTEC) models, compared to standard ionospheric models. A set of observations carried out in the Indian longitude sector have been reported in this paper in order to find the amount of improvement in performance accuracy of an ANN-based VTEC model after incorporation of neutral wind as model input. The variations of this improvement in prediction accuracy with respect to latitude, longitude, season, and solar activity have also been reported in this paper.
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NASA Astrophysics Data System (ADS)
Panda, S. K.; Gedam, S. S.; Rajaram, G.
2015-04-01
The present study investigates variation of the ionospheric total electron content (TEC) in the low latitude Indian sub-continental region from the GPS observations and its comparison with the global ionosphere maps (GIMs), standard international reference ionosphere (IRI 2012), and the standard plasmasphere-ionosphere model (SPIM) for the period from November 2011 to October 2012 that corresponds to the progressive phase towards the midst of the solar cycle-24. Observations during quiet period show diurnal maximum of TEC occurring around 14:00-16:00 IST, with relatively broader and longer duration of local maximum at Bangalore and behave reversely towards Delhi. The secondary maximum of TEC was markedly noticeable at Bangalore during the months of March and September, and only in the month of September at Hyderabad and Mumbai. However, the relatively higher TEC during December month than the June is ascribed to the winter anomaly which is more prevalent during the high solar activity periods. The prevailing instability in latitudes of anomaly crest during January 2012 is possibly due to the seasonal variation of lunar tidal effects, modulating the EEJ strength at the equator. The studies covered the period of a strong geomagnetic storm during 6-11 March 2012 (SYM-H: -149 nT) which resulted in positive deviation of GPS-TEC at Bangalore (↑ 20%), Hyderabad (↑ 22%), and Lucknow (↑ 94%) compared to the mean quiet days level. The relatively large deviation of TEC at Lucknow could be attributed to the poleward shifting of the anomaly crest, manifested by enhanced fountain effect at the equator. Studies confirm excellent agreement (80-85%) of GPS-TEC with IGS-GIM at Bangalore and Hyderabad with the exception of the night-time hours (Deviations >50%). However relatively larger deviation of GPS-TEC from GIM-TEC at Delhi could be due to the unavailability of IGS stations in the proximity of the position. Predictions of the SPIM model (extension of IRI up to GPS
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3D tomography of midlatitude sporadic-E in Japan from GNSS-TEC data
NASA Astrophysics Data System (ADS)
Muafiry, Ihsan Naufal; Heki, Kosuke; Maeda, Jun
2018-03-01
We studied ionospheric irregularities caused by midlatitude sporadic-E ( Es) in Japan using ionospheric total electron content (TEC) data from a dense GNSS array, GEONET, with a 3D (three-dimensional) tomography technique. Es is a thin layer of unusually high ionization that appears at altitudes of 100 km. Here, we studied five cases of Es irregularities in 2010 and 2012, also reported in previous studies, over the Kanto and Kyushu Districts. We used slant TEC residuals as the input and estimated the number of electron density anomalies of more than 2000 small blocks with dimensions of 20-30 km covering a horizontal region of 300 × 500 km. We applied a continuity constraint to stabilize the solution and performed several different resolution tests with synthetic data to assess the accuracy of the results. The tomography results showed that positive electron density anomalies occurred at the E region height, and the morphology and dynamics were consistent with those reported by earlier studies.
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Improving Science Teacher Preparation through the APS PhysTEC and NSF Noyce Programs
NASA Astrophysics Data System (ADS)
Williams, Tasha; Tyler, Micheal; van Duzor, Andrea; Sabella, Mel
2013-03-01
Central to the recruitment of students into science teaching at a school like CSU, is a focus on the professional nature of teaching. The purpose of this focus is twofold: it serves to change student perceptions about teaching and it prepares students to become teachers who value continued professional development and value the science education research literature. The Noyce and PhysTEC programs at CSU place the professional nature of teaching front and center by involving students in education research projects, paid internships, attendance at conferences, and participation in a new Teacher Immersion Institute and a Science Education Journal Reading Class. This poster will focus on specific components of our teacher preparation program that were developed through these two programs. In addition we will describe how these new components provide students with diverse experiences in the teaching of science to students in the urban school district. Supported by the NSF Noyce Program (0833251) and the APS PhysTEC Program.
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NASA Astrophysics Data System (ADS)
Zettergren, M. D.; Snively, J. B.; Inchin, P.; Komjathy, A.; Verkhoglyadova, O. P.
2017-12-01
Ocean and solid earth responses during earthquakes are a significant source of large amplitude acoustic and gravity waves (AGWs) that perturb the overlying ionosphere-thermosphere (IT) system. IT disturbances are routinely detected following large earthquakes (M > 7.0) via GPS total electron content (TEC) observations, which often show acoustic wave ( 3-4 min periods) and gravity wave ( 10-15 min) signatures with amplitudes of 0.05-2 TECU. In cases of very large earthquakes (M > 8.0) the persisting acoustic waves are estimated to have 100-200 m/s compressional velocities in the conducting ionospheric E and F-regions and should generate significant dynamo currents and magnetic field signatures. Indeed, some recent reports (e.g. Hao et al, 2013, JGR, 118, 6) show evidence for magnetic fluctuations, which appear to be related to AGWs, following recent large earthquakes. However, very little quantitative information is available on: (1) the detailed spatial and temporal dependence of these magnetic fluctuations, which are usually observed at a small number of irregularly arranged stations, and (2) the relation of these signatures to TEC perturbations in terms of relative amplitudes, frequency, and timing for different events. This work investigates space- and time-dependent behavior of both TEC and magnetic fluctuations following recent large earthquakes, with the aim to improve physical understanding of these perturbations via detailed, high-resolution, two- and three-dimensional modeling case studies with a coupled neutral atmospheric and ionospheric model, MAGIC-GEMINI (Zettergren and Snively, 2015, JGR, 120, 9). We focus on cases inspired by the large Chilean earthquakes from the past decade (viz., the M > 8.0 earthquakes from 2010 and 2015) to constrain the sources for the model, i.e. size, frequency, amplitude, and timing, based on available information from ocean buoy and seismometer data. TEC data are used to validate source amplitudes and to constrain
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PET imaging of T cells: Target identification and feasibility assessment.
Auberson, Yves P; Briard, Emmanuelle; Rudolph, Bettina; Kaupmann, Klemen; Smith, Paul; Oberhauser, Berndt
2018-06-01
Imaging T cells using positron emission tomography (PET) would be highly useful for diagnosis and monitoring in immunology and oncology patients. There are however no obvious targets that can be used to develop imaging agents for this purpose. We evaluated several potential target proteins with selective expression in T cells, and for which lead molecules were available: PKC , Lck, ZAP70 and Itk. Ultimately, we focused on Itk (interleukin-2-inducible T cell kinase) and identified a tool molecule with properties suitable for in vivo imaging of T cells, (5aR)-5,5-difluoro-5a-methyl-N-(1-((S)-3-(methylsulfonyl)-phenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-1,4,4a,5,5a,6-hexahydro-cyclopropa[f]-indazole-3-carboxamide (23). While not having the optimal profile for clinical use, this molecule indicates that it might be possible to develop Itk-selective PET ligands for imaging the distribution of T cells in patients. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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NASA Astrophysics Data System (ADS)
Contadakis, Michael; Arabelos, Dimitrios; Vergos, Georgios; Spatalas, Spyridon
2014-05-01
In this paper the Total Electron Content (TEC) data of 9 Global Positioning System (GPS) stations of the EUREF network, which are being provided by IONOLAB (Turkey), were analysed using Discrete Fourier Analysis in order to investigate the TEC variations over Mediteranean before and during the strong earthquake of 12th of October 2013, Which occur in western of Crete, Greece. In accordance to the results of similar analysis on the occasion of earthquakes in the area (Contadakis et al 2008, 2012a,2012b) the main conclusions of this analysis are the following. (a) TEC oscillations in a broad range of frequencies occur randomly over a broad area of several hundred km from the earthquake and (b) high frequency oscillations (f ≥ 0.0003Hz, periods T ≤ 60m) seems to point to the location of the earthquake with a questionable accuracy but the fractal characteristics of the frequencies distribution, points to the locus of the earthquake with a rather higher accuracy. We conclude that the LAIC mechanism through acoustic or gravity wave could explain this phenomenology. Key words: GPS network, ionospheric total electron content, wavelet analysis References Contadakis, M.E., Arabelos, D.N. G. Asteriadis, S.D. Spatalas and Ch. Pikridas, 2008. TEC variations over the Mediterranean during the seismic activity period of the last quarter of 2005 in the area of Greece, Nat. Hazards Earth Syst. Sci., 8, 1267-1276 M.E. Contadakis, D.N. Arabelos, Ch. Pikridas and S.D. Spatalas, 2012a,TEC variations over Southern Europe before and during the M6.3 Abruzzo earthquake of 6th April 2009, Annals of Geophysics, Vol.55,1, p.83-93 M.E.Contadakis, D.N.Arabelos, and G.Vergos, 2012b, TEC variations over North-western Balkan peninsula before and during the seismic activity of 24th May 2009, EGU GA, Geoph. Res. Abs., Vol. 14, EGU2012-2319-2
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Philip, Joseph; Biswas, Amit Kumar; Chatterjee, Tathagata; Mallhi, Rajiv Singh
2014-01-01
To compare the Fenwal Amicus and the Fresenius COM.TEC apheresis instruments regarding donor peripheral blood parameters, operational variables of the instruments, and quality control parameters of the product obtained. We performed 100 platelet collections from 100 voluntary donors using the 2 studied devices. We measured platelet count using an automated analyzer and analyzed the activation statuses using a flow cytometer. The median time needed to perform the procedures was significantly longer with the COM.TEC. However, the product we obtained using the Amicus instrument showed higher degrees of platelet-activation. All products we obtained with both instruments had white blood cell counts of less than 5 × 10(6) per bag. We observed no statistical difference regarding collection efficiency and collection rates between the devices. Both instruments collected platelets efficiently, with minimal donor discomfort. Compared with the COM.TEC instrument, the Amicus reached the platelet target yield more quickly; however, it displayed an increase in platelet activation. Copyright© by the American Society for Clinical Pathology (ASCP).
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DOE Office of Scientific and Technical Information (OSTI.GOV)
De Lucca, George V.; Shi, Qing; Liu, Qingjie
Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
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Submillimeter Galaxy Surveys with AzTEC
NASA Astrophysics Data System (ADS)
Wilson, Grant W.; Ade, P. A.; Aretxaga, I.; Austermann, J.; Battersby, C.; Bock, J. J.; Glenn, J.; Golwala, S. R.; Haig, D.; Hughes, D. H.; Kang, Y.; Kim, S.; Lowenthal, J.; Mauskopf, P. D.; Perera, T.; Scott, K.; Roberts, C.; Yoon, I.; Yun, M. S.
2006-06-01
We describe a recent large scale survey of the Submillimeter Galaxy (SMG) population by AzTEC, a 144 element bolometer camera, on the 15m diameter James Clerk Maxwell Telescope. From November 2005 to February 2006, over 400 hours of telescope time were spent imaging over 1 square degree of sky with an area weighted target sensitivity of 0.7 mJy rms. Several fields with large multi-wavelength data sets were mapped including the Subaru/XMM-Newton Deep Survey field, the Lockmann Hole, GOODS-N, and a subset of the COSMOS field. In addition we mapped fields spanning a wide range of environments including several regions with known mass over-density. Together this represents the largest/deepest survey of the SMG population. Herein we report on the technical details of the surveys, describe the reduction pipeline, and show preliminary results from a subsection of the survey fields.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Pattisahusiwa, Asis; Liong, The Houw; Purqon, Acep
Seismo-Ionospheric is a study of ionosphere disturbances associated with seismic activities. In many previous researches, heliogeomagnetic or strong earthquake activities can caused the disturbances in the ionosphere. However, it is difficult to separate these disturbances based on related sources. In this research, we proposed a method to separate these disturbances/outliers by using nu-SVR with the world-wide GPS data. TEC data related to the 26th December 2004 Sumatra and the 11th March 2011 Honshu earthquakes had been analyzed. After analyzed TEC data in several location around the earthquake epicenter and compared with geomagnetic data, the method shows a good result inmore » the average to detect the source of these outliers. This method is promising to use in the future research.« less
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VizieR Online Data Catalog: AzTEC/ASTE source catalogue (Aretxaga+, 2011)
NASA Astrophysics Data System (ADS)
Aretxaga, I.; Wilson, G. W.; Aguilar, E.; Alberts, S.; Scott, K. S.; Scoville, N.; Yun, M. S.; Austermann, J.; Downes, T. P.; Ezawa, H.; Hatsukade, B.; Hughes, D. H.; Kawabe, R.; Kohno, K.; Oshima, T.; Perera, T. A.; Tamura, Y.; Zeballos, M.
2013-02-01
We imaged a 2800 arcmin2 field centred at right ascension RA(J2000.0)=10:00:30.00 and declination DE(J2000.0)=2:14.00 with AzTEC mounted on the 10-m ASTE, located at 4800m in the Atacama Desert of Chile. The survey was carried out from 2008 October 20 to November 30. (1 data file).
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Fresenius AS.TEC204 blood cell separator.
Sugai, Mikiya
2003-02-01
Fresenius AS.TEC204 is a third-generation blood cell separator that incorporates the continuous centrifugal separation method and automatic control of the cell separation process. Continuous centrifugation separates cell components according to their specific gravity, and different cell components are either harvested or eliminated as needed. The interface between the red blood cell and plasma is optically detected, and the Interface Control (IFC) cooperates with different pumps, monitors and detectors to harvest required components automatically. The system is composed of three major sections; the Front Panel Unit; the Pump Unit, and the Centrifuge Unit. This unit can be used for a wide variety of clinical applications including collection of platelets, peripheral blood stem cells, bone marrow stem cells, granulocytes, mononuclear cells, and exchange of plasma or red cells, and for plasma treatment.
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GNSS derived TEC data ingestion into IRI 2012
NASA Astrophysics Data System (ADS)
Migoya-Orué, Yenca; Nava, Bruno; Radicella, Sandro; Alazo-Cuartas, Katy
2015-04-01
Experimental vertical total electron content (VTEC) data given by Global Ionospheric Maps (GIM) has been ingested into the IRI version 2012, aiming to obtain grids of effective input parameter values that allow to minimize the difference between the experimental and modeled vertical TEC. Making use of the experience gained with the technique of model adaptation applied to NeQuick (Nava et al., 2005), it has been found possible to compute IRI world grids of effective ionosphere index parameters (IG). The IG grids thus obtained can be interpolated in space and time to calculate with IRI the 3D electron density at any location and also the TEC along any ground-to-satellite ray-path for a given epoch. In this study, the ingestion technique is presented and a posteriori validation, along with an assessment of the capability of the 'ingested' IRI to reproduce the ionosphere day-to-day foF2 variability during disturbed and quiet periods. The foF2 values retrieved are compared with data from about 20 worldwide ionosondes for selected periods of high (year 2000) and moderate to low solar activity (year 2006). It was found that the use of the ingestion scheme enhances the performance of the model when compared with its standard use based on solar activity drivers (R12 and F10.7), especially for high solar activity. As an example, the mean and standard deviation of the differences between experimental and reconstructed F2-peak values for April of year 2000 is 0.09 and 1.28 MHz for ingested IRI, compared to -0.81 and 1.27 MHz (IRI with R12 input) and -0.02 and 1.46 MHz (IRI with F10.7 input).
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GPS-TEC of the Ionospheric Disturbances as a Tool for Early Tsunami Warning
NASA Astrophysics Data System (ADS)
Kunitsyn, Viacheslav E.; Nesterov, Ivan A.; Shalimov, Sergey L.; Krysanov, Boris Yu.; Padokhin, Artem M.; Rekenthaler, Douglas
2013-04-01
Recently, the GPS measurements were used for retrieving the information on the various types of ionospheric responses to seismic events (earthquakes, seismic Rayleigh waves, and tsunami) which generate atmospheric waves propagating up to the ionospheric altitudes where the collisions between the neutrals and charge particles give rise to the motion of the ionospheric plasma. These experimental results can well be used in architecture of the future tsunami warning system. The point is an earlier (in comparison with seismological methods) detection of the ionospheric signal that can indicate the moment of tsunami generation. As an example we consider the two-dimensional distributions of the vertical total electron content (TEC) variations in the ionosphere both close to and far from the epicenter of the Japan undersea earthquake of March 11, 2011 using radio tomographic (RT) reconstruction of high-temporal-resolution (2-minute) data from the Japan and the US GPS networks. Near-zone TEC variations shows a diverging ionospheric perturbation with multi-component spectral composition emerging after the main shock. The initial phase of the disturbance can be used as an indicator of the tsunami generation and subsequently for the tsunami early warning. Far-zone TEC variations reveals distinct wave train associated with gravity waves generated by tsunami. According to observations tsunami arrives at Hawaii and further at the coast of Southern California with delay relative to the gravity waves. Therefore the gravity wave pattern can be used in the early tsunami warning. We support this scenario by the results of modeling with the parameters of the ocean surface perturbation corresponding to the considered earthquake. In addition it was observed in the modeling that at long distance from the source the gravity wave can pass ahead of the tsunami. The work was supported by the Russian Foundation for Basic Research (grants 11-05-01157 and 12-05-33065).
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Fung, J C; Donta, S T; Tilton, R C
1986-01-01
Eighty-three serum specimens from 24 patients infected with Candida albicans were examined for circulating Candida protein antigens with the Candida Detection System (CAND-TEC; Ramco Laboratories, Inc., Houston, Tex.). The medical records of each patient were reviewed for clinical evidence of Candida colonization or disease, predisposing factors for infection, underlying illness, the presence of a contaminated indwelling venous catheter, intravenous amphotericin B therapy, and outcome. Forty-nine serum specimens with antigen titers of 1:2 or less were obtained either from colonized patients or at a time when disseminated disease was not yet clinically suspected. Except for five specimens from two colonized patients, one with a contaminated arterial line, the other specimens with titers of 1:8 or greater (n = 14) were obtained from patients who had been clinically diagnosed and treated for disseminated candidiasis. Serum specimens with titers of 1:4 were often from patients with deep-seated candidal infection but were not uniformly diagnostic; in this situation additional specimens should be tested for Candida antigen titers. Only 1 of 24 serum specimens from patients with no evidence of C. albicans infection had a Candida protein antigen titer of 1:8. With a 1:8 or greater titer as a criterion for dissemination, the sensitivity of the CAND-TEC system was 71%, with a specificity of 98%. If the 1:8 titer for the colonized patient with a contaminated arterial line is not considered a false-positive result, the CAND-TEC sensitivity was 83%. The latex agglutination assay appears to be a useful, rapid, and noninvasive means of laboratory diagnosis of systemic candidiasis. The recovery of C. albicans from at least three body sites may also be a useful predictor of disseminated disease. PMID:3533975
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NASA Astrophysics Data System (ADS)
Nogueira, P. A. B.; Abdu, M. A.; Souza, J. R.; Batista, I. S.; Bailey, G. J.; Santos, A. M.; Takahashi, H.
2013-11-01
The equatorial ionization anomaly (EIA) development is studied using the total electron content (TEC) observed by the Global Positioning System (GPS) satellites, the F2-layer critical frequency (foF2) as measured by digisondes operated in the Brazilian sector, and by model simulation using the SUPIM (Sheffield University Plasmasphere Ionosphere Model). We have used two indices based on foF2 and TEC to represent the strength of the EIA Southern Anomaly Crest (SAC), which are denoted, respectively, by SAC(foF2) and SAC(TEC). Significant differences in the local time variations of the EIA intensity, as represented by these two indices, are investigated. The observed SAC indices are compared with their values modeled by the SUPIM and also by the International Reference Ionosphere (IRI)-2012. The SUPIM simulations that use the standard E×B plasma drift and neutral air wind models are found to provide acceptable representations of the observed foF2 and TEC, and hence the indices SAC(foF2) and SAC(TEC) during daytime, whereas the IRI-2012 model is not, except during the post-midnight/sunrise hours. It is found that the differences in the local time variations between the SAC(foF2) and SAC(TEC) can be reduced by limiting the TEC integrations in height up to an altitude of 630 km in the SUPIM calculations. It is also found that when the EIA intensity is calculated for an intermediate dip latitude (12°S) the difference between the local time variation patterns of the two corresponding indices in the experimental data and in the SUPIM results is reduced. For the IRI-2012 values, the subequatorial station modification does not appear to have any effect.
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NASA Astrophysics Data System (ADS)
Gulyaeva, Tamara; Poustovalova, Ljubov
The International Reference Ionosphere model extended to the plasmasphere, IRI-Plas, has been recently updated for assimilation of total electron content, TEC, derived from observations with Global Navigation Satellite System, GNSS. The ionosonde products of the F2 layer peak density (NmF2) and height (hmF2) ensure true electron density maximum at the F2 peak. The daily solar and magnetic indices used by IRI-Plas code are compiled in data files including the 3-hour ap and kp magnetic index from 1958 onward, 12-monthly smoothed sunspot number R12 and Global Electron Content GEC12, daily solar radio flux F10.7 and daily sunspot number Ri. The 3-h ap-index is available in Real Time, RT, mode from GFZ, Potsdam, Germany, daily update of F10.7 is provided by Space Weather Canada service, and daily estimated international sunspot number Ri is provided by Solar Influences Data Analysis Center, SIDC, Belgium. For IRI-Plas-RT operation in regime of the daily update and prediction of the F2 layer peak parameters, the proxy kp and ap forecast for 3 to 24 hours ahead based on data for preceding 12 hours is applied online at http://www.izmiran.ru/services/iweather/. The topside electron density profile of IRI-Plas code is expressed with complementary half-peak density anchor height above hmF2 which corresponds to transition O+/H+ height. The present investigation is focused on reconstruction of topside ionosphere scale height using vertical total electron content (TEC) data derived from the Global Positioning System GPS observations and the ionosonde derived F2 layer peak parameters from 25 observatories ingested into IRI-Plas model. GPS-TEC and ionosonde measurements at solar maximum (September, 2002, and October, 2003) for quiet, positively disturbed, and negatively disturbed days of the month are used to obtain the topside scale height, Htop, representing the range of altitudes from hmF2 to the height where NmF2 decay by e times occurs. Mapping of the F2 layer peak parameters
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NASA Astrophysics Data System (ADS)
Afraimovich, E. L.; Edemsky, I. K.; Voeykov, S. V.; Yasukevich, Y. V.; Zhivetiev, I. V.
2009-04-01
The great variety of solar terminator (ST) -linked phenomena in the atmosphere gave rise to a num¬ber of studies on the analysis of ionosphere parameter variations obtained by different ionosphere sounding methods. Main part of experimental data was obtained using methods for analyzing the spectrum of ionosphere parameter variations in separate local points. To identify ST-generated wave disturbances it is necessary to measure the dynamic and spectral characteristics of the wave disturbances and to compare it with spatial-temporal characteristics of ST. Using TEC measurements from the dense network of GPS sites GEONET (Japan), we have obtained the first GPS-TEC image of the space structure of medium-scale traveling wave packets (MS TWP) excited by the solar terminator. We use two known forms of the 2D GPS-TEC image for our presentation of the space structure of ST-generated MS TWP: 1) - the diagram "distance-time"; 2) - the 2D-space distribution of the values of filtered TEC series dI (λ, φ, t) on the latitude φ and longitude λ for each 30-sec TEC counts. We found that the time period and wave-length of ST-generated wave packets are about 10-20 min and 200-300 km, respectively. Dynamic images analysis of dI (λ, φ, t) gives precise estimation of velocity and azimuth of TWP wave front propagation. We use the method of determining velocity of traveling ionosphere disturbances (SADM-GPS), which take into account the relative moving of subionosphere points. We found that the velocity of the TWP phase front, traveling along GEONET sites, varies in accordance with the velocity of the ST line displacement. The space image of MS TWP manifests itself in pronounced anisotropy and high coherence over a long distance of about 2000 km. The TWP wave front extends along the ST line with the angular shift of about 20°. The hypothesis on the connection between the TWP generation and the solar terminator can be tested in the terminator local time (TLT) system: d
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NASA Astrophysics Data System (ADS)
Moral, A. C.; Shiokawa, K.; Otsuka, Y.; Liu, H.; Nishioka, M.; Tsugawa, T.
2017-12-01
We report results of simultaneous ground-satellite measurements of daytime travelling ionospheric disturbances (TIDs) over Japan by using the GEONET GPS receiver network and the CHAMP satellite. For the two years of 2002 and 2008, we examined GPS measurements of TEC (Total Electron Content) and neutral and electron densities measured by CHAMP satellite. Total of fifteen TID events with clear southward moving structures in the GPS-TEC measurements are found by simultaneous ground-satellite measurements. On 2002, simultaneous events are only observed in January (1 event) and February (4 events). On 2008, ten events are observed around winter months (January (3 events), February (5), March (1), and October (1)). Neutral and electron densities measured by CHAMP show quasi-periodic fluctuations throughout the passages for all events. The CHAMP satellite crossed at least one clear TID phase front for all the events. We fitted a sinusoidal function to both ground and satellite data to obtain the frequencies and phase of the observed variations. We calculated the corresponding phase relationships between TEC variations and neutral and electron densities measured by CHAMP to categorize the events. In the presentations we report correspondence of these TID structures seen in the simultaneous ground-satellite observations by GPS-TEC and CHAMP, and discuss their phase relationship to identify the source of the daytime TIDs and specify how much of the observed variations are showing clear frequencies/or not in the nature at middle latitudes.
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NASA Astrophysics Data System (ADS)
Tsugawa, Takuya; Otsuka, Yuichi; Saito, Akinori; Ishii, Mamoru; Nishioka, Michi
Ionospheric disturbances following the 2011 Tohoku earthquake and the 2013 Moore tornado were observed by high-resolution GPS total electron content (TEC) observations using dense GPS receiver networks. After the 2011 Tohoku earthquake, concentric waves with short propagation distance propagated in the radial direction in the propagation velocity of 3,457, 783, 423 m/s for the first, second, third peak, respectively. Following these waves, concentric waves with long propagation distance appeared to propagate at the velocity of 138-288 m/s. In the vicinity of the epicenter, sudden TEC depletions and short-period oscillations with a period of approximately 4 minutes were also observed. The center of these ionospheric variations, termed the "ionospheric epicenter", corresponded to the tsunami source. Comparing to the results of a numerical simulation using non-hydrostatic compressible atmosphere-ionosphere model, the first peak of circular wave would be caused by the acoustic waves generated from the propagating Rayleigh wave. The second and third waves would be caused by atmospheric gravity waves excited in the lower ionosphere due to the acoustic wave propagations from the tsunami source. The fourth and following waves are considered to be caused by the atmospheric gravity waves induced by the wavefronts of traveling tsunami. After the EF5 tornado hit Moore, Oklahoma, USA, on 20 May 2013, clear concentric waves and short-period oscillations were observed. These concentric waves were non-dispersive waves with a horizontal wavelength of approximately 120 km and a period of approximately 13 minutes. They were observed for more than seven hours throughout North America. TEC oscillations with a period of approximately 4 minutes were also observed in the south of Moore for more than eight hours. Comparison between the GPS-TEC observations and the infrared cloud images from the GOES satellite indicates that the concentric waves and the short-period oscillations would be
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Mueller, Helena; Stadtmann, Anika; Van Aken, Hugo; Hirsch, Emilio; Wang, Demin; Ley, Klaus; Zarbock, Alexander
2010-04-15
Selectins mediate leukocyte rolling, trigger beta(2)-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) gamma2- and phosphoinositide 3-kinase (PI3K) gamma-dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP(3)), and inducing E-selectin-mediated slow rolling. Inhibition of this signal-transduction pathway diminished Galpha(i)-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Galpha(i)-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk(-/-) and Plcg2(-/-) mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.
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Sreeram, Roopa Rani S; Prasad, L Krishna; Chakravarthi, P Srinivas; Devi, Naga Neelima; Kattimani, Vivekanand S; Sreeram, Sanjay Krishna
2015-08-01
Missing teeth lead to loss of structural balance, inefficient function, poor aesthetics and psychological effects on human beings, which needs restoration for normal contour, function and aesthetics. Several natural or synthetic substitutes are being used for replacement of missing tooth since centuries. Implants are the latest modality of replacement. So, the study was aimed to assess clinical success rate of Hi-Tec implant; which is economical and new in market. Results of the study will help clinician for appropriate implant selection. The study included 10 patients from 19 to 31 years and needed restoration of missing mandibular first molar. Restoration had done using Hi Tec Single-tooth implants with metal-ceramic single crown prosthesis after three months of osseointegration. The implants were evaluated clinically (bleeding on probing, probing depth, implant mobility- periotest) and radiographically (marginal bone loss and peri-implant radiolucency) for six years. The observers were blinded for the duration of the study to prevent bias. All the patients had uneventful post-surgical healing. No bleeding on probing, Implant mobility, peri-implant radiolucency with minimal marginal bone loss and constant probing depths were observed well within the normal range during follow-up periods. Two stage single-tooth Hi Tec implant restoration can be used as a successful treatment modality for replacing mandibular first molar in an economic way. However, these results were obtained after 6 years of follow up with a smaller sample size, so long term multi center studies with a larger sample size is recommended for the predictability of success rate conclusively.
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NASA Astrophysics Data System (ADS)
Mengistu, E.; Damtie, B.; Moldwin, M. B.; Nigussie, M.
2018-03-01
This paper examines the performances of NeQuick2, the latest available IRI-2016, IRI-2012 and IRI-2007 models in describing the monthly and seasonal mean total electron content (TEC) over the East African region. This is to gain insight into the success of the various model types and versions at characterizing the ionosphere within the equatorial ionization anomaly. TEC derived from five Global Positioning System (GPS) receivers installed at Addis Ababa (ADD, 5.33°N, 111.99°E Geog.), Asab (ASAB, 8.67°N, 116.44°E Geog.), Ambo (ABOO, 5.43°N, 111.05°E Geog.), Nairobi (RCMN, -4.48°N, 108.46°E Geog.) and Nazret (NAZR, 4.78°N, 112.43°E Geog.), are compared with the corresponding values computed using those models during varying solar activity period (1998 and 2008-2015). We found that different models describe the equatorial and anomaly region ionosphere best depending on solar cycle, season and geomagnetic activity levels. Our results show that IRI-2016 is the best model (compared to others in terms of discrepancy range) in estimating the monthly mean GPS-TEC at NAZR, ADD and RCMN stations except at ADD during 2008 and 2012. It is also found that IRI-2012 is the best model in estimating the monthly mean TEC at ABOO station in 2014. IRI show better agreement with observations during June solstice for all the years studied at ADD except in 2012 where NeQuick2 better performs. At NAZR, NeQuick2 better performs in estimating seasonal mean GPS-TEC during 2011, while IRI models are best during 2008-2009. Both NeQuick2 and IRI models underestimate measured TEC for all the seasons at ADD in 2010 but overestimate at NAZR in 2009 and RCMN in 2008. The periodic variations of experimental and modeled TEC have been compared with solar and geomagnetic indices at ABOO and ASAB in 2014 and results indicate that the F10.7 and sunspot number as indices of solar activity seriously affects the TEC variations with periods of 16-32 days followed by the geomagnetic activity on
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
..., Inc., Fort Smith, AR; Amended Certification Regarding Eligibility To Apply for Worker Adjustment... Career Solutions TEC Staffing, Fort Smith, Arkansas. The workers are engaged in the production of...., Prodriver, and Arkansas Warehouse, Inc. were employed on-site at the Fort Smith, Arkansas location of...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-28
..., TEK Systems, Penske Logistics, Eurest, and Canteen, Fort Smith, AR; Amended Certification Regarding... Corporation, including on-site leased workers from Career Solutions TEC Staffing, Fort Smith, Arkansas. The... Corporation, TEK Systems, Penske Logistics, Eurest, and Canteen were employed on-site at the Fort Smith...
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NASA Astrophysics Data System (ADS)
Pundhir, Devbrat; Singh, Birbal; Singh, O. P.; Gupta, Saral Kumar; Karia, S. P.; Pathak, K. N.
2017-11-01
In this paper, we have examined the diurnal variations of GPS-TEC observed at two Indian stations of Agra (27.2°N, 78°E) and Surat (21.16°N, 72.78°E) and global ionospheric maps data (GIM-TEC) for the months of April and September 2013 in search of ionospheric precursors of three major earthquakes (M > 6.5) that occurred in these months. The well-established quartile based statistical technique is adopted for the analysis of TEC data. The results show two kinds of anomalies, one in which simultaneous enhancements in TEC occurred in the three sets of data, 1-9 days and 3 days before the main shock in the two months respectively, and another in which anomalies occurred 15 days before in April, and 21 days before in September at Surat respectively. The depletions have also been found in three data sets but they are not significant. These anomalies are unlikely be influenced by geomagnetic parameters due to quiet magnetic conditions. The effect of also solar activity have also been considered and examined very precisely. The results are interpreted in terms of Lithosphere-Atmosphere-Ionosphere coupling (LAIC) mechanisms available in the literature.
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New LMT High Resolution Imaging and CO Spectroscopic Studies of the Brightest AzTEC 1.1mm Sources
NASA Astrophysics Data System (ADS)
Yun, Min S.; Aretxaga, Itziar; Hughes, David; Montana, A.; Pope, A.; Bruzual, Gustavo; Ferrusca, D.; Rosa Gonzalez, D.; Sanchez-Arguelles, D.; Narayanan, G.; Wilson, Grant; Gim, Hansung; Ibarra, H.; Mo, H.; Lowenthal, James; Zavala, J.; Carrasco, L.; Chavez, M.; Valazquez, M.; Zeballos, M.; Vega, O.; Schloerb, P.; Cybulsky, J. R.; Casey, Caitlin M.; Tang, Y.
2015-08-01
A substantial population of quiescent galaxies with stellar masses exceeding 10 billion solar masses have been found to z~4, suggesting a rapid formation and quenching of massive galaxies at z~6 or earlier. The submillimeter bright galaxies (SMGs) with SFR > 100-1000 solar masses per year represent natural candidates for the progenitor systems undergoing an epoch of rapid formation and cessation of stellar mass build up. Many of the most luminous SMGs are also extremely red and faint in the optical, suggesting a high redshift and are beyond the reach of the current optical spectroscopic redshift surveys. There is also a growing concern that these most luminous SMGs may be blends of several unrelated sources as a result of a poor angular resolution of the existing surveys (18" & 28" for the AzTEC 1.1mm surveys on JCMT and ASTE, respectively). We have obtained new 8" resolution AzTEC images of 40 brightest AzTEC sources previously found in the GOODS and COSMOS fields using the Large Millimeter Telescope (LMT) to examine the multiplicity question and for the identification of multi-wavelength counterparts. We have also conducted a CO redshift survey using the Redshift Search Receiver on the LMT. We will report the results of these analysis and several new CO redshifts.
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Higgins, Owen; Clancy, Eoin; Cormican, Martin; Boo, Teck Wee; Cunney, Robert; Smith, Terry J
2018-02-09
Bacterial meningitis infection is a leading global health concern for which rapid and accurate diagnosis is essential to reduce associated morbidity and mortality. Loop-mediated isothermal amplification (LAMP) offers an effective low-cost diagnostic approach; however, multiplex LAMP is difficult to achieve, limiting its application. We have developed novel real-time multiplex LAMP technology, TEC-LAMP, using Tth endonuclease IV and a unique LAMP primer/probe. This study evaluates the analytical specificity, limit of detection (LOD) and clinical application of an internally controlled multiplex TEC-LAMP assay for detection of leading bacterial meningitis pathogens: Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae . Analytical specificities were established by testing 168 bacterial strains, and LODs were determined using Probit analysis. The TEC-LAMP assay was 100% specific, with LODs for S. pneumoniae , N. meningitidis and H. influenzae of 39.5, 17.3 and 25.9 genome copies per reaction, respectively. Clinical performance was evaluated by testing 65 archived PCR-positive samples. Compared to singleplex real-time PCR, the multiplex TEC-LAMP assay demonstrated diagnostic sensitivity and specificity of 92.3% and 100%, respectively. This is the first report of a single-tube internally controlled multiplex LAMP assay for bacterial meningitis pathogen detection, and the first report of Tth endonuclease IV incorporation into nucleic acid amplification diagnostic technology.
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Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms.
Roskoski, Robert
2016-11-01
The Bruton non-receptor protein-tyrosine kinase (BTK), a deficiency of which leads to X-linked agammaglobulinemia, plays a central role in B cell antigen receptor signaling. Owing to the exclusivity of this enzyme in B cells, the acronym could represent B cell tyrosine kinase. BTK is activated by the Lyn and SYK protein kinases following activation of the B cell receptor. BTK in turn catalyzes the phosphorylation and activation of phospholipase Cγ2 leading to the downstream activation of the Ras/RAF/MEK/ERK pathway and the NF-κB pathways. Both pathways participate in the maturation of antibody-producing B cells. The BTK domains include a PH (pleckstrin homology) domain that interacts with membrane-associated phosphatidyl inositol trisphosphate, a TH (TEC homology) domain, which is followed by an SH3, SH2, and finally a protein kinase domain. Dysregulation of B cell receptor signaling occurs in several B cell neoplasms including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Ibrutinib is FDA-approved as first-line or second line treatment for these diseases. The drug binds tightly in the ATP-binding pocket of BTK making salt bridges with residues within the hinge that connects the two lobes of the enzyme; then its unsaturated acrylamide group forms a covalent bond with BTK cysteine 481 to form an inactive adduct. In addition to the treatment of various B cell lymphomas, ibrutinib is under clinical trials for the treatment of numerous solid tumors owing to the role of tumor-promoting inflammation in the pathogenesis of neoplastic diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.
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NASA Astrophysics Data System (ADS)
Contadakis, M. E.; Arabelos, D. N.; Vergos, G.; Spatalas, S. D.; Skordilis, M.
In this paper, the total electron content (TEC) data from eight global positioning system (GPS) stations of the EUREF network, provided by IONOLAB (Turkey), were analyzed using discrete Fourier analysis to investigate the TEC variations over the Mediterranean before and during the strong earthquake of 12th October 2013, which occurred west of Crete, Greece. In accordance with the results of similar analyses in the area, the main conclusions of this study are the following: (a) TEC oscillations in a broad range of frequencies occur randomly over an area of several hundred km from the earthquake and (b) high frequency oscillations (f ⩾ 0.0003 Hz, periods T ⩽ 60 m) may point to the location of the earthquake with questionable accuracy. The fractal characteristics of the frequency distribution may point to the locus of the earthquake with higher accuracy. We conclude that the lithosphere-atmosphere-ionosphere coupling (LAIC) mechanism through acoustic or gravity waves could explain this phenomenology.
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NASA Astrophysics Data System (ADS)
Shih, A. L.; Liu, J. Y. G.
2015-12-01
A median-based method and a z test are employed to find characteristics of seismo-ionospheric precursor (SIP) of the total electron content (TEC) in global ionosphere map (GIM) associated with 129 M≥5.5 earthquakes in Taiwan during 1999-2014. Results show that both negative and positive anomalies in the GIM TEC with the statistical significance of the z test appear few days before the earthquakes. The receiver operating characteristic (ROC) curve is further applied to see whether the SIPs exist in Taiwan.
