ATLAS ITk Strip Detector for High-Luminosity LHC

CERN Document Server

Kroll, Jiri; The ATLAS collaboration

2017-01-01

The ATLAS experiment is currently preparing for an upgrade of the tracking system in the course of the High-Luminosity LHC that is scheduled for 2026. The expected peak instantaneous luminosity up to 7.5E34 per second and cm2 corresponding to approximately 200 inelastic proton-proton interactions per beam crossing, radiation damage at an integrated luminosity of 3000/fb and hadron fluencies over 1E16 1 MeV neutron equivalent per cm2, as well as fast hardware tracking capability that will bring Level-0 trigger rate of a few MHz down to a Level-1 trigger rate below 1 MHz require a replacement of existing Inner Detector by an all-silicon Inner Tracker (ITk) with a pixel detector surrounded by a strip detector. The current prototyping phase, that is working with ITk Strip Detector consisting of a four-layer barrel and a forward region composed of six discs on each side of the barrel, has resulted in the ATLAS ITk Strip Detector Technical Design Report (TDR), which starts the pre-production readiness phase at the ...

Purification, crystallization and preliminary crystallographic analysis of the SH2 domain of IL-2-inducible T-cell kinase

International Nuclear Information System (INIS)

Joseph, Raji E.; Ginder, Nathaniel D.; Hoy, Julie A.; Nix, Jay C.; Honzatko, Richard B.; Andreotti, Amy H.

2011-01-01

Crystallization conditions are described for the cis- and trans-imide bond-containing SH2 domain of IL-2-inducible T-cell kinase. 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

A new strips tracker for the upgraded ATLAS ITk detector

Science.gov (United States)

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).

Structure of the interleukin-2 tyrosine kinase Src homology 2 domain; comparison between X-ray and NMR-derived structures

International Nuclear Information System (INIS)

Joseph, Raji E.; Ginder, Nathaniel D.; Hoy, Julie A.; Nix, Jay C.; Fulton, D. Bruce; Honzatko, Richard B.; Andreotti, Amy H.

2012-01-01

The interleukin-2 tyrosine kinase Src homology 2 domain was crystallized and its structure was solved to 2.35 Å resolution. The structure reveals a domain-swapped dimer that is related to other dimeric SH2 domains solved previously. The cis–trans-prolyl isomerization that is evident from solution studies of Itk SH2 cannot be observed in the crystal structure. The crystal structure of the interleukin-2 tyrosine kinase Src homology domain (Itk SH2) is described and it is found that unlike in studies of this domain using NMR spectroscopy, cis–trans-prolyl isomerization is not readily detected in the crystal structure. Based on similarities between the Itk SH2 crystal form and the cis form of the Itk SH2 NMR structure, it is concluded that it is likely that the prolyl imide bond at least in part adopts the cis conformation in the crystal form. However, the lack of high-resolution data and the dynamic nature of the proline-containing loop mean that the precise imide-bond conformation cannot be determined and prolyl cis–trans isomerization in the crystal cannot be ruled out. Given the preponderance of structures that have been solved by X-ray crystallography in the Protein Data Bank, this result supports the notion that prolyl isomerization in folded proteins has been underestimated among known structures. Interestingly, while the precise status of the proline residue is ambiguous, Itk SH2 crystallizes as a domain-swapped dimer. The domain-swapped structure of Itk SH2 is similar to the domain-swapped SH2 domains of Grb2 and Nck, with domain swapping occurring at the β-meander region of all three SH2 domains. Thus, for Itk SH2 structural analysis by NMR spectroscopy and X-ray crystallography revealed very different structural features: proline isomerization versus domain-swapped dimerization, respectively

Module and electronics developments for the ATLAS ITK pixel system

CERN Document Server

Munoz Sanchez, Francisca Javiela; The ATLAS collaboration

2017-01-01

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 2017. 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.

ITK optical links backup document

CERN Document Server

Huffman, B T; The ATLAS collaboration; Flick, T; Ye, J

2013-01-01

This document describes the proposed optical links to be used for the ITK in the phase II upgrade. The current R&D for optical links pursued in the Versatile Link group is reviewed. In particular the results demonstrating the radiation tolerance of all the on-detector components are documented. The bandwidth requirements and the resulting numerology are given.

Test-beam activities and results for the ATLAS ITk pixel detector

Science.gov (United States)

Bisanz, T.

2017-12-01

The Phase-II upgrade of the LHC aims at an increase of the instantaneous luminosity up to about 5×1034 cm-2 s-1. To cope with the resulting challenges the current Inner Detector will be replaced by an all-silicon Inner Tracker (ITk) system. The Pixel Detector will have to deal with occupancies of about 300 hits/FE/s as well as a fluence of around 2×1016 neq cm-2. Various sensor layouts are under development, aiming at providing a high performance, cost effective pixel instrumentation to cover an active area of about 10 m2. These range from thin planar silicon, 3D silicon, to active CMOS sensors. After extensive characterization of the sensors in the lab, their charge collection properties and hit efficiency are measured in common testbeam campaigns, which provide valuable feedback for improvements of the layout. Testbeam measurements of the final prototypes will be used for the decision of which sensor types will be installed in ITk. The setups used in the ITk Pixel testbeam campaigns will be presented, including the common track reconstruction and analysis software. Results from the latest measurements will be shown, highlighting some of the developments and challenges for the ITk Pixel sensors.

Module and electronics developments for the ATLAS ITK pixel system

CERN Document Server

Nellist, Clara; The ATLAS collaboration

2016-01-01

Summary ATLAS is preparing for an extensive modification of its detector in the course of the planned HL‐ LHC accelerator upgrade around 2025 which includes a replacement of the entire tracking system by an all‐silicon detector (Inner Tracker, ITk). A revised trigger and data taking system is foreseen with triggers expected at lowest level at an average rate of 1 MHz. The five innermost layers of ITk will comprise of 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 that is expected to take place in early 2017. A new on‐detector readout chip is designed in the context of the RD53 collaboration in 65 nm CMOS technology. This paper will present the on‐going R&D within the ATLAS ITK project towards the new pixel modules and the off‐detector electronics. Pla...

High-Voltage Multiplexing for ATLAS ITk

CERN Document Server

Hommels, Bart; The ATLAS collaboration

2017-01-01

The High Luminosity upgrade to the Large Hadron Collider (HL-LHC) requires a replacement of the present ATLAS inner tracker with an all-silicon inner tracker (ITk). The outer radii of the ITk will consist of groups of silicon strip sensors mounted on common support structures. Lack of space for additional cabling will require groups of sensors to share a common HV bus (-500 V). This creates a need to remotely disable a failing sensor from the common HV bus to permit continued operation of the other sensors. We have developed circuitry consisting of a Gallium Nitride Field-Effect transistor (GaNFET) and a HV Multiplier circuit to disable a failed sensor. The devices have been shown to survive radiation doses as high as 1 x 1016 neutrons/cm2 and ionizing doses over 200 Mrad. We will present the HV Mux circuitry and show irradiation results on individual components with an emphasis on the GaNFET results with neutrons, protons, pions, and gammas. We will present a dual-stage variation of the HV Mux that will perm...

The Phase-2 ATLAS ITk Pixel Upgrade

CERN Document Server

Benoit, Mathieu; The ATLAS collaboration

2017-01-01

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 the ITk will consist of a pixel detector with stave-like support structures in the most central region and ring-shaped supports in the endcap regions; there may also be novel inclined support structures in the barrel-endcap overlap regions. The new detector could have as much as 14 m2 of sensitive silicon. Support structures will be based on low mass, highly stable and highly thermally conductive carbon-based materials cooled by evaporative carbon dioxide. The ITk will be instrumented with new sensors and readout electronics to provide improved tracking performance compared to the current detector. All the module components must be performant enough and robust enough to cope with the expected high particle multiplicity and severe radiation background of the High-Luminosity LHC. Readout...

Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate

Science.gov (United States)

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

Module and electronics developments for the ATLAS ITK pixel system

CERN Document Server

Munoz Sanchez, Francisca Javiela; The ATLAS collaboration

2017-01-01

ATLAS is preparing for an extensive modification of its detector in the course of the planned HL-LHC accelerator upgrade around 2025 which includes a replacement of the entire tracking system by an all-silicon detector (Inner Tracker, ITk). The five innermost layers of ITk will comprise of 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 that is expected to take place in 2017. A new on-detector readout chip is designed in the context of the RD53 collaboration in 65 nm CMOS technology. This paper will present the on-going R&D within the ATLAS ITK project towards the new pixel modules and the off-detector electronics. Planar and 3D sensors are being re-designed with cell sizes of 50x50 or 25x100 μm2, compatible with the RD53 chip. A sensor thickness equal or less th...

Test-beam activities and results for the ATLAS ITk pixel detector

CERN Document Server

Bisanz, Tobias; The ATLAS collaboration

2017-01-01

The Phase-II upgrade of the LHC will result in an increase of the instantaneous luminosity up to about 5×1034 cm−2s−1. To cope with the challenges the current Inner Detector will be replaced by an all-silicon Inner Tracker (ITk) system. The Pixel Detector will have to deal with occupancies of about 300~hits/FE/s as well as a fluence of 2×1016neqcm−2. Various sensor layouts are under development, aiming at providing a high performance, cost effective pixel instrumentation to cover an active area of about 10~m2. These range from thin planar silicon, over 3D silicon, to active CMOS sensors. After extensive characterization of the sensors in the lab, their charge collection properties and hit efficiency are measured in common testbeam campaigns, which provide valuable feedback for improvements of the layout. Testbeam measurements of the final prototypes will be used for the decision of which sensor types will be installed in ITk. The setups used in the ITk Pixel testbeam campaigns will be presented, inclu...

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice

Science.gov (United States)

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

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

Directory of Open Access Journals (Sweden)

Steven D Schutt

Full Text Available 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.

ITK: Enabling Reproducible Research and Open Science

Directory of Open Access Journals (Sweden)

Matthew Michael McCormick

2014-02-01

Full Text Available 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.

The Phase II ATLAS ITk Pixel Upgrade

CERN Document Server

Terzo, Stefano; The ATLAS collaboration

2017-01-01

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 and ring-shaped supports in the endcap 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. The total surface area of silicon in the new pixel system could measure up to 14 m$^2$ , depending on the final layout choice, which is expected to take place in early 2017. Several layout options are being investigated at the moment, including some with novel inclined support structures in the barrel-endcap overlap region and others with very long innermost barrel layers. Forward coverage could be as high as $|\\eta| < 4$. Supporting structures will be ...

The Phase-II ATLAS ITk Pixel Upgrade

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00349918; The ATLAS collaboration

2017-01-01

The entire tracking system of the ATLAS experiment will be replaced during the LHC Phase~2 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 $\\mathrm{m^2}$ 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 stabl...

The Phase-2 ATLAS ITk Pixel Upgrade

CERN Document Server

Macchiolo, Anna; The ATLAS collaboration

2018-01-01

The new ATLAS ITk pixel system will be installed during the LHC Phase-II shutdown, to better take advantage of the increased luminosity of the HL-LHC. The detector will consist of 5 layers of stave-like support structures in the most central region and ring-shaped supports in the endcap regions, covering up to |η| < 4. While the outer 3 layers of the Pixel Detector are designed to operate for the full HL-LHC data taking period, the innermost 2 layers of the detector will be replaced around half of the lifetime. The ITk pixel detector will be instrumented with new sensors and readout electronics to provide improved tracking performance and radiation hardness compared to the current detector. Sensors will be read out by new ASICs based on the chip developed by the RD53 Collaboration. The pixel off-detector readout electronics will be implemented in the framework of the general ATLAS trigger and DAQ system with a readout speed of up to 5 Gb/s per data link for the innermost layers. Results of extensive tests...

Purification, crystallization and preliminary crystallographic analysis of the SH2 domain of IL-2-inducible T-cell kinase.

Science.gov (United States)

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.

Modules and Front-End Electronics Developments for the ATLAS ITk Strips Upgrade

CERN Document Server

Garcia-Argos, Carlos; The ATLAS collaboration

2017-01-01

The ATLAS experiment is currently preparing for an upgrade of the tracking system in the course of the High Luminosity LHC, scheduled for 2024. The existing Inner Detector will be replaced by an all-silicon Inner Tracker (ITk) with a pixel detector surrounded by a strip detector. The ITk strip detector consists of a four layer barrel and a forward region composed of six discs on each side of the barrel. The basic unit of the detector is the silicon-strip module, consisting of a sensor and one or more hybrid circuits that hold the read-out electronics. The geometries of the barrel and end-cap modules take into account the regions that they have to cover. In the central region, the detectors are rectangular with straight strips, whereas on the forward region the modules require wedge shaped sensors with varying strip length and pitch. The current prototyping phase has resulted in the ITk Strip Detector Technical Design Report (TDR), which kicks-off the pre-production readiness phase at the involved institutes. ...

Modules and Front-End Electronics Developments for the ATLAS ITk Strips Upgrade

CERN Document Server

Garcia-Argos, Carlos; The ATLAS collaboration

2017-01-01

The ATLAS experiment is currently preparing for an upgrade of the tracking system in the course of the High Luminosity LHC, scheduled for 2024. The existing Inner Detector will be replaced by an all-silicon Inner Tracker (ITk) with a pixel detector surrounded by a strip detector. The ITk strip detector consists of a four layer barrel and a forward region composed of six discs on each side of the barrel. The basic unit of the detector is the silicon-strip module, consisting of a sensor and one or more hybrid circuits that hold the read-out electronics. The geometries of the barrel and end-cap modules take into account the regions that they have to cover. In the central region, the detectors are rectangular with straight strips, whereas in the forward region the modules require wedge shaped sensors with varying strip length and pitch. The current prototyping phase has resulted in the ITk Strip Detector Technical Design Report (TDR), which kicks-off the pre-production readiness phase at the involved institutes. ...

SimpleITK Image-Analysis Notebooks: a Collaborative Environment for Education and Reproducible Research.

Science.gov (United States)

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 .

A Characterisation of the ATLAS ITk High Rapidity Modules in AllPix and EUTelescope

CERN Document Server

Atkin, Ryan Justin

2017-01-01

The upgrade of the LHC to the high luminosity LHC (HL-LHC) will result in far more collisions occurring per bunch crossing, in turn producing more particles per second. Consequently, the current detectors will need to be upgraded to accommodate the large increase in radiation and data acquisition as well as a need to improve the tracking efficiency for the high pile-up environment. One of the main upgrades to the ATLAS detector is the complete overhaul of the inner detector (ID) by replacing it with an all silicon Inner Tracker (ITk). A simulation of the ITk will be required for performance predictions as well as for testing sample sensors in testbeams. The current testbeam software of Allpix and EUTelescope are written completely using Cartesian definitions, however some of the geometries in the ITk have radial definitions. In particular, the R0 geometry of the strip end-cap is in need of a radial description. Presented is the work behind creating a radial geometry for the R0 module in Allpix (using Geant4 d...

ATLAS ITk short-strip stave prototype module with integrated DCDC powering and control

CERN Document Server

AUTHOR|(SzGeCERN)397167; The ATLAS collaboration

2017-01-01

During the Phase II upgrade, the ATLAS detector at the LHC will be upgraded with a new Inner Tracker (ITk) detector. The ITk prototype barrel module design has adopted an integrated low mass assembly featuring single-sided flexible circuits, with readout ASICs, glued to the silicon strip sensor. Further integration has been achieved by the attachment of module DCDC powering, a HV sensor biasing switch and autonomous monitoring and control to the sensor. This low mass integrated module approach benefits further in a reduced width stave structure to which the modules are attached. The results of preliminary electrical tests of such an integrated module are presented.

Atrioventricular junction (AVJ) motion tracking: a software tool with ITK/VTK/Qt.

Science.gov (United States)

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.

Estimating immunoregulatory gene networks in human herpesvirus type 6-infected T cells

International Nuclear Information System (INIS)

Takaku, Tomoiku; Ohyashiki, Junko H.; Zhang, Yu; Ohyashiki, Kazuma

2005-01-01

The immune response to viral infection involves complex network of dynamic gene and protein interactions. We present here the dynamic gene network of the host immune response during human herpesvirus type 6 (HHV-6) infection in an adult T-cell leukemia cell line. Using a pathway-focused oligonucleotide DNA microarray, we found a possible association between chemokine genes regulating Th1/Th2 balance and genes regulating T-cell proliferation during HHV-6B infection. Gene network analysis using an integrated comprehensive workbench, VoyaGene, revealed that a gene encoding a TEC-family kinase, ITK, might be a putative modulator in the host immune response against HHV-6B infection. We conclude that Th2-dominated inflammatory reaction in host cells may play an important role in HHV-6B-infected T cells, thereby suggesting the possibility that ITK might be a therapeutic target in diseases related to dysregulation of Th1/Th2 balance. This study describes a novel approach to find genes related with the complex host-virus interaction using microarray data employing the Bayesian statistical framework

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

Science.gov (United States)

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

1997-01-01

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

Module and Electronics Developments for the ATLAS ITK Pixel System

CERN Document Server

Nellist, Clara; The ATLAS collaboration

2016-01-01

ATLAS is preparing for an extensive modification of its detector in the course of the planned HL-LHC accelerator upgrade around 2025 which includes a replacement of the entire tracking system by an all-silicon detector (Inner Tracker, ITk). The five innermost layers of ITk will comprise of 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 m$^{2}$, depending on the final layout choice that is expected to take place in early 2017. An intense R\\&D activity is taking place in the field of planar, 3D, CMOS sensors to identify the optimal technology for the different pixel layers. In parallel various sensor-chip interconnection options are explored to identify reliable technologies when employing 100-150~$\\mu$m thin chips. While the new read-out chip is being developed by the RD53 Collaboration, the pixel off de...

GNSS Derived Ionospheric TEC Observed Through Different TEC Calibration Techniques in the Brazilian Sector

Science.gov (United States)

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.