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NASA Astrophysics Data System (ADS)
Huang, He; Liu, Libo; Chen, Yiding; Le, Huijun; Wan, Weixing
2016-01-01
The ionospheric equivalent slab thickness (EST), defined as the ratio of total electron content (TEC) to F2 layer peak electron density (NmF2), describes the thickness of the ionospheric profile. In this study, we retrieve EST from TEC data obtained from Global Ionospheric Map (GIM) and NmF2 retrieved from Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC) ionospheric radio occultation data. The diurnal, seasonal, and solar activity variations of global EST are analyzed as the excellent spatial coverage of GIM and COSMIC data. During solstices, daytime EST in the summer hemisphere is larger than that in the winter hemisphere, except in some high-latitude regions, and the reverse is true for the nighttime EST. The peaks of EST often appear at 0400 local time. The presunrise enhancement in EST appears in all seasons, while the postsunset enhancement in EST is not readily observed in equinox. Both enhancements are attributed to the more remarkable electron density decay of NmF2 compared to that of TEC. The dependence of EST on solar activity is related to the inconsistent solar activity dependences of electron density at different altitudes. Furthermore, it is interesting that EST is enhanced from 0° to 120°E in longitude and 30° to 75°S in latitude during nighttime, just to the east of Weddell Sea Anomaly, during equinox and the Southern Hemisphere summer. This phenomenon is supposed to be related to the effects of geomagnetic declination-related plasma vertical drifts.
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Clancy, Eoin; Cormican, Martin; Boo, Teck Wee; Cunney, Robert
2018-01-01
Bacterial meningitis infection is a leading global health concern for which rapid and accurate diagnosis is essential to reduce associated morbidity and mortality. Loop-mediated isothermal amplification (LAMP) offers an effective low-cost diagnostic approach; however, multiplex LAMP is difficult to achieve, limiting its application. We have developed novel real-time multiplex LAMP technology, TEC-LAMP, using Tth endonuclease IV and a unique LAMP primer/probe. This study evaluates the analytical specificity, limit of detection (LOD) and clinical application of an internally controlled multiplex TEC-LAMP assay for detection of leading bacterial meningitis pathogens: Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae. Analytical specificities were established by testing 168 bacterial strains, and LODs were determined using Probit analysis. The TEC-LAMP assay was 100% specific, with LODs for S. pneumoniae, N. meningitidis and H. influenzae of 39.5, 17.3 and 25.9 genome copies per reaction, respectively. Clinical performance was evaluated by testing 65 archived PCR-positive samples. Compared to singleplex real-time PCR, the multiplex TEC-LAMP assay demonstrated diagnostic sensitivity and specificity of 92.3% and 100%, respectively. This is the first report of a single-tube internally controlled multiplex LAMP assay for bacterial meningitis pathogen detection, and the first report of Tth endonuclease IV incorporation into nucleic acid amplification diagnostic technology. PMID:29425124
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Stiff, Andrew; Trikha, Prashant; Wesolowski, Robert; Kendra, Kari; Hsu, Vincent; Uppati, Sarvani; McMichael, Elizabeth; Duggan, Megan; Campbell, Amanda; Keller, Karen; Landi, Ian; Zhong, Yiming; Dubovsky, Jason; Howard, John Harrison; Yu, Lianbo; Harrington, Bonnie; Old, Matthew; Reiff, Sean; Mace, Thomas; Tridandapani, Susheela; Muthusamy, Natarajan; Caligiuri, Michael A.; Byrd, John C.; Carson, William E.
2016-01-01
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that expand in tumor bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wildtype mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo. Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. PMID:26880800
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A 1.1mm AzTEC Survey Tracing Accelerated Galaxy Formation Towards a Protocluster at z 3.8
NASA Astrophysics Data System (ADS)
Hughes, David H.; Montana, A.; Aretxaga, I.; Plionis, M.; Porras, A.; Wagg, J.; Gaztanaga, E.; Huang, J.; Fazio, G.; Wilson, G.; Yun, M.; Lowenthal, J.; Perera, T.; Austermann, J.; Scott, K.; Dunlop, J.; Ivison, R.; Stevens, J.; Smail, I.; Appleton, P.
2006-12-01
Aztec has recently conducted a sensitive, wide-area (300 sq. Armin's) continuum survey at 1.1mm using the 15-m James Clerk Maxwell Telescope towards 4C41.17, a powerful high-redshift (z 3.8) radio galaxy. These Aztec data, which cover an area >40 times larger than our previous SCUBA survey, reveal a significant over-density of luminous, massive dust-enshrouded galaxies, compared to the results from lower-redshift blank-field sub-mm surveys. One natural interpretation of these new AzTEC data is that the over-density is tracing a large (5 x 5 Mpc) "proto-cluster" structure at z 3.8 associated with the environment of 4C41.17, within which the formation of ultra-luminous starburst galaxies (with rest-frame FIR luminosities >5 x 1012 Lsun or SFRs > 500 Msun/yr) is taking place at an accelerated rate. Proving the physical association of these massive optically-faint starbursts with the environment of this high-z AGN, and not with the blank-field sub-mm population, for which 50% of the population lies at 1.9 < z < 2.9, remains an outstanding problem. In this presentation we will describe the AzTEC survey, the empirical evidence for this protocluster structure in the early universe, and the planned multi-wavelength follow-up observations of the brightest AzTEC sources towards 4C41.17 that may demonstrate that we are witnessing accelerated galaxy formation, via an increased rate of merging gas-rich galaxies within a rapidly-developing gravitational potential. AzTEC is one of the suite of instruments destined for the 50-m Large Millimeter Telescope (LMT). We will conclude this presentation with a summary of future LMT observations that will trace the evolution of obscured starformation in the dynamic environments towards a significant sample of intermediate and high-z powerful AGN with greater sensitivity and spatial resolution.
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Firefly Algorithm in detection of TEC seismo-ionospheric anomalies
NASA Astrophysics Data System (ADS)
Akhoondzadeh, Mehdi
2015-07-01
Anomaly detection in time series of different earthquake precursors is an essential introduction to create an early warning system with an allowable uncertainty. Since these time series are more often non linear, complex and massive, therefore the applied predictor method should be able to detect the discord patterns from a large data in a short time. This study acknowledges Firefly Algorithm (FA) as a simple and robust predictor to detect the TEC (Total Electron Content) seismo-ionospheric anomalies around the time of the some powerful earthquakes including Chile (27 February 2010), Varzeghan (11 August 2012) and Saravan (16 April 2013). Outstanding anomalies were observed 7 and 5 days before the Chile and Varzeghan earthquakes, respectively and also 3 and 8 days prior to the Saravan earthquake.
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Comparison of COSMIC RO Data with European Digisondes and GPS TEC measurements
NASA Astrophysics Data System (ADS)
Zakharenkova, Irina; Krypiak-Gregorczyk, Anna; Shagimuratov, Irk; Krankowski, Andrzej; Lagovsky, Anatoly
variation of NmF2 for the considered seasons depending on day-time and night-time conditions. Also it was analyzed the total elec-tron content values calculated for the nearest ground-based GPS stations located in European region. To compare GPS TEC with RO and ionosondes' data these profiles were integrated. In general bottom parts of COSMIC and ionosondes' data are in a rather good agreement while the topside can be varied greatly that is the evidence of difference in the topside parts of these profiles. GPS TEC values are greater than COSMIC and ionosondes' data as TEC contains IEC and PEC. This procedure can be useful to estimate the impact of PEC into TEC. Results of the given comparisons can be important to validate the reliability of the COSMIC iono-spheric observations using the RO technique. We acknowledge the Taiwan's National Space Organization (NSPO) and the University Corporation for Atmospheric Research (UCAR) for providing the COSMIC Data. We are grateful to European Digital Upper Atmosphere Server (DIAS) for providing the ionosondes' products and to International GNSS Service (IGS) for GPS Data.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-13
..., Including On-Site Leased Workers From Career Solutions TEC Staffing and Andrews International, Fort Smith... Staffing, Fort Smith, Arkansas. The notice was published in the Federal Register on October 25, 2010 (75 FR... reports that workers leased from Andrews International were employed on-site at the Fort Smith, Arkansas...
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A comparison of TEC fluctuations and scintillations at Ascension Island
NASA Astrophysics Data System (ADS)
Basu, S.; Groves, K. M.; Quinn, J. M.; Doherty, P.
1999-11-01
With increasing reliance on space-based platforms for global navigation and communication, concerns about the impact of ionospheric scintillation on these systems have become a high priority. Recently, the Air Force Research Laboratory (AFRL) performed amplitude scintillation measurements of L1 (1.575 MHz) signals from GPS satellites at Ascension Island (14.45° W, 7.95° S; magnetic latitude 16° S) during February-April, 1998, to compare amplitude scintillations with fluctuations of the total electron content (TEC). Ascension Island is located in the South Atlantic under the southern crest of the equatorial anomaly of F2 ionization where scintillations will be much enhanced during the upcoming solar maximum period. Ascension Island is included in the global network of the International GPS Service (IGS) and the GPS receivers in this network report the carrier to noise (C/N) ratio, the dual frequency carrier phase and pseudorange data at 30-s intervals. Such data with a sampling interval of 30 s were analyzed to determine TEC, the rate of change of TEC (ROT) and also ROTI, defined as the standard deviation of ROT. The spatial scale of ROTI, sampled at 30 s interval, will correspond to 6 km when the vector sum of the ionospheric projection of the satellite velocity and the irregularity drift orthogonal to the propagation path is of the order of 100 m/s. On the other hand, the scale-length of the amplitude scintillation index corresponds to the Fresnel dimension which is about 400 m for the GPS L1 frequency and an ionospheric height of 400 km. It is shown that, in view of the co-existence of large and small scale irregularities in equatorial irregularity structures, during the early evening hours, and small magnitude of irregularity drifts, ROTI measurements can be used to predict the presence of scintillation causing irregularities. The quantitative relationship between ROTI and S4, however, varies considerably due to variations of the ionospheric projection of the
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NASA Astrophysics Data System (ADS)
Rakoto, Virgile; Lognonné, Philippe; Rolland, Lucie; Coïsson, Pierdavide; Drilleau, Mélanie
2017-04-01
Large underwater earthquakes (Mw > 7) can transmit part of their energy to the surrounding ocean through large sea-floor motions, generating tsunamis that propagate over long distances. The forcing effect of tsunami waves on the atmosphere generate internal gravity waves which produce detectable ionospheric perturbations when they reach the upper atmosphere. Theses perturbations are frequently observed in the total electron content (TEC) measured by the multi-frequency Global navigation Satellite systems (GNSS) data (e.g., GPS,GLONASS). In this paper, we performed for the first time an inversion of the sea level anomaly using the GPS TEC data using a least square inversion (LSQ) through a normal modes summation modeling technique. Using the tsunami of the 2012 Haida Gwaii in far field as a test case, we showed that the amplitude peak to peak of the sea level anomaly inverted using this method is below 10 % error. Nevertheless, we cannot invert the second wave arriving 20 minutes later. This second wave is generaly explain by the coastal reflection which the normal modeling does not take into account. Our technique is then applied to two other tsunamis : the 2006 Kuril Islands tsunami in far field, and the 2011 Tohoku tsunami in closer field. This demonstrates that the inversion using a normal mode approach is able to estimate fairly well the amplitude of the first arrivals of the tsunami. In the future, we plan to invert in real the TEC data in order to retrieve the tsunami height.
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Temporal evolution of the EIA along 95°E as obtained from GNSS TEC measurements and SAMI3 model
NASA Astrophysics Data System (ADS)
Kakoti, Geetashree; Kalita, Bitap Raj; Hazarika, Rumajyoti; Bhuyan, Pradip Kumar; Sharma, Sanjay; Tiwari, Ramesh Chandra
2018-06-01
The total electron content (TEC) derived from GNSS measurements at a trans-hemispheric meridional chain of ground stations around 95°E longitude are used to study the quiet time inter-hemispheric structure and dynamics of the equatorial ionization anomaly (EIA) during the period March 2015 to February 2016. The stations are Dibrugarh (27.5°N, 95°E, 43° dip), Kohima (25.6°N, 94.1°E, 39° dip), Aizawl (23.7°N, 92.8°E, 36° dip), Port Blair (11.63°N, 92.71°E, 9° dip) and Cocos Islands (12.2°S, 96.8°E, 43° dip). The observation shows that the northern crest of the EIA lies in the south of 23°N (Aizawl) in all seasons but recedes further south towards the equator during December solstice. The largest poleward expansion of the northern (southern) EIA is observed in the March equinox (December solstice). The equinoctial and hemispherical asymmetry of TEC is noted. The winter anomaly is observed in the northern hemisphere but not in the southern hemisphere. The highest midday TEC over any station is observed in the March equinox. The TEC in southern summer (December solstice) is significantly higher than that in the northern summer (June solstice). The observed northern EIA contracts equatorward in the postsunset period of solstice but the southern EIA persists late into the midnight in the December solstice. The asymmetry may be attributed to the different geographic location of the magnetically conjugate stations. The SAMI3 simulations broadly capture the EIA structure and the inter-hemispheric asymmetry during solstices. The difference between observations and the SAMI3 is higher in March equinox and December solstice. The higher E × B vertical drift in the 90-100°E sector and the large geographic-geomagnetic offset in observing stations may have contributed to the observed differences.
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NASA Astrophysics Data System (ADS)
Akhoondzadeh, M.
2014-02-01
A powerful earthquake of Mw = 7.7 struck the Saravan region (28.107° N, 62.053° E) in Iran on 16 April 2013. Up to now nomination of an automated anomaly detection method in a non linear time series of earthquake precursor has been an attractive and challenging task. Artificial Neural Network (ANN) and Particle Swarm Optimization (PSO) have revealed strong potentials in accurate time series prediction. This paper presents the first study of an integration of ANN and PSO method in the research of earthquake precursors to detect the unusual variations of the thermal and total electron content (TEC) seismo-ionospheric anomalies induced by the strong earthquake of Saravan. In this study, to overcome the stagnation in local minimum during the ANN training, PSO as an optimization method is used instead of traditional algorithms for training the ANN method. The proposed hybrid method detected a considerable number of anomalies 4 and 8 days preceding the earthquake. Since, in this case study, ionospheric TEC anomalies induced by seismic activity is confused with background fluctuations due to solar activity, a multi-resolution time series processing technique based on wavelet transform has been applied on TEC signal variations. In view of the fact that the accordance in the final results deduced from some robust methods is a convincing indication for the efficiency of the method, therefore the detected thermal and TEC anomalies using the ANN + PSO method were compared to the results with regard to the observed anomalies by implementing the mean, median, Wavelet, Kalman filter, Auto-Regressive Integrated Moving Average (ARIMA), Support Vector Machine (SVM) and Genetic Algorithm (GA) methods. The results indicate that the ANN + PSO method is quite promising and deserves serious attention as a new tool for thermal and TEC seismo anomalies detection.
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NASA Technical Reports Server (NTRS)
Choi, Michael K.
2017-01-01
An innovative thermal design concept to maintain comet surface samples cold (for example, 263 degrees Kelvin, 243 degrees Kelvin or 223 degrees Kelvin) from Earth approach through retrieval is presented. It uses paraffin phase change material (PCM), Cryogel insulation and thermoelectric cooler (TEC), which are commercially available.
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Stiff, Andrew; Trikha, Prashant; Wesolowski, Robert; Kendra, Kari; Hsu, Vincent; Uppati, Sarvani; McMichael, Elizabeth; Duggan, Megan; Campbell, Amanda; Keller, Karen; Landi, Ian; Zhong, Yiming; Dubovsky, Jason; Howard, John Harrison; Yu, Lianbo; Harrington, Bonnie; Old, Matthew; Reiff, Sean; Mace, Thomas; Tridandapani, Susheela; Muthusamy, Natarajan; Caligiuri, Michael A; Byrd, John C; Carson, William E
2016-04-15
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125-36. ©2016 AACR. ©2016 American Association for Cancer Research.
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Qadri, S M; Johnson, S; Smith, J C; Zubairi, S; Gillum, R L
1981-01-01
The ability of several anaerobic bacteria to hydrolyze esculin to esculetin is used by clinical microbiologists and taxonomists in the differentiation and identification of both gram-positive and gram-negative microorganisms. Conventional methods used for determining esculin hydrolysis by anaerobic bacteria require 24 to 48 h for completion. In this paper we evaluate two procedures which yield rapid results. A total of 738 anaerobic bacteria were used in this study. A total of 99% of the esculin-hydrolyzing anaerobic bacteria gave positive results with the spot test in 1 h, whereas the other test method, the PathoTec strip test (General Diagnostics, Morris Plains, N.J.), required 4 h for 96% of the strains tested to yield positive reactions. Both tests showed a 100% specificity when compared with the standard broth test and are easy to perform, accurate, and economical. The spot test is superior to the PathoTec strip test in yielding results more rapidly. PMID:7016896
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NASA Technical Reports Server (NTRS)
Ho, C.; Wilson, B.; Mannucci, A.; Lindqwister, U.; Yuan, D.
1997-01-01
Global ionospheric mapping (GIM) is a new, emerging technique for determining global ionospheric TEC (total electron content) based on measurements from a worldwide network of Global Positioning System (GPS) receivers.
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NASA Astrophysics Data System (ADS)
Bhuyan, Pradip; Yokoyama, Tatsuhiro; Kalita, Bitap Raj; Seemala, G. K.; Hazarika, Rumajyoti; Komolmis, Tharadol; Yatini, Clara; Chakrabarty, Dibyendu; Supnithi, Pornchai
2016-07-01
The response of the ionosphere along 100°E to the strong geomagnetic storm of 17-18 March 2015 has been investigated combining TEC and NmF2 data from multiple stations spanning low latitudes in the northern and southern hemispheres to the equator. The GPS TEC data measured over Dibrugarh (27.4°N, 95°E), Kohima (25.6°N, 94.1°E) and Ahmedabad (23.0°N, 72.5°E) and NmF2 measured along a chain of ionosonde stations Dibrugarh (27.5°N, 95°E), Chiang Mai (18.76ºN, 98.93ºE), Chumphon (10.72ºN,99.37ºE), Kototabang (0.2ºS,100.32ºE) and Cocos Island (12.2ºS,96.8ºE ) were used to examine the signature of the storm around the low-mid latitude ionosphere in this sector. Nearly similar TEC variation has been observed over Dibrugarh and Kohima located at the northern edge of the EIA. The maximum TEC on 18 March over Dibrugarh and Kohima was reduced by more than ~80 TECU compared to that on the geomagnetically quiet day of 16 March 2015. In contrast to the substantial reduction in TEC over ~100°E TEC from the ~75°E longitude station Ahmedabad showed insignificant variations on the same day. Strong reduction in NmF2 at the crest of the anomaly in both northern and southern hemisphere (Dibrugarh, Ching Mai and Cocos Island) and enhancement near the equator (Cumphon and Kototbang) has been observed. The O/N2 ratio as obtained from the TIMED/GUVI reduced substantially along 100°E on 18 March compared to other longitude sectors. Equatorward meridional winds depleted the ionization at the crest region and enhanced the same near the equator. No L band scintillation was observed in the evening of 17 March at Dibrugarh and Kohima indicating absence of F region irregularity along this longitude while strong scintillations were observed at 75°E. The reversal of the IMF Bz from southward to northward direction in the dusk to evening sector inhibited the growth of the irregularity due to reversal of the PPEF at 100°E while the PPEF favoured generation and growth of Spread F
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Detection of Natural Hazards Generated TEC Perturbations and Related New Applications
NASA Astrophysics Data System (ADS)
Komjathy, A.; Yang, Y.; Langley, R. B.
2013-12-01
Natural hazards, including earthquakes, volcanic eruptions, and tsunamis, have been significant threats to humans throughout recorded history. The Global Positioning System satellites have become primary sensors to measure signatures associated with such natural hazards. These signatures typically include GPS-derived seismic deformation measurements, co-seismic vertical displacements, and real-time GPS-derived ocean buoy positioning estimates. Another way to use GPS observables is to compute the ionospheric total electron content (TEC) to measure and monitor post-seismic ionospheric disturbances caused by earthquakes, volcanic eruptions, and tsunamis. Research at the University of New Brunswick (UNB) laid the foundations to model the three-dimensional ionosphere at NASA's Jet Propulsion Laboratory by ingesting ground- and space-based GPS measurements into the state-of-the-art Global Assimilative Ionosphere Modeling (GAIM) software. As an outcome of the UNB and NASA research, new and innovative GPS applications have been invented including the use of ionospheric measurements to detect tiny fluctuations in the GPS signals between the spacecraft and GPS receivers caused by natural hazards occurring on or near the Earth's surface. This continuing research is expected to provide early warning for tsunamis, earthquakes, volcanic eruptions, and meteor impacts, for example, using GPS and other global navigation satellite systems. We will demonstrate new and upcoming applications including recent natural hazards and artificial explosions that generated TEC perturbations to perform state-of-the-art imaging and modeling of earthquakes, tsunamis and meteor impacts. By studying the propagation properties of ionospheric perturbations generated by natural hazards along with applying sophisticated first-principles physics-based modeling, we are on track to develop new technologies that can potentially save human lives and minimize property damage.
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NASA Astrophysics Data System (ADS)
Paul, K. S.; Das, A.; Ray, S.; Paul, A.
2016-01-01
The equatorial ionosphere presents some of the highest TEC values in the world coupled with observations of periodic structures. Total Electron Content (TEC) and scintillation data were analyzed from a chain of stations Calcutta (22.58°N, 88.38°E geographic; 32°N magnetic dip), Baharampore (24.09°N, 88.25°E geographic; 35°N magnetic dip) and Farakka (24.79°N, 87.89°E geographic; 36.04°N magnetic dip) situated almost same meridian (88.5°E) during September 2011 and March-April 2012 for elevation greater than 20° so that the ionosphere can be tracked from the 15.50°N south of Calcutta to 31.80°N north of Farakka. Periodic variation of TEC was noticed before TEC bite out, predominantly within a particular latitudinal swath (19°N ‒26°N) along 88.5°E meridian. No periodic structures were observed over the magnetic equator during the observation period on ionosonde records from the magnetic equator station Trivandrum and COSMIC, GRACE and C/NOFS electron density measurements. The present paper reports, perhaps for the first time from the Indian longitude sector, confinement of such periodic structures in TEC primarily within a latitude swath of 19.00-26.00 °N almost along the same longitude of 88.5 °E.
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NASA Astrophysics Data System (ADS)
Akhoondzadeh, M.
2013-08-01
On 6 February 2013, at 12:12:27 local time (01:12:27 UTC) a seismic event registering Mw 8.0 struck the Solomon Islands, located at the boundaries of the Australian and Pacific tectonic plates. Time series prediction is an important and widely interesting topic in the research of earthquake precursors. This paper describes a new computational intelligence approach to detect the unusual variations of the total electron content (TEC) seismo-ionospheric anomalies induced by the powerful Solomon earthquake using genetic algorithm (GA). The GA detected a considerable number of anomalous occurrences on earthquake day and also 7 and 8 days prior to the earthquake in a period of high geomagnetic activities. In this study, also the detected TEC anomalies using the proposed method are compared to the results dealing with the observed TEC anomalies by applying the mean, median, wavelet, Kalman filter, ARIMA, neural network and support vector machine methods. The accordance in the final results of all eight methods is a convincing indication for the efficiency of the GA method. It indicates that GA can be an appropriate non-parametric tool for anomaly detection in a non linear time series showing the seismo-ionospheric precursors variations.
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NASA Astrophysics Data System (ADS)
Chapin, Edward L.; Pope, Alexandra; Scott, Douglas; Aretxaga, Itziar; Austermann, Jason E.; Chary, Ranga-Ram; Coppin, Kristen; Halpern, Mark; Hughes, David H.; Lowenthal, James D.; Morrison, Glenn E.; Perera, Thushara A.; Scott, Kimberly S.; Wilson, Grant W.; Yun, Min S.
2009-10-01
We present results from a multiwavelength study of 29 sources (false detection probabilities <5 per cent) from a survey of the Great Observatories Origins Deep Survey-North (GOODS-N) field at 1.1mm using the Astronomical Thermal Emission Camera (AzTEC). Comparing with existing 850μm Submillimetre Common-User Bolometer Array (SCUBA) studies in the field, we examine differences in the source populations selected at the two wavelengths. The AzTEC observations uniformly cover the entire survey field to a 1σ depth of ~1mJy. Searching deep 1.4GHz Very Large Array (VLA) and Spitzer 3-24μm catalogues, we identify robust counterparts for 21 1.1mm sources, and tentative associations for the remaining objects. The redshift distribution of AzTEC sources is inferred from available spectroscopic and photometric redshifts. We find a median redshift of z = 2.7, somewhat higher than z = 2.0 for 850μm selected sources in the same field, and our lowest redshift identification lies at a spectroscopic redshift z = 1.1460. We measure the 850μm to 1.1mm colour of our sources and do not find evidence for `850μm dropouts', which can be explained by the low signal-to-noise ratio of the observations. We also combine these observed colours with spectroscopic redshifts to derive the range of dust temperatures T, and dust emissivity indices β for the sample, concluding that existing estimates T ~ 30K and β ~ 1.75 are consistent with these new data.
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Panariello, Beatriz Helena Dias; Klein, Marlise I; Pavarina, Ana Claudia; Duarte, Simone
2017-01-01
Background : Infections caused by Candida spp. have been associated with formation of a biofilm, i.e. a complex microstructure of cells adhering to a surface and embedded within an extracellular matrix (ECM). Methods : The ECMs of a wild-type (WT, SN425) and two Candida albicans mutant strains, Δ/Δ tec1 (CJN2330) and Δ/Δ efg1 (CJN2302), were evaluated. Colony-forming units (cfu), total biomass (mg), water-soluble polysaccharides (WSPs), alkali-soluble polysaccharides (ASPs), proteins (insoluble part of biofilms and matrix proteins), and extracellular DNA (eDNA) were quantified. Variable-pressure scanning electron microscopy and confocal scanning laser microscopy were performed. The biovolume (μm 3 /μm 2 ) and maximum thickness (μm) of the biofilms were quantified using COMSTAT2. Results : ASP content was highest in WT (mean ± SD: 74.5 ± 22.0 µg), followed by Δ/Δ tec1 (44.0 ± 24.1 µg) and Δ/Δ efg1 (14.7 ± 5.0 µg). The protein correlated with ASPs ( r = 0.666) and with matrix proteins ( r = 0.670) in the WT strain. The population in Δ/Δ efg1 correlated with the protein ( r = 0.734) and its biofilms exhibited the lowest biomass and biovolume, and maximum thickness. In Δ/Δ tec1, ASP correlated with eDNA ( r = 0.678). Conclusion : ASP production may be linked to C. albicans cell filamentous morphology.
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NASA Astrophysics Data System (ADS)
Liu, Jann-Yenq; Chen, Yuh-Ing; Huang, Ching-Chi; Parrot, Michel; Pulinets, Sergey; Ouzounov, Dimitar
2015-04-01
This paper examines seismo-ionospheric precursors (SIPs) in the total electron content (TEC) of the global ionosphere map (GIM) and observations in the French satellite DEMETER (Detection of Electro-Magnetic Emissions Transmitted from Earthquake Regions) during the 12 May 2008 M8.0 Wenchuan earthquake. The temporal and spatial analyses on the GIM TEC are used to search SIPs of the Wenchuan earthquake. Meanwhile, both daytime and nighttime electron density (Ne), electron temperature (Te), ion density (Ni) and ion temperature (Ti) probed by DEMETER are investigated. A statistical analysis of the box-and-whisker method is utilized to see if the four DEMETER data sets 1-6 days before and after the earthquake are significantly different. The analysis is employed to investigate the epicenter and three reference areas along the same magnetic latitude discriminating the SIPs from global effects. Results show that the nighttime Ne and Ni (daytime Ti) over the epicenter significantly decrease (increase) 1-6 days before the earthquake. The intersections of the global distribution of the significant differences (or anomalous changes) in the nighttime Ne, the nighttime Ni, and the daytime Ti 1-6 days before and after the earthquake specifically appear over the epicenter. The spatial analyses confirm that SIPs of GIM TEC and DEMETER observations appearing 2-6 days before are related to the 2008 M8.0 Wenchuan earthquake.
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NASA Astrophysics Data System (ADS)
Sunda, Surendra; Vyas, B. M.
2013-10-01
global wave number 4 structure in the Indian longitudinal region spanning from ~70 to 95°E forming the upward slope of the peak in the total electron content (TEC) are reported along the crest of equatorial ionization anomaly (EIA). The continuous and simultaneous measurements from five GPS stations of GPS Aided Geo Augmented Navigation (GAGAN) network are used in this study. The long-term database (2004-2012) is utilized for examining the local time, seasonal, and solar cycle dependency on the longitudinal variations of TEC. Our results confirm the existence of longitudinal variations of TEC in accordance with wave number 4 longitudinal structure including its strength. The results suggest that these variations, in general, start to develop at ~09 LT, achieve maximum strength at 12-15 LT, and decay thereafter, the decay rate depending on the season. They are more pronounced in equinoctial season followed by summer and winter. The longitudinal variations persist beyond midnight in equinox seasons, whereas in winter, they are conspicuously absent. Interestingly, they also exhibit significant solar cycle dependence in the solstices, whereas in the equinoxes, they are independent of solar activity. The comparison of crest-to-trough ratio (CTR) in the eastern (92°E) and western (72°E) extreme longitudes reveals higher CTR on the eastern side than over the western extreme, suggesting the role of nonmigrating tides in modulating the ExB vertical drift and the consequential EIA crest formation.
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TEC data ingestion into IRI and NeQuick over the antarctic region
NASA Astrophysics Data System (ADS)
Nava, Bruno; Pezzopane, Michael; Radicella, Sandro M.; Scotto, Carlo; Pietrella, Marco; Migoya Orue, Yenca; Alazo Cuartas, Katy; Kashcheyev, Anton
2016-07-01
In the present work a comparative analysis to evaluate the IRI and NeQuick 2 models capabilities in reproducing the ionospheric behaviour over the Antarctic Region has been performed. A technique to adapt the two models to GNSS-derived vertical Total Electron Content (TEC) has been therefore implemented to retrieve the 3-D ionosphere electron density at specific locations where ionosonde data were available. In particular, the electron density profiles used in this study have been provided in the framework of the AUSPICIO (AUtomatic Scaling of Polar Ionograms and Cooperative Ionospheric Observations) project applying the Adaptive Ionospheric Profiler (AIP) to ionograms recorded at eight selected mid, high-latitude and polar ionosondes. The relevant GNSS-derived vertical TEC values have been obtained from the Global Ionosphere Maps (GIM) produced by the Center for Orbit Determination in Europe (CODE). The effectiveness of the IRI and NeQuick 2 in reconstructing the ionosphere electron density at the given locations and epochs has been primarily assessed in terms of statistical comparison between experimental and model-retrieved peak parameters values (foF2 and hmF2). The analysis results indicate that in general the models are equivalent in their ability to reproduce the critical frequency of the F2 layer and they also tend to overestimate the height of the peak electron density, especially during high solar activity periods. Nevertheless this tendency is more noticeable in NeQuick 2 than in IRI. For completeness, the statistics indicating the models bottomside reconstruction capabilities, computed as height integrated electron density profile mismodeling, will also be discussed.
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Testasicca, Miriam C de Souza; dos Santos, Mariana Silva; Machado, Leopoldo Marques; Serufo, Angela Vieira; Doro, Daniel; Avelar, Daniel; Tibúrcio, Ana Maria Leonardi; Abrantes, Christiane de Freitas; Machado-Coelho, George Luiz Lins; Grimaldi, Gabriel; Gazzinelli, Ricardo Tostes; Fernandes, Ana Paula
2014-08-29
Zoonotic visceral leishmaniasis (VL) is a widespread disease, and dogs are the main reservoirs for human parasite transmission. Hence, development of an effective vaccine that prevents disease and reduces the transmission of VL is required. As euthanasia of seropositive dogs is recommended in Brazil for VL epidemiological control, to include anti-VL canine vaccines as a mass control measure it is necessary to characterize the humoral responses induced by vaccination and if they interfere with the reactivity of vaccinated dogs in serological diagnostic tests. Leish-Tec(®) is an amastigote-specific A2 recombinant protein vaccine against canine visceral leishmaniasis (CVL) that is commercially available in Brazil. Here, we tested the immunogenicity of Leish-Tec(®) in a heterogeneous dog population by measuring A2-specific antibody responses. Healthy dogs (n=140) of various breeds were allocated to two groups: one group received Leish-Tec(®) (n=70), and the other group received a placebo (n=70). Anti-A2 or anti-Leishmania promastigote antigen (LPA) antibody levels were measured by ELISA in serum samples collected before and after vaccination. An immunochromatographic test (DPP) based on the recombinant K28 antigen was also used for serodiagnosis of CVL. Vaccinated animals, except one, remained seronegative for anti-LPA total IgG and anti-K28 antibodies. Conversely, seropositivity for anti-A2 total IgG antibodies was found in 98% of animals after vaccination. This value decreased to 81.13% at 6 months before rising again (98%), after the vaccination boost. Anti-A2 IgG2 and IgG1 titers were also increased in vaccinated animals relative to control animals. These data indicate that Leish-Tec(®) is immunogenic for dogs of different genetic backgrounds and that humoral responses induced by vaccination can be detected by A2-ELISA, but do not interfere with the LPA-ELISA and DPP diagnostic tests for CVL. Copyright © 2014 Elsevier B.V. All rights reserved.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-03-12
... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-71,714] Arkansas Lamp Manufacturing, Including On-Site Leased Workers From TEC, Van Buren, AR; Notice of Termination of Investigation... a petition filed on July 17, 2009, by a company official on behalf of workers of Arkansas Lamp...
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A new ionospheric storm scale based on TEC and foF2 statistics
NASA Astrophysics Data System (ADS)
Nishioka, Michi; Tsugawa, Takuya; Jin, Hidekatsu; Ishii, Mamoru
2017-01-01
In this paper, we propose the I-scale, a new ionospheric storm scale for general users in various regions in the world. With the I-scale, ionospheric storms can be classified at any season, local time, and location. Since the ionospheric condition largely depends on many factors such as solar irradiance, energy input from the magnetosphere, and lower atmospheric activity, it had been difficult to scale ionospheric storms, which are mainly caused by solar and geomagnetic activities. In this study, statistical analysis was carried out for total electron content (TEC) and F2 layer critical frequency (foF2) in Japan for 18 years from 1997 to 2014. Seasonal, local time, and latitudinal dependences of TEC and foF2 variabilities are excluded by normalizing each percentage variation using their statistical standard deviations. The I-scale is defined by setting thresholds to the normalized numbers to seven categories: I0, IP1, IP2, IP3, IN1, IN2, and IN3. I0 represents a quiet state, and IP1 (IN1), IP2 (IN2), and IP3 (IN3) represent moderate, strong, and severe positive (negative) storms, respectively. The proposed I-scale can be used for other locations, such as polar and equatorial regions. It is considered that the proposed I-scale can be a standardized scale to help the users to assess the impact of space weather on their systems.
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Detection of the mid-latitude Sporadic-E signal using GNSS/TEC and ALOS2 InSAR data
NASA Astrophysics Data System (ADS)
Suzuki, T.; Maeda, J.; Furuya, M.; Heki, K.
2016-12-01
Sporadic E (Es) is known to generate unusual propagation of VHF waves over long distances, which is caused by a layer of ionization that irregularly appears within the E region of the ionosphere. However, the generation mechanism of Es remains unclear, because the conventional ionosonde observation of Es has limited spatial resolution. Maeda et al. (2016) succeeded in capturing mid-latitude Es signal over Japan two-dimensionally as an image, using InSAR, and demonstrated the detailed spatial structure of Es. As InSAR is clearly useful for capturing Es, we aim to detect mid-latitude Es over Japan by InSAR, following Maeda et al. (2016). First, we chose the dates whose critical frequencies of Es (foEs) were more than 15MHz at ionosonde in Kokubunji, Wakkanai and Yamagawa in the morning and noon in 2016 from May to June; Es is known to be frequent in the local daytime of summer season. Secondly, we chose the ALOS-2/PALSAR-2 data sets whose observation area, dates and time matches the data above as closely as possible. Thirdly, we generated Global Navigation Satellite System - Total Electron Content (GNSS-TEC) map whose areas, dates and time become the same as the above and if Es appeared in GNSS-TEC map, we generate interferogram. We could detect interesting phase changes in the pair of February 17, 2016 (Master) and May 25, 2016 (Slave) along a track from Tottori to Okayama. The location of the phase shift is close to the Es on the GNSS-TEC image. Therefore, we can consider the phase shift as the edge of Es. This is the second successful detection of Es signals, using InSAR. Also, we are going to separate the Es signal from other non-dispersive signals, using split-band InSAR technique.
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Phosphorylation of the Yeast Choline Kinase by Protein Kinase C
Choi, Mal-Gi; Kurnov, Vladlen; Kersting, Michael C.; Sreenivas, Avula; Carman, George M.
2005-01-01
The Saccharomyces cerevisiae CKI1-encoded choline kinase catalyzes the committed step in phosphatidylcholine synthesis via the Kennedy pathway. The enzyme is phosphorylated on multiple serine residues, and some of this phosphorylation is mediated by protein kinase A. In this work, we examined the hypothesis that choline kinase is also phosphorylated by protein kinase C. Using choline kinase as a substrate, protein kinase C activity was dose- and time-dependent, and dependent on the concentrations of choline kinase (Km = 27 μg/ml) and ATP (Km = 15 μM). This phosphorylation, which occurred on a serine residue, was accompanied by a 1.6-fold stimulation of choline kinase activity. The synthetic peptide SRSSS25QRRHS (Vmax/Km = 17.5 mM-1 μmol min-1 mg-1) that contains the protein kinase C motif for Ser25 was a substrate for protein kinase C. A Ser25 to Ala (S25A) mutation in choline kinase resulted in a 60% decrease in protein kinase C phosphorylation of the enzyme. Phosphopeptide mapping analysis of the S25A mutant enzyme confirmed that Ser25 was a protein kinase C target site. In vivo, the S25A mutation correlated with a decrease (55%) in phosphatidylcholine synthesis via the Kennedy pathway whereas an S25D phosphorylation site mimic correlated with an increase (44%) in phosphatidylcholine synthesis. Whereas the S25A (protein kinase C site) mutation did not affect the phosphorylation of choline kinase by protein kinase A, the S30A (protein kinase A site) mutation caused a 46% reduction in enzyme phosphorylation by protein kinase C. A choline kinase synthetic peptide (SQRRHS30LTRQ) containing Ser30 was a substrate (Vmax/Km = 3.0 mM−1 μmol min−1 mg−1) for protein kinase C. Comparison of phosphopeptide maps of the wild type and S30A mutant choline kinase enzymes phosphorylated by protein kinase C confirmed that Ser30 was also a target site for protein kinase C. PMID:15919656
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NASA Astrophysics Data System (ADS)
Tao, Dan; Cao, Jinbin; Battiston, Roberto; Li, Liuyuan; Ma, Yuduan; Liu, Wenlong; Zhima, Zeren; Wang, Lanwei; Wray Dunlop, Malcolm
2017-04-01
In this paper, we report significant evidence for preseismic ionospheric anomalies in total electron content (TEC) of the global ionosphere map (GIM) and plasma density appearing on day 2 before the 17 July 2006 M7.7 south of Java earthquake. After distinguishing other anomalies related to the geomagnetic activities, we found a temporal precursor around the epicenter on day 2 before the earthquake (15 July 2006), which agrees well with the spatial variations in latitude-longitude-time (LLT) maps. Meanwhile, the sequences of latitude-time-TEC (LTT) plots reveal that the TECs on epicenter side anomalously decrease and lead to an anomalous
asymmetric
structure with respect to the magnetic equator in the daytime from day 2 before the earthquake. This anomalousasymmetric
structure disappears after the earthquake. To further confirm these anomalies, we studied the plasma data from DEMETER satellite in the earthquake preparation zone (2046.4 km in radius) during the period from day 45 before to day 10 after the earthquake, and also found that the densities of both electron and total ion in the daytime significantly increase on day 2 before the earthquake. Very interestingly, O+ density increases significantly and H+ density decreases, while He+ remains relatively stable. These results indicate that there exists a distinct preseismic signal (preseismic ionospheric anomaly) over the epicenter. -
NASA Astrophysics Data System (ADS)
Huang, C. H.; Chen, Y. I.; Liu, J. Y. G.; Huang, Y. H.
2014-12-01
Statistical evidence of the Seismo-Ionospheric Precursors (SIPs) is reported by statistically investigating the relationship between the Total Electron Content (TEC) in Global Ionosphere Map (GIM) and 56 M≥6.0 earthquakes during 1998-2013 in China. A median-based method and a z test are employed to detect the overall earthquake signatures. It is found that a reduction of positive signatures and an enhancement of negative signatures appear simultaneously on 3-5 days prior to the earthquakes in China. Finally, receiver operating characteristic (ROC) curves are used to measure the power of TEC for predicting M≥6.0 earthquakes in China.
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Sagiv-Barfi, Idit; Kohrt, Holbrook E K; Czerwinski, Debra K; Ng, Patrick P; Chang, Betty Y; Levy, Ronald
2015-03-03
Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.
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Comparison between IRI-2012 and GPS-TEC observations over the western Black Sea
NASA Astrophysics Data System (ADS)
Inyurt, Samed; Yildirim, Omer; Mekik, Cetin
2017-07-01
The ionosphere is a dynamic layer which generally changes according to radiation emitted by the sun, the movement of the earth around the sun, and sunspot activity. Variations can generally be categorized as regular or irregular variations. Both types of variation have a huge effect on radio wave propagation. In this study, we have focused on the seasonal variation effect, which is one of the regular forms of variation in terms of the ionosphere. We examined the seasonal variation over the ZONG station in Turkey for the year 2014. Our analysis results and IRI-2012 present different ideas about ionospheric activity. According to our analysed results, the standard deviation reached a maximum value in April 2014. However, the maximum standard deviation obtained from IRI-2012 was seen in February 2014. Furthermore, it is clear that IRI-2012 underestimated the VTEC values when compared to our results for all the months analysed. The main source of difference between the two models is the IRI-2012 topside ionospheric representation. IRI-2012 VTEC has been produced as a result of the integration of an electron density profile within altitudinal limits of 60-2000 km. In other words, the main problem with regard to the IRI-2012 VTEC representation is not being situated in the plasmaspheric part of the ionosphere. Therefore we propose that the plasmaspheric part should be taken into account to calculate the correct TEC values in mid-latitude regions, and we note that IRI-2012 does not supply precise TEC values for use in ionospheric studies.
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NASA Astrophysics Data System (ADS)
Jonah, O. F.; Kherani, E. A.; De Paula, E. R.
2016-03-01
In the present study, we document daytime total electron content (TEC) disturbances associated with medium-scale traveling ionospheric disturbances (MSTIDs), on few chosen geomagnetically quiet days over Southern Hemisphere of Brazilian longitude sector. These disturbances are derived from TEC data obtained using Global Navigation Satellite System (GNSS) receiver networks. From the keograms and cross-correlation maps, the TEC disturbances are identified as the MSTIDs that are propagating equatorward-eastward, having most of their average wavelengths longer in latitude than in longitude direction. These are the important outcomes of the present study which suggest that the daytime MSTIDs over Southern Hemisphere are similar to their counterparts in the Northern Hemisphere. Another important outcome is that the occurrence characteristics of these MSTIDs and that of atmospheric gravity wave (AGW) activities in the thermosphere are found to be similar on day-to-day basis. This suggests a possible connection between them, confirming the widely accepted AGW forcing mechanism for the generation of these daytime MSTIDs. The source of this AGW is investigated using the Geostationary Operational Environmental Satellite system (GOES) and Constellation Observing System for Meteorology, Ionosphere, and Climate satellite data. Finally, we provided evidences that AGWs are generated by convection activities from the tropospheric region.
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Manne, Bhanu Kanth; Badolia, Rachit; Dangelmaier, Carol; Eble, Johannes A.; Ellmeier, Wilfried; Kahn, Mark; Kunapuli, Satya P.
2015-01-01
Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an immune tyrosine activation motif (ITAM) and hemITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the intracellular domain. The mechanisms by which this receptor activates Syk are not completely understood. In this study, we identified a novel signaling mechanism in CLEC-2-mediated Syk activation. CLEC-2-mediated, but not GPVI-mediated, platelet activation and Syk phosphorylation were abolished by inhibition of PI3K, which demonstrates that PI3K regulates Syk downstream of CLEC-2. Ibrutinib, a Tec family kinase inhibitor, also completely abolished CLEC-2-mediated aggregation and Syk phosphorylation in human and murine platelets. Furthermore, embryos lacking both Btk and Tec exhibited cutaneous edema associated with blood-filled vessels in a typical lymphatic pattern similar to CLEC-2 or Syk-deficient embryos. Thus, our data show, for the first time, that PI3K and Tec family kinases play a crucial role in the regulation of platelet activation and Syk phosphorylation downstream of the CLEC-2 receptor. PMID:25767114
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Manne, Bhanu Kanth; Badolia, Rachit; Dangelmaier, Carol; Eble, Johannes A; Ellmeier, Wilfried; Kahn, Mark; Kunapuli, Satya P
2015-05-01
Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an immune tyrosine activation motif (ITAM) and hemITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the intracellular domain. The mechanisms by which this receptor activates Syk are not completely understood. In this study, we identified a novel signaling mechanism in CLEC-2-mediated Syk activation. CLEC-2-mediated, but not GPVI-mediated, platelet activation and Syk phosphorylation were abolished by inhibition of PI3K, which demonstrates that PI3K regulates Syk downstream of CLEC-2. Ibrutinib, a Tec family kinase inhibitor, also completely abolished CLEC-2-mediated aggregation and Syk phosphorylation in human and murine platelets. Furthermore, embryos lacking both Btk and Tec exhibited cutaneous edema associated with blood-filled vessels in a typical lymphatic pattern similar to CLEC-2 or Syk-deficient embryos. Thus, our data show, for the first time, that PI3K and Tec family kinases play a crucial role in the regulation of platelet activation and Syk phosphorylation downstream of the CLEC-2 receptor. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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ERIC Educational Resources Information Center
Ramsey, Sarah; Neathery, Faye; Fholer, Gwen; Weger, Elayne; Voth, Bonnie; Townsend, Joyce; Campbell, DeAnn; Boedecker, Martha
Master teachers can be influential in course revision. The Oklahoma Teacher Education Collaborative (O-TEC) teacher reform effort is a consortium of nine higher education institutions working with the National Science Foundation's (NSF's) reform effort to produce teachers better equipped for teaching science and mathematics. The reform emphasizes…
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NASA Astrophysics Data System (ADS)
Chen, Zhou; Wang, Jing-Song; Deng, Yue; Huang, Chun-Ming
2017-03-01
The spectral whitening method (SWM) has been previously proved to be very effective at identifying ionospheric disturbances on foF2 (the critical frequency of ionospheric F2 layer). To continuously investigate the strength of the new method, in this paper SWM has been used to extract the effect of geomagnetic activity on total electron content (TEC) and has been compared with the traditional 28 day running median centered (RMC) method. First, ionospheric variations during quiet and disturbed conditions are analyzed by both SWM and RMC. The results from RMC, compared with those from SWM, overestimate the disturbance occurrence by about 5-20% during the geomagnetic storms and up to 35% during the quiet time. The possible reason is that the results can be contaminated by the residuals of periodic components in the RMC identified disturbances. Meanwhile, the power spectral analysis of the disturbance field shows that the annual and diurnal variations are still significant in RMC results but very weak in SWM results, which indicates that SWM has some advantage to clean up the background variation. Finally, the analysis of the spatial correlation of the disturbance field with F10.7 and Ap illustrates that the effects of solar and geomagnetic activities from SWM are significantly reduced and enhanced, respectively. It suggests that the SWM is more effective in extracting the effect of geomagnetic activity from TEC than RMC. The relative deviation of TEC derived by SWM is more sensitive to geomagnetic activity than solar activity.
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de Mendonça, Ludmila Zanandreis; Resende, Lucilene Aparecida; Lanna, Mariana Ferreira; Aguiar-Soares, Rodrigo Dian de Oliveira; Roatt, Bruno Mendes; Castro, Renata Alves de Oliveira E; Batista, Maurício Azevedo; Silveira-Lemos, Denise; Gomes, Juliana de Assis Silva; Fujiwara, Ricardo Toshio; Rezende, Simone Aparecida; Martins-Filho, Olindo Assis; Corrêa-Oliveira, Rodrigo; Dutra, Walderez Ornelas; Reis, Alexandre Barbosa; Giunchetti, Rodolfo Cordeiro
2016-08-30
In past years, many researchers have sought canine visceral leishmaniasis (CVL) prevention through the characterization of Leishmania antigens as vaccine candidates. Despite these efforts, there is still no efficient vaccine for CVL control. In the present study, we performed a pre-clinical vaccine trial using BALB/c mice to compare the effects of the multicomponent LBSap vaccine with those of Leish-Tec® and Leishmune®. Blood was collected to determine the frequency of peripheral blood cells and to evaluate hematologic and immunophenotypic parameters. Liver and spleen samples were collected for parasitological quantification, and spleen samples were used to access the cytokine profile. When measuring total IgG and IgG1 anti-Leishmania levels after the third vaccination and L. infantum challenge, it was evident that all vaccines were able to induce humoral immune response. Regarding the innate immune response, increased levels of NK CD3(-)CD49(+) cells were the hallmark of all vaccinated groups, whereas only the Leish-Tec® group displayed a high frequency of CD14(+) monocytes after L. infantum challenge. Moreover, CD3(+)CD4(+) T cells were the main circulating lymphocytes induced after L. infantum challenge with all evaluated vaccines. Importantly, after L. infantum challenge, splenocytes from the Leishmune® vaccine produced high levels of IL-2, whereas a prominent type 1 immune response was the hallmark of the LBSap vaccine, which presented high levels of IL-2, IL-6, TNF-α, and IFN-γ. The efficacy analysis using real-time polymerase chain reaction demonstrated a reduction in the parasitism in the spleen (Leishmune®: 64 %; LBSap: 42 %; and Leish-Tec®: 36 %) and liver (Leishmune®: 71 %; LBSap: 62 %; and Leish-Tec®: 48 %). The dataset led to the conclusion that the LBSap vaccination was able to induce immune and efficacy profiles comparable with those of commercial vaccines, thus demonstrating its potential as a promising vaccine candidate for visceral
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NASA Astrophysics Data System (ADS)
Amelia, A. R.; Jusoh, MA; Shamira Idris, Ida
2017-11-01
Photovoltaic (PV) panel suffers in low conversion efficiency of the output performance affected by the elevated operating temperature of the PV panel. It is important to keep the PV panel to operate at low temperature. To address this issue, this paper proposes the cooling system using thermoelectric cooling (TEC) and water block heatsink for enhancing the PV panel output performance. These both types cooling system were designed located on the back side of the PV panel to cool down the operating temperature of the PV panel. To evaluate the function for the existing cooling systems, the experiment was subsequently performed for PV panel without and with different design of the cooling system in outdoor weather conditions. By comparing the experimental results, it is concluded that by the hybrid cooling system which combining TEC module and the water block heatsink could improve the output performance of the PV panel. By the reduction temperature of the PV panel by 16.04 %, the average output power of the PV panel has been boosted up from 8.59 W to 9.03 W. In short, the output power of the PV panel was enhanced by the reduction of the operating temperature of the PV panel.
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NASA Astrophysics Data System (ADS)
Kumar, Sanjay; Singh, Abhay Kumar
The dual frequency Global Positioning System (GPS) data recorded at Varanasi (geographic latitude 250, 16 N longitude 820, 59 E) and Kanpur (geographic latitude 260, 30 N longitude 800, 12 E) stations, near the equatorial ionosphere anomaly (EIA) in India, have been analyzed to retrieve total electron content (TEC). The daily peak value of vertical total electron content (VTEC) has been utilized to study the variability of EIA. Present paper studied monthly, seasonal and annual variations as well as solar and geomagnetic effects on EIA. It has been found that EIA yield their maximum values during the equinox months and minimum during summer and winter. The correlations of EIA with solar as well as geomagnetic indices have been also discussed. Key words: Total electron contents (TECs), EIA, GPS.
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NASA Astrophysics Data System (ADS)
Pathak, K.; Devi, M.; Barbara, A. K.; Zahan, Y.
2018-01-01
The paper aims at to study the sources associated with growth of L band scintillation over Guwahati, an Appleton anomaly region. Starting with the analysis of diurnal and seasonal characteristic features of scintillation from a minimum sunspot number (Rz) of 10 to a maximum of 140, the paper shows that scintillations are more likely to develop during high solar activity period. It also highlights the explosive increase in occurrence of scintillation from post sunset to pre midnight hours in vernal equinoctial months when the background TEC is 50% more than on a normal day, accompanied by enhanced TEC decay rate. The role of equatorial anomaly effects through EXB drift processes are brought into discussion as possible sources on the growth of small scale irregularities leading to such scintillations.
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NASA Astrophysics Data System (ADS)
Pathak, K.; Devi, M.; Barbara, A. K.; Zahan, Y.
2018-07-01
The paper aims at to study the sources associated with growth of L band scintillation over Guwahati, an Appleton anomaly region. Starting with the analysis of diurnal and seasonal characteristic features of scintillation from a minimum sunspot number (Rz) of 10 to a maximum of 140, the paper shows that scintillations are more likely to develop during high solar activity period. It also highlights the explosive increase in occurrence of scintillation from post sunset to pre midnight hours in vernal equinoctial months when the background TEC is 50% more than on a normal day, accompanied by enhanced TEC decay rate. The role of equatorial anomaly effects through EXB drift processes are brought into discussion as possible sources on the growth of small scale irregularities leading to such scintillations.
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Okuno, S; Kitani, T; Fujisawa, H
2001-10-01
Ca(2+)/calmodulin-dependent protein kinases (CaM-kinases) I and IV are activated upon phosphorylation of their Thr(177) and Thr(196), respectively, by the upstream Ca(2+)/calmodulin-dependent protein kinases CaM-kinase kinase alpha and beta, and deactivated upon dephosphorylation by protein phosphatases such as CaM-kinase phosphatase. Recent studies demonstrated that the activity of CaM-kinase kinase alpha is decreased upon phosphorylation by cAMP-dependent protein kinase (PKA), and the relationship between the inhibition and phosphorylation of CaM-kinase kinase alpha by PKA has been studied. In the present study, we demonstrate that the activity of CaM-kinase kinase alpha toward PKIV peptide, which contains the sequence surrounding Thr(196) of CaM-kinase IV, is increased by incubation with PKA in the presence of Ca(2+)/calmodulin but decreased in its absence, while the activity toward CaM-kinase IV is decreased by incubation with PKA in both the presence and absence of Ca(2+)/calmodulin. Six phosphorylation sites on CaM-kinase kinase alpha, Ser(24) for autophosphorylation, and Ser(52), Ser(74), Thr(108), Ser(458), and Ser(475) for phosphorylation by PKA, were identified by amino acid sequence analysis of the phosphopeptides purified from the tryptic digest of the phosphorylated enzymes. The presence of Ca(2+)/calmodulin suppresses phosphorylation on Ser(52), Ser(74), Thr(108), and Ser(458) by PKA, but accelerates phosphorylation on Ser(475). The changes in the activity of the enzyme upon phosphorylation appear to occur as a result of conformational changes induced by phosphorylation on several sites.
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Willey, Christopher D.; Palanisamy, Arun P.; Johnston, Rebecca K.; Mani, Santhosh K.; Shiraishi, Hirokazu; Tuxworth, William J.; Zile, Michael R.; Balasubramanian, Sundaravadivel; Kuppuswamy, Dhandapani
2008-01-01
Growth, survival and cytoskeletal rearrangement of cardiomyocytes are critical for cardiac hypertrophy. Signal transducer and activator of transcription-3 (STAT3) activation is an important cardioprotective factor associated with cardiac hypertrophy. Although STAT3 activation has been reported via signaling through Janus Kinase 2 (JAK2) in several cardiac models of hypertrophy, the importance of other nonreceptor tyrosine kinases (NTKs) has not been explored. Utilizing an in vivo feline right ventricular pressure-overload (RVPO) model of hypertrophy, we demonstrate that in 48 h pressure-overload (PO) myocardium, STAT3 becomes phosphorylated and redistributed to detergent-insoluble fractions with no accompanying JAK2 activation. PO also caused increased levels of phosphorylated STAT3 in both cytoplasmic and nuclear fractions. To investigate the role of other NTKs, we used our established in vitro cell culture model of hypertrophy where adult feline cardiomyocytes are embedded three-dimensionally (3D) in type-I collagen and stimulated with an integrin binding peptide containing an Arg-Gly-Asp (RGD) motif that we have previously shown to recapitulate the focal adhesion complex (FAC) formation of 48 h RVPO. RGD stimulation of adult cardiomyocytes in vitro caused both STAT3 redistribution and activation that were accompanied by the activation and redistribution of c-Src and the TEC family kinase, BMX, but not JAK2. However, infection with dominant negative c-Src adenovirus was unable to block RGD-stimulated changes on either STAT3 or BMX. Further analysis in vivo in 48 h PO myocardium showed the presence of both STAT3 and BMX in the detergent-insoluble fraction with their complex formation and phosphorylation. Therefore, these studies indicate a novel mechanism of BMX-mediated STAT3 activation within a PO model of cardiac hypertrophy that might contribute to cardiomyocyte growth and survival. PMID:18612371
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Willey, Christopher D; Palanisamy, Arun P; Johnston, Rebecca K; Mani, Santhosh K; Shiraishi, Hirokazu; Tuxworth, William J; Zile, Michael R; Balasubramanian, Sundaravadivel; Kuppuswamy, Dhandapani
2008-06-27
Growth, survival and cytoskeletal rearrangement of cardiomyocytes are critical for cardiac hypertrophy. Signal transducer and activator of transcription-3 (STAT3) activation is an important cardioprotective factor associated with cardiac hypertrophy. Although STAT3 activation has been reported via signaling through Janus Kinase 2 (JAK2) in several cardiac models of hypertrophy, the importance of other nonreceptor tyrosine kinases (NTKs) has not been explored. Utilizing an in vivo feline right ventricular pressure-overload (RVPO) model of hypertrophy, we demonstrate that in 48 h pressure-overload (PO) myocardium, STAT3 becomes phosphorylated and redistributed to detergent-insoluble fractions with no accompanying JAK2 activation. PO also caused increased levels of phosphorylated STAT3 in both cytoplasmic and nuclear fractions. To investigate the role of other NTKs, we used our established in vitro cell culture model of hypertrophy where adult feline cardiomyocytes are embedded three-dimensionally (3D) in type-I collagen and stimulated with an integrin binding peptide containing an Arg-Gly-Asp (RGD) motif that we have previously shown to recapitulate the focal adhesion complex (FAC) formation of 48 h RVPO. RGD stimulation of adult cardiomyocytes in vitro caused both STAT3 redistribution and activation that were accompanied by the activation and redistribution of c-Src and the TEC family kinase, BMX, but not JAK2. However, infection with dominant negative c-Src adenovirus was unable to block RGD-stimulated changes on either STAT3 or BMX. Further analysis in vivo in 48 h PO myocardium showed the presence of both STAT3 and BMX in the detergent-insoluble fraction with their complex formation and phosphorylation. Therefore, these studies indicate a novel mechanism of BMX-mediated STAT3 activation within a PO model of cardiac hypertrophy that might contribute to cardiomyocyte growth and survival.
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Held, Jürgen; Kohlberger, Isabelle; Rappold, Elfriede; Busse Grawitz, Andrea; Häcker, Georg
2013-04-01
We conducted a case-control study using the Fungitell assay, the novel Platelia Candida Antigen (Ag) Plus and Candida Antibody (Ab) Plus assays, and the Cand-Tec latex agglutination test to evaluate the usefulness of (1→3)-β-D-glucan (BDG), mannan antigen with/without anti-mannan antibody, and Cand-Tec Candida antigen measurement for the diagnosis of candidemia. A total of 56 patients fulfilled the inclusion criteria and were enrolled. One hundred patients with bacteremia and 100 patients with sterile blood cultures served as negative controls. In the candidemia group, median (1→3)-β-D-glucan, mannan antigen, and anti-mannan antibody levels were 427 pg/ml, 190 pg/ml, and 18.6 antibody units (AU)/ml, respectively. All three parameters were significantly elevated in patients with candidemia. The sensitivity and specificity were, respectively, 87.5% and 85.5% for (1→3)-β-D-glucan, 58.9% and 97.5% for mannan antigen, 62.5% and 65.0% for anti-mannan antibody, 89.3% and 63.0% for mannan antigen plus anti-mannan antibody, 89.3% and 85.0% for BDG plus mannan antigen, and 13.0% and 93.9% for Cand-Tec Candida antigen. The low mannan antigen sensitivity was in part caused by Candida parapsilosis and Candida guilliermondii fungemias, which were not detected by the Platelia Candida Ag Plus assay. When the cutoff was lowered from 125 pg/ml to 50 pg/ml, mannan antigen sensitivity increased to 69.6% without severely affecting the specificity (93.5%). Contrary to recently published data, superficial candidiasis was not associated with elevated mannan antigen levels, not even after the cutoff was lowered. Combining procalcitonin (PCT) with (1→3)-β-D-glucan to increase specificity provided a limited advantage because the benefit of the combination did not outweigh the loss of sensitivity. Our results demonstrate that the Cand-Tec Candida antigen and the mannan antigen plus anti-mannan antibody measurements have unacceptably low sensitivity or specificity. Of the four
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Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases.
Chan, Tung O; Pascal, John M; Armen, Roger S; Rodeck, Ulrich
2012-02-01
AGC kinases, including the three Akt (protein kinase B) isoforms, protein kinase A (PKA) and all protein kinase C (PKC) isoforms, require activation loop phosphorylation (threonine 308 in Akt1) as well as phosphorylation of a C-terminal residue (serine 473 in Akt1) for catalytic activity and phosphorylation of downstream targets. Conversely, phosphatases reverse these phosphorylations. Virtually all cellular processes are affected by AGC kinases, a circumstance that has led to intense scrutiny of the molecular mechanisms that regulate phosphorylation of these kinases. Here, we review a new layer of control of phosphorylation in Akt, PKA and PKC pointing to ATP binding pocket occupancy as a means to decelerate dephosphorylation of these and, potentially, other kinases. This additional level of kinase regulation opens the door to search for new functional motifs for the rational design of non- ATP-competitive kinase inhibitors that discriminate within and between protein kinase families.
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The Village Marine Tec. Generation 1 Expeditionary Unit Water Purifier (EUWP) is a mobile skid-mounted system employing ultrafiltration (UF) and reverse osmosis (RO) to produce drinking water from a variety of different water quality sources. The UF components were evaluated to t...
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Autoregulation of kinase dephosphorylation by ATP binding to AGC protein kinases
Pascal, John M; Armen, Roger S
2012-01-01
AGC kinases, including the three Akt (protein kinase B) isoforms, protein kinase A (PKA) and all protein kinase C (PKC) isoforms, require activation loop phosphorylation (threonine 308 in Akt1) as well as phosphorylation of a C-terminal residue (serine 473 in Akt1) for catalytic activity and phosphorylation of downstream targets. Conversely, phosphatases reverse these phosphorylations. Virtually all cellular processes are affected by AGC kinases, a circumstance that has led to intense scrutiny of the molecular mechanisms that regulate phosphorylation of these kinases. Here, we review a new layer of control of phosphorylation in Akt, PKA and PKC pointing to ATP binding pocket occupancy as a means to decelerate dephosphorylation of these and, potentially, other kinases. This additional level of kinase regulation opens the door to search for new functional motifs for the rational design of non-ATP-competitive kinase inhibitors that discriminate within and between protein kinase families. PMID:22262182
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NASA Astrophysics Data System (ADS)
Ansari, Kutubuddin; Panda, Sampad Kumar; Althuwaynee, Omar F.; Corumluoglu, Ozsen
2017-09-01
The present study investigates the ionospheric Total Electron Content (TEC) variations in the lower mid-latitude Turkish region from the Turkish Permanent GNSS Network (TPGN) and International GNSS Services (IGS) observations during the year 2016. The corresponding vertical TEC (VTEC) predicted by Auto Regressive Moving Average (ARMA) and International Reference Ionosphere 2016 (IRI-2016) models are evaluated to realize their effectiveness over the region. The spatial, diurnal and seasonal behavior of VTEC and the relative VTEC variations are modeled with Ordinary Least Square Estimator (OLSE). The spatial behavior of modeled result during March equinox and June solstice indicates an inverse relationship of VTEC with the longitude across the region. On the other hand, the VTEC variation during September equinox and December solstice including March equinox and June solstice are decreasing with increase in latitude. The GNSS observed and modeled diurnal variation of the VTEC show that the VTEC slowly increases with dawn, attains a broader duration of peak around 09.00 to 12.00 UT, and thereafter decreases gradually reaching minimum around 21.00 UT. The seasonal variation of VTEC shows an annual mode, maxima in equinox and minima in solstice. The average value of VTEC during the June solstice is with slightly higher value than the March equinox though variations during the latter season is more. Moreover, the study shows minimum average value during December solstice compared to June solstice at all stations. The comparative analysis demonstrates the prediction errors by OLSE, ARMA and IRI remaining between 0.23 to 1.17%, 2.40 to 4.03% and 24.82 to 25.79% respectively. Also, the observed VTEC seasonal variation has good agreement with OLSE and ARMA models whereas IRI-VTEC often underestimated the observed value at each location. Hence, the deviations of IRI estimated VTEC compared to ARMA and OLSE models claim further improvements in IRI model over the Turkish region
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Roth Flach, Rachel J; Danai, Laura V; DiStefano, Marina T; Kelly, Mark; Menendez, Lorena Garcia; Jurczyk, Agata; Sharma, Rohit B; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K; Bortell, Rita; Alonso, Laura C; Czech, Michael P
2016-07-29
Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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Regina-Silva, Shara; Feres, Ana Maria Leonardi Tibúrcio; França-Silva, João Carlos; Dias, Edelberto Santos; Michalsky, Érika Monteiro; de Andrade, Hélida Monteiro; Coelho, Eduardo Antonio Ferraz; Ribeiro, Gustavo Meirelles; Fernandes, Ana Paula; Machado-Coelho, George Luiz Lins
2016-04-27
A canine vaccine remains a promising approach for effective control of visceral leishmaniasis (VL), given its complex epidemiology in areas where zoonotic VL is prevalent. Leish-Tec(®) is a recombinant vaccine, based on the Leishmania A2 antigen, against canine VL (CVL). It is, since 2014, the single commercial vaccine licensed in Brazil. Here, Leish-Tec(®) efficacy was estimated through a randomized field trial (RFT), in a highly VL endemic area. The RFT was conducted from 2008 to 2010 in an endemic area of southeastern Brazil, presenting a CVL seroprevalence of 41.9%. Eight hundred forty-seven seronegative dogs were randomly selected to receive Leish-Tec(®) (n=429) or placebo (n=418). Animals were followed up by clinical, serological, and parasitological exams for 18 months. The CVL incidence in both groups was compared through proportion analysis. A significant reduction in the number of cases of CVL was observed in the vaccine group, as compared with the placebo group, whether efficacy was estimated according to parasitological results (71.4%; 95% CI: 34.9-87.3%; p=0.001; risk ratio=0.287), by adding results of xenodiagnosis and parasitological exams (58.1%; 95% CI: 26.0-76.3%; p=0.002; risk ratio=0.419). Among the animals that converted to a positive anti-A2 serology, efficacy reached 80.8% (95% CI: 37.6-94.1%, p=0.001; risk ratio=0.192). Xenodiagnosis has detected a reduction of 46.6% (p=0.05) in transmission to sand flies from vaccinated animals presenting anti-A2 positive serology. The Leish-Tec(®) vaccine proved significantly effective for prophylaxis of CVL, after natural challenge assured by transmission of Leishmania parasites, in a highly endemic area. Noteworthy, this report has unveiled the complexity of performing a RFT for anti-CVL vaccines in Brazil, which may be helpful for designing of future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates
Xue, Liang; Wang, Wen-Horng; Iliuk, Anton; Hu, Lianghai; Galan, Jacob A.; Yu, Shuai; Hans, Michael; Geahlen, Robert L.; Tao, W. Andy
2012-01-01
Our understanding of the molecular control of many disease pathologies requires the identification of direct substrates targeted by specific protein kinases. Here we describe an integrated proteomic strategy, termed kinase assay linked with phosphoproteomics, which combines a sensitive kinase reaction with endogenous kinase-dependent phosphoproteomics to identify direct substrates of protein kinases. The unique in vitro kinase reaction is carried out in a highly efficient manner using a pool of peptides derived directly from cellular kinase substrates and then dephosphorylated as substrate candidates. The resulting newly phosphorylated peptides are then isolated and identified by mass spectrometry. A further comparison of these in vitro phosphorylated peptides with phosphopeptides derived from endogenous proteins isolated from cells in which the kinase is either active or inhibited reveals new candidate protein substrates. The kinase assay linked with phosphoproteomics strategy was applied to identify unique substrates of spleen tyrosine kinase (Syk), a protein-tyrosine kinase with duel properties of an oncogene and a tumor suppressor in distinctive cell types. We identified 64 and 23 direct substrates of Syk specific to B cells and breast cancer cells, respectively. Both known and unique substrates, including multiple centrosomal substrates for Syk, were identified, supporting a unique mechanism that Syk negatively affects cell division through its centrosomal kinase activity. PMID:22451900
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NASA Astrophysics Data System (ADS)
Thampi, Smitha V.; Yamamoto, Mamoru
2010-03-01
A chain of newly designed GNU (GNU is not UNIX) Radio Beacon Receivers (GRBR) has recently been established over Japan, primarily for tomographic imaging of the ionosphere over this region. Receivers installed at Shionomisaki (33.45°N, 135.8°E), Shigaraki (34.8°N, 136.1°E), and Fukui (36°N, 136°E) continuously track low earth orbiting satellites (LEOS), mainly OSCAR, Cosmos, and FORMOSAT-3/COSMIC, to obtain simultaneous total electron content (TEC) data from these three locations, which are then used for the tomographic reconstruction of ionospheric electron densities. This is the first GRBR network established for TEC observations, and the first beacon-based tomographic imaging in Japanese longitudes. The first tomographic images revealed the temporal evolution with all of the major features in the ionospheric electron density distribution over Japan. A comparison of the tomographically reconstructed electron densities with the ƒ o F 2 data from Kokubunji (35°N, 139°E) revealed that there was good agreement between the datasets. These first results show the potential of GRBR and its network for making continuous, unattended ionospheric TEC measurements and for tomographic imaging of the ionosphere.
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NASA Astrophysics Data System (ADS)
Miettinen, O.; Delvecchio, I.; Smolčić, V.; Novak, M.; Aravena, M.; Karim, A.; Murphy, E. J.; Schinnerer, E.; Capak, P.; Ilbert, O.; Intema, H. T.; Laigle, C.; McCracken, H. J.
2017-01-01
Context. Submillimetre galaxies (SMGs) in the early Universe are potential antecedents of the most massive galaxies we see in the present-day Universe. An important step towards quantifying this galactic evolutionary connection is to investigate the fundamental physical properties of SMGs, such as their stellar mass content (M⋆) and star formation rate (SFR). Aims: We attempt to characterise the physical nature of a 1.1 mm selected, flux-limited, and interferometrically followed up sample of SMGs in the COSMOS field. Methods: We used the latest release of the MAGPHYS code to fit the multiwavelength (UV to radio) spectral energy distributions (SEDs) of 16 of the target SMGs, which lie at redshifts z ≃ 1.6-5.3. We also constructed the pure radio SEDs of our SMGs using three different radio bands (325 MHz, 1.4 GHz, and 3 GHz). Moreover, since two SMGs in our sample, AzTEC 1 and AzTEC 3, benefit from previous 12C16O line observations, we studied their properties in more detail. Results: The median and 16th-84th percentile ranges of M⋆, infrared (8-1000 μm) luminosity (LIR), SFR, dust temperature (Tdust), and dust mass (Mdust) were derived to be log (M⋆/M⊙) = 10.96+ 0.34-0.19, log (LIR/L⊙) = 12.93+ 0.09-0.19, SFR = 856+ 191-310M⊙ yr-1, Tdust = 40.6+ 7.5-8.1 K, and log (Mdust/M⊙) = 9.17+ 0.03-0.33, respectively. We found that 63% of our target SMGs lie above the galaxy main sequence by more than a factor of 3 and, hence, are starbursts. The 3 GHz radio sizes we have previously measured for the target SMGs were compared with the present M⋆ estimates, and we found that the z> 3 SMGs are fairly consistent with the mass-size relationship of z 2 compact, quiescent galaxies (cQGs). The median radio spectral index is found to be α = -0.77+ 0.28-0.42. The median IR-radio correlation parameter is found to be q = 2.27+ 0.27-0.13, which is lower than was measured locally (median q = 2.64). The gas-to-dust mass ratio for AzTEC 1 is derived to be δgdr = 90+ 23
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NASA Astrophysics Data System (ADS)
Singh, Dhananjali; Singh, Birbal; Pundhir, Devbrat
2018-04-01
Employing SoftPAL receiver, amplitude variations of VLF transmitter signals NWC (19.8 kHz) and NPM (21.4 kHz) are analyzed at Agra station in India (Geograph. lat. 27.2°N, long. 78°E) ±15 days from five major earthquakes of magnitude M = 6.9-8.5 occurred in Indian subcontinent during the years 2011-2013. We apply nighttime fluctuation (NF) method and show that in almost all cases the trend decreases and dispersion and NF increase on the same days corresponding to each earthquake about 11-15 days prior to the main shock. Assuming that the ionospheric perturbations are caused by atmospheric gravity waves (AGW), we also calculate AGW modulation index for each case and find its values increased on the days amplitude fluctuations take place. Its value is decreased in one case only where the perturbations may be attributed to penetration of seismogenic electric field. In order to support the above results we also present GPS-TEC data analyzed by us corresponding to three of the above earthquakes. We study the TEC anomalies (unusual enhancements) and find that in one case the precursory period is almost the same as that found in NF method.
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NASA Astrophysics Data System (ADS)
Contadakis, Michael E.; Arabelos, Demetrios N.; Vergos, George; Spatala, Spyrous; Skeberis, Christos; Xenos, Tomas D.; Biagi, Pierfrancesco; Scordilis, Emmanuel M.
2017-04-01
In this paper we investigate the ionospheric turbulence from TEC variations and VLF/LF transmitter signal observations before and during the disastrous seismic activity of August and October 2016 in Central Italy . The Total Electron Content (TEC) data of 8 Global Positioning System (GPS) stations of the EUREF network, which are being provided by IONOLAB (Turkey), were analysed using Discrete Fourier Analysis in order to investigate the TEC variations (Contadakis et al. 2009, Contadakis et al. 2012, Contadakis et al. 2015). The data acquired for VLF/LF signal observations are from the receiver of Thessaloniki(40.59N, 22,78E), Greece (Skeberis et al. 2015) which monitor the VLF/LF transmitters of the International Network for Frontier Research on Earthquake Precursors (INFREP). A method of normalization according to the distance between the receiver and the transmitter is applied on the above data and then they are processed by the Hilbert Huang Transform (HHT) to produce the corresponding spectra for visual analysis. The results of this investigation indicate that the High- Frequency limit fo, of the ionospheric turbulence content, increases as the site and the moment of the earthquake occurrence is approaching, pointing to the earthquake locus. In accordence ,the analyzed data from the receiver of INFREP network in Thessaloniki, Greece show that the signals from the two VLF European transmitters, Tavolara ( Italy) and Le Blanc (France), for wich the transmission path crosses the epicentral zones, indicate enhanced high frequency variations, the last ten days before the moment of the earthquake occurrence. We conclude that the LAIC mechanism through acoustic or gravity wave could explain this phenomenology. Reference Contadakis, M.E., Arabelos, D.N., Asteriadis, G., Spatalas, S.D., Pikridas, C. TEC variations over the Mediterranean during the seismic activity period of the last quarter of 2005 in the area of Greece, Nat. Hazards and Earth Syst. Sci., 8, 1267
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Digital beacon receiver for ionospheric TEC measurement developed with GNU Radio
NASA Astrophysics Data System (ADS)
Yamamoto, M.
2008-11-01
A simple digital receiver named GNU Radio Beacon Receiver (GRBR) was developed for the satellite-ground beacon experiment to measure the ionospheric total electron content (TEC). The open-source software toolkit for the software defined radio, GNU Radio, is utilized to realize the basic function of the receiver and perform fast signal processing. The software is written in Python for a LINUX PC. The open-source hardware called Universal Software Radio Peripheral (USRP), which best matches the GNU Radio, is used as a front-end to acquire the satellite beacon signals of 150 and 400 MHz. The first experiment was successful as results from GRBR showed very good agreement to those from the co-located analog beacon receiver. Detailed design information and software codes are open at the URL http://www.rish.kyoto-u.ac.jp/digitalbeacon/.
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Kohlberger, Isabelle; Rappold, Elfriede; Busse Grawitz, Andrea; Häcker, Georg
2013-01-01
We conducted a case-control study using the Fungitell assay, the novel Platelia Candida Antigen (Ag) Plus and Candida Antibody (Ab) Plus assays, and the Cand-Tec latex agglutination test to evaluate the usefulness of (1→3)-β-d-glucan (BDG), mannan antigen with/without anti-mannan antibody, and Cand-Tec Candida antigen measurement for the diagnosis of candidemia. A total of 56 patients fulfilled the inclusion criteria and were enrolled. One hundred patients with bacteremia and 100 patients with sterile blood cultures served as negative controls. In the candidemia group, median (1→3)-β-d-glucan, mannan antigen, and anti-mannan antibody levels were 427 pg/ml, 190 pg/ml, and 18.6 antibody units (AU)/ml, respectively. All three parameters were significantly elevated in patients with candidemia. The sensitivity and specificity were, respectively, 87.5% and 85.5% for (1→3)-β-d-glucan, 58.9% and 97.5% for mannan antigen, 62.5% and 65.0% for anti-mannan antibody, 89.3% and 63.0% for mannan antigen plus anti-mannan antibody, 89.3% and 85.0% for BDG plus mannan antigen, and 13.0% and 93.9% for Cand-Tec Candida antigen. The low mannan antigen sensitivity was in part caused by Candida parapsilosis and Candida guilliermondii fungemias, which were not detected by the Platelia Candida Ag Plus assay. When the cutoff was lowered from 125 pg/ml to 50 pg/ml, mannan antigen sensitivity increased to 69.6% without severely affecting the specificity (93.5%). Contrary to recently published data, superficial candidiasis was not associated with elevated mannan antigen levels, not even after the cutoff was lowered. Combining procalcitonin (PCT) with (1→3)-β-d-glucan to increase specificity provided a limited advantage because the benefit of the combination did not outweigh the loss of sensitivity. Our results demonstrate that the Cand-Tec Candida antigen and the mannan antigen plus anti-mannan antibody measurements have unacceptably low sensitivity or specificity. Of the four
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NASA Astrophysics Data System (ADS)
Komjathy, A.; Yang, Y. M.; Meng, X.; Verkhoglyadova, O. P.; Mannucci, A. J.; Langley, R. B.