TCT and TFM measurements for ATLAS ITK

CERN Document Server

Dungs, Sascha

2016-01-01

The ATLAS ITK Pixel detector for the Phase-II upgrade of LHC is in a prototyping phase. The CERN ATLAS Pixel group is involved in different activities. One activity is the characterization of pixel sensors with an infrared Laser using a transient current technique (TCT) to measure the depletion depth and charge collection properties and compare it to effective field theory simulations. Another activity is the measurement of the Thermal Figure of Merit (TFM) of different stave prototypes using silicon heaters and an evaporative CO2 cooling system. This document describes the contributions to each of the two activities.

Latitudinal variations of TEC over Europe obtained from GPSobservations

Directory of Open Access Journals (Sweden)

P. Wielgosz

2004-01-01

Full Text Available GPS technique has opened broad possibilities to study the TEC distribution on a regular basis. In this paper, the latitudinal dependence of TEC over Europe for geographic latitudes ranging from 40°N to 75°N is presented. We discuss the day-to-day variations of the latitudinal TEC profiles for a period of 1999 to 2001 for both quiet and disturbed magnetic conditions. More than 4300 TEC profiles were created from the TEC maps with a one-hour interval. GPS data from 65 European permanent stations were used to produce the TEC maps. The comparison of GPS-derived TEC profiles with the IRI model is also discussed.

Key words. Ionosphere (mid-latitude ionosphere; ionospheric disturbances

Latitudinal variations of TEC over Europe obtained from GPSobservations

Directory of Open Access Journals (Sweden)

P. Wielgosz

2004-01-01

Full Text Available GPS technique has opened broad possibilities to study the TEC distribution on a regular basis. In this paper, the latitudinal dependence of TEC over Europe for geographic latitudes ranging from 40°N to 75°N is presented. We discuss the day-to-day variations of the latitudinal TEC profiles for a period of 1999 to 2001 for both quiet and disturbed magnetic conditions. More than 4300 TEC profiles were created from the TEC maps with a one-hour interval. GPS data from 65 European permanent stations were used to produce the TEC maps. The comparison of GPS-derived TEC profiles with the IRI model is also discussed. Key words. Ionosphere (mid-latitude ionosphere; ionospheric disturbances

Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies.

Science.gov (United States)

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.

Comparison of GPS derived TEC with the TEC predicted by IRI 2012 model in the southern Equatorial Ionization Anomaly crest within the Eastern Africa region

Science.gov (United States)

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.

Comparison of CLASS and ITK-SNAP in segmentation of urinary bladder in CT urography

Science.gov (United States)

Cha, Kenny; Hadjiiski, Lubomir; Chan, Heang-Ping; Caoili, Elaine M.; Cohan, Richard H.; Zhou, Chuan

2014-03-01

We are developing a computerized method for bladder segmentation in CT urography (CTU) for computeraided diagnosis of bladder cancer. We have developed a Conjoint Level set Analysis and Segmentation System (CLASS) consisting of four stages: preprocessing and initial segmentation, 3D and 2D level set segmentation, and post-processing. In case the bladder contains regions filled with intravenous (IV) contrast and without contrast, CLASS segments the noncontrast (NC) region and the contrast (C) filled region separately and conjoins the contours. In this study, we compared the performance of CLASS to ITK-SNAP 2.4, which is a publicly available software application for segmentation of structures in 3D medical images. ITK-SNAP performs segmentation by using the edge-based level set on preprocessed images. The level set were initialized by manually placing a sphere at the boundary between the C and NC parts of the bladders with C and NC regions, and in the middle of the bladders that had only C or NC region. Level set parameters and the number of iterations were chosen after experimentation with bladder cases. Segmentation performances were compared using 30 randomly selected bladders. 3D hand-segmented contours were obtained as reference standard, and computerized segmentation accuracy was evaluated in terms of the average volume intersection %, average % volume error, average absolute % volume error, average minimum distance, and average Jaccard index. For CLASS, the values for these performance metrics were 79.0±8.2%, 16.1±16.3%, 19.9±11.1%, 3.5±1.3 mm, 75.7±8.4%, respectively. For ITK-SNAP, the corresponding values were 78.8±8.2%, 8.3±33.1%, 24.2±23.7%, 5.2±2.6 mm, 71.0±15.4%, respectively. CLASS on average performed better and exhibited less variations than ITK-SNAP for bladder segmentation.

Space Weather Activities of IONOLAB Group: IONOLAB-TEC

Science.gov (United States)

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

Function of Bruton's tyrosine kinase during B cell development is partially independent of its catalytic activity

NARCIS (Netherlands)

S. Middendorp; G.M. Dingjan (Gemma); A. Maas (Alex); K. Dahlenborg; R.W. Hendriks (Rudi)

2003-01-01

textabstractThe Tec family member Bruton's tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that transduces signals from the pre-B and B cell receptor (BCR). Btk is involved in pre-B cell maturation by regulating IL-7 responsiveness, cell surface phenotype changes,

The End-Of-Substructure Card for the ATLAS ITk Strip Tracker

CERN Document Server

Goettlicher, Peter; The ATLAS collaboration

2018-01-01

The End-Of-Substructure Card (EoS) is the interface between the building block of the ITk Strip Tracker (staves and petals) and the outside world. In the ITk the modules consisting of the silicon sensor itself and the hybrids with the readout ASICS are placed on a common structure called a stave (in the barrel) and petal (in the end-cap). All module use a common bus-tape co-cured to carbon-fiber based structure to distribute power and signals. The data lines and command lines are then connected from the bus-tape to EoS. The power, both low and high voltage, are also distributed via the bus tape and coonected to the EoS. All these connections will be made using wire-bonds. The card concept is build around using the lpGBT chip set and the VTRx optical link, both common developments for the LHC Upgrades. The command signals will be coming in on a 10 Gbit/s link and will be de-multiplexed by the lpGBt and send to the stave/petal. The incoming data from the sensor, which depending on the type of stave or petal wil...

Local TEC Modelling and Forecasting using Neural Networks

Science.gov (United States)

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.

Challenges for the next generation of BlueTEC emission technology; Anforderungen und Weiterentwicklungen zur naechsten Generation der BlueTEC-Antriebstechnologie

Energy Technology Data Exchange (ETDEWEB)

Enderle, C.; Binz, R.; Paule, M.; Mackensen, A.; Lindemann, B. [Daimler AG, Stuttgart (Germany)

2010-07-01

Mercedes-Benz BlueTEC vehicles have been on the cutting edge of clean diesel technology since 2006. BlueTEC vehicles furthermore passed millions of kilometres in the hands of customers without any problems. Of course SCR systems already meet the most stringent exhaust emissions standards in international markets such as the USA, Europe and Japan. Diesel engines with BlueTEC technology also reduce CO{sub 2} emissions and provide the high torque and performance associated with the diesel engine in addition to keeping exhaust emissions at the lowest possible level. The following challenges are the focus of efforts to further advance the BlueTEC drives: - Reduce development and calibration outlay. - Standardise and reduce the costs of SCR components. - Improve performance by further reducing exhaust emissions (e.g. SULEV) and meeting the special requirements associated with the ever lower exhaust temperatures of vehicles designed to minimise CO{sub 2} emissions. - Expand on BlueTEC technology by integrating additional emissions components and combining these with other CO{sub 2} technology modules such as hybrid systems. The BlueTEC diesel engines from Mercedes-Benz represents ultra-clean drive technology, with low CO{sub 2} emissions, that can be adapted for specific markets and vehicles in a modular fashion, ideally combined with other CO{sub 2} technologies, and refined to meet future requirements. (orig.)

78 FR 64207 - Application To Export Electric Energy; TEC Energy Inc.

Science.gov (United States)

2013-10-28

... DEPARTMENT OF ENERGY [OE Docket No. EA-388] Application To Export Electric Energy; TEC Energy Inc.... SUMMARY: TEC Energy Inc. (TEC) has applied for authority to transmit electric energy from the United... received an application from TEC for authority to transmit electric energy from the United States to Canada...

Observing Traveling Ionospheric Disturbances Caused by Tsunamis Using GPS TEC Measurements

Science.gov (United States)

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.

Long-term trends in the total electron content (TEC)

Science.gov (United States)

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.

A dual-stage sodium thermal electrochemical converter (Na-TEC)

Science.gov (United States)

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.

CoLiTec software - detection of the near-zero apparent motion

Science.gov (United States)

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.

Staves and Petals: Multi-module Local Support Structures of the ATLAS ITk Strips Upgrade

CERN Document Server

Rodriguez Rodriguez, Daniel; The ATLAS collaboration

2017-01-01

The ATLAS Inner Tracker (ITk) is an all-silicon tracker that will replace the existing inner detector at the Phase-II Upgrade of ATLAS. The outermost part of the tracker consists of the strips tracker, in which the sensor elements consist of silicon micro-strip sensors with strip lengths varying from 1.7 to up to 10 cm. The current design is part of the ATLAS ITk Strip Detector Technical Design Report (TDR) and envisions a four-layer barrel and two six-disk end-cap regions. The sensor and readout units (``modules'') are directly glued onto multi-module, low-mass, high thermal performance carbon fibre structures, called “staves” for the barrel and ``petals'' for the end-cap. They provide cooling, power, data and control lines to the modules with a minimal amount of external services. An extensive prototyping program was put in place over the last years to fully characterise these structures mechanically, thermally, and electrically. Thermo-mechanical stave and petal prototypes have recently been built and ...

Design of the first full size ATLAS ITk Strip sensor for the endcap region

CERN Document Server

Lacasta, Carlos; The ATLAS collaboration

2017-01-01

The ATLAS collaboration is designing the full silicon tracker (ITk) that will operate in the HL-LHC replacing the current design. The silicon microstrip sensors for the barrel and the endcap regions in the ITk are fabricated in 6 inch, p-type, float-zone wafers, where large-area strip sensor designs are laid out together with a number of miniature sensors. The radiation tolerance and specific system issues like the need for slim edge of 450 µm have been tested with square shaped sensors intended for the barrel part of the tracker. This work presents the design of the first full size silicon microstrip sensor for the endcap region with a slim edge of 450 µm. The strip endcaps will consist of several wheels with two layers of silicon strip sensors each. The strips have to lie along the azimuthal direction, apart from a small stereo angle rotation (20 mrad on each side, giving 40 mrad total) for measuring the second coordinate of tracks. This stereo angle is built into the strip layout of the sensor and, in or...

Design of the first full size ATLAS ITk Strip sensor for the endcap region

CERN Document Server

Lacasta, Carlos; The ATLAS collaboration

2018-01-01

The ATLAS collaboration is designing the full silicon tracker (ITk) that will operate in the HL-LHC replacing the current design. The silicon microstrip sensors for the barrel and the endcap regions in the ITk are fabricated in 6 inch, p-type, float-zone wafers, where large-area strip sensor designs are laid out together with a number of miniature sensors. The radiation tolerance and specific system issues like the need for slim edge of 450 μm have been tested with square shaped sensors intended for the barrel part of the tracker. This work presents the design of the first full size silicon microstrip sensor for the endcap region with a slim edge of 450 μm. The strip endcaps will consist of several wheels with two layers of silicon strip sensors each. The strips have to lie along the azimuthal direction, apart from a small stereo angle rotation (20 mrad on each side, giving 40 mrad total) for measuring the second coordinate of tracks. This stereo angle is built into the strip layout of the sensor and, in or...

Inibidores das Tirosinacinases na Terapêutica Farmacológica

Directory of Open Access Journals (Sweden)

Sara Saraiva

2013-07-01

Full Text Available The discovery of mutations in tyrosine kinases (TKs involved in the pathogenesis of many diseases, particularly oncological, encouraged the investigation of inhibitors of tyrosine kinases (ITKs as therapeutic strategies. The aim of this study was to perform a review of the different ITKs available in the national and international markets, their therapeutic indications, and their potential directions in research. It was also a revision of the main ITKs which are currently being evaluated in various stages of clinical trials. We conducted a literature search in the PubMed electronic database using the term “tyrosine kinase inhibitors” and 219 publications were included in the present review, published from August 2011 to July 2012. We also consulted the databases of the Portuguese National Authority of Medicines and Health Products, IP (INFARMED, the European Medicines Agency (EMA and the United States Food and Drug Administration (FDA. Presently there are 14 ITKs approved by FDA. In Portugal there are 13 ITKs with marketing authorization (MA, and bosutinib currently in the authorization phase. There are ITKs approved for the treatment of chronic myeloid leukemia, acute lymphoblastic leukemia, carcinoma of non-small-cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, breast cancer, gastrointestinal stromal tumor, pancreatic neuroendocrine carcinoma, thyroid carcinoma, myelofibrosis and soft tissue sarcomas. ITKs are under investigation for other potential indications such as autoimmune diseases, namely rheumatoid arthritis and psoriasis, among others. Because there is a wide variety of TKs and not all of them are yet studied, more research is needed so that other potential therapeutic targets can be discovered in the future. The TKs are therefore a promising therapeutic target, which makes the ITKs a pharmacological class with great clinical potential.

TEC variability near northern EIA crest and comparison with IRI model

Science.gov (United States)

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.

ATLAS ITk short-strip stave prototypes with 130 nm chipset

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00116199; The ATLAS collaboration; Dopke, Jens; Sawyer, Craig

2017-01-01

The ATLAS ITk Collaboration is working to deliver a new Inner Tracking detector for use at HL-LHC. The strip tracker community has recently constructed a partially loaded, double-sided demonstrator stave using the HCC / ABC130 chipset in 130 nm CMOS technology. Mindful of the need to maximise power efficiency whilst minimising the cost and material of associated cable plant, the system design includes the integration of a low-mass DC-DC converter and sensor bias (HV) switch within each module. This paper documents the first results from the demonstrator stave. The system concept is also outlined.

Observational Analysis of Variation Characteristics of GPS-Based TEC Fluctuation over China

Directory of Open Access Journals (Sweden)

Xifeng Liu

2016-12-01

Full Text Available In this study, the characteristics of the total electron content (TEC fluctuations and their regional differences over China were analyzed by utilizing the rate of the TEC index (ROTI based on GPS data from 21 reference stations across China during a solar cycle. The results show that there were significant regional differences at different latitudes. Strong ionospheric TEC fluctuations were usually observed at lower latitudes in southern China, where the occurrence of TEC fluctuations demonstrated typical nighttime- and season-dependent (equinox months features. This phenomenon was consistent with the ionospheric scintillation characteristics of this region. Additionally, compared to low-latitude China, the intensity of TEC fluctuations over mid-latitude China was significantly weaker, and the occurrence of TEC fluctuations was not a nighttime-dependent phenomenon. Moreover, the intensity of TEC fluctuations was much stronger during high solar activity than during low solar activity. Furthermore, the summer-dependent characteristics of TEC fluctuations gradually emerged over lower mid-latitude areas as equinox characteristics weakened. Similar to the equinox characteristics, the summer-dependent characteristics gradually weakened or even disappeared with the increasing latitude. Relevant discussions of this phenomenon are still relatively rare, and it requires further study and analysis.

Integration of the End Cap TEC+ of the CMS Silicon Strip Tracker

CERN Document Server

Adler, Volker; Ageron, Michel; Agram, Jean-Laurent; Atz, Bernd; Barvich, Tobias; Baulieu, Guillaume; Beaumont, Willem; Beissel, Franz; Bergauer, Thomas; Berst, Jean-Daniel; Blüm, Peter; Bock, E; Bogelsbacher, F; de Boer, Wim; Bonnet, Jean-Luc; Bonnevaux, Alain; Boudoul, Gaelle; Bouhali, Othmane; Braunschweig, Wolfgang; Bremer, R; Brom, Jean-Marie; Butz, Erik; Chabanat, Eric; Chabert, Eric Christian; Clerbaux, Barbara; Contardo, Didier; De Callatay, Bernard; Dehm, Philip; Delaere, Christophe; Della Negra, Rodolphe; Dewulf, Jean-Paul; D'Hondt, Jorgen; Didierjean, Francois; Dierlamm, Alexander; Dirkes, Guido; Dragicevic, Marko; Drouhin, Frédéric; Ernenwein, Jean-Pierre; Esser, Hans; Estre, Nicolas; Fahrer, Manuel; Feld, Lutz; Fernández, J; Florins, Benoit; Flossdorf, Alexander; Flucke, Gero; Flügge, Günter; Fontaine, Jean-Charles; Freudenreich, Klaus; Frey, Martin; Friedl, Markus; Furgeri, Alexander; Giraud, Noël; Goerlach, Ulrich; Goorens, Robert; Graehling, Philippe; Grégoire, Ghislain; Gregoriev, E; Gross, Laurent; Hansel, S; Haroutunian, Roger; Hartmann, Frank; Heier, Stefan; Hermanns, Thomas; Heydhausen, Dirk; Heyninck, Jan; Hosselet, J; Hrubec, Josef; Jahn, Dieter; Juillot, Pierre; Kaminski, Jochen; Karpinski, Waclaw; Kaussen, Gordon; Keutgen, Thomas; Klanner, Robert; Klein, Katja; König, Stefan; Kosbow, M; Krammer, Manfred; Ledermann, Bernhard; Lemaître, Vincent; De Lentdecker, Gilles; Linn, Alexander; Lounis, Abdenour; Lübelsmeyer, Klaus; Lumb, Nicholas; Maazouzi, Chaker; Mahmoud, Tariq; Michotte, Daniel; Militaru, Otilia; Mirabito, Laurent; Müller, Thomas; Neukermans, Lionel; Ollivetto, C; Olzem, Jan; Ostapchuk, Andrey; Pandoulas, Demetrios; Pein, Uwe; Pernicka, Manfred; Perriès, Stephane; Piaseki, C; Pierschel, Gerhard; Piotrzkowski, Krzysztof; Poettgens, Michael; Pooth, Oliver; Rouby, Xavier; Sabellek, Andreas; Schael, Stefan; Schirm, Norbert; Schleper, Peter; Schmitz, Stefan Antonius; Schultz von Dratzig, Arndt; Siedling, Rolf; Simonis, Hans-Jürgen; Stahl, Achim; Steck, Pia; Steinbruck, G; Stoye, Markus; Strub, Roger; Tavernier, Stefaan; Teyssier, Daniel; Theel, Andreas; Trocmé, Benjamin; Udo, Fred; Van der Donckt, M; Van der Velde, C; Van Hove, Pierre; Vanlaer, Pascal; Van Lancker, Luc; Van Staa, Rolf; Vanzetto, Sylvain; Weber, Markus; Weiler, Thomas; Weseler, Siegfried; Wickens, John; Wittmer, Bruno; Wlochal, Michael; De Wolf, Eddi A; Zhukov, Valery; Zoeller, Marc Henning

2009-01-01

The silicon strip tracker of the CMS experiment has been completed and inserted into the CMS detector in late 2007. The largest sub-system of the tracker is its end cap system, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted into the TEC support structures. Each end cap consists of 144 petals, and the insertion of these petals into the end cap structure is referred to as TEC integration. The two end caps were integrated independently in Aachen (TEC+) and at CERN (TEC--). This note deals with the integration of TEC+, describing procedures for end cap integration and for quality control during testing of integrated sections of the end cap and presenting results from the testing.