2015-12-01
Natural hazards, including earthquakes, volcanic eruptions, and tsunamis, have been significant threats to humans throughout recorded history. The Global Positioning System satellites have become primary sensors to measure signatures associated with such natural hazards. These signatures typically include GPS-derived seismic deformation measurements, co-seismic vertical displacements, and real-time GPS-derived ocean buoy positioning estimates. Another way to use GPS observables is to compute the ionospheric total electron content (TEC) to measure and monitor post-seismic ionospheric disturbances caused by earthquakes, volcanic eruptions, and tsunamis. Research at the University of New Brunswick (UNB) laid the foundations to model the three-dimensional ionosphere at NASA's Jet Propulsion Laboratory by ingesting ground- and space-based GPS measurements into the state-of-the-art Global Assimilative Ionosphere Modeling (GAIM) software. As an outcome of the UNB and NASA research, new and innovative GPS applications have been invented including the use of ionospheric measurements to detect tiny fluctuations in the GPS signals between the spacecraft and GPS receivers caused by natural hazards occurring on or near the Earth's surface.We will show examples for early detection of natural hazards generated ionospheric signatures using ground-based and space-borne GPS receivers. We will also discuss recent results from the U.S. Real-time Earthquake Analysis for Disaster Mitigation Network (READI) exercises utilizing our algorithms. By studying the propagation properties of ionospheric perturbations generated by natural hazards along with applying sophisticated first-principles physics-based modeling, we are on track to develop new technologies that can potentially save human lives and minimize property damage. It is also expected that ionospheric monitoring of TEC perturbations might become an integral part of existing natural hazards warning systems.
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Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity
Anastassiadis, Theonie; Deacon, Sean W.; Devarajan, Karthik; Ma, Haiching; Peterson, Jeffrey R.
2011-01-01
Small-molecule protein kinase inhibitors are central tools for elucidating cellular signaling pathways and are promising therapeutic agents. Due to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments utilizing these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we profiled the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases using a functional assay. Quantitative analysis revealed complex and often unexpected kinase-inhibitor interactions, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can be used to identify multi-targeted inhibitors of specific, diverse kinases. The results have significant implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments that use them. PMID:22037377
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An AzTEC 1.1-mm survey for ULIRGs in the field of the Galaxy Cluster MS0451.6-0305
NASA Astrophysics Data System (ADS)
Wardlow, J. L.; Smail, Ian; Wilson, G. W.; Yun, M. S.; Coppin, K. E. K.; Cybulski, R.; Geach, J. E.; Ivison, R. J.; Aretxaga, I.; Austermann, J. E.; Edge, A. C.; Fazio, G. G.; Huang, J.; Hughes, D. H.; Kodama, T.; Kang, Y.; Kim, S.; Mauskopf, P. D.; Perera, T. A.; Scott, K. S.
2010-02-01
We have undertaken a deep (σ ~ 1.1 mJy) 1.1-mm survey of the z = 0.54 cluster MS0451.6-0305 using the AzTEC camera on the James Clerk Maxwell Telescope. We detect 36 sources with signal-to-noise ratio (S/N) >= 3.5 in the central 0.10 deg2 and present the AzTEC map, catalogue and number counts. We identify counterparts to 18 sources (50 per cent) using radio, mid-infrared, Spitzer InfraRed Array Camera (IRAC) and Submillimetre Array data. Optical, near- and mid-infrared spectral energy distributions are compiled for the 14 of these galaxies with detectable counterparts, which are expected to contain all likely cluster members. We then use photometric redshifts and colour selection to separate background galaxies from potential cluster members and test the reliability of this technique using archival observations of submillimetre galaxies. We find two potential MS0451-03 members, which, if they are both cluster galaxies, have a total star formation rate (SFR) of ~100Msolaryr-1 - a significant fraction of the combined SFR of all the other galaxies in MS0451-03. We also examine the stacked rest-frame mid-infrared, millimetre and radio emission of cluster members below our AzTEC detection limit, and find that the SFRs of mid-IR-selected galaxies in the cluster and redshift-matched field populations are comparable. In contrast, the average SFR of the morphologically classified late-type cluster population is nearly three times less than the corresponding redshift-matched field galaxies. This suggests that these galaxies may be in the process of being transformed on the red sequence by the cluster environment. Our survey demonstrates that although the environment of MS0451-03 appears to suppress star formation in late-type galaxies, it can support active, dust-obscured mid-IR galaxies and potentially millimetre-detected LIRGs.
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Archaeal Shikimate Kinase, a New Member of the GHMP-Kinase Family
Daugherty, Matthew; Vonstein, Veronika; Overbeek, Ross; Osterman, Andrei
2001-01-01
Shikimate kinase (EC 2.7.1.71) is a committed enzyme in the seven-step biosynthesis of chorismate, a major precursor of aromatic amino acids and many other aromatic compounds. Genes for all enzymes of the chorismate pathway except shikimate kinase are found in archaeal genomes by sequence homology to their bacterial counterparts. In this study, a conserved archaeal gene (gi|1500322 in Methanococcus jannaschii) was identified as the best candidate for the missing shikimate kinase gene by the analysis of chromosomal clustering of chorismate biosynthetic genes. The encoded hypothetical protein, with no sequence similarity to bacterial and eukaryotic shikimate kinases, is distantly related to homoserine kinases (EC 2.7.1.39) of the GHMP-kinase superfamily. The latter functionality in M. jannaschii is assigned to another gene (gi|1591748), in agreement with sequence similarity and chromosomal clustering analysis. Both archaeal proteins, overexpressed in Escherichia coli and purified to homogeneity, displayed activity of the predicted type, with steady-state kinetic parameters similar to those of the corresponding bacterial kinases: Km,shikimate = 414 ± 33 μM, Km,ATP = 48 ± 4 μM, and kcat = 57 ± 2 s−1 for the predicted shikimate kinase and Km,homoserine = 188 ± 37 μM, Km,ATP = 101 ± 7 μM, and kcat = 28 ± 1 s−1 for the homoserine kinase. No overlapping activity could be detected between shikimate kinase and homoserine kinase, both revealing a >1,000-fold preference for their own specific substrates. The case of archaeal shikimate kinase illustrates the efficacy of techniques based on reconstruction of metabolism from genomic data and analysis of gene clustering on chromosomes in finding missing genes. PMID:11114929
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Ibrutinib treatment ameliorates murine chronic graft-versus-host disease
Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Luznik, Leo; Hill, Geoffrey R.; Wong, Henry K.; MacDonald, Kelli K.P.; Maillard, Ivan; Koreth, John; Elias, Laurence; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Panoskaltsis-Mortari, Angela; Byrd, John C.; Blazar, Bruce R.
2014-01-01
Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell–driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell–mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. PMID:25271622
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Duong-Ly, Krisna C.; Devarajan, Karthik; Liang, Shuguang; Horiuchi, Kurumi Y.; Wang, Yuren; Ma, Haiching; Peterson, Jeffrey R.
2016-01-01
Summary Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant, mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases including ALK, LRRK2, RET, and EGFR as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development. PMID:26776524
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Marlowe, Timothy A.; Lenzo, Felicia L.; Figel, Sheila A.; Grapes, Abigail T.; Cance, William G.
2016-01-01
Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms which drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTKs) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK’s critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. Additionally, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: 1) the rapid phosphorylation and activation of RTK signaling pathways in RTKHigh cells and 2) the long-term acquisition of RTKs novel to the parental cell line in RTKLow cells. Finally, HER2+ cancer cells displayed resistance to FAK-kinase inhibition in 3D–growth assays using a HER2 isogenic system and HER2+ cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. PMID:27638858
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AzTEC half square degree survey of the SHADES fields - I. Maps, catalogues and source counts
NASA Astrophysics Data System (ADS)
Austermann, J. E.; Dunlop, J. S.; Perera, T. A.; Scott, K. S.; Wilson, G. W.; Aretxaga, I.; Hughes, D. H.; Almaini, O.; Chapin, E. L.; Chapman, S. C.; Cirasuolo, M.; Clements, D. L.; Coppin, K. E. K.; Dunne, L.; Dye, S.; Eales, S. A.; Egami, E.; Farrah, D.; Ferrusca, D.; Flynn, S.; Haig, D.; Halpern, M.; Ibar, E.; Ivison, R. J.; van Kampen, E.; Kang, Y.; Kim, S.; Lacey, C.; Lowenthal, J. D.; Mauskopf, P. D.; McLure, R. J.; Mortier, A. M. J.; Negrello, M.; Oliver, S.; Peacock, J. A.; Pope, A.; Rawlings, S.; Rieke, G.; Roseboom, I.; Rowan-Robinson, M.; Scott, D.; Serjeant, S.; Smail, I.; Swinbank, A. M.; Stevens, J. A.; Velazquez, M.; Wagg, J.; Yun, M. S.
2010-01-01
We present the first results from the largest deep extragalactic mm-wavelength survey undertaken to date. These results are derived from maps covering over 0.7deg2, made at λ = 1.1mm, using the AzTEC continuum camera mounted on the James Clerk Maxwell Telescope. The maps were made in the two fields originally targeted at λ = 850μm with the Submillimetre Common-User Bolometer Array (SCUBA) in the SCUBA Half-Degree Extragalactic Survey (SHADES) project, namely the Lockman Hole East (mapped to a depth of 0.9-1.3 mJy rms) and the Subaru/XMM-Newton Deep Field (mapped to a depth of 1.0-1.7 mJy rms). The wealth of existing and forthcoming deep multifrequency data in these two fields will allow the bright mm source population revealed by these new wide-area 1.1mm images to be explored in detail in subsequent papers. Here, we present the maps themselves, a catalogue of 114 high-significance submillimetre galaxy detections, and a thorough statistical analysis leading to the most robust determination to date of the 1.1mm source number counts. These new maps, covering an area nearly three times greater than the SCUBA SHADES maps, currently provide the largest sample of cosmological volumes of the high-redshift Universe in the mm or sub-mm. Through careful comparison, we find that both the Cosmic Evolution Survey (COSMOS) and the Great Observatories Origins Deep Survey (GOODS) North fields, also imaged with AzTEC, contain an excess of mm sources over the new 1.1mm source-count baseline established here. In particular, our new AzTEC/SHADES results indicate that very luminous high-redshift dust enshrouded starbursts (S1.1mm > 3mJy) are 25-50 per cent less common than would have been inferred from these smaller surveys, thus highlighting the potential roles of cosmic variance and clustering in such measurements. We compare number count predictions from recent models of the evolving mm/sub-mm source population to these sub-mm bright galaxy surveys, which provide important
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Crystal structure of casein kinase-1, a phosphate-directed protein kinase.
Xu, R M; Carmel, G; Sweet, R M; Kuret, J; Cheng, X
1995-01-01
The structure of a truncated variant of casein kinase-1 from Schizosaccharomyces pombe, has been determined in complex with MgATP at 2.0 A resolution. The model resembles the 'closed', ATP-bound conformations of the cyclin-dependent kinase 2 and the cAMP-dependent protein kinase, with clear differences in the structure of surface loops that impart unique features to casein kinase-1. The structure is of unphosphorylated, active conformation of casein kinase-1 and the peptide-binding site is fully accessible to substrate. Images PMID:7889932
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Marlowe, Timothy A; Lenzo, Felicia L; Figel, Sheila A; Grapes, Abigail T; Cance, William G
2016-12-01
Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTK) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. In addition, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: (i) the rapid phosphorylation and activation of RTK signaling pathways in RTK High cells and (ii) the long-term acquisition of RTKs novel to the parental cell line in RTK Low cells. Finally, HER2 +: cancer cells displayed resistance to FAK-kinase inhibition in 3D growth assays using a HER2 isogenic system and HER2 + cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. Mol Cancer Ther; 15(12); 3028-39. ©2016 AACR. ©2016 American Association for Cancer Research.
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Yu, J S; Chen, W J; Ni, M H; Chan, W H; Yang, S D
1998-08-15
Autophosphorylation-dependent protein kinase (auto-kinase) was identified from pig brain and liver on the basis of its unique autophosphorylation/activation property [Yang, Fong, Yu and Liu (1987) J. Biol. Chem. 262, 7034-7040; Yang, Chang and Soderling (1987) J. Biol. Chem. 262, 9421-9427]. Its substrate consensus sequence motif was determined as being -R-X-(X)-S*/T*-X3-S/T-. To characterize auto-kinase further, we partly sequenced the kinase purified from pig liver. The N-terminal sequence (VDGGAKTSDKQKKKAXMTDE) and two internal peptide sequences (EKLRTIV and LQNPEK/ILTP/FI) of auto-kinase were obtained. These sequences identify auto-kinase as a C-terminal catalytic fragment of p21-activated protein kinase 2 (PAK2 or gamma-PAK) lacking its N-terminal regulatory region. Auto-kinase can be recognized by an antibody raised against the C-terminal peptide of human PAK2 by immunoblotting. Furthermore the autophosphorylation site sequence of auto-kinase was successfully predicted on the basis of its substrate consensus sequence motif and the known PAK2 sequence, and was further demonstrated to be RST(P)MVGTPYWMAPEVVTR by phosphoamino acid analysis, manual Edman degradation and phosphopeptide mapping via the help of phosphorylation site analysis of a synthetic peptide corresponding to the sequence of PAK2 from residues 396 to 418. During the activation process, auto-kinase autophosphorylates mainly on a single threonine residue Thr402 (according to the sequence numbering of human PAK2). In addition, a phospho-specific antibody against a synthetic phosphopeptide containing this identified sequence was generated and shown to be able to differentially recognize the activated auto-kinase autophosphorylated at Thr402 but not the non-phosphorylated/inactive auto-kinase. Immunoblot analysis with this phospho-specific antibody further revealed that the change in phosphorylation level of Thr402 of auto-kinase was well correlated with the activity change of the kinase during both
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Yu, J S; Chen, W J; Ni, M H; Chan, W H; Yang, S D
1998-01-01
Autophosphorylation-dependent protein kinase (auto-kinase) was identified from pig brain and liver on the basis of its unique autophosphorylation/activation property [Yang, Fong, Yu and Liu (1987) J. Biol. Chem. 262, 7034-7040; Yang, Chang and Soderling (1987) J. Biol. Chem. 262, 9421-9427]. Its substrate consensus sequence motif was determined as being -R-X-(X)-S*/T*-X3-S/T-. To characterize auto-kinase further, we partly sequenced the kinase purified from pig liver. The N-terminal sequence (VDGGAKTSDKQKKKAXMTDE) and two internal peptide sequences (EKLRTIV and LQNPEK/ILTP/FI) of auto-kinase were obtained. These sequences identify auto-kinase as a C-terminal catalytic fragment of p21-activated protein kinase 2 (PAK2 or gamma-PAK) lacking its N-terminal regulatory region. Auto-kinase can be recognized by an antibody raised against the C-terminal peptide of human PAK2 by immunoblotting. Furthermore the autophosphorylation site sequence of auto-kinase was successfully predicted on the basis of its substrate consensus sequence motif and the known PAK2 sequence, and was further demonstrated to be RST(P)MVGTPYWMAPEVVTR by phosphoamino acid analysis, manual Edman degradation and phosphopeptide mapping via the help of phosphorylation site analysis of a synthetic peptide corresponding to the sequence of PAK2 from residues 396 to 418. During the activation process, auto-kinase autophosphorylates mainly on a single threonine residue Thr402 (according to the sequence numbering of human PAK2). In addition, a phospho-specific antibody against a synthetic phosphopeptide containing this identified sequence was generated and shown to be able to differentially recognize the activated auto-kinase autophosphorylated at Thr402 but not the non-phosphorylated/inactive auto-kinase. Immunoblot analysis with this phospho-specific antibody further revealed that the change in phosphorylation level of Thr402 of auto-kinase was well correlated with the activity change of the kinase during both
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NASA Astrophysics Data System (ADS)
Yun, Min S.; Scott, K. S.; Guo, Yicheng; Aretxaga, I.; Giavalisco, M.; Austermann, J. E.; Capak, P.; Chen, Yuxi; Ezawa, H.; Hatsukade, B.; Hughes, D. H.; Iono, D.; Johnson, S.; Kawabe, R.; Kohno, K.; Lowenthal, J.; Miller, N.; Morrison, G.; Oshima, T.; Perera, T. A.; Salvato, M.; Silverman, J.; Tamura, Y.; Williams, C. C.; Wilson, G. W.
2012-02-01
We report the results of the counterpart identification and a detailed analysis of the physical properties of the 48 sources discovered in our deep 1.1-mm wavelength imaging survey of the Great Observatories Origins Deep Survey-South (GOODS-S) field using the AzTEC instrument on the Atacama Submillimeter Telescope Experiment. One or more robust or tentative counterpart candidate is found for 27 and 14 AzTEC sources, respectively, by employing deep radio continuum, Spitzer/Multiband Imaging Photometer for Spitzer and Infrared Array Camera, and Large APEX Bolometer Camera 870 μm data. Five of the sources (10 per cent) have two robust counterparts each, supporting the idea that these galaxies are strongly clustered and/or heavily confused. Photometric redshifts and star formation rates (SFRs) are derived by analysing ultraviolet(UV)-to-optical and infrared(IR)-to-radio spectral energy distributions (SEDs). The median redshift of zmed˜ 2.6 is similar to other earlier estimates, but we show that 80 per cent of the AzTEC-GOODS sources are at z≥ 2, with a significant high-redshift tail (20 per cent at z≥ 3.3). Rest-frame UV and optical properties of AzTEC sources are extremely diverse, spanning 10 mag in the i- and K-band photometry (a factor of 104 in flux density) with median values of i= 25.3 and K= 22.6 and a broad range of red colour (i-K= 0-6) with an average value of i-K≈ 3. These AzTEC sources are some of the most luminous galaxies in the rest-frame optical bands at z≥ 2, with inferred stellar masses M*= (1-30) × 1010 M⊙ and UV-derived SFRs of SFRUV≳ 101-3 M⊙ yr-1. The IR-derived SFR, 200-2000 M⊙ yr-1, is independent of z or M*. The resulting specific star formation rates, SSFR ≈ 1-100 Gyr-1, are 10-100 times higher than similar mass galaxies at z= 0, and they extend the previously observed rapid rise in the SSFR with redshift to z= 2-5. These galaxies have a SFR high enough to have built up their entire stellar mass within their Hubble time
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NASA Astrophysics Data System (ADS)
Sridharan, S.
2017-10-01
The Global Positioning System deduced total electron content (TEC) data at 15°N (geomagnetic), which is the crest region of equatorial ionization anomaly, are used to study tidal variabilities during the 2013 sudden stratospheric warming (SSW) event. The results from space-time spectral analysis reveal that the amplitudes of migrating diurnal (DW1) and semidiurnal (SW2) tides are larger than those of nonmigrating tides. After the SSW onset, the amplitudes of DW1, SW2, SW1, and DS0 increase. Moreover, they show 16 day variations similar to the periodicity of the high-latitude stratospheric planetary wave (PW), suggesting that the nonmigrating tides (SW1 and DS0) are possibly generated due to nonlinear interaction of migrating tides with PW. Similar spectral analysis on temperature at 10°N obtained from the Sounding of Atmosphere by Broadband Emission Radiometry (SABER) shows that the SW2 enhances at stratospheric heights and the SW2 is more dominant at 80-90 km, but its amplitude decreases around 100 km. The amplitudes of nonmigrating tides become comparable to those of SW2 around 100 km, and their contribution becomes increasingly important at higher heights. This suggests that the nonlinear interaction between migrating tides and PW occurs at low-latitude upper mesospheric heights, as SW2 exhibits 16 day periodicity in SABER temperature at 100 km as observed in TEC. Besides, it is observed that the eastward propagating tides are less dominant than westward propagating tides in both TEC and SABER temperatures.
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NASA Astrophysics Data System (ADS)
Yu, C. Y.; Liu, J. Y. G.
2014-12-01
In this study, we examine the pre-earthquake ionospheric anomalies (PEIAs) by the electron density (Ne) and ion temperature (Ti) observed by FORMOSAT-1 (ROCSAT-1) satellite during magnitude greater than 7.0 worldwide earthquakes during 1999-2004. Meanwhile, PEIAs is also currently investigated to have a better understanding of the spatial distribution of the ROCSAT-1 SIPs. Total electron density (TEC) of the global ionosphere map (GIM) confirm that the anomalous feature appear near the epicenters before the earthquakes.
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NASA Astrophysics Data System (ADS)
Li, Zishen; Yuan, Yunbin; Wang, Ningbo; Hernandez-Pajares, Manuel; Huo, Xingliang
2015-04-01
To take maximum advantage of the increasing Global Navigation Satellite Systems (GNSS) data to improve the accuracy and resolution of global ionospheric TEC map (GIM), an approach, named Spherical Harmonic plus generalized Trigonometric Series functions (SHPTS), is proposed by integrating the spherical harmonic and the generalized trigonometric series functions on global and local scales, respectively. The SHPTS-based GIM from January 1st, 2001 to December 31st, 2011 (about one solar cycle) is validated by the ionospheric TEC from raw global GPS data, the GIM released by the current Ionospheric Associate Analysis Center (IAAC), the TOPEX/Poseidon satellite and the DORIS. The present results show that the SHPTS-based GIM over the area where no real data are available has the same accuracy level (approximately 2-6 TECu) to that released by the current IAAC. However, the ionospheric TEC in the SHPTS-based GIM over the area covered by real data is more accurate (approximately 1.5 TECu) than that of the GIM (approximately 3.0 TECu) released by the current IAAC. The external accuracy of the SHPTS-based GIM validated by the TOPEX/Poseidon and DORIS is approximately 2.5-5.5 and 1.5-4.5 TECu, respectively. In particular, the SHPTS-based GIM is the best or almost the best ranked, along with those of JPL and UPC, when they are compared with TOPEX/Poseidon measurements, and the best (in addition to UPC) when they are validated with DORIS data. With the increase in the number of GNSS satellites and contributing stations, the performance of the SHPTS-based GIM can be further improved. The SHPTS-based GIM routinely calculated using global GPS, GLONASS and BDS data will be found at the website http://www.gipp.org.cn.
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NASA Astrophysics Data System (ADS)
Thampi, S. V.; Ravindran, S.; Devasia, C. V.; Pant, T. K.; Sreelatha, P.; Sridharan, R.
The Coherent Radio Beacon Experiment (CRABEX) is aimed at investigating the equatorial ionospheric processes like the Equatorial Ionization Anomaly (EIA) and Equatorial Spread F (ESF) and their inter relationships. As a part of CRABEX program, a network of six stations covering the region from Trivandrum (8.5°N) to Nainital (29.3°N) is set up along the 77-78° E meridian. These ground receivers basically measure the slant Total Electron Content (TEC) along the line of sight from the Low Earth Orbiting satellites (NIMS). These simultaneous TEC measurements are inverted to obtain the tomographic image of the latitudinal distribution of electron densities in the meridional plane. In this paper, the tomographic images of the equatorial ionosphere along the 77-78°E meridian are presented. The crest intensities in the southern and northern hemispheres also show significant differences with seasons, showing the variability in the EIA asymmetry. The evening images give an indication of the prevailing electrodynamical conditions on different days, preceding the occurrence/non-occurrence of ESF. Apart from this, the single station TEC measurements from the Trivandrum station itself is used to estimate the EIA strength and asymmetry. Since this station is situated at the trough of the EIA, right over the dip equator, the latitudinal gradients on both northern (N) and southern (S) sides can be used to compute the EIA strength and asymmetry. These two parameters, obtained well ahead of the onset time of ESF, are shown to have a definite role on the subsequent ESF activity. Hence, both these factors are combined to define a new `forecast parameter' for the generation of ESF. It has been shown that this parameter can uniquely define the state of the `background ionosphere' conducive for the generation of ESF irregularities as early as 1600 IST. A critical value for the `forecast parameter' has been identified such that when the estimated value for `forecast parameter' exceeds
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Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase.
Qin, Qining; Downey, James M; Cohen, Michael V
2003-02-01
Adenosine and acetylcholine (ACh) trigger preconditioning by different signaling pathways. The involvement of phosphatidylinositol 3-kinase (PI3-kinase), a protein tyrosine kinase, and Src family tyrosine kinase in preconditioning was evaluated in isolated rabbit hearts. Either wortmannin (PI3-kinase blocker), genistein (tyrosine kinase blocker), lavendustin A (tyrosine kinase blocker), or 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2; Src family tyrosine kinase blocker) was given for 15 min to bracket a 5-min infusion of either adenosine or ACh (trigger phase). The hearts then underwent 30 min of regional ischemia. Infarct size for ACh alone was 9.3 +/- 3.5% of the risk zone versus 34.3 +/- 4.1% in controls. All four inhibitors blocked ACh-induced protection. When wortmannin or PP2 was infused only during the 30-min ischemic period (mediator phase), ACh-induced protection was not affected (7.4 +/- 2.1% and 9.7 +/- 1.7% infarction, respectively). Adenosine-triggered protection was not blocked by any of the inhibitors. Therefore, PI3-kinase and at least one protein tyrosine kinase, probably Src kinase, are involved in the trigger phase of ACh-induced, but not adenosine-induced, preconditioning. Neither PI3-kinase nor Src kinase is a mediator of the protection of ACh.
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NASA Astrophysics Data System (ADS)
Hughes, David; Ade, P. A.; Aretxaga, I.; Austermann, J.; Bock, J. J.; Dunlop, J.; Gaztanagal, E.; Ivison, R.; Kang, Y.; Kim, S.; Lowenthal, J.; Mauskopf, P.; Montana, A.; Plionis, M.; Scott, K.; Smail, I.; Stevens, J.; Wagg, J.; Wilson, G.; Yun, M.
2006-12-01
Aztec has recently conducted a sensitive, wide-area (300 sq. arcmin's) continuum survey at 1.1mm using the 15-m James Clerk Maxwell Telescope towards 4C41.17, a powerful high-redshift (z 3.8) radio galaxy. These Aztec data, which cover an area >40 times larger than our previous SCUBA survey, reveal a significant over-density of luminous, massive dust-enshrouded galaxies, compared to the results from lower-redshift blank-field sub-mm surveys. One natural interpretation of these new AzTEC data is that the over-density is tracing a large (5 x 5 Mpc) "proto-cluster" structure at z 3.8 associated with the environment of 4C41.17, within which the formation of ultra-luminous starburst galaxies (with rest-frame FIR luminosities >5 x 10^12 Lsun or SFRs > 500 Msun/yr) is taking place at an accelerated rate. Proving the physical association of these massive optically-faint starbursts with the environment of this high-z AGN, and not with the blank-field sub-mm population, for which 50% of the population lies at 1.9 < z < 2.9, remains an outstanding problem. In this presentation we will describe the AzTEC survey, the empirical evidence for this protocluster structure in the early universe, and the planned multi-wavelength follow-up observations of the brightest AzTEC sources towards 4C41.17 that may demonstrate that we are witnessing accelerated galaxy formation, via an increased rate of merging gas-rich galaxies within a rapidly-developing gravitational potential. AzTEC is one of the suite of instruments destined for the 50-m Large Millimeter Telescope (LMT). We will conclude this presentation with a summary of future LMT observations that will trace the evolution of obscured starformation in the dynamic environments towards a significant sample of intermediate and high-z powerful AGN with greater sensitivity and spatial resolution.
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Watterson, Scott H; De Lucca, George V; Shi, Qing; Langevine, Charles M; Liu, Qingjie; Batt, Douglas G; Beaudoin Bertrand, Myra; Gong, Hua; Dai, Jun; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Wang, Chunlei; Zhang, Yingru; Traeger, Sarah C; Pattoli, Mark A; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T; Vickery, Rodney; Discenza, Lorell N; D'Arienzo, Celia J; Zhang, Yifan; Heimrich, Elizabeth; Gillooly, Kathleen M; Taylor, Tracy L; Pulicicchio, Claudine; McIntyre, Kim W; Galella, Michael A; Tebben, Andy J; Muckelbauer, Jodi K; Chang, ChiehYing; Rampulla, Richard; Mathur, Arvind; Salter-Cid, Luisa; Barrish, Joel C; Carter, Percy H; Fura, Aberra; Burke, James R; Tino, Joseph A
2016-10-13
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
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Zhelev, Zhivko; Bakalova, Rumiana; Ohba, Hideki; Ewis, Ashraf; Ishikawa, Mitsuru; Shinohara, Yasuo; Baba, Yoshinobu
2004-07-16
Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.
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NASA Astrophysics Data System (ADS)
Akhoondzadeh, M.
2013-09-01
Anomaly detection is extremely important for forecasting the date, location and magnitude of an impending earthquake. In this paper, an Adaptive Network-based Fuzzy Inference System (ANFIS) has been proposed to detect the thermal and Total Electron Content (TEC) anomalies around the time of the Varzeghan, Iran, (Mw = 6.4) earthquake jolted in 11 August 2012 NW Iran. ANFIS is the famous hybrid neuro-fuzzy network for modeling the non-linear complex systems. In this study, also the detected thermal and TEC anomalies using the proposed method are compared to the results dealing with the observed anomalies by applying the classical and intelligent methods including Interquartile, Auto-Regressive Integrated Moving Average (ARIMA), Artificial Neural Network (ANN) and Support Vector Machine (SVM) methods. The duration of the dataset which is comprised from Aqua-MODIS Land Surface Temperature (LST) night-time snapshot images and also Global Ionospheric Maps (GIM), is 62 days. It can be shown that, if the difference between the predicted value using the ANFIS method and the observed value, exceeds the pre-defined threshold value, then the observed precursor value in the absence of non seismic effective parameters could be regarded as precursory anomaly. For two precursors of LST and TEC, the ANFIS method shows very good agreement with the other implemented classical and intelligent methods and this indicates that ANFIS is capable of detecting earthquake anomalies. The applied methods detected anomalous occurrences 1 and 2 days before the earthquake. This paper indicates that the detection of the thermal and TEC anomalies derive their credibility from the overall efficiencies and potentialities of the five integrated methods.
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Hussain, Alamdar; Mohammad, Dara K.; Mohamed, Abdalla J.; Nguyen, Vivian; Metalnikov, Pavel; Colwill, Karen; Pawson, Tony; Nore, Beston F.
2012-01-01
Bruton's tyrosine kinase (Btk), belonging to the Tec family of tyrosine kinases (TFKs), is essential for B-lymphocyte development. Abrogation of Btk signaling causes human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). We employed affinity purification of Flag-tagged Btk, combined with tandem mass spectrometry, to capture and identify novel interacting proteins. We here characterize the interaction with ankryin repeat domain 54 protein (ANKRD54), also known as Lyn-interacting ankyrin repeat protein (Liar). While Btk is a nucleocytoplasmic protein, the Liar pool was found to shuttle at a higher rate than Btk. Importantly, our results suggest that Liar mediates nuclear export of both Btk and another TFK, Txk/Rlk. Liar-mediated Btk shuttling was enriched for activation loop, nonphosphorylated Btk and entirely dependent on Btk's SH3 domain. Liar also showed reduced binding to an aspartic acid phosphomimetic SH3 mutant. Three other investigated nucleus-located proteins, Abl, estrogen receptor β (ERβ), and transcription factor T-bet, were all unaffected by Liar. We mapped the interaction site to the C terminus of the Btk SH3 domain. A biotinylated, synthetic Btk peptide, ARDKNGQEGYIPSNYVTEAEDS, was sufficient for this interaction. Liar is the first protein identified that specifically influences the nucleocytoplasmic shuttling of Btk and Txk and belongs to a rare group of known proteins carrying out this activity in a Crm1-dependent manner. PMID:22527282
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Nomura, Takahiro; Uehara, Yoshimasa; Kawajiri, Hiroo; Ryoyama, Kazuo; Yamori, Takao; Fuke, Yoko
2009-10-01
We have reported the in vitro and in vivo anticancer activities of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) derived from a Japanese spice, wasabi. In order to obtain some clues about the mechanism of the anticancer activity, we have studied the effect of alkyl isothiocyanates (MITCs) on protein kinase activities. The anti-autophosphorylation activity of MITCs with respect to the epidermal growth factor (EGF)-stimulated receptor kinase of A431 epidermoid carcinoma cells was examined by incorporation of radioactive ATP into an acid-insoluble fraction. Their anti-phosphorylation activity with respect to the non-receptor protein kinase was analyzed by a standard SDS-PAGE method. All the tested MITCs interfered with the EGF-stimulated receptor kinase activity in a dose-dependent manner, although their effects were less than 1/10 of that of erbstatin in microg/ml. On the other hand, the MITCs did not interfere with non-receptor kinases (kinase A, kinase C, tyrosine kinase and calmodulin dependent kinase III), but enhanced non-receptor tyrosine kinase. A possible anticancer mechanism of MITCs may involve the suppression of EGF receptor kinase activity and augmentation of non-receptor PTK.
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NASA Astrophysics Data System (ADS)
Smolčić, V.; Miettinen, O.; Tomičić, N.; Zamorani, G.; Finoguenov, A.; Lemaux, B. C.; Aravena, M.; Capak, P.; Chiang, Y.-K.; Civano, F.; Delvecchio, I.; Ilbert, O.; Jurlin, N.; Karim, A.; Laigle, C.; Le Fèvre, O.; Marchesi, S.; McCracken, H. J.; Riechers, D. A.; Salvato, M.; Schinnerer, E.; Tasca, L.; Toft, S.
2017-01-01
We investigate the environment of 23 submillimetre galaxies (SMGs) drawn from a signal-to-noise (S/N)-limited sample of SMGs originally discovered in the James Clerk Maxwell Telescope (JCMT)/AzTEC 1.1 mm continuum survey of a Cosmic Evolution Survey (COSMOS) subfield and then followed up with the Submillimetre Array and Plateau de Bure Interferometer at 890 μm and 1.3 mm, respectively. These SMGs already have well-defined multiwavelength counterparts and redshifts. We also analyse the environments of four COSMOS SMGs spectroscopically confirmed to lie at redshifts zspec > 4.5, and one at zspec = 2.49 resulting in a total SMG sample size of 28. We search for overdensities using the COSMOS photometric redshifts based on over 30 UV-NIR photometric measurements including the new UltraVISTA data release 2 and Spitzer/SPLASH data, and reaching an accuracy of σΔz/ (1 + z) = 0.0067 (0.0155) at z < 3.5 (>3.5). To identify overdensities we apply the Voronoi tessellation analysis, and estimate the redshift-space overdensity estimator δg as a function of distance from the SMG and/or overdensity centre. We test and validate our approach via simulations, X-ray detected groups or clusters, and spectroscopic verifications using VUDS and zCOSMOS catalogues which show that even with photometric redshifts in the COSMOS field we can efficiently retrieve overdensities out to z ≈ 5. Our results yield that 11 out of 23 (48%) JCMT/AzTEC 1.1 mm SMGs occupy overdense environments. Considering the entire JCMT/AzTEC 1.1 mm S/N ≥ 4 sample and taking the expected fraction of spurious detections into account, this means that 35-61% of the SMGs in the S/N-limited sample occupy overdense environments. We perform an X-ray stacking analysis in the 0.5-2 keV band using a 32″ aperture and our SMG positions, and find statistically significant detections. For our z < 2 subsample we find an average flux of (4.0 ± 0.8) × 10-16 erg s-1 cm-2 and a corresponding total mass of M200 = 2.8 × 1013M
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Kitani, Takako; Okuno, Sachiko; Takeuchi, Masayuki; Fujisawa, Hitoshi
2003-07-01
Ca2+/Calmodulin-dependent protein kinase (CaM kinase) regulatory system is composed of multifunctional CaM kinases such as CaM kinases IV and I, upstream CaM kinases such as CaM kinase kinases alpha and beta, which activate multifunctional CaM kinases, and CaM kinase phosphatases such as CaM kinase phosphatase and CaM kinase phosphatase N, which deactivate the activated multifunctional CaM kinases. To understand the combinations of CaM kinases I and IV, CaM kinase kinases alpha and beta, and CaM kinase phosphatases, the locations of the enzymes in the cell were examined by immunocytochemical studies of cultured cells. The results indicate that CaM kinase I, CaM kinase kinase beta, and CaM kinase phosphatase occur in the cytoplasm and that CaM kinase IV, CaM kinase kinase alpha (and CaM kinase kinase beta in some cell types and tissues), and CaM kinase phosphatase N occur inside the cellular nucleus, suggesting that there are at least two different sets of CaM kinase regulatory systems, one consisting of CaM kinase I, CaM kinase kinase beta, and CaM kinase phosphatase in the cytoplasm and the other consisting of CaM kinase IV, CaM kinase kinase alpha (and CaM kinase kinase beta in some cell types and tissues), and CaM kinase phosphatase N in the nucleus.
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Ibrutinib-A double-edge sword in cancer and autoimmune disorders.
Kokhaei, Parviz; Jadidi-Niaragh, Farhad; Sotoodeh Jahromi, Abdolreza; Osterborg, Anders; Mellstedt, Håkan; Hojjat-Farsangi, Mohammad
2016-01-01
Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton's tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.
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The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold*
Gutmann, Sascha; Hinniger, Alexandra; Fendrich, Gabriele; Drückes, Peter; Antz, Sylvie; Mattes, Henri; Möbitz, Henrik; Ofner, Silvio; Schmiedeberg, Niko; Stojanovic, Aleksandar; Rieffel, Sebastien; Strauss, André; Troxler, Thomas; Glatthar, Ralf; Sparrer, Helmut
2015-01-01
Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult, and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the x-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors. PMID:25918157
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p21-Activated kinase 5: a pleiotropic kinase.
Wen, Yi-Yang; Wang, Xiao-Xia; Pei, Dong-Sheng; Zheng, Jun-Nian
2013-12-15
The PAKs (p21-activated kinases) are highly conserved serine/threonine protein kinases which comprise six mammalian PAKs. PAK5 (p21-activated kinase 5) is the least understood member of PAKs that regulate many intracellular processes when they are stimulated by activated forms of the small GTPases Cdc42 and Rac. PAK5 takes an important part in multiple signal pathways in mammalian cells and controls a variety of cellular functions including cytoskeleton organization, cell motility and apoptosis. The main goal of this review is to describe the structure, mechanisms underlying its activity regulation, its role in apoptosis and the likely directions of further research. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Integrating segmentation methods from the Insight Toolkit into a visualization application.
Martin, Ken; Ibáñez, Luis; Avila, Lisa; Barré, Sébastien; Kaspersen, Jon H
2005-12-01
The Insight Toolkit (ITK) initiative from the National Library of Medicine has provided a suite of state-of-the-art segmentation and registration algorithms ideally suited to volume visualization and analysis. A volume visualization application that effectively utilizes these algorithms provides many benefits: it allows access to ITK functionality for non-programmers, it creates a vehicle for sharing and comparing segmentation techniques, and it serves as a visual debugger for algorithm developers. This paper describes the integration of image processing functionalities provided by the ITK into VolView, a visualization application for high performance volume rendering. A free version of this visualization application is publicly available and is available in the online version of this paper. The process for developing ITK plugins for VolView according to the publicly available API is described in detail, and an application of ITK VolView plugins to the segmentation of Abdominal Aortic Aneurysms (AAAs) is presented. The source code of the ITK plugins is also publicly available and it is included in the online version.
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NASA Astrophysics Data System (ADS)
Siefring, C. L.; Bernhardt, P. A.; Huba, J.; Krall, J.; Roddy, P. A.
2009-12-01
Unique data on ionospheric plasma irregularities from the Naval Research Laboratory (NRL) CITRIS (Scintillation and TEC Receiver in Space) instrument will be presented. CITRIS is a multi-band receiver that recorded TEC (Total Electron Content) and radio scintillations from Low-Earth Orbit (LEO) on STPSat1. The 555+/5 km altitude 35° inclination orbit covers low and mid-latitudes. The measurements require propagation from a transmitter to a receiver through the F-region plasma. CITRIS used both 1) satellite beacons in LEO, such as the NRL CERTO (Coherent Electromagnetic Radio TOmography) beacons and 2) the global network of ground-based DORIS (Doppler Orbitography and Radiopositioning Integrated by Satellite) beacons. The TEC measurements allow for tracking of ionospheric disturbances and irregularities while the measurements of scintillations can simultaneously characterize their effects. CITRIS was operated in a complementary fashion with the C/NOFS (Communication/Navigations Outages Forecasting System) satellite during most of its first year of operations. C/NOFS carries a three-frequency 150/400/1067 MHz CERTO beacon and is dedicated to the study of Spread-F. In the case of Spread-F, ionospheric irregularities start with large scale size density gradients (100s of km) and cascade through complex processes to short scale sizes (10s of meters). It is typically the 100m-1km scale features that harm communication and navigation systems through scintillations. A multi-sensor approach is needed to completely understand this complex system, such as, the combination of CITRIS remote radio sensing and C/NOFS in-situ data. Several types of irregularities have been studied including Spread-F and the newly discovered dawn-side depletions. Comparisons with the physics based SAMI3 model are being performed to help our understanding of the morphology of the irregularities.
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Human Protein Kinases and Obesity.
Engin, Atilla
2017-01-01
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified by the target amino acid in their substrates. Some protein kinases can phosphorylate both serine/threonine, as well as tyrosine residues. This group of kinases has been known as dual specificity kinases. Unlike the dual specificity kinases, a heterogeneous group of protein phosphatases are known as dual-specificity phosphatases. These phosphatases remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases. The protein kinase-phosphoproteins interactions play an important role in obesity . In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signaling pathways mainly involve the nuclear factor kappa B (NF-kappaB) and the c-Jun N-terminal kinase (JNK) systems as well as the inhibitor of kappaB-kinase beta (IKK beta). Impairment of insulin signaling in obesity is largely mediated by the activation of the IKKbeta and the JNK. Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2alpha kinase (PERK) and activating transcription factor-6. The transcriptional regulation of
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PRAK, a novel protein kinase regulated by the p38 MAP kinase.
New, L; Jiang, Y; Zhao, M; Liu, K; Zhu, W; Flood, L J; Kato, Y; Parry, G C; Han, J
1998-01-01
We have identified and cloned a novel serine/ threonine kinase, p38-regulated/activated protein kinase (PRAK). PRAK is a 471 amino acid protein with 20-30% sequence identity to the known MAP kinase-regulated protein kinases RSK1/2/3, MNK1/2 and MAPKAP-K2/3. PRAK was found to be expressed in all human tissues and cell lines examined. In HeLa cells, PRAK was activated in response to cellular stress and proinflammatory cytokines. PRAK activity was regulated by p38alpha and p38beta both in vitro and in vivo and Thr182 was shown to be the regulatory phosphorylation site. Activated PRAK in turn phosphorylated small heat shock protein 27 (HSP27) at the physiologically relevant sites. An in-gel kinase assay demonstrated that PRAK is a major stress-activated kinase that can phosphorylate small heat shock protein, suggesting a potential role for PRAK in mediating stress-induced HSP27 phosphorylation in vivo. PMID:9628874
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NASA Astrophysics Data System (ADS)
Cassol, Gian Luca; Bianucci, Giovanni; Murai, Shiaki; Falk, Günther; Scheuring, Gerd; Döbereiner, Stefan; Brück, Hans-Jürgen
2006-06-01
A 10-year old MueTec2010, white light CD measurement system, installed at DNP Photomask Europe and previously owned by STMicroelectronics, has been upgraded to fulfill the high-end optical CD measurement requirements, and to add the film thickness measurement capability. That is the ultimate upgrade, consisting of two new computers with WINDOWS 2000 operating system, a new 150X measurement objective, a new 16-bit CCD digital camera, a new tube lens for the old Leica Ergoplan microscope, and the NanoStar software with the pattern recognition option. The upgrade yielded an average 45% repeatability improvement for isolated and dense lines and spaces, with 1.2nm average repeatability in a 0.3-10μm CD nominal range. Contact holes report an average 50% repeatability improvement, with 2.5nm average repeatability. The improved precision allows a +/-2-nm CD calibration and correlation down to 0.4μm CD nominal. Overall, the upgraded MueTec2010 shows same or better performance than the already installed Leica LWM250UV CD measurement system, despite the longer illumination wavelength of the former. The improved short and long term repeatability reduced the Gauge RandR figure from 24% to 11% at +/-20nm tolerance, which qualifies the system for high-end binary mask down to 0.5μm CD nominal. The feasibility to calibrate the system for 248nm Molybdenum Silicide Phase Shifting Masks is currently being investigated. In addition to that, the new measurement algorithms, the capability to take multiple measurements within the FOV, and the pattern recognition capability included in the NanoStar software gave a 75% throughput boost to the fully automated macros for the weekly calibration tests of the laser writing tools, compared to the LWM250UV run time. With little additional hardware and software, the system has also been upgraded to include the film thickness measurement capability for the PSM resist coating process (2nd exposure), without the need for a dedicated, more expensive
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Wang, Sha-Sha; Thornton, Keith; Kuhn, Andrew M; Nadeau, James G; Hellyer, Tobin J
2003-10-01
The BD ProbeTec ET System is based on isothermal strand displacement amplification (SDA) of target nucleic acid coupled with homogeneous real-time detection using fluorescent probes. We have developed a novel, rapid method using this platform that incorporates a universal detection format for identification of single-nucleotide polymorphisms (SNPs) and other genotypic variations. The system uses a common pair of fluorescent Detector Probes in conjunction with unlabeled allele-specific Adapter Primers and a universal buffer chemistry to permit analysis of multiple SNP loci under generic assay conditions. We used Detector Probes labeled with different dyes to facilitate differentiation of two alternative alleles in a single reaction with no postamplification manipulation. We analyzed six SNPs within the human beta(2)-adrenergic receptor (beta(2)AR) gene, using whole blood, buccal swabs, and urine samples, and compared results with those obtained by DNA sequencing. Unprocessed whole blood was successfully genotyped with as little as 0.1-1 micro L of sample per reaction. All six beta(2)AR assays were able to accommodate >/==" BORDER="0">20 micro L of unprocessed whole blood. For the 14 individuals tested, genotypes determined with the six beta(2)AR assays agreed with DNA sequencing results. SDA-based allelic differentiation on the BD ProbeTec ET System can detect SNPs rapidly, using whole blood, buccal swabs, or urine.
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Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery.
Shi, Yuan; Mader, Mary
2018-06-15
A recent review of kinase inhibitors in clinical trials for brain cancer noted differences in the properties of these compounds relative to the mean property parameters associated with drugs marketed for CNS-associated conditions. However, many of these kinase drugs arose from opportunistic observations of brain activity, rather than design or flow schemes focused on optimizing CNS penetration. Thus, this digest examines kinase inhibitors that have been developed specifically for neurodegenerative indications such as Alzheimer's or Parkinson's disease, and considers design, flow scheme, and the physicochemical properties associated with compounds that have demonstrated brain penetrance. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Filippakopoulos, Panagis; Kofler, Michael; Hantschel, Oliver; Gish, Gerald D; Grebien, Florian; Salah, Eidarus; Neudecker, Philipp; Kay, Lewis E; Turk, Benjamin E; Superti-Furga, Giulio; Pawson, Tony; Knapp, Stefan
2008-09-05
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.
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Allosteric monofunctional aspartate kinases from Arabidopsis.
Curien, Gilles; Laurencin, Mathieu; Robert-Genthon, Mylène; Dumas, Renaud
2007-01-01
Plant monofunctional aspartate kinase is unique among all aspartate kinases, showing synergistic inhibition by lysine and S-adenosyl-l-methionine (SAM). The Arabidopsis genome contains three genes for monofunctional aspartate kinases. We show that aspartate kinase 2 and aspartate kinase 3 are inhibited only by lysine, and that aspartate kinase 1 is inhibited in a synergistic manner by lysine and SAM. In the absence of SAM, aspartate kinase 1 displayed low apparent affinity for lysine compared to aspartate kinase 2 and aspartate kinase 3. In the presence of SAM, the apparent affinity of aspartate kinase 1 for lysine increased considerably, with K(0.5) values for lysine inhibition similar to those of aspartate kinase 2 and aspartate kinase 3. For all three enzymes, the inhibition resulted from an increase in the apparent K(m) values for the substrates ATP and aspartate. The mechanism of aspartate kinase 1 synergistic inhibition was characterized. Inhibition by lysine alone was fast, whereas synergistic inhibition by lysine plus SAM was very slow. SAM by itself had no effect on the enzyme activity, in accordance with equilibrium binding analyses indicating that SAM binding to aspartate kinase 1 requires prior binding of lysine. The three-dimensional structure of the aspartate kinase 1-Lys-SAM complex has been solved [Mas-Droux C, Curien G, Robert-Genthon M, Laurencin M, Ferrer JL & Dumas R (2006) Plant Cell18, 1681-1692]. Taken together, the data suggest that, upon binding to the inactive aspartate kinase 1-Lys complex, SAM promotes a slow conformational transition leading to formation of a stable aspartate kinase 1-Lys-SAM complex. The increase in aspartate kinase 1 apparent affinity for lysine in the presence of SAM thus results from the displacement of the unfavorable equilibrium between aspartate kinase 1 and aspartate kinase 1-Lys towards the inactive form.
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Kitani, T; Okuno, S; Fujisawa, H
2001-10-01
We previously reported that rat brain Ca(2+)/calmodulin-dependent protein kinase (CaM-kinase) IV is inactivated by cAMP-dependent protein kinase (PKA) [Kameshita, I. and Fujisawa, H. (1991) Biochem. Biophys. Res. Commun. 180, 191-196]. In the preceding paper, we demonstrated that changes in the activity of CaM-kinase IV by PKA results from the phosphorylation of CaM-kinase kinase alpha by PKA and identified six phosphorylation sites, Ser(24) for autophosphorylation, and Ser(52), Ser(74), Thr(108), Ser(458), and Ser(475) for phosphorylation by PKA. In the present study, a causal relationship between the phosphorylation and change in the activity toward PKIV peptide has been studied using mutant enzymes with amino acid substitutions at the six phosphorylation sites. The following conclusions can be drawn from the experimental results: (i) Phosphorylation of Ser74 and/or unidentified sites causes an increase in activity; (ii) phosphorylation of Thr(108) or Ser(458) causes a decrease in the activity; (iii) the inhibitory effect of the phosphorylation of Thr(108) is canceled by the stimulatory effect of the phosphorylation, but that of Ser(458) is not; and (iv) the inhibitory effects of Thr(108) and Ser(458) are synergistic. In contrast to the activity toward PKIV peptide, the activity toward CaM-kinase IV appears to be decreased by the phosphorylation of Thr(108), but not significantly affected by the phosphorylation of Ser(458).
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2016-12-18
Seniors with chronic diseases such as heart failure have complex care needs. They are vulnerable to their condition deteriorating and, without timely intervention, may require multiple emergency department visits and/or repeated hospitalizations. Upon discharge, the transition from the emergency department to home can be a vulnerable time for recovering patients with disruptions in the continuity of care. Remote monitoring of heart failure patients using home telemonitoring, coupled with clear communication protocols between health care professionals, can be effective in increasing the safety and quality of care for seniors with heart failure discharged from the emergency department. The aim of the Telehealth for Emergency-Community Continuity of Care Connectivity via Home Telemonitoring (TEC4Home) study is to generate evidence through a programmatic evaluation and a clinical trial to determine how home telemonitoring may improve care and increase patient safety during the transition of care and determine how it is best implemented to support patients with heart failure within this context. This 4-year project consists of 3 studies to comprehensively evaluate the outcomes and effectiveness of TEC4Home. Study 1 is a feasibility study with 90 patients recruited from 2 emergency department sites to test implementation and evaluation procedures. Findings from the feasibility study will be used to refine protocols for the larger trial. Study 2 is a cluster randomized controlled trial that will include 30 emergency department sites and 900 patients across British Columbia. The primary outcome of the randomized controlled trial will be emergency department revisits and hospital readmission rates. Secondary outcomes include health care resource utilization/costs, communication between members of the care team, and patient quality of life. Study 3 will run concurrently to study 2 and test the effectiveness of predictive analytic software to detect patient deterioration
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Visualizing autophosphorylation in histidine kinases.
Casino, Patricia; Miguel-Romero, Laura; Marina, Alberto
2014-01-01
Reversible protein phosphorylation is the most widespread regulatory mechanism in signal transduction. Autophosphorylation in a dimeric sensor histidine kinase is the first step in two-component signalling, the predominant signal-transduction device in bacteria. Despite being the most abundant sensor kinases in nature, the molecular bases of the histidine kinase autophosphorylation mechanism are still unknown. Furthermore, it has been demonstrated that autophosphorylation can occur in two directions, cis (intrasubunit) or trans (intersubunit) within the dimeric histidine kinase. Here, we present the crystal structure of the complete catalytic machinery of a chimeric histidine kinase. The structure shows an asymmetric histidine kinase dimer where one subunit is caught performing the autophosphorylation reaction. A structure-guided functional analysis on HK853 and EnvZ, two prototypical cis- and trans-phosphorylating histidine kinases, has allowed us to decipher the catalytic mechanism of histidine kinase autophosphorylation, which seems to be common independently of the reaction directionality.
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Chiu, Yi-Yuan; Lin, Chih-Ta; Huang, Jhang-Wei; Hsu, Kai-Cheng; Tseng, Jen-Hu; You, Syuan-Ren; Yang, Jinn-Moon
2013-01-01
Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms. PMID:23193279
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Chang, Yu-Wen E; Bean, Ronald R; Jakobi, Rolf
2009-06-01
Elevated RhoA/Rho kinase and p21-activated kinase signaling have been shown to promote cancer development and metastasis and have drawn much attention as potential targets of anti-cancer therapy. Elevated RhoA and Rho kinase activity promote cancer cell invasion and eventually lead to metastasis by disrupting E-cadherin-mediated adherens junctions and degradation of the extracellular matrix. Elevated p21-activated kinase activity promotes invasion by stimulating cell motility but also promotes cancer cell survival and growth. In this review we describe normal functions of RhoA/Rho kinase and p21-activated kinase signaling, mechanisms that lead to constitutive activation of RhoA/Rho kinase and p21-activated kinase pathways, and processes by which constitutive RhoA/Rho kinase and p21-activated kinase activity promote cancer development and progression to more aggressive and metastatic phenotypes. In addition, we summarize relevant patents on RhoA/Rho kinase and p21-activated kinase as targets of anti-cancer therapy and discuss the clinical potential of different approaches to modulate RhoA/Rho kinase and p21-activated kinase signaling.
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NASA Astrophysics Data System (ADS)
Steussy, Calvin Nicklaus, Jr.
2001-07-01
Pyruvate Dehydrogenase Kinase is an enzyme that controls the flow of glucose through the eukaryotic cell and contributes to the pathology of diabetes mellitus. Early work on this kinase demonstrated that it has an amino acid sequence much like bacterial histidine kinases, but an activity similar to that of modern serine/threonine kinases. This project utilized the techniques of X-ray crystallography to determine molecular structure of pyruvate dehydrogenase kinase, isozyme 2. The structure was phased using selenium substituted for sulfur in methionine residues, and data at multiple wavelengths was collected at the National Synchrotron Light Source, Brookhaven National Laboratories. PDK 2 was found to fold into a two-domain monomer that forms a dimer through two beta sheets in the C-terminal domain. The N-terminal domain is an alpha-helical bundle while the C-terminal domain is an alpha/beta sandwich. The fold of the C-terminal domain is very similar to that of the prokaryotic histidine kinases, indicating that they share a common ancestor. The catalytic mechanism, however, has evolved to use general base catalysis to activate the serine substrate, rather than the direct nucleophilic attack by the imidazole sidechain used in the prokaryotic kinases. Thus, the structure of the protein echoes its prokaryotic ancestor, while the chemical mechanism has adapted to a serine substrate. The electrostatic surface of PDK2 leads to the suggestion that the lipoyl domain of the pyruvate dehydrogenase kinase, an important associated structure, may bind in the cleft formed between the N- and C-terminal domains. In addition, a network of hydrogen bonds directly connects the nucleotide binding pocket to the dimer interface, suggesting that there may be some interaction between dimer formation and ATP binding or ADP release.
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The Structure of Lombricine Kinase
Bush, D. Jeffrey; Kirillova, Olga; Clark, Shawn A.; Davulcu, Omar; Fabiola, Felcy; Xie, Qing; Somasundaram, Thayumanasamy; Ellington, W. Ross; Chapman, Michael S.
2011-01-01
Lombricine kinase is a member of the phosphagen kinase family and a homolog of creatine and arginine kinases, enzymes responsible for buffering cellular ATP levels. Structures of lombricine kinase from the marine worm Urechis caupo were determined by x-ray crystallography. One form was crystallized as a nucleotide complex, and the other was substrate-free. The two structures are similar to each other and more similar to the substrate-free forms of homologs than to the substrate-bound forms of the other phosphagen kinases. Active site specificity loop 309–317, which is disordered in substrate-free structures of homologs and is known from the NMR of arginine kinase to be inherently dynamic, is resolved in both lombricine kinase structures, providing an improved basis for understanding the loop dynamics. Phosphagen kinases undergo a segmented closing on substrate binding, but the lombricine kinase ADP complex is in the open form more typical of substrate-free homologs. Through a comparison with prior complexes of intermediate structure, a correlation was revealed between the overall enzyme conformation and the substrate interactions of His178. Comparative modeling provides a rationale for the more relaxed specificity of these kinases, of which the natural substrates are among the largest of the phosphagen substrates. PMID:21212263
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Targeting cancer with kinase inhibitors
Gross, Stefan; Rahal, Rami; Stransky, Nicolas; Lengauer, Christoph; Hoeflich, Klaus P.
2015-01-01
Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology. PMID:25932675
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Momose, Munetake; Hiramatsu, Masaaki; Tsukagoshi, Takashi
2009-08-05
We carried out an imaging survey of dust continuum emissions toward the Chamaeleon and Lupus regions. Observations were made with the 144-element bolometer array camera AzTEC mounted on the 10-meter sub-millimeter telescope ASTE during 2007-2008. The preliminary results of disk search and the cloud structure of Lupus III are presented.
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Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I; Hantschel, Oliver
2014-11-17
The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.
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NASA Astrophysics Data System (ADS)
Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I.; Hantschel, Oliver
2014-11-01
The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.
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Kim, Pora; Jia, Peilin; Zhao, Zhongming
2018-01-01
Abstract Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies. Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet. To this end, we analyzed kinase domain retention (KDR) status in chimeric protein sequences of 914 KFGs covering 312 kinases across 13 major cancer types. Based on 171 kinase domain-retained KFGs including 101 kinases, we studied their recurrence, kinase groups, fusion partners, exon-based expression depth, short DNA motifs around the break points and networks. Our results, such as more KDR than 5′-kinase fusion genes, combinatorial effects between 3′-KDR kinases and their 5′-partners and a signal transduction-specific DNA sequence motif in the break point intronic sequences, supported positive selection on 3′-kinase fusion genes in cancer. We introduced a degree-of-frequency (DoF) score to measure the possible number of KFGs of a kinase. Interestingly, kinases with high DoF scores tended to undergo strong gene expression alteration at the break points. Furthermore, our KDR gene fusion network analysis revealed six of the seven kinases with the highest DoF scores (ALK, BRAF, MET, NTRK1, NTRK3 and RET) were all observed in thyroid carcinoma. Finally, we summarized common features of ‘effective’ (highly recurrent) kinases in gene fusions such as expression alteration at break point, redundant usage in multiple cancer types and 3′-location tendency. Collectively, our findings are useful for prioritizing driver kinases and FGs and provided insights into KFGs’ clinical implications. PMID:28013235
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Heisler, Michele; Mase, Rebecca; Brown, Brianne; Wilson, Shayla; Reeves, Pamela J.
2017-01-01
Background Racial and ethnic minority adults with diabetes living in under-resourced communities face multiple barriers to sustaining self-management behaviors necessary to improve diabetes outcomes. Peer support and decision support tools each have been associated with improved diabetes outcomes. Methods 289 primarily African American adults with poor glycemic control will be recruited from the Detroit Veteran’s Administration Hospital and randomized to Technology-Enhanced Coaching (TEC) or Peer Coaching alone. Participants in both arms will be assigned a peer coach trained in autonomy-supportive approaches. Coaches are diabetes patients with prior poor glycemic control who now have good control. All participants meet face-to-face initially with their coach to review diabetes education materials and develop an action plan. Educational materials in the TEC arm are delivered via a web-based, educational tool tailored with each participant’s personalized health data (iDecide). Over the next six months, Coaches call their assigned participants once a week to provide support for weekly action steps. Data are also collected on an Observational Control group with no contact with study staff. Changes in A1c, blood pressure, other patient-centered outcomes and mediators and moderators of intervention effects will be assessed. Discussion Tailored e-Health tools with educational content may enhance the effectiveness of peer coaching programs to better prepare patients to set self-management goals, identify action plans, and discuss treatment options with their health care providers. The study will provide insights for scalable self-management support programs for diabetes and chronic illnesses that require high levels of sustained patient self-management. PMID:28132876
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Akt-RSK-S6-kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases
Moritz, Albrecht; Li, Yu; Guo, Ailan; Villén, Judit; Wang, Yi; MacNeill, Joan; Kornhauser, Jon; Sprott, Kam; Zhou, Jing; Possemato, Anthony; Ren, Jian Min; Hornbeck, Peter; Cantley, Lewis C.; Gygi, Steven P.; Rush, John; Comb, Michael J.
2011-01-01
Receptor tyrosine kinases (RTKs) activate pathways mediated by serine/threonine (Ser/Thr) kinases such as the PI3K (phosphatidylinositol 3-kinase)-Akt pathway, the Ras-MAPK (mitogen-activated protein kinase)-RSK pathway, and the mTOR (mammalian target of rapamycin)-p70 S6 pathway that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmit signals by phosphorylating substrates on a RxRxxS/T motif. Here, we developed a large-scale proteomic approach to identify over 200 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor a (PDGFRα) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTKIs as well as by inhibitors of the PI3K, mTOR, and MAPK pathways and determined the effects of siRNA directed against these substrates on cell viability. We found that phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) at Ser305 is essential for PDGFRα stabilization and cell survival in PDGFRα-dependent cancer cells. Our approach provides a new view of RTK and Akt-RSK-S6 kinase signaling, revealing many previously unidentified Akt-RSK-S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs. PMID:20736484
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Redox Regulation of Protein Kinases
Truong, Thu H.; Carroll, Kate S.
2015-01-01
Protein kinases represent one of the largest families of genes found in eukaryotes. Kinases mediate distinct cellular processes ranging from proliferation, differentiation, survival, and apoptosis. Ligand-mediated activation of receptor kinases can lead to the production of endogenous H2O2 by membrane-bound NADPH oxidases. In turn, H2O2 can be utilized as a secondary messenger in signal transduction pathways. This review presents an overview of the molecular mechanisms involved in redox regulation of protein kinases and its effects on signaling cascades. In the first half, we will focus primarily on receptor tyrosine kinases (RTKs), whereas the latter will concentrate on downstream non-receptor kinases involved in relaying stimulant response. Select examples from the literature are used to highlight the functional role of H2O2 regarding kinase activity, as well as the components involved in H2O2 production and regulation during cellular signaling. In addition, studies demonstrating direct modulation of protein kinases by H2O2 through cysteine oxidation will be emphasized. Identification of these redox-sensitive residues may help uncover signaling mechanisms conserved within kinase subfamilies. In some cases, these residues can even be exploited as targets for the development of new therapeutics. Continued efforts in this field will further basic understanding of kinase redox regulation, and delineate the mechanisms involved in physiologic and pathological H2O2 responses. PMID:23639002
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Grose, C.; Jackson, W.; Traugh, J.A.
1989-09-01
Varicella-zoster virus (VZV) glycoprotein gpI is the predominant viral glycoprotein within the plasma membranes of infected cells. This viral glycoprotein is phosphorylated on its polypeptide backbone during biosynthesis. In this report, the authors investigated the protein kinases which participate in the phosphorylation events. Under in vivo conditions, VZV gpI was phosphorylated on its serine and threonine residues by protein kinases present within lysates of either VZV-infected or uninfected cells. Because this activity was diminished by heparin, a known inhibitor of casein kinase II, isolated gpI was incubated with purified casein kinase II and shown to be phosphorylated in an inmore » vitro assay containing ({gamma}-{sup 32}P)ATP. The same glycoprotein was phosphorylated when ({sup 32}P)GTP was substituted for ({sup 32}P)ATP in the protein kinase assay. They also tested whether VZV gpI was phosphorylated by two other ubiquitous mammalian protein kinases--casein kinase I and cyclic AMP-dependent kinase--and found that only casein kinase I modified gpI. When the predicted 623-amino-acid sequence of gpI was examined, two phosphorylation sites known to be optimal for casein kinase II were observed. In summary, this study showed that VZV gpI was phosphorylated by each of two mammalian protein kinases (casein kinase I and casein kinase II) and that potential serine-threonine phosphorylation sites for each of these two kinases were present in the viral glycoprotein.« less
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Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats.
Erickson, Rebecca I; Schutt, Leah K; Tarrant, Jacqueline M; McDowell, Michelle; Liu, Lichuan; Johnson, Adam R; Lewin-Koh, Sock-Cheng; Hedehus, Maj; Ross, Jed; Carano, Richard A D; Staflin, Karin; Zhong, Fiona; Crawford, James J; Zhong, Shelly; Reif, Karin; Katewa, Arna; Wong, Harvey; Young, Wendy B; Dambach, Donna M; Misner, Dinah L
2017-01-01
Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans. Copyright © 2016 by
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A Real-Time Earthquake Precursor Detection Technique Using TEC from a GPS Network
NASA Astrophysics Data System (ADS)
Alp Akyol, Ali; Arikan, Feza; Arikan, Orhan
2016-07-01
Anomalies have been observed in the ionospheric electron density distribution prior to strong earthquakes. However, most of the reported results are obtained by earthquake analysis. Therefore, their implementation in practice is highly problematic. Recently, a novel earthquake precursor detection technique based on spatio-temporal analysis of Total Electron Content (TEC) data obtained from Turkish National Permanent GPS Network (TNPGN) is developed by IONOLAB group (www.ionolab.org). In the present study, the developed detection technique is implemented in a causal setup over the available data set in test phase that enables the real time implementation. The performance of the developed earthquake prediction technique is evaluated by using 10 fold cross validation over the data obtained in 2011. Among the 23 earthquakes that have magnitudes higher than 5, the developed technique can detect precursors of 14 earthquakes while producing 8 false alarms. This study is supported by TUBITAK 115E915 and Joint TUBITAK 114E092 and AS CR 14/001 projects.
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A MASSIVE MOLECULAR GAS RESERVOIR IN THE z = 5.3 SUBMILLIMETER GALAXY AzTEC-3
DOE Office of Scientific and Technical Information (OSTI.GOV)
Riechers, Dominik A.; Scoville, Nicholas Z.; Capak, Peter L.
2010-09-10
We report the detection of CO J = 2{yields}1, 5{yields}4, and 6{yields}5 emission in the highest-redshift submillimeter galaxy (SMG) AzTEC-3 at z = 5.298, using the Expanded Very Large Array and the Plateau de Bure Interferometer. These observations ultimately confirm the redshift, making AzTEC-3 the most submillimeter-luminous galaxy in a massive z {approx_equal} 5.3 protocluster structure in the COSMOS field. The strength of the CO line emission reveals a large molecular gas reservoir with a mass of 5.3 x 10{sup 10}({alpha}{sub CO}/0.8) M {sub sun}, which can maintain the intense 1800 M {sub sun} yr{sup -1} starburst in this systemmore » for at least 30 Myr, increasing the stellar mass by up to a factor of six in the process. This gas mass is comparable to 'typical' z {approx} 2 SMGs and constitutes {approx_gt}80% of the baryonic mass (gas+stars) and 30%-80% of the total (dynamical) mass in this galaxy. The molecular gas reservoir has a radius of <4 kpc and likely consists of a 'diffuse', low-excitation component, containing (at least) 1/3 of the gas mass (depending on the relative conversion factor {alpha}{sub CO}), and a 'dense', high-excitation component, containing {approx}2/3 of the mass. The likely presence of a substantial diffuse component besides highly excited gas suggests different properties between the star-forming environments in z > 4 SMGs and z > 4 quasar host galaxies, which perhaps trace different evolutionary stages. The discovery of a massive, metal-enriched gas reservoir in an SMG at the heart of a large z = 5.3 protocluster considerably enhances our understanding of early massive galaxy formation, pushing back to a cosmic epoch where the universe was less than 1/12 of its present age.« less
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Yousuf, R; Abdul Ghani, S A; Abdul Khalid, N; Leong, C F
2018-04-01
'InTec Blood Grouping Test kit' using solid-phase technology is a new method which may be used at outdoor blood donation site or at bed side as an alternative to the conventional tile method in view of its stability at room temperature and fulfilled the criteria as point of care test. This study aimed to compare the efficiency of this solid phase method (InTec Blood Grouping Test Kit) with the conventional tile method in determining the ABO and RhD blood group of healthy donors. A total of 760 voluntary donors who attended the Blood Bank, Penang Hospital or offsite blood donation campaigns from April to May 2014 were recruited. The ABO and RhD blood groups were determined by the conventional tile method and the solid phase method, in which the tube method was used as the gold standard. For ABO blood grouping, the tile method has shown 100% concordance results with the gold standard tube method, whereas the solid-phase method only showed concordance result for 754/760 samples (99.2%). Therefore, for ABO grouping, tile method has 100% sensitivity and specificity while the solid phase method has slightly lower sensitivity of 97.7% but both with good specificity of 100%. For RhD grouping, both the tile and solid phase methods have grouped one RhD positive specimen as negative each, thus giving the sensitivity and specificity of 99.9% and 100% for both methods respectively. The 'InTec Blood Grouping Test Kit' is suitable for offsite usage because of its simplicity and user friendliness. However, further improvement in adding the internal quality control may increase the test sensitivity and validity of the test results.
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Ryan, Christine E.; Sahaf, Bita; Logan, Aaron C.; O’Brien, Susan; Byrd, John C.; Hillmen, Peter; Brown, Jennifer R.; Dyer, Martin J. S.; Mato, Anthony R.; Keating, Michael J.; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R.; Styles, Lori; Coutre, Steven E.
2016-01-01
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton’s tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism–associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell–mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre–germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. PMID:27802969
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Properties of Acetate Kinase Isozymes and a Branched-Chain Fatty Acid Kinase from a Spirochete
Harwood, Caroline S.; Canale-Parola, Ercole
1982-01-01
Spirochete MA-2, which is anaerobic, ferments glucose, forming acetate as a major product. The spirochete also ferments (but does not utilize as growth substrates) small amounts of l-leucine, l-isoleucine, and l-valine, forming the branched-chain fatty acids isovalerate, 2-methylbutyrate, and isobutyrate, respectively, as end products. Energy generated through the fermentation of these amino acids is utilized to prolong cell survival under conditions of growth substrate starvation. A branched-chain fatty acid kinase and two acetate kinase isozymes were resolved from spirochete MA-2 cell extracts. Kinase activity was followed by measuring the formation of acyl phosphate from fatty acid and ATP. The branched-chain fatty acid kinase was active with isobutyrate, 2-methylbutyrate, isovalerate, butyrate, valerate, or propionate as a substrate but not with acetate as a substrate. The acetate kinase isozymes were active with acetate and propionate as substrates but not with longer-chain fatty acids as substrates. The acetate kinase isozymes and the branched-chain fatty acid kinase differed in nucleoside triphosphate and cation specificities. Each acetate kinase isozyme had an apparent molecular weight of approximately 125,000, whereas the branched-chain fatty acid kinase had a molecular weight of approximately 76,000. These results show that spirochete MA-2 synthesizes a branched-chain fatty acid kinase specific for leucine, isoleucine, and valine fermentation. It is likely that a phosphate branched-chain amino acids is also synthesized by spirochete MA-2. Thus, in spirochete MA-2, physiological mechanisms have evolved which serve specifically to generate maintenance energy from branched-chain amino acids. PMID:6288660
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2015-01-01
We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors. PMID:25075558
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GPS TEC Fluctuations in the Low and High Latitudes During the 2015 St. Patrick`s Day Storm
NASA Astrophysics Data System (ADS)
Chung, Jong-Kyun; Hong, Junseok; Yoo, Sung-Moon; Kim, Jeong-Han; Jee, Geonhwa; Hegai, Valery V.
2017-12-01
As a part of collaborative efforts to understand ionospheric irregularities, the Korea ionospheric scintillation sites (KISS) network has been built based on global positioning system (GPS) receivers with sampling rates higher than 1 Hz. We produce the rate of TEC index (ROTI) to represent GPS TEC fluctuations related to ionospheric irregularities. In the KISS network, two ground-based GPS sites at Kiruna (marker: KIRN; geographic: 67.9° N, 21.4° E; geomagnetic: 65.2° N) and Chuuk (marker: CHUK; geographic: 7.5° N, 151.9° E; geomagnetic: 0.4° N) were selected to evaluate the ROTI value for ionospheric irregularities during the occurrence of the 2015 St. Patrick’s Day storm. The KIRN ROTI values in the aurora region appear to be generally much higher than the CHUK ROTI values in the EIA region. The CHUK ROTI values increased to 0.5 TECU/min around UT=13:00 (LT=23:00) on March 16 in the quiet geomagnetic condition. On March 17, 2015, CHUK ROTI values more than 1.0 TECU/min were measured between UT=9:00 and 12:00 (LT=19:00 and 22:00) during the first main phase of the St. Patrick’s Day storm. This may be due to ionospheric irregularities by increased pre-reversal enhancement (PRE) after sunset during the geomagnetic storm. Post-midnight, the CHUK ROTI showed two peaks of 0.5 TECU/min and 0.3 TECU/min near UT=15:00 (LT=01:00) and UT=18:00 (LT=04:00) at the second main phase. The KIRN site showed significant peaks of ROTI around geomagnetic latitude=63.3° N and MLT=15:40 on the same day. These can be explained by enhanced ionospheric irregularities in the auroral oval at the maximum of AE index
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The crystal structure of choline kinase reveals a eukaryotic protein kinase fold
DOE Office of Scientific and Technical Information (OSTI.GOV)
Peisach, D.; Gee, P.; Kent, K.
2010-03-08
Choline kinase catalyzes the ATP-dependent phosphorylation of choline, the first committed step in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. The 2.0 {angstrom} crystal structure of a choline kinase from C. elegans (CKA-2) reveals that the enzyme is a homodimeric protein with each monomer organized into a two-domain fold. The structure is remarkably similar to those of protein kinases and aminoglycoside phosphotransferases, despite no significant similarity in amino acid sequence. Comparisons to the structures of other kinases suggest that ATP binds to CKA-2 in a pocket formed by highly conserved and catalytically important residues. In addition, a choline bindingmore » site is proposed to be near the ATP binding pocket and formed by several structurally flexible loops.« less
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The ultraviolet detection component based on Te-Cs image intensifier
NASA Astrophysics Data System (ADS)
Qian, Yunsheng; Zhou, Xiaoyu; Wu, Yujing; Wang, Yan; Xu, Hua
2017-05-01
Ultraviolet detection technology has been widely focused and adopted in the fields of ultraviolet warning and corona detection for its significant value and practical meaning. The component structure of ultraviolet ICMOS, imaging driving and the photon counting algorithm are studied in this paper. Firstly, the one-inch and wide dynamic range CMOS chip with the coupling optical fiber panel is coupled to the ultraviolet image intensifier. The photocathode material in ultraviolet image intensifier is Te-Cs, which contributes to the solar blind characteristic, and the dual micro-channel plates (MCP) structure ensures the sufficient gain to achieve the single photon counting. Then, in consideration of the ultraviolet detection demand, the drive circuit of the CMOS chip is designed and the corresponding program based on Verilog language is written. According to the characteristics of ultraviolet imaging, the histogram equalization method is applied to enhance the ultraviolet image and the connected components labeling way is utilized for the ultraviolet single photon counting. Moreover, one visible light video channel is reserved in the ultraviolet ICOMS camera, which can be used for the fusion of ultraviolet and visible images. Based upon the module, the ultraviolet optical lens and the deep cut-off solar blind filter are adopted to construct the ultraviolet detector. At last, the detection experiment of the single photon signal is carried out, and the test results are given and analyzed.
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NASA Astrophysics Data System (ADS)
Austermann, Jason Edward
One of the primary drivers in the development of large format millimeter detector arrays is the study of sub-millimeter galaxies (SMGs) - a population of very luminous high-redshift dust-obscured starbursts that are widely believed to be the dominant contributor to the Far-Infrared Background (FIB). The characterization of such a population requires the ability to map large patches of the (sub-)millimeter sky to high sensitivity within a feasible amount of time. I present this dissertation on the design, integration, and characterization of the 144-pixel AzTEC millimeter-wave camera and its application to the study of the sub-millimeter galaxy population. In particular, I present an unprecedented characterization of the "blank-field" (fields with no known mass bias) SMG number counts by mapping over 0.5 deg^2 to 1.1mm depths of ~1mJy - a previously unattained depth on these scales. This survey provides the tightest SMG number counts available, particularly for the brightest and rarest SMGs that require large survey areas for a significant number of detections. These counts are compared to the predictions of various models of the evolving mm/sub-mm source population, providing important constraints for the ongoing refinement of semi-analytic and hydrodynamical models of galaxy formation. I also present the results of an AzTEC 0.15 deg^2 survey of the COSMOS field, which uncovers a significant over-density of bright SMGs that are spatially correlated to foreground mass structures, presumably as a result of gravitational lensing. Finally, I compare the results of the available SMG surveys completed to date and explore the effects of cosmic variance on the interpretation of individual surveys.
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Purification and characterization of a casein kinase 2-type protein kinase from pea nuclei
NASA Technical Reports Server (NTRS)
Li, H.; Roux, S. J.
1992-01-01
Almost all the polyamine-stimulated protein kinase activity associated with the chromatin fraction of nuclei purified from etiolated pea (Pisum sativum L.) plumules is present in a single enzyme that can be extracted from chromatin by 0.35 molar NaCl. This protein kinase can be further purified over 2000-fold by salt fractionation and anion-exchange and casein-agarose column chromatography, after which it is more than 90% pure. The purified kinase has a specific activity of about 650 nanomoles per minute per milligram protein in the absence of polyamines, with either ATP or GTP as phosphoryl donor. Spermidine can stimulate its activity fourfold, with half-maximal activation at about 2 millimolar. Spermine and putrescine also stimulate activity, although somewhat less effectively. This kinase has a tetrameric alpha 2 beta 2 structure with a native molecular weight of 130,000, and subunit molecular weights of 36,000 for the catalytic subunit (alpha) and 29,000 for the regulatory subunit (beta). In western blot analyses, only the alpha subunit reacts strongly with polyclonal antibodies to a Drosophila casein kinase II. The pea kinase can use casein and phosvitin as artificial substrates, phosphorylating both the serine and threonine residues of casein. It has a pH optimum near 8.0, a Vmax of 1.5 micromoles per minute per milligram protein, and a Km for ATP of approximately 75 micromolar. Its activity can be almost completely inhibited by heparin at 5 micrograms per milliliter, but is relatively insensitive to concentrations of staurosporine, K252a, and chlorpromazine that strongly antagonize Ca(2+) -regulated protein kinases. These results are discussed in relation to recent findings that casein kinase 2-type kinases may phosphorylate trans-acting factors that bind to light-regulated promoters in plants.
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Myosin 3A kinase activity is regulated by phosphorylation of the kinase domain activation loop.