Increases of equatorial total electron content (TEC) during magnetic storms

International Nuclear Information System (INIS)

Yeboah-Amankwah, D.

1976-01-01

This paper is a report on the analysis of equatorial electron content, TEC, during magnetic storms. Storms between 1969 and 1972 have been examined as part of an on-going study of TEC morphology during magnetically disturbed days. The published magnetic Ksup(p) indices and TEC data from the Legon abservatory have been employed. The general picture arising from the analysis is that the total electron content of the ionosphere is significantly enhanced during magnetic storms. (author)

Derivation of GPS TEC and receiver bias for Langkawi station in Malaysia

International Nuclear Information System (INIS)

Teh, W L; Abdullah, M; Chen, W S

2017-01-01

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 (10 16 electrons/m 2 ), 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. (paper)

Ionospheric earthquake effects detection based on Total Electron Content (TEC) GPS Correlation

Science.gov (United States)

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.

ATLAS ITk Short-Strip Stave prototypes with 130nm chipset

CERN Document Server

Phillips, Peter William; The ATLAS collaboration

2017-01-01

The ATLAS ITk is working to deliver a new Inner Tracking detector for use at HL-LHC. The strip tracker community has recently constructed partially loaded, double sided demonstrator staves using the HCC / ABC130 chipset in 130nm CMOS technology. Mindful of the need to maximise power efficiency whilst minimising the cost and material of associated cable plant, the system design includes the integration of a low-mass DC-DC converter and sensor bias (HV) switch within each module. This paper documents the first results from the demonstrator staves. The system concept and the roadmap toward a full system test are also outlined.

Te/C nanocomposites for Li-Te Secondary Batteries

Science.gov (United States)

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.

Application of Kalman filter in detecting pre-earthquake ionospheric TEC anomaly

Directory of Open Access Journals (Sweden)

Zhu Fuying

2011-05-01

Full Text Available : As an attempt, the Kalman filter was used to study the anomalous variations of ionospheric Total Electron Content (TEC before and after Wenchuan Ms8.0 earthquake, these TEC data were calculated from the GPS data observed by the Crustal Movement Observation Network of China. The result indicates that this method is reasonable and reliable in detecting TEC anomalies associated with large earthquakes.

Comparison of GPS-derived TEC with IRI-2012 and IRI-2007 TEC predictions at Surat, a location around the EIA crest in the Indian sector, during the ascending phase of solar cycle 24

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

Jennifer C. C. Neale

2004-01-01

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

Thermo-ecological cost (TEC evaluation of metallurgical processes

Directory of Open Access Journals (Sweden)

W. Stanek

2015-01-01

Full Text Available Metallurgy represents a complex production system of fuel and mineral non-renewable resources transformation. The effectiveness of resource management in metallurgical chains depends on the applied ore grade and on the irreversibility of components of the system. TEC can be applied to measure the influence of metallurgy on the depletion of natural resources. The paper discusses the possibility of application of TEC in metallurgy and presents illustrative example concerning blast-furnace process.

ATLAS ITk and new pixel sensors technologies

CERN Document Server

Gaudiello, A

2016-01-01

During the 2023–2024 shutdown, the Large Hadron Collider (LHC) will be upgraded to reach an instantaneous luminosity up to 7×10$^{34}$ cm$^{−2}$s$^{−1}$. This upgrade of the accelerator is called High-Luminosity LHC (HL-LHC). The ATLAS detector will be changed to meet the challenges of HL-LHC: an average of 200 pile-up events in every bunch crossing, and an integrated luminosity of 3000 fb $^{−1}$ over ten years. The HL-LHC luminosity conditions are too extreme for the current silicon (pixel and strip) detectors and straw tube transition radiation tracker (TRT) of the current ATLAS tracking system. Therefore the ATLAS inner tracker is being completely rebuilt for data-taking and the new system is called Inner Tracker (ITk). During this upgrade the TRT will be removed in favor of an all-new all-silicon tracker composed only by strip and pixel detectors. An overview of new layouts in study will be reported and the new pixel sensor technologies in development will be explained.

The Phase-2 ATLAS ITk Pixel Upgrade

CERN Document Server

Rossi, Leonardo Paolo; The ATLAS collaboration

2018-01-01

The entire tracking system of the ATLAS experiment will be replaced in 2025 during the LHC Phase-II shutdown by an all-silicon detector called the “ITk” (Inner Tracker). The innermost part of ITk will be a pixel detector containing about 12.5m2 of sensitive silicon. The silicon modules are arranged on 5 layers of stave-like support structures in the most central region and ring-shaped supports in the endcap regions covering out to |η| < 4; a mid-eta region (~1 < |η| < ~2) will be occupied by novel inclined support structures which keep the angle of incidence of high-momentum tracks more closely normal to the sensitive silicon. All supports will be based on low mass, highly stable and highly thermally-conductive carbon-based materials cooled by evaporative carbon dioxide flowing in thin-walled titanium pipes. An extensive prototyping programme, including thermal, mechanical and electrical studies, is being carried out on all the types of support structures. The HL-LHC is expected to deliver up t...

Assembly and Electrical Tests of the First Full-size Forward Module for the ATLAS ITk Strip Detector

CERN Document Server

Garcia-Argos, Carlos; The ATLAS collaboration

2018-01-01

The ATLAS experiment will replace the existing Inner Detector by an all-silicon detector named the Inner Tracker (ITk) for the High Luminosity LHC upgrades. In the outer region of the Inner Tracker is the strip detector, which consists of a four layer barrel and six discs to each side of the barrel, with silicon-strip modules as basic units. Each module is composed of a sensor and one or more flex circuits that hold the read-out electronics. In the experiment, the modules are mounted on support structures with integrated power and cooling. The modules are designed with geometries that accommodate the central and forward regions, with rectangular sensors in the barrels and wedge shaped sensors in the end-caps. The strips lengths and pitch sizes vary according to the occupancy of the region. In this contribution, we present the construction and results of the electrical tests of the first full-size module of the innermost forward region, named \\textit{Ring 0} in the ATLAS ITk strip detector nomenclature. This m...

Assembly and Electrical Tests of the First Full-size Forward Module for the ATLAS ITk Strip Detector

CERN Document Server

Garcia-Argos, Carlos; The ATLAS collaboration

2017-01-01

The ATLAS experiment will replace the existing Inner Detector by an all-silicon detector named the Inner Tracker (ITk) for the High Luminosity LHC upgrades. In the outer region of the Inner Tracker is the strip detector, which consists of a four layer barrel and six discs to each side of the barrel, with silicon-strip modules as basic units. Each module is composed of a sensor and one or more flex circuits that hold the read-out electronics. In the experiment, the modules are mounted on support structures with integrated power and cooling. The modules are designed with geometries that accommodate the central and forward regions, with rectangular sensors in the barrels and wedge shaped sensors in the end-caps. The strips lengths and pitch sizes vary according to the occupancy of the region. In this contribution, we present the construction and the results of the electrical tests of the first full-size module of the innermost forward region, named Ring 0 in the ATLAS ITk strip detector nomenclature. This module...

Validation of measured poleward TEC gradient using multi-station GPS with Artificial Neural Network based TEC model in low latitude region for developing predictive capability of ionospheric scintillation

Science.gov (United States)

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

Linear time series modeling of GPS-derived TEC observations over the Indo-Thailand region

Science.gov (United States)

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.

Empirical model of TEC response to geomagnetic and solar forcing over Balkan Peninsula

Science.gov (United States)

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.

Thermodynamic Analysis of TEG-TEC Device Including Influence of Thomson Effect

Science.gov (United States)

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.

Southern European ionospheric TEC maps based on Kriging technique to monitor ionosphere behavior

Science.gov (United States)

Rodríguez-Bouza, Marta; Paparini, Claudia; Otero, Xurxo; Herraiz, Miguel; Radicella, Sandro M.; Abe, Oladipo E.; Rodríguez-Caderot, Gracia

2017-10-01

Global or regional Maps of the ionospheric Total Electron Content (TEC) are an efficient tool to monitor the delay introduced by the ionosphere in the satellite signals. Ionospheric disturbance periods are of particular interest because these conditions can strongly affect satellite navigation range measurements. This work presents post-processing regional vertical TEC maps over Southern Europe ([35°N-50°N] latitude) obtained by applying Kriging interpolation to GPS derived TEC over more than 100 Global Navigation Satellite System (GNSS) stations. These maps are used to study the behavior of the ionosphere during space weather events and their effects. To validate these maps, hereafter called Southern European Ionospheric Maps (SEIMs), their TEC values have been compared with those obtained from EGNOS Message Server (EMS) and with direct experimental TEC data from GNSS stations. Ionospheric space weather events related to geomagnetic storms of March 17th, 2013, February 19th, 2014 and March 17th, 2015 have been selected. To test the methodology, one period of quiet days has been also analyzed. TEC values obtained by SEIMs in the Ionospheric Grid Points (IGPs) defined by EGNOS are very close to those given by EMS and in the period of major geomagnetic storms the difference does not exceed 6 TEC units. These results confirm the good performance of the technique used for obtaining the SEIMs that can be a useful tool to study the ionosphere behavior during geomagnetic storms and their effects in the region of interest.

A comparison between TEC obtained by the TOPEX/Poseidon borne GPS receiver and TEC from the Gallagher model

International Nuclear Information System (INIS)

Ciraolo, L.

2003-01-01

JPL archived RINEX files relative to the GPS receiver of TOPEX at the site bodhi.jplnasa.gov/pub/topex/rinex for years 1992, 1993, 1994, 1995, 1997. The GPS receiver on board was intended as a tool for precise orbitography, but from such data it is possible to extract Differential Phase and Group Delays providing with a biased estimate of slant Total Electron Content (TEC) from TOPEX to GPS. This means a very useful information about TEC in an area above 1340 up to 20000 km, or high topside and plasmasphere. It was possible to get some estimate of the minimum magnitude of slants that can be observed in such region. A comparison with slants obtained by the Gallagher was carried out, with interesting results

A comparison between TEC obtained by the TOPEX/Poseidon borne GPS receiver and TEC from the Gallagher model

CERN Document Server

Ciraolo, L

2002-01-01

JPL archived RINEX files relative to the GPS receiver of TOPEX at the site bodhi.jplnasa.gov/pub/topex/rinex for years 1992, 1993, 1994, 1995, 1997. The GPS receiver on board was intended as a tool for precise orbitography, but from such data it is possible to extract Differential Phase and Group Delays providing with a biased estimate of slant Total Electron Content (TEC) from TOPEX to GPS. This means a very useful information about TEC in an area above 1340 up to 20000 km, or high topside and plasmasphere. It was possible to get some estimate of the minimum magnitude of slants that can be observed in such region. A comparison with slants obtained by the Gallagher was carried out, with interesting results.

Storm induced large scale TIDs observed in GPS derived TEC

Directory of Open Access Journals (Sweden)

C. Borries

2009-04-01

Full Text Available This work is a first statistical analysis of large scale traveling ionospheric disturbances (LSTID in Europe using total electron content (TEC data derived from GNSS measurements. The GNSS receiver network in Europe is dense enough to map the ionospheric perturbation TEC with high horizontal resolution. The derived perturbation TEC maps are analysed studying the effect of space weather events on the ionosphere over Europe. Equatorward propagating storm induced wave packets have been identified during several geomagnetic storms. Characteristic parameters such as velocity, wavelength and direction were estimated from the perturbation TEC maps. Showing a mean wavelength of 2000 km, a mean period of 59 min and a phase speed of 684 ms−1 in average, the perturbations are allocated to LSTID. The comparison to LSTID observed over Japan shows an equal wavelength but a considerably faster phase speed. This might be attributed to the differences in the distance to the auroral region or inclination/declination of the geomagnetic field lines. The observed correlation between the LSTID amplitudes and the Auroral Electrojet (AE indicates that most of the wave like perturbations are exited by Joule heating. Particle precipitation effects could not be separated.

Epizootic rabbit enteropathy inoculum (TEC4): antibiograms and antibiotic fractionation.

Science.gov (United States)

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.

ATLAS ITk Strip Detector for High-Luminosity LHC

CERN Document Server

Kroll, Jiri; The ATLAS collaboration

2017-01-01

The ATLAS experiment is currently preparing for an upgrade of the tracking system in the course of the High-Luminosity LHC that is scheduled for 2026. The expected peak instantaneous luminosity up to $7.5\\times10^{34}\\;\\mathrm{cm}^{-2}\\mathrm{s}^{-1}$ corresponding to approximately 200 inelastic proton-proton interactions per beam crossing, radiation damage at an integrated luminosity of $3000\\;\\mathrm{fb}^{-1}$ and hadron fluencies over $2\\times10^{16}\\;\\mathrm{n}_{\\mathrm{eq}}/\\mathrm{cm}^{2}$, as well as fast hardware tracking capability that will bring Level-0 trigger rate of a few MHz down to a Level-1 trigger rate below 1 MHz require a replacement of existing Inner Detector by an all-silicon Inner Tracker with a pixel detector surrounded by a strip detector. The current prototyping phase, that is working with ITk Strip Detector consisting of a four-layer barrel and a forward region composed of six disks on each side of the barrel, has resulted in the ATLAS Inner Tracker Strip Detector Technical Design R...

TEC variability over Havana

International Nuclear Information System (INIS)

Lazo, B.; Alazo, K.; Rodriguez, M.; Calzadilla, A.

2003-01-01

The variability of total electron content (TEC) measured over Havana using ATS-6, SMS-1 and GOES-3 geosynchronous satellite signals has been investigated for low, middle and high solar activity periods from 1974 to 1982. The obtained results show that standard deviation is smooth during nighttime hours and maximum at noon or postnoon hours. Strong solar activity dependence of standard deviation with a maximum values during HSA has been found. (author)

Regional TEC model under quiet geomagnetic conditions and low-to-moderate solar activity based on CODE GIMs

Science.gov (United States)

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.

Interactive deformation registration of endorectal prostate MRI using ITK thin plate splines.

Science.gov (United States)

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.

Storm induced large scale TIDs observed in GPS derived TEC

Directory of Open Access Journals (Sweden)

C. Borries

2009-04-01

Full Text Available This work is a first statistical analysis of large scale traveling ionospheric disturbances (LSTID in Europe using total electron content (TEC data derived from GNSS measurements. The GNSS receiver network in Europe is dense enough to map the ionospheric perturbation TEC with high horizontal resolution. The derived perturbation TEC maps are analysed studying the effect of space weather events on the ionosphere over Europe.

Equatorward propagating storm induced wave packets have been identified during several geomagnetic storms. Characteristic parameters such as velocity, wavelength and direction were estimated from the perturbation TEC maps. Showing a mean wavelength of 2000 km, a mean period of 59 min and a phase speed of 684 ms⁻¹ in average, the perturbations are allocated to LSTID. The comparison to LSTID observed over Japan shows an equal wavelength but a considerably faster phase speed. This might be attributed to the differences in the distance to the auroral region or inclination/declination of the geomagnetic field lines.

The observed correlation between the LSTID amplitudes and the Auroral Electrojet (AE indicates that most of the wave like perturbations are exited by Joule heating. Particle precipitation effects could not be separated.

Ionospheric TEC Weather Map Over South America

Science.gov (United States)

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) 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.