Quintero, Omar A; Unrath, William C; Stevens, Stanley M; Manor, Uri; Kachar, Bechara; Yengo, Christopher M
2013-12-27
Class III myosins are unique members of the myosin superfamily in that they contain both a motor and kinase domain. We have found that motor activity is decreased by autophosphorylation, although little is known about the regulation of the kinase domain. We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919). The kinase activity of MYO3A 2IQ with the phosphomimic (T184E) or phosphoblock (T184A) mutations demonstrates that kinase activity is reduced 30-fold as a result of the T184A mutation, although the Thr-178 site only had a minor impact on kinase activity. Interestingly, the actin-activated ATPase activity of MYO3A 2IQ is slightly reduced as a result of the T178A and T184A mutations suggesting coupling between motor and kinase domains. Full-length GFP-tagged T184A and T184E MYO3A constructs transfected into COS7 cells do not disrupt the ability of MYO3A to localize to filopodia structures. In addition, we demonstrate that T184E MYO3A reduces filopodia elongation in the presence of espin-1, whereas T184A enhances filopodia elongation in a similar fashion to kinase-dead MYO3A. Our results suggest that as MYO3A accumulates at the tips of actin protrusions, autophosphorylation of Thr-184 enhances kinase activity resulting in phosphorylation of the MYO3A motor and reducing motor activity. The differential regulation of the kinase and motor activities allows for MYO3A to precisely self-regulate its concentration in the actin bundle-based structures of cells.
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Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop*
Quintero, Omar A.; Unrath, William C.; Stevens, Stanley M.; Manor, Uri; Kachar, Bechara; Yengo, Christopher M.
2013-01-01
Class III myosins are unique members of the myosin superfamily in that they contain both a motor and kinase domain. We have found that motor activity is decreased by autophosphorylation, although little is known about the regulation of the kinase domain. We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919). The kinase activity of MYO3A 2IQ with the phosphomimic (T184E) or phosphoblock (T184A) mutations demonstrates that kinase activity is reduced 30-fold as a result of the T184A mutation, although the Thr-178 site only had a minor impact on kinase activity. Interestingly, the actin-activated ATPase activity of MYO3A 2IQ is slightly reduced as a result of the T178A and T184A mutations suggesting coupling between motor and kinase domains. Full-length GFP-tagged T184A and T184E MYO3A constructs transfected into COS7 cells do not disrupt the ability of MYO3A to localize to filopodia structures. In addition, we demonstrate that T184E MYO3A reduces filopodia elongation in the presence of espin-1, whereas T184A enhances filopodia elongation in a similar fashion to kinase-dead MYO3A. Our results suggest that as MYO3A accumulates at the tips of actin protrusions, autophosphorylation of Thr-184 enhances kinase activity resulting in phosphorylation of the MYO3A motor and reducing motor activity. The differential regulation of the kinase and motor activities allows for MYO3A to precisely self-regulate its concentration in the actin bundle-based structures of cells. PMID:24214986
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NASA Astrophysics Data System (ADS)
Chakravarty, S. C.; Nagaraja, Kamsali; Jakowski, N.
2017-03-01
The annual variations of ionospheric Total Electron Content (TEC), F-region peak ionisation (NmF2) and the ionospheric slab thickness (τ) over the Indian region during the low solar activity period of May 2007-April 2008 have been studied. For this purpose the ground based TEC data obtained from GAGAN measurements and the space based data from GPS radio occultation technique using CHAMP have been utilised. The results of these independent measurements are combined to derive additional parameters such as the equivalent slab thickness of the total and the bottom-side ionospheric regions (τT and τB). The one year hourly average values of all these parameters over the ionospheric anomaly latitude region (10-26°N) are presented here along with the statistical error estimates. It is expected that these results are potentially suited to be used as base level values during geomagnetically quiet and undisturbed solar conditions.
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Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon
2015-12-01
Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Tan, Li; Nomanbhoy, Tyzoon; Gurbani, Deepak
Here, we developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16more » and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. Lastly, a 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.« less
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Tan, Li; Nomanbhoy, Tyzoon; Gurbani, Deepak; ...
2014-07-17
Here, we developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16more » and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. Lastly, a 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.« less
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Fluorophore Labeled Kinase Detects Ligands That Bind within the MAPK Insert of p38α Kinase
Termathe, Martin; Grütter, Christian; Rabiller, Matthias; van Otterlo, Willem A. L.; Rauh, Daniel
2012-01-01
The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38α mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38α, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38α signaling pathway. PMID:22768308
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Roux, Philippe P.; Blenis, John
2004-01-01
Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries. PMID:15187187
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Tyrosine kinase gene rearrangements in epithelial malignancies
Shaw, Alice T.; Hsu, Peggy P.; Awad, Mark M.; Engelman, Jeffrey A.
2014-01-01
Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which validates these fusion kinases as ‘druggable’ targets. In this Review, we examine the aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clinical outcomes with targeted therapies and explore strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours. PMID:24132104
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Star and Dust Formation Activities in AzTEC-3, a Starburst Galaxy at z = 5.3
NASA Astrophysics Data System (ADS)
Dwek, Eli; Staguhn, Johannes G.; Arendt, Richard G.; Capak, Peter L.; Kovacs, Attila; Benford, Dominic J.; Fixsen, Dale; Karim, Alexander; Leclercq, Samuel; Maher, Stephen F.; Moseley, Samuel H.; Schinnerer, Eva; Sharp, Elmer H.
2011-09-01
Analyses of high-redshift ultraluminous infrared (IR) galaxies traditionally use the observed optical to submillimeter spectral energy distribution (SED) and estimates of the dynamical mass as observational constraints to derive the star formation rate (SFR), the stellar mass, and age of these objects. An important observational constraint neglected in the analysis is the mass of dust giving rise to the IR emission. In this paper we add this constraint to the analysis of AzTEC-3. Adopting an upper limit to the mass of stars and a bolometric luminosity for this object, we construct different stellar and chemical evolutionary scenarios, constrained to produce the inferred dust mass and observed luminosity before the associated stellar mass exceeds the observational limit. We use the PÉGASE population synthesis code and a chemical evolution model to follow the evolution of the galaxy's SED and its stellar and dust masses as a function of galactic age for seven different stellar initial mass functions (IMFs). We find that the model with a Top Heavy IMF provided the most plausible scenario consistent with the observational constraints. In this scenario the dust formed over a period of ~200 Myr, with an SFR of ~500 M sun yr-1. These values for the age and SFR in AzTEC-3 are significantly higher and lower, respectively, from those derived without the dust mass constraint. However, this scenario is not unique, and others cannot be completely ruled out because of the prevailing uncertainties in the age of the galaxy, its bolometric luminosity, and its stellar and dust masses. A robust result of our models is that all scenarios require most of the radiating dust mass to have been accreted in molecular clouds. Our new procedure highlights the importance of a multiwavelength approach, and of the use of dust evolution models in constraining the age and the star formation activity and history in galaxies.
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STAR AND DUST FORMATION ACTIVITIES IN AzTEC-3, A STARBURST GALAXY AT z = 5.3
DOE Office of Scientific and Technical Information (OSTI.GOV)
Dwek, Eli; Staguhn, Johannes G.; Arendt, Richard G.
2011-09-01
Analyses of high-redshift ultraluminous infrared (IR) galaxies traditionally use the observed optical to submillimeter spectral energy distribution (SED) and estimates of the dynamical mass as observational constraints to derive the star formation rate (SFR), the stellar mass, and age of these objects. An important observational constraint neglected in the analysis is the mass of dust giving rise to the IR emission. In this paper we add this constraint to the analysis of AzTEC-3. Adopting an upper limit to the mass of stars and a bolometric luminosity for this object, we construct different stellar and chemical evolutionary scenarios, constrained to producemore » the inferred dust mass and observed luminosity before the associated stellar mass exceeds the observational limit. We use the PEGASE population synthesis code and a chemical evolution model to follow the evolution of the galaxy's SED and its stellar and dust masses as a function of galactic age for seven different stellar initial mass functions (IMFs). We find that the model with a Top Heavy IMF provided the most plausible scenario consistent with the observational constraints. In this scenario the dust formed over a period of {approx}200 Myr, with an SFR of {approx}500 M{sub sun} yr{sup -1}. These values for the age and SFR in AzTEC-3 are significantly higher and lower, respectively, from those derived without the dust mass constraint. However, this scenario is not unique, and others cannot be completely ruled out because of the prevailing uncertainties in the age of the galaxy, its bolometric luminosity, and its stellar and dust masses. A robust result of our models is that all scenarios require most of the radiating dust mass to have been accreted in molecular clouds. Our new procedure highlights the importance of a multiwavelength approach, and of the use of dust evolution models in constraining the age and the star formation activity and history in galaxies.« less
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Klaus-Heisen, Dörte; Nurisso, Alessandra; Pietraszewska-Bogiel, Anna; Mbengue, Malick; Camut, Sylvie; Timmers, Ton; Pichereaux, Carole; Rossignol, Michel; Gadella, Theodorus W J; Imberty, Anne; Lefebvre, Benoit; Cullimore, Julie V
2011-04-01
Phylogenetic analysis has previously shown that plant receptor-like kinases (RLKs) are monophyletic with respect to the kinase domain and share an evolutionary origin with the animal interleukin-1 receptor-associated kinase/Pelle-soluble kinases. The lysin motif domain-containing receptor-like kinase-3 (LYK3) of the legume Medicago truncatula shows 33% amino acid sequence identity with human IRAK-4 over the kinase domain. Using the structure of this animal kinase as a template, homology modeling revealed that the plant RLK contains structural features particular to this group of kinases, including the tyrosine gatekeeper and the N-terminal extension α-helix B. Functional analysis revealed the importance of these conserved features for kinase activity and suggests that kinase activity is essential for the biological role of LYK3 in the establishment of the root nodule nitrogen-fixing symbiosis with rhizobia bacteria. The kinase domain of LYK3 has dual serine/threonine and tyrosine specificity, and mass spectrometry analysis identified seven serine, eight threonine, and one tyrosine residue as autophosphorylation sites in vitro. Three activation loop serine/threonine residues are required for biological activity, and molecular dynamics simulations suggest that Thr-475 is the prototypical phosphorylated residue that interacts with the conserved arginine in the catalytic loop, whereas Ser-471 and Thr-472 may be secondary sites. A threonine in the juxtamembrane region and two threonines in the C-terminal lobe of the kinase domain are important for biological but not kinase activity. We present evidence that the structure-function similarities that we have identified between LYK3 and IRAK-4 may be more widely applicable to plant RLKs in general.
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The Insight ToolKit image registration framework
Avants, Brian B.; Tustison, Nicholas J.; Stauffer, Michael; Song, Gang; Wu, Baohua; Gee, James C.
2014-01-01
Publicly available scientific resources help establish evaluation standards, provide a platform for teaching and improve reproducibility. Version 4 of the Insight ToolKit (ITK4) seeks to establish new standards in publicly available image registration methodology. ITK4 makes several advances in comparison to previous versions of ITK. ITK4 supports both multivariate images and objective functions; it also unifies high-dimensional (deformation field) and low-dimensional (affine) transformations with metrics that are reusable across transform types and with composite transforms that allow arbitrary series of geometric mappings to be chained together seamlessly. Metrics and optimizers take advantage of multi-core resources, when available. Furthermore, ITK4 reduces the parameter optimization burden via principled heuristics that automatically set scaling across disparate parameter types (rotations vs. translations). A related approach also constrains steps sizes for gradient-based optimizers. The result is that tuning for different metrics and/or image pairs is rarely necessary allowing the researcher to more easily focus on design/comparison of registration strategies. In total, the ITK4 contribution is intended as a structure to support reproducible research practices, will provide a more extensive foundation against which to evaluate new work in image registration and also enable application level programmers a broad suite of tools on which to build. Finally, we contextualize this work with a reference registration evaluation study with application to pediatric brain labeling.1 PMID:24817849
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Src kinase regulation by phosphorylation and dephosphorylation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Roskoski, Robert
2005-05-27
Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTP{alpha}, PTP{epsilon}, and PTP{lambda}. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shownmore » to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined.« less
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Identification and characterization of plant Haspin kinase as a histone H3 threonine kinase
2011-01-01
Background Haspin kinases are mitotic kinases that are well-conserved from yeast to human. Human Haspin is a histone H3 Thr3 kinase that has important roles in chromosome cohesion during mitosis. Moreover, phosphorylation of histone H3 at Thr3 by Haspin in fission yeast, Xenopus, and human is required for accumulation of Aurora B on the centromere, and the subsequent activation of Aurora B kinase activity for accurate chromosome alignment and segregation. Although extensive analyses of Haspin have been carried out in yeast and animals, the function of Haspin in organogenesis remains unclear. Results Here, we identified a Haspin kinase, designated AtHaspin, in Arabidopsis thaliana. The purified AtHaspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro. Live imaging of AtHaspin-tdTomato and GFP-α-tubulin in BY-2 cells showed that AtHaspin-tdTomato localized on chromosomes during prometaphase and metaphase, and around the cell plate during cytokinesis. This localization of AtHaspin overlapped with that of phosphorylated Thr3 and Thr11 of histone H3 in BY-2 cells. AtHaspin-GFP driven by the native promoter was expressed in root meristems, shoot meristems, floral meristems, and throughout the whole embryo at stages of high cell division. Overexpression of a kinase domain mutant of AtHaspin decreased the size of the root meristem, which delayed root growth. Conclusions Our results indicated that the Haspin kinase is a histone H3 threonine kinase in A. thaliana. AtHaspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro. The expression and dominant-negative analysis showed that AtHaspin may have a role in mitotic cell division during plant growth. Further analysis of coordinated mechanisms involving Haspin and Aurora kinases will shed new light on the regulation of chromosome segregation in cell division during plant growth and development. PMID:21527018
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Hsp90 Promotes Kinase Evolution
Lachowiec, Jennifer; Lemus, Tzitziki; Borenstein, Elhanan; Queitsch, Christine
2015-01-01
Heat-shock protein 90 (Hsp90) promotes the maturation and stability of its client proteins, including many kinases. In doing so, Hsp90 may allow its clients to accumulate mutations as previously proposed by the capacitor hypothesis. If true, Hsp90 clients should show increased evolutionary rate compared with nonclients; however, other factors, such as gene expression and protein connectivity, may confound or obscure the chaperone’s putative contribution. Here, we compared the evolutionary rates of many Hsp90 clients and nonclients in the human protein kinase superfamily. We show that Hsp90 client status promotes evolutionary rate independently of, but in a small magnitude similar to that of gene expression and protein connectivity. Hsp90’s effect on kinase evolutionary rate was detected across mammals, specifically relaxing purifying selection. Hsp90 clients also showed increased nucleotide diversity and harbored more damaging variation than nonclient kinases across humans. These results are consistent with the central argument of the capacitor hypothesis that interaction with the chaperone allows its clients to harbor genetic variation. Hsp90 client status is thought to be highly dynamic with as few as one amino acid change rendering a protein dependent on the chaperone. Contrary to this expectation, we found that across protein kinase phylogeny Hsp90 client status tends to be gained, maintained, and shared among closely related kinases. We also infer that the ancestral protein kinase was not an Hsp90 client. Taken together, our results suggest that Hsp90 played an important role in shaping the kinase superfamily. PMID:25246701
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HiTEC: a connectionist model of the interaction between perception and action planning.
Haazebroek, Pascal; Raffone, Antonino; Hommel, Bernhard
2017-11-01
Increasing evidence suggests that perception and action planning do not represent separable stages of a unidirectional processing sequence, but rather emerging properties of highly interactive processes. To capture these characteristics of the human cognitive system, we have developed a connectionist model of the interaction between perception and action planning: HiTEC, based on the Theory of Event Coding (Hommel et al. in Behav Brain Sci 24:849-937, 2001). The model is characterized by representations at multiple levels and by shared representations and processes. It complements available models of stimulus-response translation by providing a rationale for (1) how situation-specific meanings of motor actions emerge, (2) how and why some aspects of stimulus-response translation occur automatically and (3) how task demands modulate sensorimotor processing. The model is demonstrated to provide a unitary account and simulation of a number of key findings with multiple experimental paradigms on the interaction between perception and action such as the Simon effect, its inversion (Hommel in Psychol Res 55:270-279, 1993), and action-effect learning.
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A rice kinase-protein interaction map.
Ding, Xiaodong; Richter, Todd; Chen, Mei; Fujii, Hiroaki; Seo, Young Su; Xie, Mingtang; Zheng, Xianwu; Kanrar, Siddhartha; Stevenson, Rebecca A; Dardick, Christopher; Li, Ying; Jiang, Hao; Zhang, Yan; Yu, Fahong; Bartley, Laura E; Chern, Mawsheng; Bart, Rebecca; Chen, Xiuhua; Zhu, Lihuang; Farmerie, William G; Gribskov, Michael; Zhu, Jian-Kang; Fromm, Michael E; Ronald, Pamela C; Song, Wen-Yuan
2009-03-01
Plants uniquely contain large numbers of protein kinases, and for the vast majority of the 1,429 kinases predicted in the rice (Oryza sativa) genome, little is known of their functions. Genetic approaches often fail to produce observable phenotypes; thus, new strategies are needed to delineate kinase function. We previously developed a cost-effective high-throughput yeast two-hybrid system. Using this system, we have generated a protein interaction map of 116 representative rice kinases and 254 of their interacting proteins. Overall, the resulting interaction map supports a large number of known or predicted kinase-protein interactions from both plants and animals and reveals many new functional insights. Notably, we found a potential widespread role for E3 ubiquitin ligases in pathogen defense signaling mediated by receptor-like kinases, particularly by the kinases that may have evolved from recently expanded kinase subfamilies in rice. We anticipate that the data provided here will serve as a foundation for targeted functional studies in rice and other plants. The application of yeast two-hybrid and TAPtag analyses for large-scale plant protein interaction studies is also discussed.
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NASA Astrophysics Data System (ADS)
Afraimovich, E.
2009-04-01
Recent investigations have shown that movement of the solar terminator (ST) causes generation of acoustic-gravity waves (AGW), turbulence and instabilities in the ionosphere plasma. Among all the sources of gravity waves, the moving ST has a special status, since it is a predictable phenomenon, whose characteristics are well known. Considering the ST as a stable and repetitive source of AGW, one can derive information about atmospheric conditions from the response of the medium to this input. The great variety of ST-linked phenomena in the atmosphere gave rise to a number of studies on the analysis of ionosphere parameter variations obtained by different ionosphere sounding methods. However, virtually all experimental data were obtained using indirect methods for analyzing the spectrum of ionosphere parameter variations, which can result from a number of factors. This causes difficulties in the reliable identification of ST-linked AGW, because in general case AGW can be generated by different sources either of natural or of anthropogenic origin. To identify ST-generated wave disturbances it is insufficient to register the time dependence of ionosphere parameters or their spectrum. It is necessary to measure the spatial structure of these disturbances and to compare it with spatial-temporal characteristics of ST. Another important requirement implies the continuous, global character of observations. Using long-term (1998-2007) total electron content (TEC) measurements from the IGS GPS global network and dense networks of GPS sites in USA (CORS) and Japan (GEONET), we have obtained the first evidence for the wave structure excited by the solar terminator (ST). We have found two main types of the observed TEC disturbances: large-scale (LS) 60-min variations with amplitude of about 0.5-1 TECU and medium-scale (MS) 15-min variations with amplitude of about 0.05-0.1 TECU. The first type of disturbances was predicted in theoretical investigations and registered earlier
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Receptor Tyrosine Kinases in Drosophila Development
Sopko, Richelle; Perrimon, Norbert
2013-01-01
Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases. PMID:23732470
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Chandran, Anil Kumar Nalini; Yoo, Yo-Han; Cao, Peijian; Sharma, Rita; Sharma, Manoj; Dardick, Christopher; Ronald, Pamela C; Jung, Ki-Hong
2016-12-01
Protein kinases catalyze the transfer of a phosphate moiety from a phosphate donor to the substrate molecule, thus playing critical roles in cell signaling and metabolism. Although plant genomes contain more than 1000 genes that encode kinases, knowledge is limited about the function of each of these kinases. A major obstacle that hinders progress towards kinase characterization is functional redundancy. To address this challenge, we previously developed the rice kinase database (RKD) that integrated omics-scale data within a phylogenetics context. An updated version of rice kinase database (RKD) that contains metadata derived from NCBI GEO expression datasets has been developed. RKD 2.0 facilitates in-depth transcriptomic analyses of kinase-encoding genes in diverse rice tissues and in response to biotic and abiotic stresses and hormone treatments. We identified 261 kinases specifically expressed in particular tissues, 130 that are significantly up- regulated in response to biotic stress, 296 in response to abiotic stress, and 260 in response to hormones. Based on this update and Pearson correlation coefficient (PCC) analysis, we estimated that 19 out of 26 genes characterized through loss-of-function studies confer dominant functions. These were selected because they either had paralogous members with PCC values of <0.5 or had no paralog. Compared with the previous version of RKD, RKD 2.0 enables more effective estimations of functional redundancy or dominance because it uses comprehensive expression profiles rather than individual profiles. The integrated analysis of RKD with PCC establishes a single platform for researchers to select rice kinases for functional analyses.
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Jayaraman, Dhileepkumar; Richards, Alicia L; Westphall, Michael S; Coon, Joshua J; Ané, Jean-Michel
2017-06-01
Detecting the phosphorylation substrates of multiple kinases in a single experiment is a challenge, and new techniques are being developed to overcome this challenge. Here, we used a multiplexed assay for kinase specificity (MAKS) to identify the substrates directly and to map the phosphorylation site(s) of plant symbiotic receptor-like kinases. The symbiotic receptor-like kinases nodulation receptor-like kinase (NORK) and lysin motif domain-containing receptor-like kinase 3 (LYK3) are indispensable for the establishment of root nodule symbiosis. Although some interacting proteins have been identified for these symbiotic receptor-like kinases, very little is known about their phosphorylation substrates. Using this high-throughput approach, we identified several other potential phosphorylation targets for both these symbiotic receptor-like kinases. In particular, we also discovered the phosphorylation of LYK3 by NORK itself, which was also confirmed by pairwise kinase assays. Motif analysis of potential targets for these kinases revealed that the acidic motif xxxsDxxx was common to both of them. In summary, this high-throughput technique catalogs the potential phosphorylation substrates of multiple kinases in a single efficient experiment, the biological characterization of which should provide a better understanding of phosphorylation signaling cascade in symbiosis. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.
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USDA-ARS?s Scientific Manuscript database
Calcium-dependent protein kinases (CDPKs or CPKs) are classified as serine/threonine protein kinases but we made the surprising observation that soybean CDPK' and several Arabidopsis isoforms (AtCPK4 and AtCPK34) could also autophosphorylate on tyrosine residues. In studies with His6-GmCDPK', we ide...
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A cGMP kinase mutant with increased sensitivity to the protein kinase inhibitor peptide PKI(5-24).
Ruth, P; Kamm, S; Nau, U; Pfeifer, A; Hofmann, F
1996-01-01
Synthetic peptides corresponding to the active domain of the heat-stable inhibitor protein PKI are very potent inhibitors of cAMP-dependent protein kinase, but are extremely weak inhibitors of cGMP-dependent protein kinase. In this study, we tried to confer PKI sensitivity to cGMP kinase by site-directed mutagenesis. The molecular requirements for high affinity inhibition by PKI were deduced from the crystal structure of the cAMP kinase/PKI complex. A prominent site of interaction are residues Tyr235 and Phe239 in the catalytic subunit, which from a sandwich-like structure with Phe10 of the PKI(5-24) peptide. To increase the sensitivity for PKI, the cGMP kinase codons at the corresponding sites, Ser555 and Ser559, were changed to Tyr and Phe. The mutant cGMP kinase was stimulated half maximally by cGMP at 3-fold higher concentrations (240 nM) than the wild type (77 nM). Wild type and mutant cGMP kinase did not differ significantly in their Km and Vmax for three different substrate peptides. The PKI(5-24) peptide inhibited phosphotransferase activity of the mutant cGMP kinase with higher potency than that of wild type, with Ki values of 42 +/- .3 microM and 160 +/- .7 microM, respectively. The increased affinity of the mutant cGMP kinase was specific for the PKI(5-24) peptide. Mutation of the essential Phe10 in the PKI(5-24) sequence to an Ala yielded a peptide that inhibited mutant and wild type cGMP kinase with similar potency, with Ki values of 160 +/- 11 and 169 +/- 27 microM, respectively. These results suggest that the mutations Ser555Tyr and Ser559Phe are required, but not sufficient, for high affinity inhibition of cGMP kinase by PKI.
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2016-01-01
Background Seniors with chronic diseases such as heart failure have complex care needs. They are vulnerable to their condition deteriorating and, without timely intervention, may require multiple emergency department visits and/or repeated hospitalizations. Upon discharge, the transition from the emergency department to home can be a vulnerable time for recovering patients with disruptions in the continuity of care. Remote monitoring of heart failure patients using home telemonitoring, coupled with clear communication protocols between health care professionals, can be effective in increasing the safety and quality of care for seniors with heart failure discharged from the emergency department. Objective The aim of the Telehealth for Emergency-Community Continuity of Care Connectivity via Home Telemonitoring (TEC4Home) study is to generate evidence through a programmatic evaluation and a clinical trial to determine how home telemonitoring may improve care and increase patient safety during the transition of care and determine how it is best implemented to support patients with heart failure within this context. Methods This 4-year project consists of 3 studies to comprehensively evaluate the outcomes and effectiveness of TEC4Home. Study 1 is a feasibility study with 90 patients recruited from 2 emergency department sites to test implementation and evaluation procedures. Findings from the feasibility study will be used to refine protocols for the larger trial. Study 2 is a cluster randomized controlled trial that will include 30 emergency department sites and 900 patients across British Columbia. The primary outcome of the randomized controlled trial will be emergency department revisits and hospital readmission rates. Secondary outcomes include health care resource utilization/costs, communication between members of the care team, and patient quality of life. Study 3 will run concurrently to study 2 and test the effectiveness of predictive analytic software to
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Schaenzer, Adam J.; Wlodarchak, Nathan; Drewry, David H.; Zuercher, William J.; Rose, Warren E.; Striker, Rob; Sauer, John-Demian
2017-01-01
Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial Penicillin-binding-protein And Serine/Threonine kinase-Associated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to β-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to β-lactam therapy. Despite this interest, only limited progress has been made in identifying functional inhibitors of the PASTA kinases that have both activity against the intact microbe and high kinase specificity. Here, we report the results of a small-molecule screen that identified GSK690693, an imidazopyridine aminofurazan-type kinase inhibitor that increases the sensitivity of the intracellular pathogen Listeria monocytogenes to various β-lactams by inhibiting the PASTA kinase PrkA. GSK690693 potently inhibited PrkA kinase activity biochemically and exhibited significant selectivity for PrkA relative to the Staphylococcus aureus PASTA kinase Stk1. Furthermore, other imidazopyridine aminofurazans could effectively inhibit PrkA and potentiate β-lactam antibiotic activity to varying degrees. The presence of the 2-methyl-3-butyn-2-ol (alkynol) moiety was important for both biochemical and antimicrobial activity. Finally, mutagenesis studies demonstrated residues in the back pocket of the active site are important for GSK690693 selectivity. These data suggest that targeted screens can successfully identify PASTA kinase inhibitors with both biochemical and antimicrobial specificity. Moreover, the imidazopyridine aminofurazans represent a family of PASTA kinase inhibitors that have the potential to be optimized for selective PASTA kinase inhibition. PMID:28821610
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Schaenzer, Adam J; Wlodarchak, Nathan; Drewry, David H; Zuercher, William J; Rose, Warren E; Striker, Rob; Sauer, John-Demian
2017-10-13
Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial P enicillin-binding-protein A nd S erine/ T hreonine kinase- A ssociated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to β-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to β-lactam therapy. Despite this interest, only limited progress has been made in identifying functional inhibitors of the PASTA kinases that have both activity against the intact microbe and high kinase specificity. Here, we report the results of a small-molecule screen that identified GSK690693, an imidazopyridine aminofurazan-type kinase inhibitor that increases the sensitivity of the intracellular pathogen Listeria monocytogenes to various β-lactams by inhibiting the PASTA kinase PrkA. GSK690693 potently inhibited PrkA kinase activity biochemically and exhibited significant selectivity for PrkA relative to the Staphylococcus aureus PASTA kinase Stk1. Furthermore, other imidazopyridine aminofurazans could effectively inhibit PrkA and potentiate β-lactam antibiotic activity to varying degrees. The presence of the 2-methyl-3-butyn-2-ol (alkynol) moiety was important for both biochemical and antimicrobial activity. Finally, mutagenesis studies demonstrated residues in the back pocket of the active site are important for GSK690693 selectivity. These data suggest that targeted screens can successfully identify PASTA kinase inhibitors with both biochemical and antimicrobial specificity. Moreover, the imidazopyridine aminofurazans represent a family of PASTA kinase inhibitors that have the potential to be optimized for selective PASTA kinase inhibition.
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Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B
2016-12-22
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.
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CIKS, a connection to IκB kinase and stress-activated protein kinase
Leonardi, Antonio; Chariot, Alain; Claudio, Estefania; Cunningham, Kirk; Siebenlist, Ulrich
2000-01-01
Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF-κB and AP-1/ATF families. Activation of NF-κB factors is thought to be mediated primarily via IκB kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs). IKKα and IKKβ are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-κB essential modulator)/IKKγ. The latter protein is essential for activation of the IKKs, but its mechanism of action is not known. Here we describe the molecular cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKKγ in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-κB-dependent reporter. Activation of NF-κB is prevented in the presence of kinase-deficient, interfering mutants of the IKKs. CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways, functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins. PMID:10962033
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CIKS, a connection to Ikappa B kinase and stress-activated protein kinase.
Leonardi, A; Chariot, A; Claudio, E; Cunningham, K; Siebenlist, U
2000-09-12
Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF-kappaB and AP-1/ATF families. Activation of NF-kappaB factors is thought to be mediated primarily via IkappaB kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs). IKKalpha and IKKbeta are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-kappaB essential modulator)/IKKgamma. The latter protein is essential for activation of the IKKs, but its mechanism of action is not known. Here we describe the molecular cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKKgamma in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-kappaB-dependent reporter. Activation of NF-kappaB is prevented in the presence of kinase-deficient, interfering mutants of the IKKs. CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways, functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins.
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Bye, Alexander P.; Unsworth, Amanda J.; Desborough, Michael J.; Hildyard, Catherine A. T.; Appleby, Niamh; Bruce, David; Kriek, Neline; Nock, Sophie H.; Sage, Tanya; Hughes, Craig E.
2017-01-01
The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII. PMID:29296914
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Kinases Involved in Both Autophagy and Mitosis.
Li, Zhiyuan; Zhang, Xin
2017-08-31
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.
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Kinases Involved in Both Autophagy and Mitosis
2017-01-01
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations. PMID:28858266
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S6 Kinase Inhibits Intrinsic Axon Regeneration Capacity via AMP Kinase in Caenorhabditis elegans
Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.
2014-01-01
The ability of axons to regrow after injury is determined by the complex interplay of intrinsic growth programs and external cues. In Caenorhabditis elegans mechanosensory neuron, axons exhibit robust regenerative regrowth following laser axotomy. By surveying conserved metabolic signaling pathways, we have identified the ribosomal S6 kinase RSKS-1 as a new cell-autonomous inhibitor of axon regeneration. RSKS-1 is not required for axonal development but inhibits axon regrowth after injury in multiple neuron types. Loss of function in rsks-1 results in more rapid growth cone formation after injury and accelerates subsequent axon extension. The enhanced regrowth of rsks-1 mutants is partly dependent on the DLK-1 MAPK cascade. An essential output of RSKS-1 in axon regrowth is the metabolic sensor AMP kinase, AAK-2. We further show that the antidiabetic drug phenformin, which activates AMP kinase, can promote axon regrowth. Our data reveal a new function for an S6 kinase acting through an AMP kinase in regenerative growth of injured axons. PMID:24431434
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The MPS1 family of protein kinases.
Liu, Xuedong; Winey, Mark
2012-01-01
MPS1 protein kinases are found widely, but not ubiquitously, in eukaryotes. This family of potentially dual-specific protein kinases is among several that regulate a number of steps of mitosis. The most widely conserved MPS1 kinase functions involve activities at the kinetochore in both the chromosome attachment and the spindle checkpoint. MPS1 kinases also function at centrosomes. Beyond mitosis, MPS1 kinases have been implicated in development, cytokinesis, and several different signaling pathways. Family members are identified by virtue of a conserved C-terminal kinase domain, though the N-terminal domain is quite divergent. The kinase domain of the human enzyme has been crystallized, revealing an unusual ATP-binding pocket. The activity, level, and subcellular localization of Mps1 family members are tightly regulated during cell-cycle progression. The mitotic functions of Mps1 kinases and their overexpression in some tumors have prompted the identification of Mps1 inhibitors and their active development as anticancer drugs.
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The MPS1 Family of Protein Kinases
Liu, Xuedong; Winey, Mark
2014-01-01
MPS1 protein kinases are found widely, but not ubiquitously, in eukaryotes. This family of potentially dual-specific protein kinases is among several that regulate a number of steps of mitosis. The most widely conserved MPS1 kinase functions involve activities at the kinetochore in both the chromosome attachment and the spindle checkpoint. MPS1 kinases also function at centrosomes. Beyond mitosis, MPS1 kinases have been implicated in development, cytokinesis, and several different signaling pathways. Family members are identified by virtue of a conserved C-terminal kinase domain, though the N-terminal domain is quite divergent. The kinase domain of the human enzyme has been crystallized, revealing an unusual ATP-binding pocket. The activity, level, and subcellular localization of Mps1 family members are tightly regulated during cell-cycle progression. The mitotic functions of Mps1 kinases and their overexpression in some tumors have prompted the identification of Mps1 inhibitors and their active development as anticancer drugs. PMID:22482908
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Mitogen-activated protein kinase cascades in Vitis vinifera
Çakır, Birsen; Kılıçkaya, Ozan
2015-01-01
Protein phosphorylation is one of the most important mechanisms to control cellular functions in response to external and endogenous signals. Mitogen-activated protein kinases (MAPK) are universal signaling molecules in eukaryotes that mediate the intracellular transmission of extracellular signals resulting in the induction of appropriate cellular responses. MAPK cascades are composed of four protein kinase modules: MAPKKK kinases (MAPKKKKs), MAPKK kinases (MAPKKKs), MAPK kinases (MAPKKs), and MAPKs. In plants, MAPKs are activated in response to abiotic stresses, wounding, and hormones, and during plant pathogen interactions and cell division. In this report, we performed a complete inventory of MAPK cascades genes in Vitis vinifera, the whole genome of which has been sequenced. By comparison with MAPK, MAPK kinases, MAPK kinase kinases and MAPK kinase kinase kinase kinase members of Arabidopsis thaliana, we revealed the existence of 14 MAPKs, 5 MAPKKs, 62 MAPKKKs, and 7 MAPKKKKs in Vitis vinifera. We identified orthologs of V. vinifera putative MAPKs in different species, and ESTs corresponding to members of MAPK cascades in various tissues. This work represents the first complete inventory of MAPK cascades in V. vinifera and could help elucidate the biological and physiological functions of these proteins in V. vinifera. PMID:26257761
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Moravcevic, Katarina; Mendrola, Jeannine M.; Schmitz, Karl R.
Phospholipid-binding modules such as PH, C1, and C2 domains play crucial roles in location-dependent regulation of many protein kinases. Here, we identify the KA1 domain (kinase associated-1 domain), found at the C terminus of yeast septin-associated kinases (Kcc4p, Gin4p, and Hsl1p) and human MARK/PAR1 kinases, as a membrane association domain that binds acidic phospholipids. Membrane localization of isolated KA1 domains depends on phosphatidylserine. Using X-ray crystallography, we identified a structurally conserved binding site for anionic phospholipids in KA1 domains from Kcc4p and MARK1. Mutating this site impairs membrane association of both KA1 domains and intact proteins and reveals the importancemore » of phosphatidylserine for bud neck localization of yeast Kcc4p. Our data suggest that KA1 domains contribute to coincidence detection, allowing kinases to bind other regulators (such as septins) only at the membrane surface. These findings have important implications for understanding MARK/PAR1 kinases, which are implicated in Alzheimer's disease, cancer, and autism.« less
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SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1.
Anafi, M; Kiefer, F; Gish, G D; Mbamalu, G; Iscove, N N; Pawson, T
1997-10-31
Ste20-related protein kinases have been implicated as regulating a range of cellular responses, including stress-activated protein kinase pathways and the control of cytoskeletal architecture. An important issue involves the identities of the upstream signals and regulators that might control the biological functions of mammalian Ste20-related protein kinases. HPK1 is a protein-serine/threonine kinase that possesses a Ste20-like kinase domain, and in transfected cells activates a protein kinase pathway leading to the stress-activated protein kinase SAPK/JNK. Here we have investigated candidate upstream regulators that might interact with HPK1. HPK1 possesses an N-terminal catalytic domain and an extended C-terminal tail with four proline-rich motifs. The SH3 domains of Grb2 bound in vitro to specific proline-rich motifs in the HPK1 tail and functioned synergistically to direct the stable binding of Grb2 to HPK1 in transfected Cos1 cells. Epidermal growth factor (EGF) stimulation did not affect the binding of Grb2 to HPK1 but induced recruitment of the Grb2.HPK1 complex to the autophosphorylated EGF receptor and to the Shc docking protein. Several activated receptor and cytoplasmic tyrosine kinases, including the EGF receptor, stimulated the tyrosine phosphorylation of the HPK1 serine/threonine kinase. These results suggest that HPK1, a mammalian Ste20-related protein-serine/threonine kinase, can potentially associate with protein-tyrosine kinases through interactions mediated by SH2/SH3 adaptors such as Grb2. Such interaction may provide a possible mechanism for cross-talk between distinct biochemical pathways following the activation of tyrosine kinases.
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Marley, K; Maier, C S; Helfand, S C
2012-09-01
Canine hemangiosarcoma (HSA) is an endothelial cell malignancy driven, in part, by activating mutations in receptor and non-receptor tyrosine kinases. Proteomics, Western blots and a tyrosine kinase inhibitor were used to elucidate activating mechanisms in HSA cell lines. Phosphotyrosine peptides from focal adhesion kinase (FAK) STAT3, Lyn, Fyn and other signal transduction kinases were identified by mass spectrometry. FAK was constitutively activated at tyrosine 397, the autophosphorylation site, and this was reversible with high concentrations of a FAK inhibitor. FAK inhibitor-14 suppressed migration and phosphorylation of FAK tyrosine 397 and tyrosines 576/577 and was cytotoxic to HSA cells suggesting FAK signalling may be an important contributor to canine HSA survival. © 2012 Blackwell Publishing Ltd.
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Kinase Pathway Database: An Integrated Protein-Kinase and NLP-Based Protein-Interaction Resource
Koike, Asako; Kobayashi, Yoshiyuki; Takagi, Toshihisa
2003-01-01
Protein kinases play a crucial role in the regulation of cellular functions. Various kinds of information about these molecules are important for understanding signaling pathways and organism characteristics. We have developed the Kinase Pathway Database, an integrated database involving major completely sequenced eukaryotes. It contains the classification of protein kinases and their functional conservation, ortholog tables among species, protein–protein, protein–gene, and protein–compound interaction data, domain information, and structural information. It also provides an automatic pathway graphic image interface. The protein, gene, and compound interactions are automatically extracted from abstracts for all genes and proteins by natural-language processing (NLP).The method of automatic extraction uses phrase patterns and the GENA protein, gene, and compound name dictionary, which was developed by our group. With this database, pathways are easily compared among species using data with more than 47,000 protein interactions and protein kinase ortholog tables. The database is available for querying and browsing at http://kinasedb.ontology.ims.u-tokyo.ac.jp/. PMID:12799355
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The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling.
Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram; Chekhovskiy, Katerina; Chator, Areeb; Chaudhry, Nauman; Dosch, Joseph; Van Dort, Marcian E; Varambally, Sooryanarayana; Kumar-Sinha, Chandan; Nyati, Mukesh Kumar; Ray, Dipankar; Walter, Nils G; Yu, Hongtao; Ross, Brian Dale; Rehemtulla, Alnawaz
2015-01-06
Transforming growth factor-β (TGF-β) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-β, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human kinome and a live-cell reporter for TGFBR activity, we identified the kinase BUB1 (budding uninhibited by benzimidazoles-1) as a key mediator of TGF-β signaling. BUB1 interacted with TGFBRI in the presence of TGF-β and promoted the heterodimerization of TGFBRI and TGFBRII. Additionally, BUB1 interacted with TGFBRII, suggesting the formation of a ternary complex. Knocking down BUB1 prevented the recruitment of SMAD3 to the receptor complex, the phosphorylation of SMAD2 and SMAD3 and their interaction with SMAD4, SMAD-dependent transcription, and TGF-β-mediated changes in cellular phenotype including epithelial-mesenchymal transition (EMT), migration, and invasion. Knockdown of BUB1 also impaired noncanonical TGF-β signaling mediated by the kinases AKT and p38 MAPK (mitogen-activated protein kinase). The ability of BUB1 to promote TGF-β signaling depended on the kinase activity of BUB1. A small-molecule inhibitor of the kinase activity of BUB1 (2OH-BNPP1) and a kinase-deficient mutant of BUB1 suppressed TGF-β signaling and formation of the ternary complex in various normal and cancer cell lines. 2OH-BNPP1 administration to mice bearing lung carcinoma xenografts reduced the amount of phosphorylated SMAD2 in tumor tissue. These findings indicated that BUB1 functions as a kinase in the TGF-β pathway in a role beyond its established function in cell cycle regulation and chromosome cohesion. Copyright © 2015, American Association for the Advancement of Science.
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Activation of MAP kinase kinase (MEK) and Ras by cholecystokinin in rat pancreatic acini.
Duan, R D; Zheng, C F; Guan, K L; Williams, J A
1995-06-01
Cholecystokinin (CCK) has recently been shown to activate mitogen-activated protein (MAP) kinase in rat pancreatic acini [Duan and Williams, Am. J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G401-G408, 1994]. To evaluate the mechanism of MAP kinase activation, we studied the effects of CCK on MAP kinase kinase (MEK) in rat pancreatic acini. Two forms of MEK were identified by immunoblotting, using antibodies specific to MEK1 and MEK2. MEK activity in acinar extracts and after immunoprecipitation with anti-MEK was detected using a recombinant fusion protein, glutathione S-transferase-MAP kinase, as a substrate. MEK activity rapidly increased after stimulation of acini by CCK, with significant stimulation at 1 min and a maximal effect at 5 min, followed by a slow decline to slightly above control levels after 30 min. The threshold concentration of CCK was approximately 10 pM, and the maximal effect was induced by 1 nM CCK, which increased MEK activity by 120%. In addition to CCK, bombesin and carbachol, but not secretin or vasoactive intestinal peptide, enhanced MEK activity. Phorbol ester mimicked the effect of CCK, whereas ionomycin and thapsigargin failed to activate MEK. We further studied the activation of Ras, an important component leading to activation of MEK by growth factors. Ras in acini was immunoprecipitated and identified by Western blotting. CCK and 12-O-tetradecanoylphorbol-13-acetate stimulated the incorporation of GTP into Ras, a requirement for its activation, reaching a maximum at 10 min of approximately 120% over control. In conclusion, the activation of MAP kinase by CCK can be explained by activation of MEK and may involve the activation of Ras by a protein kinase C-dependent mechanism.
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Conserved herpesvirus protein kinases
Gershburg, Edward; Pagano, Joseph S.
2008-01-01
Conserved herpesviral protein kinases (CHPKs) are a group of enzymes conserved throughout all subfamilies of Herpesviridae. Members of this group are serine/threonine protein kinases that are likely to play a conserved role in viral infection by interacting with common host cellular and viral factors; however along with a conserved role, individual kinases may have unique functions in the context of viral infection in such a way that they are only partially replaceable even by close homologues. Recent studies demonstrated that CHPKs are crucial for viral infection and suggested their involvement in regulation of numerous processes at various infection steps (primary infection, nuclear egress, tegumentation), although the mechanisms of this regulation remain unknown. Notwithstanding, recent advances in discovery of new CHPK targets, and studies of CHPK knockout phenotypes have raised their attractiveness as targets for antiviral therapy. A number of compounds have been shown to inhibit the activity of human cytomegalovirus (HCMV)-encoded UL97 protein kinase and exhibit a pronounced antiviral effect, although the same compounds are inactive against Epstein-Barr Virus (EBV)-encoded protein kinase BGLF4, illustrating the fact that low homology between the members of this group complicates development of compounds targeting the whole group, and suggesting that individualized, structure-based inhibitor design will be more effective. Determination of CHPK structures will greatly facilitate this task. PMID:17881303
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Bell, Ryan A V; Storey, Kenneth B
2014-01-01
The efficacy of cellular signal transduction is of paramount importance for the proper functioning of a cell and an organism as a whole. Protein kinases are responsible for much of this transmission and thus have been the focal point of extensive research. While there are numerous commercially available protein kinase assays, the Kinase-Glo luminescent kinase assay (Promega) provides an easy-to-use and high throughput platform for determining protein kinase activity. This assay is said to require the use of a microplate spectrophotometer capable of detecting a luminescent signal. This study shows that:•The ChemiGenius Bioimaging system (Syngene), typically used for visualizing chemiluminescence from Western blots, provides an alternative detection system for Kinase-Glo luminescence.•The novel detection system confers an advantage over traditional luminometers, in that it allows visualization of the luminescent wells, which allows for the real-time analysis and correction of experimental errors (i.e. bubble formation).•Determining kinase kinetics using this detection system produced comparable results to previous studies on the same enzyme (i.e. glycogen synthase kinase 3).
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Optical power of VCSELs stabilized to 35 ppm/°C without a TEC
NASA Astrophysics Data System (ADS)
Downing, John
2015-03-01
This paper reports a method and system comprising a light source, an electronic method, and a calibration procedure for stabilizing the optical power of vertical-cavity surface-emitting lasers (VCSELs) and laser diodes (LDs) without the use thermoelectric coolers (TECs). The system eliminates the needs for custom interference coatings, polarization adjustments, and the exact alignment required by the optical method reported in 2013 [1]. It can precisely compensate for the effects of temperature and wavelength drift on photodiode responsivity as well as changes in VCSEL beam quality and polarization angle over a 50°C temperature range. Data obtained from light sources built with single-mode polarization-locked VCSELs demonstrate that 30 ppm/°C stability can be readily obtained. The system has advantages over TECstabilized laser modules that include: 1) 90% lower relative RMS optical power and temperature sensitivity, 2) a five-fold enhancement of wall-plug efficiency, 3) less component testing and sorting, 4) lower manufacturing costs, and 5) automated calibration in batches at time of manufacture is practical. The system is ideally suited for battery-powered environmental and in-home medical monitoring applications.
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Yang, S D; Yu, J S; Yang, C C; Lee, S C; Lee, T T; Ni, M H; Kuan, C Y; Chen, H C
1996-05-01
Computer analysis of protein phosphorylation sites sequence revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3 alpha (kinase F(A)/GSK-3 alpha) (a member of PDPK family) has been optimized for human hepatoma and used to demonstrate for the first time significantly increased (P < 0.01) activity in poorly differentiated SK-Hep-1 hepatoma (24.2 +/- 2.8 units/mg) and moderately differentiated Mahlavu hepatoma (14.5 +/- 2.2 units/mg) when compared to well differentiated Hep 3B hepatoma (8.0 +/- 2.4 units/mg). Immunoblotting analysis revealed that increased activity of kinase FA/GSK-3 alpha is due to overexpression of the protein. Elevated kinase FA/GSK-3 alpha expression in human hepatoma biopsies relative to normal liver tissue was found to be even more profound. This kinase appeared to be fivefold overexpressed in well differentiated hepatoma and 13-fold overexpressed in poorly differentiated hepatoma when compared to normal liver tissue. Taken together, the results provide initial evidence that overexpression of kinase FA/GSK-3 alpha is involved in human hepatoma dedifferentiation/progression. Since kinase FA/GSK-3 alpha is a PDPK, the results further support a potential role of this kinase in human liver tumorigenesis, especially in its dedifferentiation/progression.
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Enterococcus faecalis phosphomevalonate kinase
Doun, Stephanie S.; Burgner, John W.; Briggs, Scott D.; Rodwell, Victor W.
2005-01-01
The six enzymes of the mevalonate pathway of isopentenyl diphosphate biosynthesis represent potential for addressing a pressing human health concern, the development of antibiotics against resistant strains of the Gram-positive streptococci. We previously characterized the first four of the mevalonate pathway enzymes of Enterococcus faecalis, and here characterize the fifth, phosphomevalonate kinase (E.C. 2.7.4.2). E. faecalis genomic DNA and the polymerase chain reaction were used to clone DNA thought to encode phosphomevalonate kinase into pET28b(+). Double-stranded DNA sequencing verified the sequence of the recombinant gene. The encoded N-terminal hexahistidine-tagged protein was expressed in Escherichia coli with induction by isopropylthiogalactoside and purified by Ni++ affinity chromatography, yield 20 mg protein per liter. Analysis of the purified protein by MALDI-TOF mass spectrometry established it as E. faecalis phosphomevalonate kinase. Analytical ultracentrifugation revealed that the kinase exists in solution primarily as a dimer. Assay for phosphomevalonate kinase activity used pyruvate kinase and lactate dehydrogenase to couple the formation of ADP to the oxidation of NADH. Optimal activity occurred at pH 8.0 and at 37°C. The activation energy was ~5.6 kcal/mol. Activity with Mn++, the preferred cation, was optimal at about 4 mM. Relative rates using different phosphoryl donors were 100 (ATP), 3.6 (GTP), 1.6 (TTP), and 0.4 (CTP). Km values were 0.17 mM for ATP and 0.19 mM for (R,S)-5-phosphomevalonate. The specific activity of the purified enzyme was 3.9 μmol substrate converted per minute per milligram protein. Applications to an immobilized enzyme bioreactor and to drug screening and design are discussed. PMID:15802646
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Mitotic Regulation by NEK Kinase Networks
Fry, Andrew M.; Bayliss, Richard; Roig, Joan
2017-01-01
Genetic studies in yeast and Drosophila led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species, Aspergillus nidulans, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied. Nevertheless, it is now clear that multiple NEK family members act in networks to regulate specific events of mitosis, including centrosome separation, spindle assembly and cytokinesis. Here, we describe our current understanding of how the NEK kinases contribute to these processes, particularly through targeted phosphorylation of proteins associated with the microtubule cytoskeleton. We also present the latest findings on molecular events that control the activation state of the NEKs and how these are revealing novel modes of enzymatic regulation relevant not only to other kinases but also to pathological mechanisms of disease. PMID:29250521
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Auto-phosphorylation Represses Protein Kinase R Activity.
Wang, Die; de Weerd, Nicole A; Willard, Belinda; Polekhina, Galina; Williams, Bryan R G; Sadler, Anthony J
2017-03-10
The central role of protein kinases in controlling disease processes has spurred efforts to develop pharmaceutical regulators of their activity. A rational strategy to achieve this end is to determine intrinsic auto-regulatory processes, then selectively target these different states of kinases to repress their activation. Here we investigate auto-regulation of the innate immune effector protein kinase R, which phosphorylates the eukaryotic initiation factor 2α to inhibit global protein translation. We demonstrate that protein kinase R activity is controlled by auto-inhibition via an intra-molecular interaction. Part of this mechanism of control had previously been reported, but was then controverted. We account for the discrepancy and extend our understanding of the auto-inhibitory mechanism by identifying that auto-inhibition is paradoxically instigated by incipient auto-phosphorylation. Phosphor-residues at the amino-terminus instigate an intra-molecular interaction that enlists both of the N-terminal RNA-binding motifs of the protein with separate surfaces of the C-terminal kinase domain, to co-operatively inhibit kinase activation. These findings identify an innovative mechanism to control kinase activity, providing insight for strategies to better regulate kinase activity.
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The Pim kinases: new targets for drug development.
Swords, Ronan; Kelly, Kevin; Carew, Jennifer; Nawrocki, Stefan; Mahalingam, Devalingam; Sarantopoulos, John; Bearss, David; Giles, Francis
2011-12-01
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.
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Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.
Lai, Justine Y Q; Langston, Steven; Adams, Ruth; Beevers, Rebekah E; Boyce, Richard; Burckhardt, Svenja; Cobb, James; Ferguson, Yvonne; Figueroa, Eva; Grimster, Neil; Henry, Andrew H; Khan, Nawaz; Jenkins, Kerry; Jones, Mark W; Judkins, Robert; Major, Jeremy; Masood, Abid; Nally, James; Payne, Helen; Payne, Lloyd; Raphy, Gilles; Raynham, Tony; Reader, John; Reader, Valérie; Reid, Alison; Ruprah, Parminder; Shaw, Michael; Sore, Hannah; Stirling, Matthew; Talbot, Adam; Taylor, Jess; Thompson, Stephen; Wada, Hiroki; Walker, David
2005-05-01
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection. Copyright (c) 2004 Wiley Periodicals, Inc.
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Becker, Elena; Huynh-Do, Uyen; Holland, Sacha; Pawson, Tony; Daniel, Tom O.; Skolnik, Edward Y.
2000-01-01
The mammalian Ste20 kinase Nck-interacting kinase (NIK) specifically activates the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase module. NIK also binds the SH3 domains of the SH2/SH3 adapter protein Nck. To determine whether Nck functions as an adapter to couple NIK to a receptor tyrosine kinase signaling pathway, we determined whether NIK is activated by Eph receptors (EphR). EphRs constitute the largest family of receptor tyrosine kinases (RTK), and members of this family play important roles in patterning of the nervous and vascular systems. In this report, we show that NIK kinase activity is specifically increased in cells stimulated by two EphRs, EphB1 and EphB2. EphB1 kinase activity and phosphorylation of a juxtamembrane tyrosine (Y594), conserved in all Eph receptors, are both critical for NIK activation by EphB1. Although pY594 in the EphB1R has previously been shown to bind the SH2 domain of Nck, we found that stimulation of EphB1 and EphB2 led predominantly to a complex between NIK/Nck, p62dok, RasGAP, and an unidentified 145-kDa tyrosine-phosphorylated protein. Tyrosine-phosphorylated p62dok most probably binds directly to the SH2 domain of Nck and RasGAP and indirectly to NIK bound to the SH3 domain of Nck. We found that NIK activation is also critical for coupling EphB1R to biological responses that include the activation of integrins and JNK by EphB1. Taken together, these findings support a model in which the recruitment of the Ste20 kinase NIK to phosphotyrosine-containing proteins by Nck is an important proximal step in the signaling cascade downstream of EphRs. PMID:10669731
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Petti, Filippo; Thelemann, April; Kahler, Jen; McCormack, Siobhan; Castaldo, Linda; Hunt, Tony; Nuwaysir, Lydia; Zeiske, Lynn; Haack, Herbert; Sullivan, Laura; Garton, Andrew; Haley, John D
2005-08-01
OSI-930, a potent thiophene inhibitor of the Kit, KDR, and platelet-derived growth factor receptor tyrosine kinases, was used to selectively inhibit tyrosine phosphorylation downstream of juxtamembrane mutant Kit in the mast cell leukemia line HMC-1. Inhibition of Kit kinase activity resulted in a rapid dephosphorylation of Kit and inhibition of the downstream signaling pathways. Attenuation of Ras-Raf-Erk (phospho-Erk, phospho-p38), phosphatidyl inositol-3' kinase (phospho-p85, phospho-Akt, phospho-S6), and signal transducers and activators of transcription signaling pathways (phospho-STAT3/5/6) were measured by affinity liquid chromatography tandem mass spectrometry, by immunoblot, and by tissue microarrays of fixed cell pellets. To more globally define additional components of Kit signaling temporally altered by kinase inhibition, a novel multiplex quantitative isobaric peptide labeling approach was used. This approach allowed clustering of proteins by temporal expression patterns. Kit kinase, which dephosphorylates rapidly upon kinase inhibition, was shown to regulate both Shp-1 and BDP-1 tyrosine phosphatases and the phosphatase-interacting protein PSTPIP2. Interactions with SH2 domain adapters [growth factor receptor binding protein 2 (Grb2), Cbl, Slp-76] and SH3 domain adapters (HS1, cortactin, CD2BP3) were attenuated by inhibition of Kit kinase activity. Functional crosstalk between Kit and the non-receptor tyrosine kinases Fes/Fps, Fer, Btk, and Syk was observed. Inhibition of Kit modulated phosphorylation-dependent interactions with pathways controlling focal adhesion (paxillin, leupaxin, p130CAS, FAK1, the Src family kinase Lyn, Wasp, Fhl-3, G25K, Ack-1, Nap1, SH3P12/ponsin) and septin-actin complexes (NEDD5, cdc11, actin). The combined use of isobaric protein quantitation and expression clustering, immunoblot, and tissue microarray strategies allowed temporal measurement signaling pathways modulated by mutant Kit inhibition in a model of mast cell
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Komandirov, Maxim A; Knyazeva, Evgeniya A; Fedorenko, Yulia P; Rudkovskii, Mikhail V; Stetsurin, Denis A; Uzdensky, Anatoly B
2011-10-01
Photodynamic treatment that causes intense oxidative stress and cell death is currently used in neurooncology. However, along with tumor cells, it may damage healthy neurons and glia. To study the involvement of signaling processes in photodynamic injury or protection of neurons and glia, we used crayfish mechanoreceptor consisting of a single neuron surrounded by glial cells. It was photosensitized with alumophthalocyanine Photosens. Application of specific inhibitors showed that phosphatidylinositol 3-kinase did not participate in photoinduced death of neurons and glia. Akt was involved in photoinduced necrosis but not in apoptosis of neurons and glia. Glycogen synthase kinase-3β participated in photoinduced apoptosis of glial cells and in necrosis of neurons. Therefore, phosphatidylinositol 3-kinase/protein kinase Akt/glycogen synthase kinase-3β pathway was not involved as a whole in photodynamic injury of crayfish neurons and glia but its components, Akt and glycogen synthase kinase-3β, independently and cell specifically regulated death of neurons and glial cells. According to these data, necrosis in this system was a controlled but not a non-regulated cell death mode. The obtained results may be used for the search of pharmacological agents selectively modulating death and survival of normal neurons and glial cells during photodynamic therapy of brain tumors.
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Szczepankiewicz, Bruce G; Kosogof, Christi; Nelson, Lissa T J; Liu, Gang; Liu, Bo; Zhao, Hongyu; Serby, Michael D; Xin, Zhili; Liu, Mei; Gum, Rebecca J; Haasch, Deanna L; Wang, Sanyi; Clampit, Jill E; Johnson, Eric F; Lubben, Thomas H; Stashko, Michael A; Olejniczak, Edward T; Sun, Chaohong; Dorwin, Sarah A; Haskins, Kristi; Abad-Zapatero, Cele; Fry, Elizabeth H; Hutchins, Charles W; Sham, Hing L; Rondinone, Cristina M; Trevillyan, James M
2006-06-15
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Liu, Jian; Guiadeen, Deodial; Krikorian, Arto
Bruton’s tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-raymore » crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.« less
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NASA Technical Reports Server (NTRS)
Li, H.; Roux, S. J.
1992-01-01
A casein kinase II (CK II)-like protein kinase was identified and partially isolated from a purified envelope-matrix fraction of pea (Pisum sativum L.) nuclei. When [gamma-32P]ATP was directly added to the envelope-matrix preparation, the three most heavily labeled protein bands had molecular masses near 71, 48, and 46 kDa. Protein kinases were removed from the preparation by sequential extraction with Triton X-100, EGTA, 0.3 M NaCl, and a pH 10.5 buffer, but an active kinase still remained bound to the remaining lamina-matrix fraction after these treatments. This kinase had properties resembling CK II kinases previously characterized from animal and plant sources: it preferred casein as an artificial substrate, could use GTP as efficiently as ATP as the phosphoryl donor, was stimulated by spermine, was calcium independent, and had a catalytic subunit of 36 kDa. Some animal and plant CK II kinases have regulatory subunits near 29 kDa, and a lamina-matrix-bound protein of this molecular mass was recognized on immunoblot by anti-Drosophila CK II polyclonal antibodies. Also found associated with the envelope-matrix fraction of pea nuclei were p34cdc2-like and Ca(2+)-dependent protein kinases, but their properties could not account for the protein kinase activity bound to the lamina. The 71-kDa substrate of the CK II-like kinase was lamin A-like, both in its molecular mass and in its cross-reactivity with anti-intermediate filament antibodies. Lamin phosphorylation is considered a crucial early step in the entry of cells into mitosis, so lamina-bound CK II kinases may be important control points for cellular proliferation.
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van Weering, David H. J.; de Rooij, Johan; Marte, Barbara; Downward, Julian; Bos, Johannes L.; Burgering, Boudewijn M. T.
1998-01-01
Regulation of phosphoinositide 3-kinase (PI 3-kinase) can occur by binding of the regulatory p85 subunit to tyrosine-phosphorylated proteins and by binding of the p110 catalytic subunit to activated Ras. However, the way in which these regulatory mechanisms act to regulate PI 3-kinase in vivo is unclear. Here we show that several growth factors (basic fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], and epidermal growth factor [EGF; to activate an EGF receptor-Ret chimeric receptor]) all activate PI 3-kinase in vivo in the neuroectoderm-derived cell line SKF5. However, these growth factors differ in their ability to activate PI 3-kinase-dependent signaling. PDGF and EGF(Ret) treatment induced PI 3-kinase-dependent lamellipodium formation and protein kinase B (PKB) activation. In contrast, bFGF did not induce lamellipodium formation but activated PKB, albeit to a small extent. PDGF and EGF(Ret) stimulation resulted in binding of p85 to tyrosine-phosphorylated proteins and strong Ras activation. bFGF, however, induced only strong activation of Ras. In addition, while RasAsn17 abolished bFGF activation of PKB, PDGF- and EGF(Ret)-induced PKB activation was only partially inhibited and lamellipodium formation was unaffected. Interestingly, in contrast to activation of only endogenous Ras (bFGF), ectopic expression of activated Ras did result in lamellipodium formation. From this we conclude that, in vivo, p85 and Ras synergize to activate PI 3-kinase and that strong activation of only endogenous Ras exerts a small effect on PI 3-kinase activity, sufficient for PKB activation but not lamellipodium formation. This differential sensitivity to PI 3-kinase activation could be explained by our finding that PKB activation and lamellipodium formation are independent PI 3-kinase-induced events. PMID:9528752
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Shaifta, Yasin; Irechukwu, Nneka; Prieto‐Lloret, Jesus; MacKay, Charles E; Marchon, Keisha A; Ward, Jeremy P T
2015-01-01
Background and Purpose The importance of tyrosine kinases in airway smooth muscle (ASM) contraction is not fully understood. The aim of this study was to investigate the role of Src‐family kinases (SrcFK) and focal adhesion kinase (FAK) in GPCR‐mediated ASM contraction and associated signalling events. Experimental Approach Contraction was recorded in intact or α‐toxin permeabilized rat bronchioles. Phosphorylation of SrcFK, FAK, myosin light‐chain‐20 (MLC20) and myosin phosphatase targeting subunit‐1 (MYPT‐1) was evaluated in cultured human ASM cells (hASMC). [Ca2+]i was evaluated in Fura‐2 loaded hASMC. Responses to carbachol (CCh) and bradykinin (BK) and the contribution of SrcFK and FAK to these responses were determined. Key Results Contractile responses in intact bronchioles were inhibited by antagonists of SrcFK, FAK and Rho‐kinase, while after α‐toxin permeabilization, they were sensitive to inhibition of SrcFK and Rho‐kinase, but not FAK. CCh and BK increased phosphorylation of MYPT‐1 and MLC20 and auto‐phosphorylation of SrcFK and FAK. MYPT‐1 phosphorylation was sensitive to inhibition of Rho‐kinase and SrcFK, but not FAK. Contraction induced by SR Ca2+ depletion and equivalent [Ca2+]i responses in hASMC were sensitive to inhibition of both SrcFK and FAK, while depolarization‐induced contraction was sensitive to FAK inhibition only. SrcFK auto‐phosphorylation was partially FAK‐dependent, while FAK auto‐phosphorylation was SrcFK‐independent. Conclusions and Implications SrcFK mediates Ca2+‐sensitization in ASM, while SrcFK and FAK together and individually influence multiple Ca2+ influx pathways. Tyrosine phosphorylation is therefore a key upstream signalling event in ASM contraction and may be a viable target for modulating ASM tone in respiratory disease. PMID:26294392
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p21-activated kinase inhibitors.
Rudolph, Joachim; Crawford, James J; Hoeflich, Klaus P; Chernoff, Jonathan
2013-01-01
The p21-activated kinases (PAKs) are Ser/Thr kinases in the STE20 kinase family with important roles in regulating cytoskeletal organization, cell migration, and signaling. The PAK enzyme family comprises six members subdivided into two groups: Group I, represented by PAK1, 2, and 3, and Group II, represented by PAK 4, 5, and 6, based on sequence and structural homology. Individual PAK isoforms were found to be overexpressed and amplified in a variety of human cancers, and in vitro and in vivo studies using genetically engineered systems as well as small-molecule tool compounds have suggested therapeutic utility of PAKs as oncology targets. The identification of potent and kinome-selective ATP-competitive PAK inhibitors has proven challenging, likely caused by the openness and unique plasticity of the ATP-binding site of PAK enzymes. Progress in achieving increased kinase selectivity has been achieved with certain inhibitors but at the expense of increased molecular weight. Allosteric inhibitors, such as IPA-3, leverage the unique Group I PAK autoregulatory domain for selective inhibition, and this approach might provide an outlet to evade the kinase selectivity challenges observed with ATP-competitive PAK inhibitors. © 2013 Elsevier Inc. All rights reserved.
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Nonreceptor Protein-Tyrosine Kinases in Neutrophil Activation
Welch; Mauran; Maridonneau-Parini
1996-06-01
Nonreceptor protein-tyrosine kinases are involved in the regulation of almost all neutrophil responses such as adhesion, chemotaxis, priming, oxidative burst, and degranulation. Here, we show that phagocytosis is also regulated by protein-tyrosine kinase activity. Using various protein-tyrosine kinase inhibitors, we further demonstrate that opsonized zymosan-induced degranulation of specific and azurophil granules is regulated by protein-tyrosine kinase activity, whereas phorbol ester-induced degranulation is not. Several of the nonreceptor protein-tyrosine kinases involving in neutrophil signal transduction are known, including Fgr, Hck, Lyn, Yes, and Syk. Among these, Hck and Fgr are localized on the azurophil and specific granules, suggesting the involvement of these two protein-tyrosine kinases in the regulation of degranulation. In this report, we characterize some of the molecular properties of Hck and Fgr. We discuss the methods generally used for the measurement of protein-tyrosine kinase activities in neutrophils highlighting precautions against proteolysis. In addition, we show that in subcellular fractions of retinoic acid-differentiated neutrophil-like NB4 cells, the 59- and 61-kDa forms of Hck are attached to the membranes of their respective compartments by different mechanisms. Finally, we discuss the functional roles of protein-tyrosine kinases in the regulation of neutrophil activation and speculate on the importance of their subcellular localization.
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Protocols for the Design of Kinase-focused Compound Libraries.
Jacoby, Edgar; Wroblowski, Berthold; Buyck, Christophe; Neefs, Jean-Marc; Meyer, Christophe; Cummings, Maxwell D; van Vlijmen, Herman
2018-05-01
Protocols for the design of kinase-focused compound libraries are presented. Kinase-focused compound libraries can be differentiated based on the design goal. Depending on whether the library should be a discovery library specific for one particular kinase, a general discovery library for multiple distinct kinase projects, or even phenotypic screening, there exists today a variety of in silico methods to design candidate compound libraries. We address the following scenarios: 1) Datamining of SAR databases and kinase focused vendor catalogues; 2) Predictions and virtual screening; 3) Structure-based design of combinatorial kinase inhibitors; 4) Design of covalent kinase inhibitors; 5) Design of macrocyclic kinase inhibitors; and 6) Design of allosteric kinase inhibitors and activators. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Ul-Haq, Zaheer; Effendi, Juweria Shahrukh; Ashraf, Sajda; Bkhaitan, Majdi M
2017-06-01
In the current study, quantitative three-dimensional structure-activity-relationship (3D-QSAR) method was performed to design a model for new chemical entities by utilizing pyrazolopyrimidines. Their inhibiting activity on receptor IL-2 Itk correlates descriptors based on topology and hydrophobicity. The best model developed by ligand-based (atom-based) approach has correlation-coefficient of r 2 : 0.987 and cross-validated squared correlation-coefficient of q 2 : 0.541 with an external prediction capability of r 2 : 0.944. Whereas the best selected model developed by structured-based (receptor-based) approach has correlation-coefficient of r 2 : 0.987, cross-validated squared correlation-coefficient of q 2 : 0.637 with an external predictive ability of r 2 : 0.941. The statistical parameters prove that structure-based gave a better model to design new chemical scaffolds. The results achieved indicated that hydrophobicity at R 1 location play a vital role in the inhibitory activity and introduction of appropriately bulky and strongly hydrophobic-groups at position 3 of the terminal phenyl-group which is highly significant to enhance the activity. Six new pyrazolopyrimidine derivatives were designed. Docking simulation study was carried out and their inhibitory activity was predicted by the best structure based model with predictive activity of ranging from 8.43 to 8.85 log unit. The interacting residues PHE435, ASP500, LYS391, GLU436, MET438, CYS442, ILE369, VAL377 of PDB 4HCT were studied with respect to type of bonding with the new compounds. This study was aimed to search out more potent inhibitors of IL-2 Itk. Copyright © 2017 Elsevier Inc. All rights reserved.
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Grimaldi, Gabriel; Teva, Antonio; Dos-Santos, Claudiney B; Santos, Fernanda Nunes; Pinto, Israel de-Souza; Fux, Blima; Leite, Gustavo Rocha; Falqueto, Aloísio
2017-01-01
Because domestic dogs are reservoir hosts for visceral leishmaniasis (VL) in Brazil, one of the approaches used to reduce human disease incidence is to cull infected dogs. However, the results of controlled intervention trials based on serological screening of dogs and killing of seropositive animals are equivocal. A prophylactic vaccine to protect dogs from being infectious to the sand fly vector could be an effective strategy to provide sustained control. Here, we investigated whether a currently licensed commercial subunit rA2 protein-saponin vaccine (Leish-tec®) had an additional effect to dog culling on reducing the canine infectious populations. This prospective study was conducted in an L. infantum highly endemic area of southeast Brazil. At the onset of the intervention, all of the eligible dogs received through subcutaneous route a three-dose vaccine course at 21-day intervals and a booster on month 12. For the purpose of comparison, newly recruited healthy dogs were included as the exposed control group. To ascertain vaccine-induced protection, dogs were screened on clinical and serological criteria every 6 months for a 2-year follow-up period. Antibody-based tests and histopathological examination of post-mortem tissue specimens from euthanized animals were used as a marker of infection. The standardized vaccine regime, apart from being safe, was immunogenic as immunized animals responded with a pronounced production of anti-A2-specific IgG antibodies. It should be noted the mean seroconversion time for infection obtained among immunized exposed dogs (~ 18 months), which was twice as high as that for unvaccinated ones (~ 9 months). After two transmission cycles completed, the cumulative incidence of infection did differ significantly (P = 0.016) between the vaccinated (27%) and unvaccinated (42%) dogs. However, the expected efficacy for the vaccine in inducing clinical protection was not evident since 43% of vaccine recipients developed disease over
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Mediator kinase module and human tumorigenesis.
Clark, Alison D; Oldenbroek, Marieke; Boyer, Thomas G
2015-01-01
Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit "kinase" module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways.
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A framework for classification of prokaryotic protein kinases.
Tyagi, Nidhi; Anamika, Krishanpal; Srinivasan, Narayanaswamy
2010-05-26
Overwhelming majority of the Serine/Threonine protein kinases identified by gleaning archaeal and eubacterial genomes could not be classified into any of the well known Hanks and Hunter subfamilies of protein kinases. This is owing to the development of Hanks and Hunter classification scheme based on eukaryotic protein kinases which are highly divergent from their prokaryotic homologues. A large dataset of prokaryotic Serine/Threonine protein kinases recognized from genomes of prokaryotes have been used to develop a classification framework for prokaryotic Ser/Thr protein kinases. We have used traditional sequence alignment and phylogenetic approaches and clustered the prokaryotic kinases which represent 72 subfamilies with at least 4 members in each. Such a clustering enables classification of prokaryotic Ser/Thr kinases and it can be used as a framework to classify newly identified prokaryotic Ser/Thr kinases. After series of searches in a comprehensive sequence database we recognized that 38 subfamilies of prokaryotic protein kinases are associated to a specific taxonomic level. For example 4, 6 and 3 subfamilies have been identified that are currently specific to phylum proteobacteria, cyanobacteria and actinobacteria respectively. Similarly subfamilies which are specific to an order, sub-order, class, family and genus have also been identified. In addition to these, we also identify organism-diverse subfamilies. Members of these clusters are from organisms of different taxonomic levels, such as archaea, bacteria, eukaryotes and viruses. Interestingly, occurrence of several taxonomic level specific subfamilies of prokaryotic kinases contrasts with classification of eukaryotic protein kinases in which most of the popular subfamilies of eukaryotic protein kinases occur diversely in several eukaryotes. Many prokaryotic Ser/Thr kinases exhibit a wide variety of modular organization which indicates a degree of complexity and protein-protein interactions in the
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The PIM kinases in hematological cancers.
Alvarado, Yesid; Giles, Francis J; Swords, Ronan T
2012-02-01
The PIM genes represent a family of proto-oncogenes that encode three different serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance. PIM kinases are overexpressed in several hematopoietic tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. PIM kinases do not have an identified regulatory domain, which means that these proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as rapamycin. Recent crystallography studies reveal that, unlike other kinases, they possess a hinge region, which creates a unique binding pocket for ATP, offering a target for an increasing number of potent small-molecule PIM kinase inhibitors. Preclinical studies in models of various hematologic cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the PIM kinases as targets for therapeutics in hematologic malignancies.
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Plasma bubble monitoring by TEC map and 630 nm airglow image
NASA Astrophysics Data System (ADS)
Takahashi, H.; Wrasse, C. M.; Otsuka, Y.; Ivo, A.; Gomes, V.; Paulino, I.; Medeiros, A. F.; Denardini, C. M.; Sant'Anna, N.; Shiokawa, K.
2015-08-01
Equatorial ionosphere plasma bubbles over the South American continent were successfully observed by mapping the total electron content (TECMAP) using data provided by ground-based GNSS receiver networks. The TECMAP could cover almost all of the continent within ~4000 km distance in longitude and latitude, monitoring TEC variability continuously with a time resolution of 10 min. Simultaneous observations of OI 630 nm all-sky image at Cachoeira Paulista (22.7°S, 45.0°W) and Cariri (7.4°S, 36.5°W) were used to compare the bubble structures. The spatial resolution of the TECMAP varied from 50 km to 1000 km, depending on the density of the observation sites. On the other hand, optical imaging has a spatial resolution better than 15 km, depicting the fine structure of the bubbles but covering a limited area (~1600 km diameter). TECMAP has an advantage in its spatial coverage and the continuous monitoring (day and night) form. The initial phase of plasma depletion in the post-sunset equatorial ionization anomaly (PS-EIA) trough region, followed by development of plasma bubbles in the crest region, could be monitored in a progressive way over the magnetic equator. In December 2013 to January 2014, periodically spaced bubble structures were frequently observed. The longitudinal spacing between the bubbles was around 600-800 km depending on the day. The periodic form of plasma bubbles may suggest a seeding process related to the solar terminator passage in the ionosphere.
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Tyrosine kinases in inflammatory dermatologic disease
Paniagua, Ricardo T.; Fiorentino, David; Chung, Lorinda; Robinson, William H.
2010-01-01
Tyrosine kinases are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific tyrosine kinases have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of tyrosine kinases are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight tyrosine kinase signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development. PMID:20584561
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Aurora kinases: structure, functions and their association with cancer.
Kollareddy, Madhu; Dzubak, Petr; Zheleva, Daniella; Hajduch, Marian
2008-06-01
Aurora kinases are a recently discovered family of kinases (A, B & C) consisting of highly conserved serine\\threonine protein kinases found to be involved in multiple mitotic events: regulation of spindle assembly checkpoint pathway, function of centrosomes and cytoskeleton, and cytokinesis. Aberrant expression of Aurora kinases may lead to cancer. For this reason the Aurora kinases are potential targets in the treatment of cancer. In this review we discuss the biology of these kinases: structure, function, regulation and association with cancer. A literature search. Many of the multiple functions of mitosis are mediated by the Aurora kinases. Their aberrant expression can lead to the deregulation of cell division and cancer. For this reason, the Aurora kinases are currently one of the most interesting targets for cancer therapy. Some Aurora kinase inhibitors in the clinic have proven effectively on a wide range of tumor types. The clinical data are very encouraging and promising for development of novel class of structurally different Aurora kinase inhibitors. Hopefully the Aurora kinases will be potentially useful in drug targeted cancer treatment.
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Tyrosine Kinase Display of Prostate Cancer Cells
2001-10-01
markers and important targets for intervention (2,4). Kinase inhibitors have recently shown tremendous efficacies and promises in the treatment of human...fully characterize this kinase. Etk is a new member of the Btk family of kinases (27), which distinguish themselves from others by having a pleckstrin- 5...Kung, Hsing-Jien DAMD 17-99-1-9021 homology (PH) domain at the N-terminus (27,28,29,30). Btk was uncovered as a kinase whose germ- line mutation
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The RLK/Pelle family of kinases.
Gish, Lindsey A; Clark, Steven E
2011-04-01
The RLK/Pelle class of proteins kinases is composed of over 600 members in Arabidopsis. Many of the proteins in this family are receptor-like kinases (RLK), while others have lost their extracellular domains and are found as cytoplasmic kinases. Proteins in this family that are RLKs have a variety of extracellular domains that drive function in a large number of processes, from cell wall interactions to disease resistance to developmental control. This review will briefly cover the major subclasses of RLK/Pelle proteins and their roles. In addition, two specific groups on RLKs will be discussed in detail, relating recent findings in Arabidopsis and how well these conclusions have been able to be translated to agronomically important species. Finally, some details on kinase activity and signal transduction will be addressed, along with the mystery of RLK/Pelle members lacking kinase enzymatic activity. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.
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Dent, P; Chow, Y H; Wu, J; Morrison, D K; Jove, R; Sturgill, T W
1994-10-01
Mitogen-activated protein (MAP) kinase kinases (MKKs) are dual-specificity protein kinases which activate p42mapk and p44mapk by phosphorylation of regulatory tyrosine and threonine residues. cDNAs for two isotypes of MKK, MKK1 and MKK2, have been isolated from several species. Here we describe construction of recombinant baculoviruses for high-level expression of histidine-tagged rat MKK1 and MKK2, and procedures for production of nearly homogeneous MKK1 and MKK2 fusion proteins, in both inactive and active forms. Co-infection of Sf9 cells with either MKK1 or MKK2 virus together with recombinant viruses for Raf-1, pp60src (Y527F) and c-Ha-Ras resulted in activations of 250-fold and 150-fold for MKK1 and MKK2 respectively. Specific activities towards kinase-defective p42mapk were of the order of several hundred nanomoles of phosphate transferred/min per mg of MKK protein. The Michaelis constants for both enzymes were approx. 1 microM. Preparations of activated MKK were apparently free of Raf-1 as assessed by Western blotting. Raf-1 phosphorylated MKK1 on one major tryptic phosphopeptide, the phosphorylation of which increased with time. This phosphopeptide contained only phosphoserine and possessed neutral overall charge at pH 1.9 on two-dimensional peptide mapping. Phosphorylation of MKK1 by Raf-1 correlated with activation and reached a plateau of approximately 2 mol/mol.