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

Science.gov (United States)

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

2010-01-01

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

Transition region of TEC enhancement phenomena during geomagnetically disturbed periods at mid-latitudes

Directory of Open Access Journals (Sweden)

K. Unnikrishnan

2005-12-01

Full Text Available Large-scale TEC perturbations/enhancements observed during the day sectors of major storm periods, 12-13 February 2000, 23 September 1999, 29 October 2003, and 21 November 2003, were studied using a high resolution GPS network over Japan. TEC enhancements described in the present study have large magnitudes (≥25×10¹⁶ electrons/m² compared to the quiet-time values and long periods (≥120 min. The sequential manner of development and the propagation of these perturbations show that they are initiated at the northern region and propagate towards the southern region of Japan, with velocities >350 m/s. On 12 February 2000, remarkably high values of TEC and background content are observed at the southern region, compared to the north, because of the poleward expansion of the equatorial anomaly crest, which is characterized by strong latitudinal gradients near 35° N (26° N geomagnetically. When the TEC enhancements, initiating at the north, propagate through the region 39-34° N (30-25° N geomagnetically, they undergo transitions characterized by a severe decrease in amplitude of TEC enhancements. This may be due to their interaction with the higher background content of the expanded anomaly crest. However, at the low-latitude region, below 34° N, an increase in TEC is manifested as an enhanced ionization pattern (EIP. This could be due to the prompt penetration of the eastward electric field, which is evident from high values of the southward Interplanetary Magnetic Field component (IMF B_z and AE index. The TEC perturbations observed on the other storm days also exhibit similar transitions, characterized by a decreasing magnitude of the perturbation component, at the region around 39-34° N. In addition to this, on the other storm days, at the low-latitude region, below 34° N, an increase in TEC (EIP feature also indicates the repeatability of the above scenario. It is found that, the latitude and

Transition region of TEC enhancement phenomena during geomagnetically disturbed periods at mid-latitudes

Directory of Open Access Journals (Sweden)

K. Unnikrishnan

2005-12-01

Full Text Available Large-scale TEC perturbations/enhancements observed during the day sectors of major storm periods, 12-13 February 2000, 23 September 1999, 29 October 2003, and 21 November 2003, were studied using a high resolution GPS network over Japan. TEC enhancements described in the present study have large magnitudes (≥25×1016 electrons/m2 compared to the quiet-time values and long periods (≥120 min. The sequential manner of development and the propagation of these perturbations show that they are initiated at the northern region and propagate towards the southern region of Japan, with velocities >350 m/s. On 12 February 2000, remarkably high values of TEC and background content are observed at the southern region, compared to the north, because of the poleward expansion of the equatorial anomaly crest, which is characterized by strong latitudinal gradients near 35° N (26° N geomagnetically. When the TEC enhancements, initiating at the north, propagate through the region 39-34° N (30-25° N geomagnetically, they undergo transitions characterized by a severe decrease in amplitude of TEC enhancements. This may be due to their interaction with the higher background content of the expanded anomaly crest. However, at the low-latitude region, below 34° N, an increase in TEC is manifested as an enhanced ionization pattern (EIP. This could be due to the prompt penetration of the eastward electric field, which is evident from high values of the southward Interplanetary Magnetic Field component (IMF Bz and AE index. The TEC perturbations observed on the other storm days also exhibit similar transitions, characterized by a decreasing magnitude of the perturbation component, at the region around 39-34° N. In addition to this, on the other storm days, at the low-latitude region, below 34° N, an increase in TEC (EIP feature also indicates the repeatability of the above scenario. It is found that, the latitude and time at which the decrease in magnitude

The Reconstruction Toolkit (RTK), an open-source cone-beam CT reconstruction toolkit based on the Insight Toolkit (ITK)

International Nuclear Information System (INIS)

Rit, S; Vila Oliva, M; Sarrut, D; Brousmiche, S; Labarbe, R; Sharp, G C

2014-01-01

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.

Methodology on sizing and selecting thermoelectric cooler from different TEC manufacturers in cooling system design

International Nuclear Information System (INIS)

Tan, F.L.; Fok, S.C.

2008-01-01

The search and selection for a suitable thermoelectric cooler (TEC) to optimize a cooling system design can be a tedious task as there are many product ranges from several TEC manufacturers. Although the manufacturers do provide proprietary manuals or electronic search facilities for their products, the process is still cumbersome as these facilities are incompatible. The electronic facilities often have different user interfaces and functionalities, while the manual facilities have different presentations of the performance characteristics. This paper presents a methodology to assist the designer to size and select the TECs from different manufacturers. The approach will allow designers to find quickly and to evaluate the devices from different TEC manufacturers. Based on the approach, the article introduces a new operational framework for an Internet based thermoelectric cooling system design process that would promote the interaction and collaboration between the designers and TEC manufacturers. It is hoped that this work would be useful for the advancement of future tools to assist designers to develop, analyze and optimize thermoelectric cooling system design in minimal time using the latest TECs available on the market

Maintenance Maneuver Automation for an Adapted Cylindrical Shape TEC

Directory of Open Access Journals (Sweden)

Rafael Morales

2016-09-01

Full Text Available Several manufacturers have developed devices with which to harness tidal/current power in areas where the depth does not exceed 40 m. These are the so-called first generation Tidal Energy Converters (TEC, and they are usually fixed to the seabed by gravity. When carrying out maintenance tasks on these devices it is, therefore, necessary to remove the nacelles from their bases and raise them to the surface of the sea. They must subsequently be placed back on their bases. These tasks require special high performance ships, signifying high maintenance costs. The automation of emersion and immersion maneuvers will undoubtedly lead to lower costs, given that ships with less demanding requirements will be required for the aforementioned maintenance tasks. This research presents a simple two degrees of freedom dynamic model that can be used to control a first generation TEC that has been conceived of to harness energy from marine currents. The control of the system is carried out by means of a water ballast system located inside the nacelle of the main power unit and is used as an actuator to produce buoying vertical forces. A nonlinear control law based on a decoupling term for the closed loop depth and/or orientation control is also proposed in order to ensure adequate behavior when the TEC performs emersion and immersion maneuvers with only hydrostatic buoyancy forces. The control scheme is composed of an inner loop consisting of a linear and decoupled input/output relationship and the vector of friction and compressibility terms and an outer loop that operates with the tracking error vector in order to ensure the asymptotically exponential stability of the TEC posture. Finally, the effectiveness of the dynamic model and the controller approach is demonstrated by means of numerical simulations when the TEC is carrying out an emersion maneuver for the development of general maintenance tasks and an emersion maneuver for blade-cleaning maintenance

Application of Geostationary GNSS and SBAS Satellites for Studying Ionospheric TEC Disturbances of Geomagnetic and Meteorological Origin

Science.gov (United States)

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.

Short-term estimation of GNSS TEC using a neural network model in Brazil

Science.gov (United States)

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

Comprehensive human resources development program for nuclear power at NuTEC/JAEA

International Nuclear Information System (INIS)

Ishimura, T.

2010-03-01

Nuclear Technology and Education Center (NuTEC) of the Japan Atomic Energy Agency (JAEA) aims at comprehensive nuclear education and training activities, which cover 1) education and training for national nuclear engineers, 2) cooperation with universities and 3) international contribution and cooperation. The main feature of NuTEC's training programs is that the curricula place emphasis on the laboratory exercises with well-equipped training facilities, including research reacotrs, and expertise of lecturers mostly from JAEA. The wide spectrum of cooperative activities have been pursued with universities and also with international organizations, such as IAEA, ENEN, CEA/INSTN and FNCA countries. The present paper descrives the overall HRD activities of NuTEC, especially in nuclear power field. (author)

Comprehensive Human Resources Development Program for Nuclear Power at NuTEC/JAEA

International Nuclear Information System (INIS)

Ishimura, T.

2012-01-01

Nuclear Technology and Education Center (NuTEC) of the Japan Atomic Energy Agency (JAEA) aims at comprehensive nuclear education and training activities, which cover 1) education and training for national nuclear engineers, 2) cooperation with universities and 3) international contribution and cooperation. The main feature of NuTEC's training programs is that the curricula place emphasis on the laboratory exercises with well-equipped training facilities, including research reacotrs, and expertise of lecturers mostly from JAEA. The wide spectrum of cooperative activities have been pursued with universities and also with international organizations, such as IAEA, ENEN, CEA/INSTN and FNCA countries. The present paper descrives the overall HRD activities of NuTEC, especially in nuclear power field. (author)

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

NARCIS (Netherlands)

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

2000-01-01

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

The effect of geomagnetic storm on GPS derived total electron content (TEC) at Varanasi, India

International Nuclear Information System (INIS)

Kumar, Sanjay; Singh, A K

2010-01-01

In this paper we studied the effect of geomagnetic storm on Global Positioning System (GPS) derived total electron content (TEC) at low latitude Varanasi (Geomagnetic lat 14 0 , 55' N, geomagnetic long 154 0 E) during the period of May 2007 to April 2008. During this period 2 storms were found, which were occurred on 20 November 2007 and 9 March 2008. In this study vertical total electron content (VTEC) of single Pseudorandom Noise (PRN) and average of VTEC of same PRN before 10 days of storm, which is called background TEC, were used to see the effect of these storms on the variation of TEC. From this study this is found that during the storm of March 2008 the TEC increases in main phase of storm while in the case of November 2007 storm, TEC decreases during the main phase of storm but increases in the recovery phase (next day) of storm.

An empirical model of ionospheric total electron content (TEC) near the crest of the equatorial ionization anomaly (EIA)

Science.gov (United States)

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.

An empirical model of ionospheric total electron content (TEC near the crest of the equatorial ionization anomaly (EIA

Directory of Open Access Journals (Sweden)

Hajra Rajkumar

2016-01-01

Full Text Available 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.

The TEC Web-Umbrella

International Nuclear Information System (INIS)

Krom, J.G.; Korten, M.; Koslowski, H.R.; Kraemer-Flecken, A.; Manduchi, G.; Nideroest, B.U.; Oosterbeek, J.W.; Schorn, R.P.; Wijnoltz, F.; Becks, B.; Biel, W.; Evrard, M.P.; Gorkom, J.C. van; Hellermann, M.G. von

2002-01-01

The TEC community operates the TEXTOR device and in doing so collects and stores data from a number of different front-end acquisition systems, processing codes and analysis systems. Due to the evolution of these systems in the past, different, distributed data storage technologies were used to record this data. In an attempt to reduce the number of interfaces client codes have to use when accessing data from these data stores, an 'umbrella' concept was developed: a software-layer that covers (as an 'umbrella') as many as possible of these stores and provides a unified access mechanism to them. We explored the possibility of using the widely supported HTTP protocol for this purpose; this is the core protocol of the World-Wide-Web and it is capable of transporting almost any type of data. The concepts behind using this protocol were based on earlier work at JET. Access via this umbrella has been provided to the most important data stores around TEXTOR and access to others is being added regularly. Clients codes, libraries and programs have been developed for several user environments. The HTTP based concepts and the data-access via this system have been found to be highly portable. This paper gives an overview of the TEC Web-Umbrella system, it describes the basic concepts of this system and it presents some of the client-side codes and programs. The paper also reports on some first (tentative) user experiences with it

Prototype Strip Barrel Modules for the ATLAS ITk Strip Detector

CERN Document Server

Sawyer, Craig; The ATLAS collaboration

2017-01-01

The module design for the Phase II Upgrade of the new ATLAS Inner Tracker (ITk) detector at the LHC employs integrated low mass assembly using single-sided flexible circuits with readout ASICs and a powering circuit incorporating control and monitoring of HV, LV and temperature on the module. Both readout and powering circuits are glued directly onto the silicon sensor surface resulting in a fully integrated, extremely low radiation length module which simultaneously reduces the material requirements of the local support structure by allowing a reduced width stave structure to be employed. Such a module concept has now been fully demonstrated using so-called ABC130 and HCC130 ASICs fabricated in 130nm CMOS technology to readout ATLAS12 n+-in-p silicon strip sensors. Low voltage powering for these demonstrator modules has been realised by utilising a DCDC powerboard based around the CERN FEAST ASIC. This powerboard incorporates an HV multiplexing switch based on a Panasonic GaN transistor. Control and monitori...

Simultaneous response of NmF2 and GPS-TEC to storm events at Ilorin

Science.gov (United States)

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.

Comparison of Plateletpheresis on the Fenwal Amicus and Fresenius Com.Tec Cell Separators.

Science.gov (United States)

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 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.

Evaluation of geomagnetic storm effects on the GPS derived Total Electron Content (TEC)

International Nuclear Information System (INIS)

Purohit, P K; Atulkar, Roshni; Mansoori, Azad A; Khan, Parvaiz A; Bhawre, Purushottam; Tripathi, Sharad C; Khatarkar, Prakash; Bhardwaj, Shivangi; Aslam, A M; Waheed, Malik A; Gwal, A K

2015-01-01

The geomagnetic storm represents the most outstanding example of solar wind- magnetospheric interaction, which causes global disturbances in the geomagnetic field as well as triggers ionospheric disturbances. We study the behaviour of ionospheric Total Electron Content (TEC) during the geomagnetic storms. For this investigation we have selected 47 intense geomagnetic storms (Dst ≤ -100nT) that were observed during the solar cycle 23 i.e. during 1998- 2006. We then categorized these storms into four categories depending upon their solar sources like Magnetic Cloud (MC), Co-rotating Interaction Region (CIR), SH+ICME and SH+MC. We then studied the behaviour of ionospheric TEC at a mid latitude station Usuda (36.13N, 138.36E), Japan during these storm events produced by four different solar sources. During our study we found that the smooth variations in TEC are replaced by rapid fluctuations and the value of TEC is strongly enhanced during the time of these storms belonging to all the four categories. However, the greatest enhancements in TEC are produced during those geomagnetic storms which are either caused by Sheath driven Magnetic cloud (SH+MC) or Sheath driven ICME (SH+ICME). We also derived the correlation between the TEC enhancements produced during storms of each category with the minimum Dst. We found the strongest correlation exists for the SH+ICME category followed by SH+MC, MC and finally CIR. Since the most intense storms were either caused by SH+ICME or SH+MC while the least intense storms were caused by CIR, consequently the correlation was strongest with SH+ICME and SH+MC and least with CIR. (paper)

Global Variations of Ionospheric Total Electron Content (TEC ...

African Journals Online (AJOL)

User

In general, there was a very high correlation between Mean TEC value ... quite differently from the prediction of the Chapman ionization theory. ... serious impact on short wave communication, satellite communication and precise navigation.

Synthesis and chemical etching of Te/C nanocables

Indian Academy of Sciences (India)

Key Laboratory of Enhanced Oil & Gas Recovery of Ministry of Education, Northeast Petroleum University, ... MS received 31 December 2010; revised 5 April 2011. Abstract. .... that the formation process of Te/C nanocables may undergo.

Early Experience with Technology-Based Eye Care Services (TECS): A Novel Ophthalmologic Telemedicine Initiative.

Science.gov (United States)

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

EDUCATION AND VOCATIONAL TRAINING OF TEC CLAIMANTS.

Science.gov (United States)

Indiana State Employment Security Div., Indianapolis.

TO COLLECT INFORMATION CONCERNING THE PERSONAL CHARACTERISTICS, FAMILY STATUS, EDUCATION AND VOCATIONAL TRAINING, WORK HISTORY, AND UNEMPLOYMENT EXPERIENCE OF TEMPORARY EXTENDED UNEMPLOYMENT COMPENSATION (TEC) CLAIMANTS IN INDIANA, A QUESTIONNAIRE-INTERVIEW WAS ADMINISTERED TO A 5 PERCENT SAMPLE OF PERSONS FILING CLAIMS DURING 3 SELECTED WEEKS,…

Comparison of plateletpheresis on the Fenwal Amicus, Fresenius COM.TEC, and Trima Accel Cell separators.

Science.gov (United States)

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.

Investigation of the TEC Changes in the vicinity of the Earthquake Preparation Zone

Science.gov (United States)

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.

PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina PBMC

Directory of Open Access Journals (Sweden)

Jennifer C. C. Neale

2005-01-01

Full Text Available Mechanisms underlying in vitro immunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs and polychlorinated biphenyls (PCBs were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs Fyn and Itk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP, 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169, a model immunotoxic PCB, or DMSO (vehicle control. Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKs Fyn and Itk were both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part by disruption of T cell receptor (TCR signaling and cytokine production.

DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration.

Directory of Open Access Journals (Sweden)

Masako Osada

2010-02-01

Full Text Available 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

Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec

Directory of Open Access Journals (Sweden)

Yu-Sheng Chen

2018-01-01

Full Text Available Proinsulin-transferrin fusion protein (ProINS-Tf has been designed and successfully expressed from the mammalian HEK293 cells (HEK-ProINS-Tf. It was found that HEK-ProINS-Tf could be converted into an activated form in the liver. Furthermore, HEK-ProINS-Tf was demonstrated as an extra-long acting insulin analogue with liver-specific insulin action in streptozotocin (STZ-induced type 1 diabetic mice. However, due to the low production yield from transfected HEK293 cells, there are other interesting features, including the oral bioavailability, which have not been fully explored and characterized. To improve the protein production yield, an alternative protein expression system, ExpressTec using transgenic rice (Oryza sativa L., was used. The intact and active rice-derived ProINS-Tf (ExpressTec-ProINS-Tf was successfully expressed from the transgenic rice expression system. Our results suggested that, although the insulin-like bioactivity of ExpressTec-ProINS-Tf was slightly lower in vitro, its potency of in vivo blood glucose control was considerably stronger than that of HEK-ProINS-Tf. The oral delivery studies in type 1 diabetic mice demonstrated a prolonged control of blood glucose to near-normal levels after oral administration of ExpressTec-ProINS-Tf. Results in this report suggest that ExpressTec-ProINS-Tf is a promising insulin analog with advantages including low cost, prolonged and liver targeting effects, and most importantly, oral bioactivity.

Ionising radiation dosimetry by measuring thermally excited currents (TEC) in irradiated highpolymers

International Nuclear Information System (INIS)

Shtol'ts, V.; Petermann, V.; Nigot, V.

1976-01-01

The first results are presented in measuring thermally excited currents (TEC) in 60 Co - gamma irradiated polyethylene and teflon. The design of measuring instruments is described. The maximum background currents in nonirradiated samples reached 10 -13 A. The TEC curves are presented which have obtained under irradiation up to 0.1-1000 rad followed by heating in the temperature range from 20 to 250 deg C. The curves exhibited maxima at about 90 deg C for polyethylene and about 200 deg C for teflon. The TEC dose range has been determined to be 0.1-1000 rad and 5-1000 rad for polyethylene and teflon, respectively. The fading at room temperature after 100 hrs has appeared to be 50% for polyethylene and 60% for teflon. The main merit of the technique is assumed to be the simplicity of the measuring instruments [ru

C-TEC: Ohio's First All-Green School

Science.gov (United States)

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…

SynTec Final Technical Report: Synthetic biology for Tailored Enzyme cocktails

Energy Technology Data Exchange (ETDEWEB)

Lin, Janine [Novozymes, Inc., Davis, CA (United States); Teter, Sarah [Novozymes, Inc., Davis, CA (United States)

2016-06-30

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. 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

TecCOMFrame : A competence framework for technical communication

NARCIS (Netherlands)

Cleary, Yvonne; Karreman, Joyce; Closs, Sissi; Drazek, Zygmunt; Engberg, Jan; Ghenghea, Voichita; Meex, Birgitta; Minacori, Patricia; Muller, J.; Straub, Daniela

2017-01-01

The role of technical communicators is expanding due to technology. However, many individuals throughout Europe gain employment as technical communicators without undergoing specialized training. TecCOMFrame, a three-year project funded by the European Union, aims to develop: 1) a common academic

Module and Electronics Developments for the ATLAS ITK Pixel System

CERN Document Server

Rummler, Andr{e}; The ATLAS collaboration

2016-01-01

The entire tracking system of the ATLAS experiment will be replaced during the LHC Phase II shutdown around 2025 by an all-silicon detector (Inner Tracker, ITk). The pixel detector will be composed by the five innermost layers, instrumented with 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 m^2, depending on the final layout choice that is expected to take place in early 2017. Different designs of planar, 3D, CMOS sensors are being investigated to identify the optimal technology for the different pixel layers. In parallel sensor-chip interconnection options are evaluated in collaboration with industrial partners to identify reliable technologies when employing 100-150 μm thin chips. While the new read-out chip is being developed by the RD53 Collaboration, the pixel off detector read-out electronics will be implemented in the frame...

The Phase II ATLAS Pixel Upgrade: The Inner Tracker (ITk)

CERN Document Server

Flick, Tobias; The ATLAS collaboration

2016-01-01

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 pixel detector will comprise the five innermost layers, and 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. The total surface area of silicon in the new pixel system could measure up to 14 m^2, depending on the final layout choice, which is expected to take place in early 2017. Four layout options are being investigated at the moment, two with forward coverage to eta < 3.2 and two to eta < 4. For each coverage option, a layout with long barrel staves and a layout with novel inclined support structures in the barrel-endcap overlap region are considered. All potential layouts include modules mounted on ring-shaped supports in the endcap regions. Support...

A new strips tracker for the upgraded ATLAS ITk detector

CERN Document Server

David, Claire; The ATLAS collaboration

2017-01-01

The inner detector of the present 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 particle densities and radiation levels will be higher by as much as a factor of ten. The new detectors must be faster, they need to be more highly segmented, and covering more area. They also need to be more resistant to radiation, and they require much greater power delivery to the front-end systems. At the same time, they cannot introduce excess material which could undermine performance. For those reasons, the inner tracker of the ATLAS detector must be redesigned and rebuilt completely. The design of the ATLAS Upgrade inner tracker (ITk) has already been defined. It consists of several layers of silicon particle detectors. The innermost layers will be composed of silicon pixel sensors, and the outer layers will consist of s...

Reconstruction of missed critical frequency of F2-layer over Mexico using TEC

Science.gov (United States)

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

Inverting Coseismic TEC Disturbances for Neutral Atmosphere Pressure Wave

Science.gov (United States)

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.

The structure of the latidudinal total electron content (T.E.C.). Gradients over mid-latitude stations

International Nuclear Information System (INIS)

Keroub, I.H.

1976-01-01

New results concerning the day gradients of Total Electron Contents (T.E.C.) in Haifa region were obtained by the method specific for the determination of TEC in the transverse zone. The latitudinal gradients thus obtained agree with the results obtained by topside sounding (Alouette 1 satellite). A quantitative explanation of the results yielded by the classical counting method is presented. Il implies that all day TEC data obtained by the counting methods in stations situated at middle geomagnetic latitudes such as Haifa, must be corrected

Comparison of double dose plateletpheresis on the Fenwal Amicus, Fresenius COM.TEC and Trima Accel cell separators.

Science.gov (United States)

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

Waddenfonds Tidal Texel Demonstration project. BlueTEC Texel Tidal Project: Environmental measurement and performance analysis

NARCIS (Netherlands)

Ponsoni, L.; Nauw, J.J.; Smit, M.; Ober, S.; Nichols, C.; Kenkhuis, J.; Schmidt, C.; Buatois, A.; de Haas, P.

2016-01-01

In the context of the BlueTEC project, this report starts by introducing theBlueTEC tidal energy platform and reviewing the patterns of circulation of theMarsdiep inlet. The energy resource assessment and the site selection for theplatform's deployment are reported. This document analyses di?erent

Millimeter-Wave Polarimeters Using Kinetic Inductance Detectors for TolTEC and Beyond

Science.gov (United States)

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.

Anomalous variation in GPS based TEC measurements prior to the 30 September 2009 Sumatra Earthquake

Science.gov (United States)

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.

Support vector machines for TEC seismo-ionospheric anomalies detection

Directory of Open Access Journals (Sweden)

M. Akhoondzadeh

2013-02-01

Full Text Available 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

First bulk and surface results for the ATLAS ITk stereo annulus sensors

CERN Document Server

Abidi, Syed Haider; The ATLAS collaboration; Bohm, Jan; Botte, James Michael; Ciungu, Bianca; Dette, Karola; Dolezal, Zdenek; Escobar, Carlos; Fadeyev, Vitaliy; Fernandez-Tejero, Xavi; Garcia-Argos, Carlos; Gillberg, Dag; Hara, Kazuhiko; Hunter, Robert Francis Holub

2018-01-01

A novel microstrip sensor geometry, the “stereo annulus”, has been developed for use in the end-cap of the ATLAS experiment’s strip tracker upgrade at the High-Luminosity Large Hadron Collider (HL- LHC). The radiation-hard, single-sided, ac-coupled, n + -in-p microstrip sensors are designed by the ITk Strip Sensor Collaboration and produced by Hamamatsu Photonics. The stereo annulus design has the potential to revolutionize the layout of end-cap microstrip trackers promising better tracking performance and more complete coverage than the contemporary configurations. These advantages are achieved by the union of equal length, radially oriented strips with a small stereo angle implemented directly into the sensor surface. The first-ever results for the stereo annulus geometry have been collected across several sites world- wide and are presented here. A number of full-size, unirradiated sensors were evaluated for their mechanical, bulk, and surface properties. The new device, the ATLAS12EC, is compared ag...

Practical use technology of coal ash (Poz-O-Tec); Sekitanbai no yuko riyo gijutsu (POZ-O-TEC)

Energy Technology Data Exchange (ETDEWEB)

Konno, K [Center for Coal Utilization, Japan, Tokyo (Japan); Saito, Y [Mitsui Mining Co. Ltd., Tokyo (Japan); Nagaya, Y [Mitsui Construction Co. Ltd., Tokyo (Japan)

1996-09-01

In order to utilize more effectively coal ash whose generation amount is increasing year after year, studies have been made on a technology to manufacture and utilize a high-strength substance solidified under normal temperature by utilizing hydration reaction of pozzolan system (Poz-O-Tec). The study works have been done as a subsidy operation of the Agency of Natural Resources and Energy, and were completed in fiscal 1995. Poz-O-Tec is a wet powder made of coal ash and stack gas desulfurization sludge (gypsum) added and mixed with lime and an adequate amount of water, which solidifies by hydration as pozzolan does. The same method as used for ordinary sands may be used as the basic application method. Because this is the material whose strength increases after construction, thickness of construction may be reduced smaller than in constructions using soils and sands. Test constructions of about sixty cases have been carried out to date, typically represented in use as a road bed material, banking, and a base material for water-barrier gutters. High-strength solid material which is stable under normal temperature may be obtained by adjusting calcium content. As a result of its effectiveness in practical use having been verified, a certificate of technological judgment has been issued for the material by the Civil Engineering Research Center. 3 refs., 11 figs., 2 tabs.

Test-beam activities and results for the ATLAS ITk pixel detector

CERN Document Server

Bisanz, Tobias; The ATLAS collaboration

2017-01-01

The Phase-II upgrade of the LHC will result in an increase of the instantaneous luminosity up to about $5\\times10^{34}~\\text{cm}^{-2}\\text{s}^{-1}$. To cope with the resulting challenges the current Inner Detector will be replaced by an all-silicon Inner Tracker (ITk) system. The Pixel Detector will have to deal with occupancies of about 300~hits/FE/s as well as a fluence of $2\\times10^{16}~\\text{n}_\\text{eq}\\text{cm}^{-2}$. Various sensor layouts are under development, aiming at providing a high performance, cost effective pixel instrumentation to cover an active area of about $10~\\text{m}^2$. These range from thin planar silicon, over 3D silicon, to active CMOS sensors.\\par After extensive characterization of the sensors in the lab, their charge collection properties and hit efficiency are measured in common testbeam campaigns, which provide valuable feedback for improvements of the layout. Testbeam measurements of the final prototypes will be used for the decision of which sensor types will be installed in...

Thermo-electro-chemical storage (TECS) of solar energy

International Nuclear Information System (INIS)

Wenger, Erez; Epstein, Michael; Kribus, Abraham

2017-01-01

Highlights: • A solar plant with thermally regenerative battery unifies energy conversion and storage. • Storage is a flow battery with thermo-chemical charging and electro-chemical discharging. • Sodium-sulfur and zinc-air systems are investigated as candidate storage materials. • Theoretical solar to electricity efficiencies of over 60% are predicted. • Charging temperature can be lowered with hybrid carbothermic reduction. - Abstract: A new approach for solar electricity generation and storage is proposed, based on the concept of thermally regenerative batteries. Concentrated sunlight is used for external thermo-chemical charging of a flow battery, and electricity is produced by conventional electro-chemical discharge of the battery. The battery replaces the steam turbine, currently used in commercial concentrated solar power (CSP) plants, potentially leading to much higher conversion efficiency. This approach offers potential performance, cost and operational advantages compared to existing solar technologies, and to existing storage solutions for management of an electrical grid with a significant contribution of intermittent solar electricity generation. Here we analyze the theoretical conversion efficiency for new thermo-electro-chemical storage (TECS) plant schemes based on the electro-chemical systems of sodium-sulfur (Na-S) and zinc-air. The thermodynamic upper limit of solar to electricity conversion efficiency for an ideal TECS cycle is about 60% for Na-S at reactor temperature of 1550 K, and 65% for the zinc-air system at 1750 K, both under sunlight concentration of 3000. A hybrid process with carbothermic reduction in the zinc-air system reaches 60% theoretical efficiency at the more practical conditions of reaction temperature <1200 K and concentration <1000. Practical TECS plant efficiency, estimated from these upper limits, may then be much higher compared to existing solar electricity technologies. The technical and economical

Investigating the performance of neural network backpropagation algorithms for TEC estimations using South African GPS data

Science.gov (United States)

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.

Comparison of the Fenwal Amicus and Fresenius Com.Tec cell separators for autologous peripheral blood progenitor cell collection.

Science.gov (United States)

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.

Variation of GPS-TEC in a low latitude Indian region during the year 2012 and 2013

Science.gov (United States)

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.

Validation of foF2 and TEC Modeling During Geomagnetic Disturbed Times: Preliminary Outcomes of International Forum for Space Weather Modeling Capabilities Assessment

Science.gov (United States)

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.

Activation of the Cph1-dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans.

Directory of Open Access Journals (Sweden)

Bernardo Ramírez-Zavala

Full Text Available 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 (Ste11(ΔN467 efficiently stimulated white cells to switch to the opaque phase, a behavior that did not occur in response to pheromone. Ste11(ΔN467-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.

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

NARCIS (Netherlands)

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

2000-01-01

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

PCA and vTEC climatology at midnight over mid-latitude regions

Science.gov (United States)

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

Solar activity indices as a proxy for the variation of ionospheric Total Electron Content (TEC) over Bahir Dar, Ethiopia during the year 2010-2014

Science.gov (United States)

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

Adjustments of the TaD electron density reconstruction model with GNSS-TEC parameters for operational application purposes

Directory of Open Access Journals (Sweden)

Belehaki Anna

2012-12-01

Full Text Available 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.

Modeling of Heat and Mass Transfer in a TEC-Driven Lyophilizer

Science.gov (United States)

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.

Informal report on measurements of slant TEC by FORTE

International Nuclear Information System (INIS)

Massey, R.S.

1997-01-01

Los Alamos National Laboratory's Space and Atmospheric Sciences group is now operating the FORTE satellite, which has two sets of instruments: optical detectors and radio detectors. In this report the author describes work with one set of radio detectors that allow measurements of the total electron content (TEC) traversed by VHF radiation originating at an electromagnetic pulse (EMP) generator located at Los Alamos

A recurrent neural network approach to quantitatively studying solar wind effects on TEC derived from GPS; preliminary results

Directory of Open Access Journals (Sweden)

J. B. Habarulema

2009-05-01

Full Text Available This paper attempts to describe the search for the parameter(s to represent solar wind effects in Global Positioning System total electron content (GPS TEC modelling using the technique of neural networks (NNs. A study is carried out by including solar wind velocity (V_sw, proton number density (N_p and the B_z component of the interplanetary magnetic field (IMF B_z obtained from the Advanced Composition Explorer (ACE satellite as separate inputs to the NN each along with day number of the year (DN, hour (HR, a 4-month running mean of the daily sunspot number (R4 and the running mean of the previous eight 3-hourly magnetic A index values (A8. Hourly GPS TEC values derived from a dual frequency receiver located at Sutherland (32.38° S, 20.81° E, South Africa for 8 years (2000–2007 have been used to train the Elman neural network (ENN and the result has been used to predict TEC variations for a GPS station located at Cape Town (33.95° S, 18.47° E. Quantitative results indicate that each of the parameters considered may have some degree of influence on GPS TEC at certain periods although a decrease in prediction accuracy is also observed for some parameters for different days and seasons. It is also evident that there is still a difficulty in predicting TEC values during disturbed conditions. The improvements and degradation in prediction accuracies are both close to the benchmark values which lends weight to the belief that diurnal, seasonal, solar and magnetic variabilities may be the major determinants of TEC variability.

GPS TEC near the crest of the EIA at 95°E during the ascending half of solar cycle 24 and comparison with IRI simulations

Science.gov (United States)

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.

Characterization of a prototype batch of long polyimide cables designed for fast data transmission on ATLAS ITk strip staves

CERN Document Server

Dopke, Jens; The ATLAS collaboration; Sawyer, Craig; Sullivan, Stephanie W

2018-01-01

The silicon-strip system in the ATLAS ITk detector has individual sensor modules mounted on staves to provide integrated solution for mechanical support, power, cooling, and data transmission. The data and power are transmitted to individual modules on polyimide tapes placed on thermo-mechanical stave cores. The 1.4 m long tapes transmit module data at the rate of 640 Mbps, along with providing several multi-drop clock and command links, and power lines. The first batch of 25 tapes has been produced. We characterized the line impedance and its variation across the batch, examined the tape cross-section, and assessed the variation between design and fabrication.

Study of TEC, slab-thickness and neutral temperature of the thermosphere in the Indian low latitude sector

Directory of Open Access Journals (Sweden)

K. Venkatesh

2011-09-01

Full Text Available The ionospheric equivalent slab-thickness is an important parameter which measures the skewness of the electron density profile of the ionosphere. In this paper, the diurnal, seasonal, day-to-day and latitudinal variations of ionospheric parameters namely total electron content (TEC, the peak ionization density of F-layer (NmF2, equivalent slab-thickness (τ and neutral temperature (Tn are presented. The simultaneous data of GPS-TEC and NmF2 from Trivandrum (8.47° N, 76.91° E, Waltair (17.7° N, 83.3° E and Delhi (28.58° N, 77.21° E are used to compute the slab-thickness (τ = TEC/NmF2 of the low sunspot period, 2004–2005. The day-time TEC values at Waltair are found to be greater than those at Trivandrum, while at Delhi the day-time TEC values are much lower compared to those at Trivandrum and Waltair. The trends of variation in the monthly mean diurnal variation of TEC and NmF2 are similar at Delhi, while they are different at Trivandrum and Waltair during the day-time. The slab-thickness (τ has shown a pre-sunrise peak around 05:00 LT at all the three stations, except during the summer months over Delhi. A consistent secondary peak in slab-thickness around noon hours has also been observed at Trivandrum and Waltair. During equinox and winter months a large night-time enhancement in the slab-thickness (comparable to the early morning peak in slab-thickness is observed at Delhi. The latitudinal variation of slab-thickness has shown a decrease from the equatorial station, Trivandrum to the low-mid latitude station, Delhi. The neutral temperatures (Tn computed from the slab-thickness (τ has shown a sharp increase around 05:00 LT over Trivandrum and Waltair. Whereas at Delhi, a double peaking around 05:00 and 23:00 LT is observed during winter and equinoctial months. The neutral temperatures computed are compare well with those of the MSIS-90 model derived temperatures.

Statistical characteristics of seismo-ionospheric GPS TEC disturbances prior to global Mw ≥ 5.0 earthquakes (1998-2014)

Science.gov (United States)

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.

The silicon strips Inner Tracker (ITk) of the ATLAS Phase-II upgrade detector

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00220523; The ATLAS collaboration

2018-01-01

The inner detector of the present 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 particle densities and radiation levels will be higher by as much as a factor of ten. The new detectors must be faster, they need to be more highly segmented, and covering more area. They also need to be more resistant to radiation, and they require much greater power delivery to the front-end systems. At the same time, they cannot introduce excess material which could undermine performance. For those reasons, the inner tracker of the ATLAS detector must be redesigned and rebuilt completely. The inner detector of the current detector will be replaced by the Inner Tracker (ITk). It consists of an innermost pixel detector and an outer strips tracker. This contribution focuses on the strips tracker. The basic detection unit of the ...