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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
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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.
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Dalton, George D; Dewey, William L
2006-02-01
Signal transduction cascades involving cAMP-dependent protein kinase are highly conserved among a wide variety of organisms. Given the universal nature of this enzyme it is not surprising that cAMP-dependent protein kinase plays a critical role in numerous cellular processes. This is particularly evident in the nervous system where cAMP-dependent protein kinase is involved in neurotransmitter release, gene transcription, and synaptic plasticity. Protein kinase inhibitor peptide (PKI) is an endogenous thermostable peptide that modulates cAMP-dependent protein kinase function. PKI contains two distinct functional domains within its amino acid sequence that allow it to: (1) potently and specifically inhibit the activity of the free catalytic subunit of cAMP-dependent protein kinase and (2) export the free catalytic subunit of cAMP-dependent protein kinase from the nucleus. Three distinct PKI isoforms (PKIalpha, PKIbeta, PKIgamma) have been identified and each isoform is expressed in the brain. PKI modulates neuronal synaptic activity, while PKI also is involved in morphogenesis and symmetrical left-right axis formation. In addition, PKI also plays a role in regulating gene expression induced by cAMP-dependent protein kinase. Future studies should identify novel physiological functions for endogenous PKI both in the nervous system and throughout the body. Most interesting will be the determination whether functional differences exist between individual PKI isoforms which is an intriguing possibility since these isoforms exhibit: (1) cell-type specific tissue expression patterns, (2) different potencies for the inhibition of cAMP-dependent protein kinase activity, and (3) expression patterns that are hormonally, developmentally and cell-cycle regulated. Finally, synthetic peptide analogs of endogenous PKI will continue to be invaluable tools that are used to elucidate the role of cAMP-dependent protein kinase in a variety of cellular processes throughout the nervous
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S -Nitrosylation inhibits the kinase activity of tomato phosphoinositide-dependent kinase 1 (PDK1)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Liu, Jian-Zhong; Duan, Jicheng; Ni, Min
It is well known that the reactive oxygen species, nitric oxide (NO), can trigger cell death in plants, but the underlying molecular mechanisms are not well understood. Here, we provide evidence that NO may trigger cell death in tomato (Solanum lycopersicon) through inhibiting the phosphoinositide-dependent kinase 1 (PDK1) kinase activity via S-nitrosylation. Biotin-switch assays and LC-MS/MS analyses demonstrated that SlPDK1 was a target of S-nitrosylation modification, which primarily occurred on the cysteine residue at position 128 (Cys128). Accordingly, the kinase activity of SlPDK1 was inhibited by S-nitrosoglutathione (GSNO) both in vitro and in vivo in a concentration-dependent manner, indicating thatmore » SlPDK1 activity is regulated by S-nitrosylation. The inhibition of SlPDK1 kinase activity by GSNO was reversible in the presence of a reducing agent but synergistically enhanced by hydrogen peroxide (H2O2). Mutation of Cys128 to serine completely abolished SlPDK1 kinase activity, suggesting that S-nitrosylation of Cys128 is responsible for the inhibition of the kinase activity of SlPDK1. In sum, our results established a potential link between NO-triggered cell death and inhibition of the kinase activity of tomato PDK1, a conserved negative regulator of cell death in yeasts, mammals and plants. Nitric oxide (NO) potentiates the induction of hypersensitive cell death in soybean cells by reactive oxygen species (ROS) (1). However, the molecular mechanism of the NO-induced cell death remains an enigma. One potential mechanism is that the activity of proteins that control cell death may be altered by a post-translational modification, S-nitrosylation. S-nitrosylation is the addition of the NO moiety to thiol groups, including cysteine (Cys) residues in proteins, to form S-nitrosothiols (SNOs). S-nitrosylation is an enzyme-independent post-translational and labile modification that can function as an on/off switch of protein activity (2- 4). Thousands of
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The role of the C8 proton of ATP in the catalysis of shikimate kinase and adenylate kinase
2012-01-01
Background It has been demonstrated that the adenyl moiety of ATP plays a direct role in the regulation of ATP binding and/or phosphoryl transfer within a range of kinase and synthetase enzymes. The role of the C8-H of ATP in the binding and/or phosphoryl transfer on the enzyme activity of a number of kinase and synthetase enzymes has been elucidated. The intrinsic catalysis rate mediated by each kinase enzyme is complex, yielding apparent KM values ranging from less than 0.4 μM to more than 1 mM for ATP in the various kinases. Using a combination of ATP deuterated at the C8 position (C8D-ATP) as a molecular probe with site directed mutagenesis (SDM) of conserved amino acid residues in shikimate kinase and adenylate kinase active sites, we have elucidated a mechanism by which the ATP C8-H is induced to be labile in the broader kinase family. We have demonstrated the direct role of the C8-H in the rate of ATP consumption, and the direct role played by conserved Thr residues interacting with the C8-H. The mechanism by which the vast range in KM might be achieved is also suggested by these findings. Results We have demonstrated the mechanism by which the enzyme activities of Group 2 kinases, shikimate kinase (SK) and adenylate kinase 1 (AK1), are controlled by the C8-H of ATP. Mutations of the conserved threonine residues associated with the labile C8-H cause the enzymes to lose their saturation kinetics over the concentration range tested. The relationship between the role C8-H of ATP in the reaction mechanism and the ATP concentration as they influence the saturation kinetics of the enzyme activity is also shown. The SDM clearly identified the amino acid residues involved in both the catalysis and regulation of phosphoryl transfer in SK and AK1 as mediated by C8H-ATP. Conclusions The data outlined serves to demonstrate the “push” mechanism associated with the control of the saturation kinetics of Group 2 kinases mediated by ATP C8-H. It is therefore conceivable
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Rho-associated coiled-coil containing kinases (ROCK)
Julian, Linda; Olson, Michael F
2014-01-01
Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase.1–5 They belong to the AGC family of serine/threonine kinases6 and play vital roles in facilitating actomyosin cytoskeleton contractility downstream of RhoA and RhoC activation. Since their discovery, ROCK kinases have been extensively studied, unveiling their manifold functions in processes including cell contraction, migration, apoptosis, survival, and proliferation. Two mammalian ROCK homologs have been identified, ROCK1 (also called ROCK I, ROKβ, Rho-kinase β, or p160ROCK) and ROCK2 (also known as ROCK II, ROKα, or Rho kinase), hereafter collectively referred to as ROCK. In this review, we will focus on the structure, regulation, and functions of ROCK. PMID:25010901
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USDA-ARS?s Scientific Manuscript database
The Homo sapiens and Arabidopsis thaliana genomes are believed to encode >500 and >1,000 protein kinases, respectively. Despite this abundance, few bona fide kinase-client relationships have been described in detail. Mass spectrometry (MS)-based approaches have been integral to the large-scale mapp...
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Non-degradative Ubiquitination of Protein Kinases
Ball, K. Aurelia; Johnson, Jeffrey R.; Lewinski, Mary K.; Guatelli, John; Verschueren, Erik; Krogan, Nevan J.; Jacobson, Matthew P.
2016-01-01
Growing evidence supports other regulatory roles for protein ubiquitination in addition to serving as a tag for proteasomal degradation. In contrast to other common post-translational modifications, such as phosphorylation, little is known about how non-degradative ubiquitination modulates protein structure, dynamics, and function. Due to the wealth of knowledge concerning protein kinase structure and regulation, we examined kinase ubiquitination using ubiquitin remnant immunoaffinity enrichment and quantitative mass spectrometry to identify ubiquitinated kinases and the sites of ubiquitination in Jurkat and HEK293 cells. We find that, unlike phosphorylation, ubiquitination most commonly occurs in structured domains, and on the kinase domain, ubiquitination is concentrated in regions known to be important for regulating activity. We hypothesized that ubiquitination, like other post-translational modifications, may alter the conformational equilibrium of the modified protein. We chose one human kinase, ZAP-70, to simulate using molecular dynamics with and without a monoubiquitin modification. In Jurkat cells, ZAP-70 is ubiquitinated at several sites that are not sensitive to proteasome inhibition and thus may have other regulatory roles. Our simulations show that ubiquitination influences the conformational ensemble of ZAP-70 in a site-dependent manner. When monoubiquitinated at K377, near the C-helix, the active conformation of the ZAP-70 C-helix is disrupted. In contrast, when monoubiquitinated at K476, near the kinase hinge region, an active-like ZAP-70 C-helix conformation is stabilized. These results lead to testable hypotheses that ubiquitination directly modulates kinase activity, and that ubiquitination is likely to alter structure, dynamics, and function in other protein classes as well. PMID:27253329
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Whalen, A M; Galasinski, S C; Shapiro, P S; Nahreini, T S; Ahn, N G
1997-01-01
The K562 erythroleukemia cell line was used to study the molecular mechanisms regulating lineage commitment of hematopoietic stem cells. Phorbol esters, which initiate megakaryocyte differentiation in this cell line, caused a rapid increase in extracellular-signal-regulated kinase (ERK), which remained elevated for 2 h and returned to near-basal levels by 24 h. In the absence of extracellular stimuli, ERK could be activated by expression of constitutively active mutants of mitogen-activated protein (MAP) kinase kinase (MKK), resulting in cell adhesion and spreading, increased cell size, inhibition of cell growth, and induction of the platelet-specific integrin alphaIIb beta3, all hallmarks of megakaryocytic differentiation. In contrast, expression of wild-type MKK had little effect. In addition, constitutively active MKK suppressed the expression of an erythroid marker, alpha-globin, indicating the ability to suppress cellular responses necessary for alternative cell lineages. The MKK inhibitor PD98059 blocked MKK/ERK activation and cellular responses to phorbol ester, demonstrating that activation of MKK is necessary and sufficient to induce a differentiation program along the megakaryocyte lineage. Thus, the MAP kinase cascade, which promotes cell growth and proliferation in many cell types, instead inhibits cell proliferation and initiates lineage-specific differentiation in K562 cells, establishing a model system to investigate the mechanisms by which this signal transduction pathway specifies cell fate and developmental processes. PMID:9121442
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Whalen, A M; Galasinski, S C; Shapiro, P S; Nahreini, T S; Ahn, N G
1997-04-01
The K562 erythroleukemia cell line was used to study the molecular mechanisms regulating lineage commitment of hematopoietic stem cells. Phorbol esters, which initiate megakaryocyte differentiation in this cell line, caused a rapid increase in extracellular-signal-regulated kinase (ERK), which remained elevated for 2 h and returned to near-basal levels by 24 h. In the absence of extracellular stimuli, ERK could be activated by expression of constitutively active mutants of mitogen-activated protein (MAP) kinase kinase (MKK), resulting in cell adhesion and spreading, increased cell size, inhibition of cell growth, and induction of the platelet-specific integrin alphaIIb beta3, all hallmarks of megakaryocytic differentiation. In contrast, expression of wild-type MKK had little effect. In addition, constitutively active MKK suppressed the expression of an erythroid marker, alpha-globin, indicating the ability to suppress cellular responses necessary for alternative cell lineages. The MKK inhibitor PD98059 blocked MKK/ERK activation and cellular responses to phorbol ester, demonstrating that activation of MKK is necessary and sufficient to induce a differentiation program along the megakaryocyte lineage. Thus, the MAP kinase cascade, which promotes cell growth and proliferation in many cell types, instead inhibits cell proliferation and initiates lineage-specific differentiation in K562 cells, establishing a model system to investigate the mechanisms by which this signal transduction pathway specifies cell fate and developmental processes.
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The AzTEC/SMA Interferometric Imaging Survey of Submillimeter-selected High-redshift Galaxies
NASA Astrophysics Data System (ADS)
Younger, Joshua D.; Fazio, Giovanni G.; Huang, Jia-Sheng; Yun, Min S.; Wilson, Grant W.; Ashby, Matthew L. N.; Gurwell, Mark A.; Peck, Alison B.; Petitpas, Glen R.; Wilner, David J.; Hughes, David H.; Aretxaga, Itziar; Kim, Sungeun; Scott, Kimberly S.; Austermann, Jason; Perera, Thushara; Lowenthal, James D.
2009-10-01
We present results from a continuing interferometric survey of high-redshift submillimeter galaxies (SMGs) with the Submillimeter Array, including high-resolution (beam size ~2 arcsec) imaging of eight additional AzTEC 1.1 mm selected sources in the COSMOS field, for which we obtain six reliable (peak signal-to-noise ratio (S/N) >5 or peak S/N >4 with multiwavelength counterparts within the beam) and two moderate significance (peak S/N >4) detections. When combined with previous detections, this yields an unbiased sample of millimeter-selected SMGs with complete interferometric follow up. With this sample in hand, we (1) empirically confirm the radio-submillimeter association, (2) examine the submillimeter morphology—including the nature of SMGs with multiple radio counterparts and constraints on the physical scale of the far infrared—of the sample, and (3) find additional evidence for a population of extremely luminous, radio-dim SMGs that peaks at higher redshift than previous, radio-selected samples. In particular, the presence of such a population of high-redshift sources has important consequences for models of galaxy formation—which struggle to account for such objects even under liberal assumptions—and dust production models given the limited time since the big bang.
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THE AzTEC/SMA INTERFEROMETRIC IMAGING SURVEY OF SUBMILLIMETER-SELECTED HIGH-REDSHIFT GALAXIES
DOE Office of Scientific and Technical Information (OSTI.GOV)
Younger, Joshua D.; Fazio, Giovanni G.; Huang Jiasheng
We present results from a continuing interferometric survey of high-redshift submillimeter galaxies (SMGs) with the Submillimeter Array, including high-resolution (beam size approx2 arcsec) imaging of eight additional AzTEC 1.1 mm selected sources in the COSMOS field, for which we obtain six reliable (peak signal-to-noise ratio (S/N) >5 or peak S/N >4 with multiwavelength counterparts within the beam) and two moderate significance (peak S/N >4) detections. When combined with previous detections, this yields an unbiased sample of millimeter-selected SMGs with complete interferometric follow up. With this sample in hand, we (1) empirically confirm the radio-submillimeter association, (2) examine the submillimeter morphology-includingmore » the nature of SMGs with multiple radio counterparts and constraints on the physical scale of the far infrared-of the sample, and (3) find additional evidence for a population of extremely luminous, radio-dim SMGs that peaks at higher redshift than previous, radio-selected samples. In particular, the presence of such a population of high-redshift sources has important consequences for models of galaxy formation-which struggle to account for such objects even under liberal assumptions-and dust production models given the limited time since the big bang.« less
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Extended-spectrum antiprotozoal bumped kinase inhibitors: A review.
Van Voorhis, Wesley C; Doggett, J Stone; Parsons, Marilyn; Hulverson, Matthew A; Choi, Ryan; Arnold, Samuel L M; Riggs, Michael W; Hemphill, Andrew; Howe, Daniel K; Mealey, Robert H; Lau, Audrey O T; Merritt, Ethan A; Maly, Dustin J; Fan, Erkang; Ojo, Kayode K
2017-09-01
Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.
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Wehrwein, Erica A; Northcott, Carrie A; Loberg, Robert D; Watts, Stephanie W
2004-06-01
Hypertension is characterized by abnormal vascular contractility and function. Arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats develop spontaneous tone that is not observed in arteries from normotensive rats. Inhibition of phosphoinositide 3-kinase (PI3-kinase) by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) reduces spontaneous tone development. The Rho/Rho-kinase pathway has been suggested to play a role in hypertension and may be dependent on PI3-kinase activity. We hypothesized that Rhokinase is involved in spontaneous tone development and that Rho/Rho-kinase is a downstream effector of PI3-kinase. Using endothelium-denuded aortic strips in isolated tissue bath, we demonstrated that (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y27632) (1 microM), a Rho-kinase inhibitor, significantly reduced spontaneous tone in the DOCA aorta but that it did not affect sham aorta basal tone (DOCA 63.5 +/- 15.9 versus sham 1.2 +/- 0.4 total change in percentage of phenylephrine contraction). We examined the interaction between the PI3-kinase and Rho pathways by observing the effects of LY294002 on a Rhokinase effector, myosin phosphatase (MYPT), and Y27632 on a PI3-kinase effector, Akt, using Western blot analysis. Inhibition of PI3-kinase reduced spontaneous tone, but it had no effect on the phosphorylation status of MYPT, indicating that PI3-kinase is not a downstream effector of Rho/Rho-kinase. These data indicate that there is little interaction between the Rho/Rhokinase and PI3-kinase pathways in the DOCA-salt aorta, and the two pathways seem to operate in parallel in supporting spontaneous arterial tone. These data reflect spontaneous tone only and do not rule out the possibility of interaction between these pathways in agonist-stimulated tone.
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Structure of the intact ATM/Tel1 kinase
NASA Astrophysics Data System (ADS)
Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang
2016-05-01
The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.
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Allosteric activation of apicomplexan calcium-dependent protein kinases
Ingram, Jessica R.; Knockenhauer, Kevin E.; Markus, Benedikt M.; ...
2015-08-24
Calcium-dependent protein kinases (CDPKs) comprise the major group of Ca 2+-regulated kinases in plants and protists. It has long been assumed that CDPKs are activated, like other Ca 2+-regulated kinases, by derepression of the kinase domain (KD). However, we found that removal of the autoinhibitory domain from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a library of heavy chain-only antibody fragments (VHHs), we isolated an antibody (1B7) that binds TgCDPK1 in a conformation-dependent manner and potently inhibits it. We uncovered the molecular basis for this inhibition by solving the crystal structure of the complex and simulating, throughmore » molecular dynamics, the effects of 1B7–kinase interactions. In contrast to other Ca 2+-regulated kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or activating the kinase in response to changes in Ca 2+ concentrations. We propose that the regulatory domain of TgCDPK1 acts as a molecular splint to stabilize the otherwise inactive KD. This dependence on allosteric stabilization reveals a novel susceptibility in this important class of parasite enzymes.« less
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Hybrid and Rogue Kinases Encoded in the Genomes of Model Eukaryotes
Rakshambikai, Ramaswamy; Gnanavel, Mutharasu; Srinivasan, Narayanaswamy
2014-01-01
The highly modular nature of protein kinases generates diverse functional roles mediated by evolutionary events such as domain recombination, insertion and deletion of domains. Usually domain architecture of a kinase is related to the subfamily to which the kinase catalytic domain belongs. However outlier kinases with unusual domain architectures serve in the expansion of the functional space of the protein kinase family. For example, Src kinases are made-up of SH2 and SH3 domains in addition to the kinase catalytic domain. A kinase which lacks these two domains but retains sequence characteristics within the kinase catalytic domain is an outlier that is likely to have modes of regulation different from classical src kinases. This study defines two types of outlier kinases: hybrids and rogues depending on the nature of domain recombination. Hybrid kinases are those where the catalytic kinase domain belongs to a kinase subfamily but the domain architecture is typical of another kinase subfamily. Rogue kinases are those with kinase catalytic domain characteristic of a kinase subfamily but the domain architecture is typical of neither that subfamily nor any other kinase subfamily. This report provides a consolidated set of such hybrid and rogue kinases gleaned from six eukaryotic genomes–S.cerevisiae, D. melanogaster, C.elegans, M.musculus, T.rubripes and H.sapiens–and discusses their functions. The presence of such kinases necessitates a revisiting of the classification scheme of the protein kinase family using full length sequences apart from classical classification using solely the sequences of kinase catalytic domains. The study of these kinases provides a good insight in engineering signalling pathways for a desired output. Lastly, identification of hybrids and rogues in pathogenic protozoa such as P.falciparum sheds light on possible strategies in host-pathogen interactions. PMID:25255313
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Live-cell Imaging with Genetically Encoded Protein Kinase Activity Reporters.
Maryu, Gembu; Miura, Haruko; Uda, Youichi; Komatsubara, Akira T; Matsuda, Michiyuki; Aoki, Kazuhiro
2018-04-25
Protein kinases play pivotal roles in intracellular signal transduction, and dysregulation of kinases leads to pathological results such as malignant tumors. Kinase activity has hitherto been measured by biochemical methods such as in vitro phosphorylation assay and western blotting. However, these methods are less useful to explore spatial and temporal changes in kinase activity and its cell-to-cell variation. Recent advances in fluorescent proteins and live-cell imaging techniques enable us to visualize kinase activity in living cells with high spatial and temporal resolutions. Several genetically encoded kinase activity reporters, which are based on the modes of action of kinase activation and phosphorylation, are currently available. These reporters are classified into single-fluorophore kinase activity reporters and Förster (or fluorescence) resonance energy transfer (FRET)-based kinase activity reporters. Here, we introduce the principles of genetically encoded kinase activity reporters, and discuss the advantages and disadvantages of these reporters.Key words: kinase, FRET, phosphorylation, KTR.
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Lindin, Inger; Wuxiuer, Yimingjiang; Ravna, Aina Westrheim; Moens, Ugo; Sylte, Ingebrigt
2014-01-01
The mitogen-activated protein kinase-activated protein kinase MK5 is a substrate of the mitogen-activated protein kinases p38, ERK3 and ERK4. Cell culture and animal studies have demonstrated that MK5 is involved in tumour suppression and promotion, embryogenesis, anxiety, cell motility and cell cycle regulation. In the present study, homology models of MK5 were used for molecular dynamics (MD) simulations of: (1) MK5 alone; (2) MK5 in complex with an inhibitor; and (3) MK5 in complex with the interaction partner p38α. The calculations showed that the inhibitor occupied the active site and disrupted the intramolecular network of amino acids. However, intramolecular interactions consistent with an inactive protein kinase fold were not formed. MD with p38α showed that not only the p38 docking region, but also amino acids in the activation segment, αH helix, P-loop, regulatory phosphorylation region and the C-terminal of MK5 may be involved in forming a very stable MK5-p38α complex, and that p38α binding decreases the residual fluctuation of the MK5 model. Electrostatic Potential Surface (EPS) calculations of MK5 and p38α showed that electrostatic interactions are important for recognition and binding. PMID:24651460
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Mediator kinase module and human tumorigenesis
Clark, Alison D.; Oldenbroek, Marieke; Boyer, Thomas G.
2016-01-01
Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit “kinase” module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways. PMID:26182352
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Whiting, Jennifer L; Nygren, Patrick J; Tunquist, Brian J; Langeberg, Lorene K; Seternes, Ole-Morten; Scott, John D
2015-08-07
The proximity of an enzyme to its substrate can influence rate and magnitude of catalysis. A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Using a combination of molecular and cellular approaches we show that GSK3β phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3β and its substrate β-catenin in membrane ruffles. Interestingly, GSK3β can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3β activity. The signaling scaffold may enhance this regulatory mechanism, as AKAP220 has the capacity to anchor two PKA holoenzymes. Site 1 on AKAP220 (residues 610-623) preferentially interacts with RII, whereas site 2 (residues 1633-1646) exhibits a dual specificity for RI and RII. In vitro affinity measurements revealed that site 2 on AKAP220 binds RII with ∼10-fold higher affinity than site 1. Occupancy of both R subunit binding sites on AKAP220 could provide a mechanism to amplify local cAMP responses and enable cross-talk between PKA and GSK3β. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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NASA Astrophysics Data System (ADS)
Verkhoglyadova, O. P.; Tsurutani, B. T.; Mannucci, A. J.; Mlynczak, M. G.; Hunt, L. A.; Paxton, L. J.
2014-08-01
A series of four geomagnetic storms (the minimum SYM-H~-148 nT) occurred during the March 6-17, 2012 in the ascending phase of the solar cycle 24. This interval was selected by CAWSES II for its campaign. The GPS total electron content (TEC) database and JPL's Global Ionospheric Maps (GIM) were used to study vertical TEC (VTEC) for different local times and latitude ranges. The largest response to geomagnetic activity is shown in increases of the low-latitude dayside VTEC. Several GPS sites feature post-afternoon VTEC “bite-outs”. During Sudden Impulse (SI+) event on March 8th a peak daytime VTEC restores to about quiet-time values. It is shown that the TIMED/SABER zonal flux of nitric oxide (NO) infrared cooling radiation correlates well with auroral heating. A factor of ~5 cooling increase is noted in some storms. The cooling radiation intensifies in the auroral zone and spreads towards the equator. Effects of the storm appear at lower latitudes ~18.6 h later. The column density ratio Σ[O/N2] is analyzed based on TIMED/GUVI measurements. Both increases (at low latitudes) and decreases (from auroral to middle latitudes) in the ratio occurs during the geomagnetic storms. We suggest that the column density ratio could be enhanced at low to middle latitudes on the dayside partially due to the superfountain effect (atomic oxygen uplift due to ion-neutral drag). It is suggested that decreases in the Σ[O/N2] ratio at high to middle-latitudes may be caused by high thermospheric temperatures. During SI+s, there is an increase in Σ[O/N2] ratio at auroral latitudes.
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Betson, Martha; Settleman, Jeffrey
2007-08-01
The Rho GTPases interact with multiple downstream effectors to exert their biological functions, which include important roles in tissue morphogenesis during the development of multicellular organisms. Among the Rho effectors are the protein kinase N (PKN) proteins, which are protein kinase C (PKC)-like kinases that bind activated Rho GTPases. The PKN proteins are well conserved evolutionarily, but their biological role in any organism is poorly understood. We previously determined that the single Drosophila ortholog of mammalian PKN proteins, Pkn, is a Rho/Rac-binding kinase essential for Drosophila development. By performing "rescue" studies with various Pkn mutant constructs, we have defined the domains of Pkn required for its role during Drosophila development. These studies suggested that Rho, but not Rac binding is important for Pkn function in development. In addition, we determined that the kinase domain of PKC53E, a PKC family kinase, can functionally substitute for the kinase domain of Pkn during development, thereby exemplifying the evolutionary strategy of "combining" functional domains to produce proteins with distinct biological activities. Interestingly, we also identified a requirement for Pkn in wing morphogenesis, thereby revealing the first postembryonic function for Pkn.
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Burch, Micah L; Getachew, Robel; Osman, Narin; Febbraio, Mark A; Little, Peter J
2013-03-08
G protein-coupled receptor signaling is mediated by three main mechanisms of action; these are the classical pathway, β-arrestin scaffold signaling, and the transactivation of protein-tyrosine kinase receptors such as those for EGF and PDGF. Recently, it has been demonstrated that G protein-coupled receptors can also mediate signals via transactivation of serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Atherosclerosis is characterized by the development of lipid-laden plaques in blood vessel walls. Initiation of plaque development occurs via low density lipoprotein retention in the neointima of vessels due to binding with modified proteoglycans secreted by vascular smooth muscle cells. Here we show that transactivation of protein-tyrosine kinase receptors is mediated by matrix metalloproteinase triple membrane bypass signaling. In contrast, serine/threonine kinase receptor transactivation is mediated by a cytoskeletal rearrangement-Rho kinase-integrin system, and both protein-tyrosine kinase and serine/threonine kinase receptor transactivation concomitantly account for the total proteoglycan synthesis stimulated by thrombin in vascular smooth muscle. This work provides evidence of thrombin-mediated proteoglycan synthesis and paves the way for a potential therapeutic target for plaque development and atherosclerosis.
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Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin; Lustig, Ana; Kim, Jie Wan; Mattson, Mark P.; Taub, Dennis D.
2014-01-01
Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levelsand impair the naïve T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age-associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T-cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID:25447526
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Peruchetti, Diogo B.; Pinheiro, Ana Acacia S.; Landgraf, Sharon S.; Wengert, Mira; Takiya, Christina M.; Guggino, William B.; Caruso-Neves, Celso
2011-01-01
In recent decades, evidence has confirmed the crucial role of albumin in the progression of renal disease. However, the possible role of signaling pathways triggered by physiologic concentrations of albumin in the modulation of proximal tubule (PT) sodium reabsorption has not been considered. In the present work, we have shown that a physiologic concentration of albumin increases the expression of the α1 subunit of (Na+ + K+)-ATPase in LLC-PK1 cells leading to an increase in enzyme activity. This process involves the sequential activation of PI3K/protein kinase B and protein kinase C pathways promoting inhibition of protein kinase A. This integrative network is inhibited when albumin concentration is increased, similar to renal disease, leading to a decrease in the α1 subunit of (Na+ + K+)-ATPase expression. Together, the results indicate that variation in albumin concentration in PT cells has an important effect on PT sodium reabsorption and, consequently, on renal sodium excretion. PMID:22057272
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The selectivity of protein kinase inhibitors: a further update
Bain, Jenny; Plater, Lorna; Elliott, Matt; Shpiro, Natalia; Hastie, C. James; Mclauchlan, Hilary; Klevernic, Iva; Arthur, J. Simon C.; Alessi, Dario R.; Cohen, Philip
2007-01-01
The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes. PMID:17850214
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Identification and characterization of two wheat Glycogen Synthase Kinase 3/ SHAGGY-like kinases.
Bittner, Thomas; Campagne, Sarah; Neuhaus, Gunther; Rensing, Stefan A; Fischer-Iglesias, Christiane
2013-04-18
Plant Glycogen Synthase Kinase 3/ SHAGGY-like kinases (GSKs) have been implicated in numerous biological processes ranging from embryonic, flower, stomata development to stress and wound responses. They are key regulators of brassinosteroid signaling and are also involved in the cross-talk between auxin and brassinosteroid pathways. In contrast to the human genome that contains two genes, plant GSKs are encoded by a multigene family. Little is known about Liliopsida resp. Poaceae in comparison to Brassicaceae GSKs. Here, we report the identification and structural characterization of two GSK homologs named TaSK1 and TaSK2 in the hexaploid wheat genome as well as a widespread phylogenetic analysis of land plant GSKs. Genomic and cDNA sequence alignments as well as chromosome localization using nullisomic-tetrasomic lines provided strong evidence for three expressed gene copies located on homoeolog chromosomes for TaSK1 as well as for TaSK2. Predicted proteins displayed a clear GSK signature. In vitro kinase assays showed that TaSK1 and TaSK2 possessed kinase activity. A phylogenetic analysis of land plant GSKs indicated that TaSK1 and TaSK2 belong to clade II of plant GSKs, the Arabidopsis members of which are all involved in Brassinosteroid signaling. Based on a single ancestral gene in the last common ancestor of all land plants, paralogs were acquired and retained through paleopolyploidization events, resulting in six to eight genes in angiosperms. More recent duplication events have increased the number up to ten in some lineages. To account for plant diversity in terms of functionality, morphology and development, attention has to be devoted to Liliopsida resp Poaceae GSKs in addition to Arabidopsis GSKs. In this study, molecular characterization, chromosome localization, kinase activity test and phylogenetic analysis (1) clarified the homologous/paralogous versus homoeologous status of TaSK sequences, (2) pointed out their affiliation to the GSK multigene
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Pea DNA topoisomerase I is phosphorylated and stimulated by casein kinase 2 and protein kinase C.
Tuteja, Narendra; Reddy, Malireddy Kodandarami; Mudgil, Yashwanti; Yadav, Badam Singh; Chandok, Meena Rani; Sopory, Sudhir Kumar
2003-08-01
DNA topoisomerase I catalyzes the relaxation of superhelical DNA tension and is vital for DNA metabolism; therefore, it is essential for growth and development of plants. Here, we have studied the phosphorylation-dependent regulation of topoisomerase I from pea (Pisum sativum). The purified enzyme did not show autophosphorylation but was phosphorylated in an Mg(2+)-dependent manner by endogenous protein kinases present in pea nuclear extracts. This phosphorylation was abolished with calf intestinal alkaline phosphatase and lambda phosphatase. It was also phosphorylated by exogenous casein kinase 2 (CK2), protein kinase C (PKC; from animal sources), and an endogenous pea protein, which was purified using a novel phorbol myristate acetate affinity chromatography method. All of these phosphorylations were inhibited by heparin (inhibitor of CK2) and calphostin (inhibitor of PKC), suggesting that pea topoisomerase I is a bona fide substrate for these kinases. Spermine and spermidine had no effect on the CK2-mediated phosphorylation, suggesting that it is polyamine independent. Phospho-amino acid analysis showed that only serine residues were phosphorylated, which was further confirmed using antiphosphoserine antibody. The topoisomerase I activity increased after phosphorylation with exogenous CK2 and PKC. This study shows that these kinases may contribute to the physiological regulation of DNA topoisomerase I activity and overall DNA metabolism in plants.
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Curry, Jayne; Angove, Hayley; Fazal, Lynsey; Lyons, John; Reule, Matthias; Thompson, Neil; Wallis, Nicola
2009-06-15
Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpoint-competent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.
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Lorenz, Sonja; Deng, Patricia; Hantschel, Oliver; Superti-Furga, Giulio; Kuriyan, John
2018-01-01
Constitutive activation of the non-receptor tyrosine kinase c-Abl (Abl1) in the Bcr-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukemia. Recent studies have indicated that an interaction between the SH2 domain and the N-lobe of the c-Abl kinase domain has a critical role in leukemogenesis. To dissect the structural basis of this phenomenon we studied c-Abl constructs comprising the SH2 and kinase domains in vitro. We present a crystal structure of an SH2-kinase domain construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the kinase domain. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2-N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the kinase domain. That the effects are small compared to the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the autoinhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity. PMID:25779001
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Teva, Antonio; dos-Santos, Claudiney B.; Santos, Fernanda Nunes; Pinto, Israel de-Souza; Fux, Blima; Leite, Gustavo Rocha; Falqueto, Aloísio
2017-01-01
Background Because domestic dogs are reservoir hosts for visceral leishmaniasis (VL) in Brazil, one of the approaches used to reduce human disease incidence is to cull infected dogs. However, the results of controlled intervention trials based on serological screening of dogs and killing of seropositive animals are equivocal. A prophylactic vaccine to protect dogs from being infectious to the sand fly vector could be an effective strategy to provide sustained control. Here, we investigated whether a currently licensed commercial subunit rA2 protein–saponin vaccine (Leish-tec®) had an additional effect to dog culling on reducing the canine infectious populations. Methodology/Principal findings This prospective study was conducted in an L. infantum highly endemic area of southeast Brazil. At the onset of the intervention, all of the eligible dogs received through subcutaneous route a three-dose vaccine course at 21-day intervals and a booster on month 12. For the purpose of comparison, newly recruited healthy dogs were included as the exposed control group. To ascertain vaccine-induced protection, dogs were screened on clinical and serological criteria every 6 months for a 2-year follow-up period. Antibody-based tests and histopathological examination of post-mortem tissue specimens from euthanized animals were used as a marker of infection. The standardized vaccine regime, apart from being safe, was immunogenic as immunized animals responded with a pronounced production of anti-A2-specific IgG antibodies. It should be noted the mean seroconversion time for infection obtained among immunized exposed dogs (~ 18 months), which was twice as high as that for unvaccinated ones (~ 9 months). After two transmission cycles completed, the cumulative incidence of infection did differ significantly (P = 0.016) between the vaccinated (27%) and unvaccinated (42%) dogs. However, the expected efficacy for the vaccine in inducing clinical protection was not evident since 43% of
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Mechanisms of aldehyde-induced adenosinetriphosphatase activities of kinases.
Rendina, A R; Cleland, W W
1984-10-23
Aldehyde analogues of the normal alcohol substrates induce ATPase activities by glycerokinase (D-glyceraldehyde), fructose-6-phosphate kinase (2,5-anhydromannose 6-phosphate), fructokinase (2,5-anhydromannose or 2,5-anhydrotalose), hexokinase (D-gluco-hexodialdose), choline kinase (betaine aldehyde), and pyruvate kinase (glyoxylate). Since purified deuterated aldehydes give V and V/K isotope effects near 1.0 for glycerokinase, fructokinase with 2,5-anhydro[1-2H]talose, hexokinase, choline kinase, and pyruvate kinase, the hydrates of these almost fully hydrated aldehydes are the activators of the ATPase reactions. Fructose-6-phosphate kinase and fructokinase with 2,5-anhydro[1-2H]mannose show V/K deuterium isotope effects of 1.10 and 1.22, respectively, suggesting either that both hydrate and free aldehyde may be activators (predicted values are 1.37 if only the free aldehyde activates the ATPase) or, more likely, that the phosphorylated hydrate breaks down in a rate-limiting step on the enzyme while MgADP is still present and the back-reaction to yield free hydrate in solution is still possible. 18O was transferred from the aldehyde hydrate to phosphate during the ATPase reactions of glycerokinase, fructose-6-phosphate kinase, fructokinase, and hexokinase but not with choline kinase or pyruvate kinase. Thus, direct phosphorylation of the hydrates by the first four enzymes gives the phosphate adduct of the aldehyde, which decomposes nonenzymatically, while with choline kinase and pyruvate kinase the hydrates induce transfer to water (metal-bound hydroxide or water with pyruvate kinase on the basis of pH profiles). Observation of a lag in the release of phosphate from the glycerokinase ATPase reaction at 15 degrees C supports the existence of a phosphorylated hydrate intermediate with a rate constant for breakdown of 0.035-0.043 s-1 at this temperature. Kinases that phosphorylate creatine, 3-phosphoglycerate, and acetate did not exhibit ATPase activities in the
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Caspases and Kinases in a Death Grip
Kurokawa, Manabu; Kornbluth, Sally
2011-01-01
The complex process of apoptosis is orchestrated by caspases, a family of cysteine proteases with unique substrate specificities. Accumulating evidence suggests that cell death pathways are finely tuned by multiple signaling events, including direct phosphorylation of caspases, whereas kinases are often substrates of active caspases. Importantly, caspase-mediated cleavage of kinases can terminate prosurvival signaling or generate proapoptotic peptide fragments that help to execute the death program and facilitate packaging of the dying cells. Here, we review caspases as kinase substrates and kinases as caspase substrates and discuss how the balance between cell survival and cell death can be shifted through crosstalk between these two enzyme families. PMID:19737514
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Syed, Sunayana Begum; Khan, Faez Iqbal; Khan, Sabab Hasan; Srivastava, Saurabha; Hasan, Gulam Mustafa; Lobb, Kevin A; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz
2018-05-01
Integrin-linked kinase (ILK), a ubiquitously expressed intracellular Ser/Thr protein kinase, plays a major role in the oncogenesis and tumour progression. The conformational stability and unfolding of kinase domain of ILK (ILK 193-446 ) was examined in the presence of increasing concentrations of urea. The stability parameters of the urea-induced denaturation were measured by monitoring changes in [θ] 222 (mean residue ellipticity at 222nm), difference absorption coefficient at 292nm (Δε 292 ) and intrinsic fluorescence emission intensity at pH7.5 and 25±0.1°C. The urea-induced denaturation was found to be reversible. The protein unfolding transition occurred in the urea concentration range 3.0-7.0M. A coincidence of normalized denaturation curves of optical properties ([θ] 222 , Δε 292 and λ max , the wavelength of maximum emission intensity) suggested that urea-induced denaturation of kinase domain of ILK is a two-state process. We further performed molecular dynamics simulation for 100ns to see the effect of urea on structural stability of kinase domain of ILK at atomic level. Structural changes with increasing concentrations of urea were analysed, and we observed a significant increase in the root mean square deviation, root mean square fluctuations, solvent accessible surface area and radius of gyration. A correlation was observed between in vitro and in silico studies. Copyright © 2018 Elsevier B.V. All rights reserved.
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Asquith, Christopher R M; Godoi, Paulo H; Couñago, Rafael M; Laitinen, Tuomo; Scott, John W; Langendorf, Christopher G; Oakhill, Jonathan S; Drewry, David H; Zuercher, William J; Koutentis, Panayiotis A; Willson, Timothy M; Kalogirou, Andreas S
2018-05-19
We demonstrate for the first time that 4 H -1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4 H -1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.