Comparison of plateletpheresis on the Fresenius AS.TEC 204 and Haemonetics MCS 3p.

Science.gov (United States)

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.

Characteristics of equatorial plasma bubbles observed by TEC map based on ground-based GNSS receivers over South America

Science.gov (United States)

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.

Long-term analysis of ionospheric polar patches based on CHAMP TEC data

DEFF Research Database (Denmark)

Noja, M.; Stolle, Claudia; Park, J.

2013-01-01

Total electron content (TEC) from LEO satellites offers great possibility to sound the upper ionosphere and plasmasphere. This paper describes a method to derive absolute TEC observations aboard CHAMP considering multipath effects and receiver differential code bias. The long-term data set of 9...... years GPS observations is used to investigate the climatological behavior of high-latitude plasma patches in both hemispheres. The occurrence of polar patches has a clear correlation with the solar cycle, which is less pronounced in the Southern Hemisphere (SH). Summed over all years, we observed...... a higher number of patches in the SH. The maximum occurrence rate of patches has been found at the dayside polar cusp during 12:00-18:00 MLT (magnetic local time) supporting the mechanisms for patch creation by local particle precipitation and by intrusion of subauroral plasma into the polar cap through...

Reception Test of Petals for the End Cap TEC+ of the CMS Silicon Strip Tracker

CERN Document Server

Bremer, R; Klein, Katja; Schmitz, Stefan Antonius; Adler, Volker; Adolphi, Roman; Ageron, Michel; Agram, Jean-Laurent; Atz, Bernd; Barvich, Tobias; Baulieu, Guillaume; Beaumont, Willem; Beissel, Franz; Bergauer, Thomas; Berst, Jean-Daniel; Blüm, Peter; Bock, E; Bogelsbacher, F; de Boer, Wim; Bonnet, Jean-Luc; Bonnevaux, Alain; Boudoul, Gaelle; Bouhali, Othmane; Braunschweig, Wolfgang; Brom, Jean-Marie; Butz, Erik; Chabanat, Eric; Chabert, Eric Christian; Clerbaux, Barbara; Contardo, Didier; De Callatay, Bernard; Dehm, Philip; Delaere, Christophe; Della Negra, Rodolphe; Dewulf, Jean-Paul; D'Hondt, Jorgen; Didierjean, Francois; Dierlamm, Alexander; Dirkes, Guido; Dragicevic, Marko; Drouhin, Frédéric; Ernenwein, Jean-Pierre; Esser, Hans; Estre, Nicolas; Fahrer, Manuel; Fernández, J; Florins, Benoit; Flossdorf, Alexander; Flucke, Gero; Flügge, Günter; Fontaine, Jean-Charles; Freudenreich, Klaus; Frey, Martin; Friedl, Markus; Furgeri, Alexander; Giraud, Noël; Goerlach, Ulrich; Goorens, Robert; Graehling, Philippe; Grégoire, Ghislain; Gregoriev, E; Gross, Laurent; Hansel, S; Haroutunian, Roger; Hartmann, Frank; Heier, Stefan; Hermanns, Thomas; Heydhausen, Dirk; Heyninck, Jan; Hosselet, J; Hrubec, Josef; Jahn, Dieter; Juillot, Pierre; Kaminski, Jochen; Karpinski, Waclaw; Kaussen, Gordon; Keutgen, Thomas; Klanner, Robert; König, Stefan; Kosbow, M; Krammer, Manfred; Ledermann, Bernhard; Lemaître, Vincent; De Lentdecker, Gilles; Linn, Alexander; Lounis, Abdenour; Lübelsmeyer, Klaus; Lumb, Nicholas; Maazouzi, Chaker; Mahmoud, Tariq; Michotte, Daniel; Militaru, Otilia; Mirabito, Laurent; Müller, Thomas; Neukermans, Lionel; Ollivetto, C; Olzem, Jan; Ostapchuk, Andrey; Pandoulas, Demetrios; Pein, Uwe; Pernicka, Manfred; Perriès, Stephane; Piaseki, C; Pierschel, Gerhard; Piotrzkowski, Krzysztof; Poettgens, Michael; Pooth, Oliver; Rouby, Xavier; Sabellek, Andreas; Schael, Stefan; Schirm, Norbert; Schleper, Peter; Schultz von Dratzig, Arndt; Siedling, Rolf; Simonis, Hans-Jürgen; Stahl, Achim; Steck, Pia; Steinbruck, G; Stoye, Markus; Strub, Roger; Tavernier, Stefaan; Teyssier, Daniel; Theel, Andreas; Trocmé, Benjamin; Udo, Fred; Van der Donckt, M; Van der Velde, C; Van Hove, Pierre; Vanlaer, Pascal; Van Lancker, Luc; Van Staa, Rolf; Vanzetto, Sylvain; Weber, Markus; Weiler, Thomas; Weseler, Siegfried; Wickens, John; Wittmer, Bruno; Wlochal, Michael; De Wolf, Eddi A; Zhukov, Valery; Zoeller, Marc Henning

2009-01-01

The silicon strip tracker of the CMS experiment has been completed and was inserted into the CMS detector in late 2007. The largest sub system of the tracker are its end caps, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted onto the TEC support structures. Each end cap consists of 144 such petals, which were built and fully qualified by several institutes across Europe. From

Ionospheric GPS TEC Anomalies and M >= 5.9 Earthquakes in Indonesia during 1993 - 2002

Directory of Open Access Journals (Sweden)

Sarmoko Saroso

2008-01-01

Full Text Available Indonesia is one of the most seismically active regions in the world, containing numerous active volcanoes and subject to frequent earthquakes with epicenters distributed along the same regions as volcanoes. In this paper, a case study is carried out to investigate pre-earthquake ionospheric anomalies in total electron content (TEC during the Sulawesi earthquakes of 1993 - 2002, and the Sumatra-Andaman earthquake of 26 December 2004, the largest earthquake in the world since 1964. It is found that the ionospheric TECs remarkably decrease within 2 - 7 days before the earthquakes, and for the very powerful Sumatra-Andaman earthquake, the anomalies extend up to about 1600 km from the epicenter.

Staves and Petals: Multi-module Local Support Structures of the ATLAS ITk Strips Upgrade

CERN Document Server

Garcia-Argos, Carlos; The ATLAS collaboration

2017-01-01

The ATLAS Inner Tracker (ITk) is an all-silicon tracker that will replace the existing inner detector at the Phase-II Upgrade of ATLAS. The outermost part of the tracker consists of the strips tracker, in which the sensors elements consist of silicon micro-strip sensors with strip lengths varying from 1.7 to up to 10 cm. The current design, at the moment under internal review in the Strips part of the Technical Design Report (TDR), envisions a four-layer barrel and two six-disk endcap regions. The sensor and readout units (“modules”) are directly glued onto multi-module, low-mass, high thermal performance carbon fiber structures, called “staves” for the barrel and “petals” for the endcap. They provide cooling, power, data and control lines to the modules with a minimal amount of external services. An extensive prototyping program was put in place over the last years to fully characterize these structures mechanically, thermally, and electrically. Thermo-mechanical stave and petal prototypes have r...

Ibrutinib treatment improves T cell number and function in CLL patients.

Science.gov (United States)

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.

Regulation of immune responsiveness in vivo by disrupting an early T-cell signaling event using a cell-permeable peptide.

Directory of Open Access Journals (Sweden)

David M Guimond

Full Text Available The inducible T cell kinase (ITK regulates type 2 (Th2 cytokines that provide defense against certain parasitic and bacterial infections and are involved in the pathogenesis of lung inflammation such as allergic asthma. Activation of ITK requires the interaction of its SH3 domain with the poly-proline region of its signaling partner, the SH2 domain containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76. The specific disruption of the ITK-SH3/SLP-76 poly-proline interaction in vitro by a cell-permeable competitive inhibitor peptide (R9-QQP interferes with the activation of ITK and the transduction of its cellular functions in T lymphocytes. In the present investigation, we assessed the effects of R9-QQP treatment on the induction of an in vivo immune response as represented by lung inflammation in a murine model of allergic asthma. We found that mice treated with R9-QQP and sensitized and challenged with the surrogate allergen ovalbumin (OVA display significant inhibition of lung inflammation in a peptide-specific manner. Thus, parameters of the allergic response, such as airway hyper-responsiveness, suppression of inflammatory cell infiltration, reduction of bronchial mucus accumulation, and production of relevant cytokines from draining lymph nodes were significantly suppressed. These findings represent the first demonstration of the biological significance of the interaction between ITK and SLP-76 in the induction of an immune response in a whole animal model and specifically underscore the significance of the ITK-SH3 domain interaction with the poly-proline region of SLP-76 in the development of an inflammatory response. Furthermore, the experimental approach of intracellular peptide-mediated inhibition might be applicable to the study of other important intracellular interactions thus providing a paradigm for dissecting signal transduction pathways.

A method for separating seismo-ionospheric TEC outliers from heliogeomagnetic disturbances by using nu-SVR

Energy Technology Data Exchange (ETDEWEB)

Pattisahusiwa, Asis [Bandung Institute of Technology (Indonesia); Liong, The Houw; Purqon, Acep [Earth physics and complex systems research group, Bandung Institute of Technology (Indonesia)

2015-09-30

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 in the average to detect the source of these outliers. This method is promising to use in the future research.

Improving Science Teacher Preparation through the APS PhysTEC and NSF Noyce Programs

Science.gov (United States)

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.

Modeling magnetic field and TEC signatures of large-amplitude acoustic and gravity waves generated by natural hazard events

Science.gov (United States)

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

PET imaging of T cells: Target identification and feasibility assessment.

Science.gov (United States)

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.

Comparative Analysis of Various Aspects of Plateletpheresis on the Fenwal Amicus and Fresenius COM.TEC Cell Separator Instruments.

Science.gov (United States)

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).

NuTEC annual report. April 1, 1996 - March 31, 1997

International Nuclear Information System (INIS)

1998-02-01

This report summarizes the educational works carried out at the NuTEC (Nuclear Technology and Education Center) of Japan Atomic Energy Research Institute during the 1996 fiscal year. It covers the educational courses provided at Tokyo and Tokai Education Centers and the activities of the International Technology Transfer Division, together with the R and D works for improving the educational programs, and related management works. Today Japan has a mature nuclear industry and Japanese nuclear engineers have highly specialized knowledges. On the other hand, they are losing wide perspective over the whole spectrum of nuclear technology. In addition, a considerable gap exists between the specialists and the public in knowledge and interpretation or acceptance of nuclear power. This gap may enlarge the public concern of specific problems caused by small accidents into a mistrust of entire nuclear power industry. The work of NuTEC is aimed at improving these problems in both specialist and the public sides. During the 1996 fiscal year, Tokyo and Tokai Education Centers accomplished all the planned courses, both domestic and international: total number of the trainees during the year reached 1868. The newly established International Technology Transfer Division proceeded the preparation works of the international training courses, particularly the Asia-Pacific Nuclear Cooperation Program. In addition, various research and development efforts were made to establish new items in educational programs. (author)

Comparison of a low and a middle latitude GPS-TEC in Africa during ...

African Journals Online (AJOL)

In this work, we compared TEC values at Libreville (a low latitude station) with Sutherland (a middle latitude station) over Africa using Global Positioning System (GPS) receivers during high solar activity (HSA), moderate solar activity (MSA) and low solar activity (LSA). Apart from our confirmation that high, moderate and low ...

ATLAS ITk Short Strip Prototype Module with Integrated DCDC Powering and Control Phase II Upgrade of the ATLAS Inner Tracker detector at the HL - LHC

CERN Document Server

Greenall, Ashley; The ATLAS collaboration

2017-01-01

The prototype Barrel module design, for the Phase II upgrade of the of the new Inner Tracker (ITk) detector at the LHC, has adopted an integrated low mass assembly featuring single-sided flexible circuits, with readout ASICs, glued to the silicon strip sensor. Further integration has been achieved by the attachment of module DCDC powering, HV sensor biasing switch and autonomous monitoring and control to the sensor. This low mass, integrated module approach benefits further in a reduced width stave structure to which the modules are attached. The results of preliminary electrical tests of such an integrated module will be presented.

Fresenius AS.TEC204 blood cell separator.

Science.gov (United States)

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.

GenBank blastx search result: AK111983 [KOME

Lifescience Database Archive (English)

Full Text Available ative exons 18 and 18a, and alternative splice products, complete cds.|ROD ROD 4e-34 +3 ... ...AK111983 001-012-H11 AF071946.1 Mus musculus protein tyrosine kinase Tec (Tec) gene, exons 16 and 17, altern

GenBank blastx search result: AK061938 [KOME

Lifescience Database Archive (English)

Full Text Available ative exons 18 and 18a, and alternative splice products, complete cds.|ROD ROD 1e-24 +2 ... ...AK061938 001-042-D07 AF071946.1 Mus musculus protein tyrosine kinase Tec (Tec) gene, exons 16 and 17, altern

GenBank blastx search result: AK060220 [KOME

Lifescience Database Archive (English)

Full Text Available ative exons 18 and 18a, and alternative splice products, complete cds.|ROD ROD 2e-36 +3 ... ...AK060220 001-002-F01 AF071946.1 Mus musculus protein tyrosine kinase Tec (Tec) gene, exons 16 and 17, altern

Planar n-in-n quad module prototypes for the ATLAS ITk upgrade at HL-LHC

Science.gov (United States)

Gisen, A.; Altenheiner, S.; Burmeister, I.; Gößling, C.; Klingenberg, R.; Kröninger, K.; Lönker, J.; Weers, M.; Wizemann, F.

2017-12-01

In order to meet the requirements of the High Luminosity LHC (HL-LHC), it will be necessary to replace the current tracker of the ATLAS experiment. Therefore, a new all-silicon tracking detector is being developed, the so-called Inner Tracker (ITk). The use of quad chip modules is intended in its pixel region. These modules consist of a silicon sensor that forms a unit along with four read-out chips. The current ATLAS pixel detector consists of planar n-in-n silicon pixel sensors. Similar sensors and four FE-I4 read-out chips were assembled to first prototypes of planar n-in-n quad modules. The main focus of the investigation of these modules was the region between the read-out chips, especially the central area between all four read-out chips. There are special pixel cells placed on the sensor which cover the gap between the read-out chips. This contribution focuses on the characterization of a non-irradiated device, including important sensor characteristics, charge collection determined with radioactive sources as well as hit efficiency measurements, performed in the laboratory and at testbeams. In addition, first laboratory results of an irradiated device are presented.

Comparison of equatorial GPS-TEC observations over an African station and an American station during the minimum and ascending phases of solar cycle 24

Directory of Open Access Journals (Sweden)

A. O. Akala

2013-11-01

Full Text Available GPS-TEC data were observed at the same local time at two equatorial stations on both longitudes: Lagos (6.52° N, 3.4° E, 3.04° S magnetic latitude, Nigeria; and Pucallpa (8.38° S, 74.57° W, 4.25° N magnetic latitude, Peru during the minimum (2009, 2010 and ascending (2011 phases of solar cycle 24. These data were grouped into daily, seasonal and solar activity sets. The day-to-day variations in vertical TEC (VTEC recorded the maximum during 14:00–16:00 LT and minimum during 04:00–06:00 LT at both longitudes. Seasonally, during solar minimum, maximum VTEC values were observed during March equinox and minimum during solstices. However, during the ascending phase of the solar activity, the maximum values were recorded during the December solstice and minimum during the June solstice. VTEC also increased with solar activity at both longitudes. On longitude by longitude comparison, the African GPS station generally recorded higher VTEC values than the American GPS station. Furthermore, harmonic analysis technique was used to extract the annual and semi-annual components of the amplitudes of the TEC series at both stations. The semi-annual variations dominated the TEC series over the African equatorial station, while the annual variations dominated those over the American equatorial station. The GPS-TEC-derived averages for non-storm days were compared with the corresponding values derived by the IRI-2007 with the NeQuick topside option. The NeQuick option of IRI-2007 showed better performance at the American sector than the African sector, but generally underestimating TEC during the early morning hours at both longitudes.

Real-time reconstruction of topside ionosphere scale height from coordinated GPS-TEC and ionosonde observations

Science.gov (United States)

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

Simultaneous ground-satellite observations of daytime traveling ionospheric disturbances over Japan using the GPS-TEC network and the CHAMP satellite

Science.gov (United States)

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.

76 FR 72978 - Whirlpool Corporation Including On-Site Leased Workers From Career Solutions TEC Staffing...

Science.gov (United States)

2011-11-28

... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-74,593] Whirlpool Corporation Including On-Site Leased Workers From Career Solutions TEC Staffing, Andrews International, IBM Corporation... workers are engaged in the production of refrigerators and trash compactors. The notice was published in...

Combined TOPEX/Poseidon TEC and ionosonde observations of negative low-latitude ionospheric storms

Directory of Open Access Journals (Sweden)

K. J. W. Lynn

2004-09-01

Full Text Available Ionospheric storms showing a strong depression in daytime foF2 values were sought which penetrated to low-latitudes, as identified by vertical ionosondes operating at Darwin and Townsville over the period 1992-1998. The 32 storms thus identified showed a seasonal occurrence peaking near the equinoxes with a bias to the summer side. Of these storms, three (27 March 1995, 25 October 1997, 8 November 1997 combined Australian and South East Asian ionosonde observations with local afternoon TOPEX/Poseidon measurements of TEC. The equatorial anomaly is usually well developed at this time of day and consequently these storms were chosen for detailed study. The TOPEX/Poseidon satellite provided vertical profiles of the ionosphere across both hemispheres, thus allowing the totality of storm behaviour to be observed for the first time at low-latitudes and related directly to the ionosonde observations. The three storms were remarkably consistent in their behaviour, the negative ionospheric storm day followed some 24-36h after the beginning of a magnetic storm and the development of the equatorial anomaly was suppressed. However, the suppression of the equatorial anomaly was not the main cause of the strong depression in foF2 observed by the Southern Hemisphere ionosondes. The latter was associated with an additional bite-out in both TEC and foF2 that occurred on the southern side of the magnetic equator. None of the three storms produced any major negative disturbance outside the range of normal variability of TEC and foF2 at the northern latitude sites for which data was available, despite the absence of the anomaly. The satellite measurements show the strength of the anomaly to be highly variable from day-to-day and anomaly peaks are frequently not present even on magnetically quiet days. Thus, an absence of anomaly peaks is contained within the normal variability of non-storm days. The north-south asymmetry and seasonal occurrence are consistent with

Comparison of GPS-TEC measurements with NeQuick2 and IRI model predictions in the low latitude East African region during varying solar activity period (1998 and 2008-2015)

Science.gov (United States)

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

76 FR 73683 - Whirlpool Corporation, Including On-Site Leased Workers From Career Solutions TEC Staffing...

Science.gov (United States)

2011-11-29

... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-74,593] Whirlpool Corporation, Including On-Site Leased Workers From Career Solutions TEC Staffing, Andrews International, IBM Corporation... refrigerators and trash compactors. The notice was published in the Federal Register on October 25, 2010 (75 FR...

arXiv Planar n-in-n quad module prototypes for the ATLAS ITk upgrade at HL-LHC

CERN Document Server

Gisen, A.; Burmeister, I.; Gößling, C.; Klingenberg, R.; Kröninger, K.; Lönker, J.; Weers, M.; Wizemann, F.

2017-12-15

In order to meet the requirements of the High Luminosity LHC (HL-LHC), it will be necessary to replace the current tracker of the ATLAS experiment. Therefore, a new all-silicon tracking detector is being developed, the so-called Inner Tracker (ITk). The use of quad chip modules is intended in its pixel region. These modules consist of a silicon sensor that forms a unit along with four read-out chips. The current ATLAS pixel detector consists of planar n-in-n silicon pixel sensors. Similar sensors and four FE-I4 read-out chips were assembled to first prototypes of planar n-in-n quad modules. The main focus of the investigation of these modules was the region between the read-out chips, especially the central area between all four read-out chips. There are special pixel cells placed on the sensor which cover the gap between the read-out chips. This contribution focuses on the characterization of a non-irradiated device, including important sensor characteristics, charge collection determined with radioactive so...

The ITk strips tracker for the phase-II upgrade of the ATLAS detector of the HL-LHC

CERN Document Server

Koutoulaki, Afroditi; The ATLAS collaboration

2016-01-01

The inner detector of the present 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 particle densities and radiation levels will be higher by as much as a factor of ten. The new detectors must be faster, they need to be more highly segmented, and covering more area. They also need to be more resistant to radiation, and they require much greater power delivery to the front-end systems. At the same time, they cannot introduce excess material which could undermine performance. For those reasons, the inner tracker of the ATLAS detector must be redesigned and rebuilt completely. The design of the ATLAS Upgrade inner tracker (ITk) has already been defined. It consists of several layers of silicon particle detectors. The innermost layers will be composed of silicon pixel sensors, and the outer layers will consist of s...

Education and training for nuclear scientists and engineers at NuTEC/JAEA

International Nuclear Information System (INIS)

Kushita, Kouhei; Sugimoto, Jun; Sakamoto, Ryuichi; Arai, Nobuyoshi; Hattori, Takamitsu; Matsuda, Kenji; Ikuta, Yuko; Sato, K.

2009-01-01

Because of the increasing demand of nuclear engineers in recent years, which is sometimes called as the age of nuclear Renaissance, while nuclear engineers have been decreasing and technical knowledge and expertise have not necessarily been transferred to the younger generations, human resources development (HRD) has been regarded as one of the most important issues in the nuclear field in Japan as well as in the world. Nuclear Technology and Education Center (NuTEC) at Japan Atomic Energy Agency (JAEA) have conducted comprehensive nuclear education and training activities in the past half century, which cover; 1) education and training for domestic nuclear engineers, 2) cooperation with universities, and 3) international cooperation. The main feature of NuTEC's training programs is that emphasis is placed on the laboratory exercise with well-equipped training facilities and expertise of lecturers mostly from JAEA. The wide spectrum of cooperative activities have been pursued with universities, which includes newly developed remote-education system, and also with international organizations, such as with FNCA countries and IAEA. For the nuclear education and trainings, utilization of nuclear reactors is of special importance. Examples of training programs using nuclear reactors are reported. Future plan to use nuclear reactors such as JMTR for the nuclear educations is also introduced. (author)

Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells.

Science.gov (United States)

Liu, Xiujuan; Hong, Quan; Wang, Zhen; Yu, Yanyan; Zou, Xin; Xu, Lihong

2016-02-01

Renal fibrosis is a progressive pathological change characterized by tubular cell apoptosis, tubulointerstitial fibroblast proliferation, and excessive deposition of extracellular matrix (ECM). miR-21 has been implicated in transforming growth factor-β (TGF-β)-stimulated tissue fibrosis. Recent studies showed that sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) are also critical for TGF-β-stimulated tissue fibrosis; however, it is not clear whether SphK/S1P interacts with miR-21 or not. In this study, we hypothesized that SphK/S1P signaling is linked to upregulation of miR-21 by TGF-β. To verify this hypothesis, we first determined that miR-21 was highly expressed in renal tubular epithelial cells (TECs) stimulated with TGF-β by using qRT-PCR and Northern blotting. Simultaneously, inhibition of miR-21, mediated by the corresponding antimir, markedly decreased the expression and deposition of type I collagen, fibronectin (Fn), cysteine-rich protein 61 (CCN1), α-smooth muscle actin, and fibroblast-specific protein1 in TGF-β-treated TECs. ELISA and qRT-PCR were used to measure the S1P and SphK1 levels in TECs. S1P production was induced by TGF-β through activation of SphK1. Furthermore, it was observed that TGF-β-stimulated upregulation of miR-21 was abolished by SphK1 siRNA and was restored by the addition of exogenous S1P. Blocking S1PR2 also inhibited upregulation of miR-21. Additionally, miR-21 overexpression attenuated the repression of TGF-β-stimulated ECM deposition and epithelial-mesenchymal transition by SphK1 and S1PR2 siRNA. In summary, our study demonstrates a link between SphK1/S1P and TGF-β-induced miR-21 in renal TECs and may represent a novel therapeutic target in renal fibrosis. © 2015 by the Society for Experimental Biology and Medicine.

TecCOMFrame : Building bridges between technical communication and translation studies through a prototype specialisation curriculum

NARCIS (Netherlands)

Cleary, Yvonne; Engberg, Jan; Karreman, Joyce; Meex, Birgitta; Closs, Sissi; Drazek, Zygmunt; Ghenghea, Voichita; Minacori, Patricia; Muller, J.; Straub, Daniela

2017-01-01

Technical communication is a new field of work compared to other professions, and therefore it does not have a standardised curriculum. In Europe, many technical communicators do not have qualifications in the area. TecCOMFrame, a project funded by the European Union, aims to develop an academic

Effectiveness of EarthTec(®) for killing invasive quagga mussels (Dreissena rostriformis bugensis) and preventing their colonization in the Western United States.

Science.gov (United States)

Watters, Ashlie; Gerstenberger, Shawn L; Wong, Wai Hing

2013-01-01

Quagga mussels (Dreissena rostriformis bugensis) have created economic and ecological impacts in the western United States since their discovery in 2007. This study focuses on chemical control for preventing the spread of these mussels. The effectiveness of EarthTec(®) in killing quagga mussels (adults, juveniles, and veligers) in Lake Mead, Nevada-Arizona, was evaluated over time across six concentrations: 0, 1, 5, 10, 17, and 83 ppm. One hundred percent mortality of adult and juvenile mussels was achieved after 96 h with 17 ppm and 5 ppm (respectively), and 100% veliger mortality occurred within 30 min at 3 ppm. From December 2010 to February 2011, the effectiveness of EarthTec(®) in preventing veliger colonization was also evaluated and the results showed that 2.8 ppm was effective in preventing veliger colonization on fiberglass panels. This study indicates that EarthTec(®) has the potential to be an effective control agent against the invasive quagga mussel, and more specifically, in preventing the colonization of veligers.

75 FR 77665 - Whirlpool Corporation, Including On-Site Leased Workers From Career Solutions TEC Staffing and...

Science.gov (United States)

2010-12-13

... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-74,593] Whirlpool Corporation, Including On-Site Leased Workers From Career Solutions TEC Staffing and Andrews International, Fort Smith... subject firm. The workers are engaged in the production of refrigerators and trash compactors. The company...

Evaluation of an Internally Controlled Multiplex Tth Endonuclease Cleavage Loop-Mediated Isothermal Amplification (TEC-LAMP Assay for the Detection of Bacterial Meningitis Pathogens

Directory of Open Access Journals (Sweden)

Owen Higgins

2018-02-01

Full Text Available 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.

Evaluation of an Internally Controlled Multiplex Tth Endonuclease Cleavage Loop-Mediated Isothermal Amplification (TEC-LAMP) Assay for the Detection of Bacterial Meningitis Pathogens

Science.gov (United States)

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

Myeloid-derived suppressor cells express Bruton’s tyrosine kinase and can be depleted in tumor bearing hosts by ibrutinib treatment

Science.gov (United States)

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

TEC promueve la matemática en la educación media

OpenAIRE

Guzmán O., Marcela

2017-01-01

Ofrecer capacitación de calidad para los docentes de matemática de colegios públicos ycolaborar en la organización de actividades que promuevan el interés por esa materia, sonlos dos objetivos principales del proyecto de extensión PROMATES (Promoción de laMatemática en la Educación Secundaria), que desarrollan académicos y estudiantes de la carrera de Enseñanza de la Matemática Asistida por Computadora del TEC.

Observations of magnetic field and TEC fluctuations caused by ionospheric responses to acoustic and gravity waves from ground-level, natural hazard sources

Science.gov (United States)

Inchin, P.; Zettergren, M. D.; Snively, J. B.; Komjathy, A.; Verkhoglyadova, O. P.

2017-12-01

Recent studies have reported magnetic field fluctuations following intense seismic hazard events [e.g. Aoyama et al., EPS, 68, 2016; Toh et al., JGR, 116, 2011]. These perturbations can be associated with ionospheric dynamo phenomena driven by seismically generated acoustic and gravity waves (AGWs). AGW-related dynamo effects can be separated from other sources of magnetic fluctuations (e.g. piezo magnetic effects, magnetospheric forcing or Rayleigh surface waves) based on time delays from event onset (corresponding closely with travel times for AGWs from ground to the ionosphere) and spectral content measured concurrently in total electron content (TEC). Modeling studies aimed at understanding these magnetic field fluctuations have demonstrated the idea that AGWs propagating through the conducting ionosphere can induce current densities sufficient to produce observable magnetic signatures [Zettergren and Snively, JGR, 120, 2017]. Here, we investigate the features of seismic-related magnetic field fluctuations in data and their generation via the effects of seismically-forced AGWs on the ionosphere [Iyemori et al., EPS, 65, 2013; Hasbi et al., JASTP, 71, 2005]. Concurrent magnetic field and TEC data are analyzed for several events: the Chilean earthquakes of 2010 and 2015, Chile's Calbuco volcano eruption and the Sumatran earthquake on March 28, 2005. We investigate the qualitative features of the disturbances as well as quantitative spectral and timing analysis of the data. For Chilean earthquakes, TEC and ground-based magnetometer data reveal fluctuations in magnetic field exhibiting 4-5 mHz frequencies, the same as in TEC. For the Calbuco volcano eruption and Sumatran earthquake both TEC and magnetic field perturbations exhibit frequencies of 4-5 mHz. The results are consistent with previous reports [Aoyama et al., EPS, 68, 2016, Hasbi et al., JASTP, 71, 2005, Iyemori et al., EPS, 65, 2013]. These observations are further interpreted through detailed numerical

Inversion of the perturbation GPS-TEC data induced by tsunamis in order to estimate the sea level anomaly.

Science.gov (United States)

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.

Temporal evolution of the EIA along 95°E as obtained from GNSS TEC measurements and SAMI3 model

Science.gov (United States)

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.

Using Paraffin PCM, Cryogel and TEC to Maintain Comet Surface Sample Cold from Earth Approach Through Retrieval

Science.gov (United States)

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.

Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment.

Science.gov (United States)

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.

Observations by the CUTLASS radar, HF Doppler, oblique ionospheric sounding, and TEC from GPS during a magnetic storm

Directory of Open Access Journals (Sweden)

D. V. Blagoveshchensky

2005-07-01

Full Text Available Multi-diagnostic observations, covering a significant area of northwest Europe, were made during the magnetic storm interval (28–29 April 2001 that occurred during the High Rate SolarMax IGS/GPS-campaign. HF radio observations were made with vertical sounders (St. Petersburg and Sodankyla, oblique incidence sounders (OIS, on paths from Murmansk to St. Petersburg, 1050 km, and Inskip to Leicester, 170 km, Doppler sounders, on paths from Cyprus to St. Petersburg, 2800 km, and Murmansk to St. Petersburg, and a coherent scatter radar (CUTLASS, Hankasalmi, Finland. These, together with total electron content (TEC measurements made at GPS stations from the Euref network in northwest Europe, are presented in this paper. A broad comparison of radio propagation data with ionospheric data at high and mid latitudes, under quiet and disturbed conditions, was undertaken. This analysis, together with a geophysical interpretation, allow us to better understand the nature of the ionospheric processes which occur during geomagnetic storms. The peculiarity of the storm was that it comprised of three individual substorms, the first of which appears to have been triggered by a compression of the magnetosphere. Besides the storm effects, we have also studied substorm effects in the observations separately, providing an improved understanding of the storm/substorm relationship. The main results of the investigations are the following. A narrow trough is formed some 10h after the storm onset in the TEC which is most likely a result of enhanced ionospheric convection. An enhancement in TEC some 2–3 h after the storm onset is most likely a result of heating and upwelling of the auroral ionosphere caused by enhanced currents. The so-called main effect on ionospheric propagation was observed at mid-latitudes during the first two substorms, but only during the first substorm at high latitudes. Ionospheric irregularities observed by CUTLASS were clearly related to the

Characteristics of Total Electron Content (TEC) observed from a chain of stations near the northern crest of the Equatorial Ionization Anomaly (EIA) along 88.5°E meridian in India

Science.gov (United States)

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.

Measurements of ionospheric TEC in the direction of GPS satellites and comparison with three ionospheric models

Directory of Open Access Journals (Sweden)

E. Zuccheretti

1997-06-01

Full Text Available The IEN Galileo Ferraris uses GPS for time and frequency synchronization. To obtain high performance it is important to reduce the error due to the ionospheric time-delay in GPS measurements. Evaluations of TEC in the direction of GPS satellites, obtained from three different ionospheric models, have been compared with corresponding measurements by GPS signal.

A comparative study of TEC response for the African equatorial and mid-latitudes during storm conditions

Czech Academy of Sciences Publication Activity Database

Habarulema, J. B.; McKinnell, L.- A.; Burešová, Dalia; Zhang, Y.; Seemala, G.; Ngwira, Ch.; Chum, Jaroslav; Opperman, B.

2013-01-01

Roč. 102, Sep (2013), s. 105-114 ISSN 1364-6826 R&D Projects: GA ČR(CZ) GAP209/11/1908 Institutional support: RVO:68378289 Keywords : Magnetic storm s * African equatorialandmidlatitudeTEC * dynamics * TIDs Subject RIV: DG - Athmosphere Sciences, Meteorology Impact factor: 1.751, year: 2013 http://www.sciencedirect.com/science/article/pii/S1364682613001545

Local time, seasonal, and solar cycle dependency of longitudinal variations of TEC along the crest of EIA over India

Science.gov (United States)

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.

Similarity and differences in morphology and mechanisms of the foF2 and TEC disturbances during the geomagnetic storms on 26–30 September 2011

Directory of Open Access Journals (Sweden)

M. V. Klimenko

2017-08-01

Full Text Available This study presents an analysis of the ground-based observations and model simulations of ionospheric electron density disturbances at three longitudinal sectors (eastern European, Siberian and American during geomagnetic storms that occurred on 26–30 September 2011. We use the Global Self-consistent Model of the Thermosphere, Ionosphere and Protonosphere (GSM TIP to reveal the main mechanisms influencing the storm-time behavior of the total electron content (TEC and the ionospheric F2 peak critical frequency (foF2 during different phases of geomagnetic storms. During the storm's main phase the long-lasting positive disturbances in TEC and foF2 at sunlit mid-latitudes are mainly explained by the storm-time equatorward neutral wind. The effects of eastward electric field can only explain the positive ionospheric storm in the first few hours of the initial storm phase. During the main phase the ionosphere was more changeable than the plasmasphere. The positive disturbances in the electron content at the plasmaspheric heights (800–20 000 km at high latitudes can appear simultaneously with the negative disturbances in TEC and foF2. The daytime positive disturbances in foF2 and TEC occurred at middle and low latitudes and at the Equator due to n(O ∕ n(N2 enhancement during later stage of the main phase and during the recovery phase of the geomagnetic storm. The plasma tube diffusional depletion and negative disturbances in electron and neutral temperature were the main formation mechanisms of the simultaneous formation of the positive disturbances in foF2 and negative disturbances in TEC at low latitudes during the storm's recovery phase.

NuTEC annual report. April 1, 1999 - March 31, 2000

Energy Technology Data Exchange (ETDEWEB)

NONE

2000-11-01

This report summarizes the educational activities and related management of the Nuclear Technology and Education Center (NuTEC) during the 1999 fiscal year. Both Tokyo and Tokai Education Centers have conducted almost all the planned domestic and international training courses successfully. In addition the latter Center has introduced a new course to educate senior specialists for nuclear emergency preparedness in response to the legal amendment after the criticality accident. The total number of participants was 1,122. The International Technology Transfer Division has not only planned and organized the international training courses, but also taken charge of the first seminar on Human Resource Development in Nuclear Field in Asian Region. Furthermore, various researches have been made to improve the educational programs. (author)

Revisión anatomofuncional de la neurología visual. Reporte de caso: discapacidad visual neurológica pos-TEC con hematomas subdurales subcrónicos bilaterales parietooccipitales

Directory of Open Access Journals (Sweden)

Esteban O. Vallejo Agudelo

2016-01-01

Full Text Available El TEC según la IBIA es la principal causa de convulsiones, muerte y discapacidad adquirida mundialmente. Las principales causas son las caídas en mayores de 65 años y los accidentes de tránsito en los menores. Los hematomas pos-TEC son una complicación muy frecuente, cuyas manifestaciones son variables, especialmente en los subdurales, presentando desde cefalea hasta síndromes demenciales o déficit neurológico focal, dentro de los cuales no es usual el reporte de casos con manifestaciones visuales. El presente artículo reporta un caso de discapacidad visual por déficit neurológico pos-TEC complicado con hematomas subdurales subcrónicos bilaterales parietooccipitales, y revisa la neuroanatomía funcional visual involucrada en ella.

A new ionospheric storm scale based on TEC and foF2 statistics

Science.gov (United States)

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.

Phosphorylation of the Yeast Choline Kinase by Protein Kinase C

Science.gov (United States)

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

NuTEC annual report. April 1, 1998 - March 31, 1999

International Nuclear Information System (INIS)

1999-11-01

This annual report summarizes the educational work carried out at the Nuclear Technology and Education Center (NuTEC) of Japan Atomic Energy Research Institute during the 1998 fiscal year. It describes all the training courses provided at Tokyo and Tokai Education Centers and the activities of the International Technology Transfer Division, together with the R and D achievements for improving the educational programs and related management work. During this fiscal year, Tokyo and Tokai Education Centers accomplished all the planned courses, both domestic and international, where the total number of the participants was 1,156. The International Technology Transfer Division conducted successfully the international training courses, including those of the Asia-Pacific Nuclear Cooperation Program. In addition, various research efforts were made to develop new items for the educational programs. (author)

NuTEC annual report (April 1, 2000 - March 31, 2001)

Energy Technology Data Exchange (ETDEWEB)

NONE

2001-10-01

This report summarizes the educational activities and related management of the Nuclear Technology and Education Center (NuTEC) during the 1999 fiscal year. Both Tokyo and Tokai Education Centers have successfully conducted almost all the planned domestic and international training courses. In addition Tokai Education Center has performed the 2nd nuclear supervisor training course and introduced a new course for special nuclear emergency preparedness in response to the legal amendment after the criticality accident. The sum total number of participants was 1,397. The International Technology Transfer Division has not only planned and organized the international training courses, but also taken charge of the 2nd workshop on Human Resource Development in Nuclear Field in Asian Region. Furthermore, various researches have been made to improve the educational programs. (author)

NuTEC annual report. April 1, 1997 - March 31, 1998

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-11-01

This annual report summarizes the educational works carried out at the Nuclear Technology and Education Center (NuTEC) of Japan Atomic Energy Research Institute during the 1997 fiscal year. It covers all the educational courses provided at Tokyo and Tokai Education Centers and the activities of the International Technology Transfer Division, together with the R and D works for improving the educational programs, and related management works. During the 1997 fiscal year, Tokyo and Tokai Education Centers accomplished all the planned courses, both domestic and international. Total number of the trainees during the year was 1,411. The International Technology Transfer Division proceeded the preparation works of the international training courses, particularly the Asia-Pacific Nuclear Cooperation Program. In addition, various research and development efforts were made to establish new items in educational programs. (author)

NuTEC annual report. April 1, 2001 - March 31, 2002

Energy Technology Data Exchange (ETDEWEB)

NONE

2003-03-01

This report summarizes the educational activities and related management of the Nuclear Technology and Education Center (NuTEC) during the 2001 fiscal year. Both Tokyo and Tokai Education Centers have successfully conducted almost all the planned domestic and international training courses. In addition, Tokai Education Center has performed the 3rd nuclear supervisor training course and other courses for special nuclear emergency preparedness in response to the legal amendment after the JCO criticality accident. The sum total number of participants was 1,310. The International Technology Transfer Division has not only planned and organized the international training courses, but also taken charge of the 3rd workshop on Human Resource Development under the framework of FNCA (Forum of Nuclear Cooperation in Asia). Various researches have been made to improve the educational program. (author)

AzTEC on ASTE Survey of Submillimeter Galaxies

Science.gov (United States)

Kohno, K.; Tamura, Y.; Hatsukade, B.; Nakanishi, K.; Iono, D.; Takata, T.; Wilson, G. W.; Yun, M. S.; Perera, T.; Austermann, J. E.; Scott, K. S.; Hughes, H.; Aretxaga, I.; Tanaka, K.; Oshima, T.; Yamaguchi, N.; Matsuo, H.; Ezawa, H.; Kawabe, R.

2008-10-01

We have conducted an unprecedented survey of submillimeter galaxies (SMGs) using the 144 pixel bolometer camera AzTEC mounted on the ASTE 10-m dish in Chile. We have already obtained many (>20) wide (typically 12' × 12' or wider) and deep (1 σ sensitivity of 0.5-1.0 mJy) 1.1 mm continuum images of known blank fields and over-density regions/protoclusters across a wide range of redshifts with a spatial resolution of ˜ 30''. It has resulted in the numerous (˜ a few 100, almost equivalent to the total number of the previously known SMGs) new and secure detections of SMGs. In this paper, we present initial results of two selected fields, SSA 22 and AKARI Deep Field South (ADF-S). A significnat clustering of bright SMGs toward the density peak of LAEs is found in SSA 22. We derived the differential and cumulative number counts from the detected sources in ADF-S, which probe the faintest flux densities (down to ˜1 mJy) among 1-mm blank field surveys to date.

Use of GPS TEC Maps for Calibrating Single Band VLBI Sessions

Science.gov (United States)

Gordon, David

2010-01-01

GPS TEC ionosphere maps were first applied to a series of K and Q band VLBA astrometry sessions to try to eliminate a declination bias in estimated source positions. Their usage has been expanded to calibrate X-band only VLBI observations as well. At K-band, approx.60% of the declination bias appears to be removed with the application of GPS ionosphere calibrations. At X-band however, it appears that up to 90% or more of the declination bias is removed, with a corresponding increase in RA and declination uncertainties of approx.0.5 mas. GPS ionosphere calibrations may be very useful for improving the estimated positions of the X-only and S-only sources in the VCS and RDV sessions.

Long-time Luminescence Kinetics of Localized excitons and conduction Band Edges Smearing in ZnSe(1-c)Tec Solid Solutions

DEFF Research Database (Denmark)

Klochikhin, O.; Ogloblin, S. G.; Permogorov, S.

2000-01-01

It is shown that the integrated luminescence intensity of localized excitons in solid solutions ZnSe(1 - c)Tec has a component slowly decaying with time. After the excitation above the mobility threshold, the long-time intensity decreases exponentially, with a fractional exponent changing from...

Effect of Thermoelectric Cooling (TEC module and the water flow heatsink on Photovoltaic (PV panel performance

Directory of Open Access Journals (Sweden)

Amelia A.R.

2017-01-01

Full Text Available 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.

Effect of Thermoelectric Cooling (TEC) module and the water flow heatsink on Photovoltaic (PV) panel performance

Science.gov (United States)

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.

Variations of TEC near the Indian Equatorial Ionospheric anomaly (EIA) stations by GPS measurements during descending phase of solar activity (2005 -2009)

Science.gov (United States)

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.

Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases.

Science.gov (United States)

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.

Removal of Inorganic, Microbial, and Particulate Contaminants from a Fresh Surface Water: Village Marine Tec. Expeditionary Unit Water Purifier, Generation 1

Science.gov (United States)

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...

Autoregulation of kinase dephosphorylation by ATP binding to AGC protein kinases

Science.gov (United States)

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

TecLines: A MATLAB-Based Toolbox for Tectonic Lineament Analysis from Satellite Images and DEMs, Part 1: Line Segment Detection and Extraction

Directory of Open Access Journals (Sweden)

Mehdi Rahnama

2014-06-01

Full Text Available Geological structures, such as faults and fractures, appear as image discontinuities or lineaments in remote sensing data. Geologic lineament mapping is a very important issue in geo-engineering, especially for construction site selection, seismic, and risk assessment, mineral exploration and hydrogeological research. Classical methods of lineaments extraction are based on semi-automated (or visual interpretation of optical data and digital elevation models. We developed a freely available Matlab based toolbox TecLines (Tectonic Lineament Analysis for locating and quantifying lineament patterns using satellite data and digital elevation models. TecLines consists of a set of functions including frequency filtering, spatial filtering, tensor voting, Hough transformation, and polynomial fitting. Due to differences in the mathematical background of the edge detection and edge linking procedure as well as the breadth of the methods, we introduce the approach in two-parts. In this first study, we present the steps that lead to edge detection. We introduce the data pre-processing using selected filters in spatial and frequency domains. We then describe the application of the tensor-voting framework to improve position and length accuracies of the detected lineaments. We demonstrate the robustness of the approach in a complex area in the northeast of Afghanistan using a panchromatic QUICKBIRD-2 image with 1-meter resolution. Finally, we compare the results of TecLines with manual lineament extraction, and other lineament extraction algorithms, as well as a published fault map of the study area.

Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.

Science.gov (United States)

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.

Kinases and Cancer

OpenAIRE

Jonas Cicenas; Egle Zalyte; Amos Bairoch; Pascale Gaudet

2018-01-01

Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...

Hydrothermal Synthesis and Mechanism of Unusual Zigzag Ag2Te and Ag2Te/C Core-Shell Nanostructures

Directory of Open Access Journals (Sweden)

Saima Manzoor

2014-01-01

Full Text Available A single step surfactant-assisted hydrothermal route has been developed for the synthesis of zigzag silver telluride nanowires with diameter of 50–60 nm and length of several tens of micrometers. Silver nitrate (AgNO3 and sodium tellurite (Na2TeO3, are the precursors and polyvinylpyrrolidone (PVP is used as surfactant in the presence of the reducing agent, that is, hydrazine hydrate (N2H4·H2O. In addition to the zigzag nanowires a facile hydrothermal reduction-carbonization route is proposed for the preparation of uniform core-shell Ag2Te/C nanowires. In case of Ag2Te/C synthesis process the same precursors are employed for Ag and Te along with the ethylene glycol used as reducing agent and glucose as the carbonizing agent. Morphological and compositional properties of the prepared products are analyzed with the help of scanning electron microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy, respectively. The detailed formation mechanism of the zigzag morphology and reduction-carbonization growth mechanism for core-shell nanowires are illustrated on the bases of experimental results.

Ionospheric perturbations due to earthquakes as determined from VLF and GPS-TEC data analysis at Agra, India

Science.gov (United States)

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.

Recent Progress in Understanding Natural-Hazards-Generated TEC Perturbations: Measurements and Modeling Results

Science.gov (United States)

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.

Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors.

Science.gov (United States)

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.

Variabilities of Low-Latitude Migrating and Nonmigrating Tides in GPS-TEC and TIMED-SABER Temperature During the Sudden Stratospheric Warming Event of 2013

Science.gov (United States)

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.

Prediction of post-sunset ESF based on the strength and asymmetry of EIA from ground based TEC measurements

Science.gov (United States)

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

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

KAUST Repository

Diaz Galicia, Miriam Escarlet

2018-05-01

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

Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study).

Science.gov (United States)

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.

Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.

Directory of Open Access Journals (Sweden)

Ting-Lei Gu

Full Text Available Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23 of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted.

A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase.

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Mutsuki Amano

Full Text Available BACKGROUND: Protein kinases are major components of signal transduction pathways in multiple cellular processes. Kinases directly interact with and phosphorylate downstream substrates, thus modulating their functions. Despite the importance of identifying substrates in order to more fully understand the signaling network of respective kinases, efficient methods to search for substrates remain poorly explored. METHODOLOGY/PRINCIPAL FINDINGS: We combined mass spectrometry and affinity column chromatography of the catalytic domain of protein kinases to screen potential substrates. Using the active catalytic fragment of Rho-kinase/ROCK/ROK as the model bait, we obtained about 300 interacting proteins from the rat brain cytosol fraction, which included the proteins previously reported as Rho-kinase substrates. Several novel interacting proteins, including doublecortin, were phosphorylated by Rho-kinase both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: This method would enable identification of novel specific substrates for kinases such as Rho-kinase with high sensitivity.

Bacterial Protein-Tyrosine Kinases

DEFF Research Database (Denmark)

Shi, Lei; Kobir, Ahasanul; Jers, Carsten

2010-01-01

in exopolysaccharide production, virulence, DNA metabolism, stress response and other key functions of the bacterial cell. BY-kinases act through autophosphorylation (mainly in exopolysaccharide production) and phosphorylation of other proteins, which have in most cases been shown to be activated by tyrosine......Bacteria and Eukarya share essentially the same family of protein-serine/threonine kinases, also known as the Hanks-type kinases. However, when it comes to protein-tyrosine phosphorylation, bacteria seem to have gone their own way. Bacterial protein-tyrosine kinases (BY-kinases) are bacterial...... and highlighted their importance in bacterial physiology. Having no orthologues in Eukarya, BY-kinases are receiving a growing attention from the biomedical field, since they represent a particularly promising target for anti-bacterial drug design....

Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.

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Daniel Thomas

Full Text Available The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K, promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting

Ibrutinib-A double-edge sword in cancer and autoimmune disorders.

Science.gov (United States)

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.

Simple preparation of thiol-ene particles in glycerol and surface functionalization by thiol-ene chemistry (TEC) and surface chain transfer free radical polymerization (SCT-FRP)

DEFF Research Database (Denmark)

Hoffmann, Christian; Chiaula, Valeria; Yu, Liyun

2018-01-01

functionalization of excess thiol groups via photochemical thiol-ene chemistry (TEC) resulting in a functional monolayer. In addition, surface chain transfer free radical polymerization (SCT-FRP) was used for the first time to introduce a thicker polymer layer on the particle surface. The application potential...

Low and Mid-Latitude Ionospheric Irregularities Studies Using TEC and Radio Scintillation Data from the CITRIS Radio Beacon Receiver in Low-Earth-Orbit

Science.gov (United States)

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.

Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.

Science.gov (United States)

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.

The Link between Protein Kinase CK2 and Atypical Kinase Rio1

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Konrad Kubiński

2017-02-01

Full Text Available The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors.

Regulation of Autophagy by Kinases

International Nuclear Information System (INIS)

Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

2011-01-01

Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets

Regulation of Autophagy by Kinases

Energy Technology Data Exchange (ETDEWEB)

Sridharan, Savitha; Jain, Kirti; Basu, Alakananda, E-mail: alakananda.basu@unthsc.edu [Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States)

2011-06-09

Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

Regulation of Autophagy by Kinases

Science.gov (United States)

Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

2011-01-01

Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets. PMID:24212825

Regulation of Autophagy by Kinases

Directory of Open Access Journals (Sweden)

Savitha Sridharan

2011-06-01

Full Text Available Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

Implementation of ESPRIT Algorithm on GPS TEC for Percussive Signatures of Earthquakes in Ionosphere

Science.gov (United States)

Kiran, Uday; Koteswara Rao, S.; Ramesh, K. S.

2017-01-01

As Global Positioning System is very effective mechanism to find out the disturbances in Ionosphere during the solar events. Spectral estimation of the ionospheric total electron content perturbations leads to better interpretation of their source mechanisms. Seismo-ionospheric perturbations of an earthquake occurred at 12th December 2013 was considered in the present work. Estimation of signal parameters via rotational in variance technique (ESPRIT) is implemented on the vertical total electron content data. It was clearly observed that during disturbance the power spectral density of the dominant frequency had reduced to -2.487 dB from 7.841 dB. The application of ESPRIT algorithm on seismic perturbations in GPS TEC has found the dominant frequency in the spectrum and new frequency present at the time of perturbations

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility

Science.gov (United States)

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.

Role of adiponectin/phosphatidylinositol 3-kinase/protein kinase B ...

African Journals Online (AJOL)

The adiponectin/phosphatidylinositol 3-kinase/protein kinase B (ADP/PI3k/Akt) signal transduction pathway has an important role in promoting cell survival. This study was designed to determine if the ADP/PI3K/Akt signaling pathway has a role in the mechanism of ischemia–reperfusion injury in vivo. Sprague–Dawley rats ...

Tyrosine kinases in rheumatoid arthritis

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Kobayashi Akiko

2011-08-01

Full Text Available Abstract Rheumatoid arthritis (RA is an inflammatory, polyarticular joint disease. A number of cellular responses are involved in the pathogenesis of rheumatoid arthritis, including activation of inflammatory cells and cytokine expression. The cellular responses involved in each of these processes depends on the specific signaling pathways that are activated; many of which include protein tyrosine kinases. These pathways include the mitogen-activated protein kinase pathway, Janus kinases/signal transducers and activators transcription pathway, spleen tyrosine kinase signaling, and the nuclear factor κ-light-chain-enhancer of activated B cells pathway. Many drugs are in development to target tyrosine kinases for the treatment of RA. Based on the number of recently published studies, this manuscript reviews the role of tyrosine kinases in the pathogenesis of RA and the potential role of kinase inhibitors as new therapeutic strategies of RA.

Thymidine kinases in archaea

DEFF Research Database (Denmark)

Clausen, A.R.; Matakos, A.; Sandrini, Michael

2006-01-01

Twenty-six fully sequenced archaeal genomes were searched for genes coding for putative deoxyribonucleoside kinases (dNKs). We identified only 5 human-like thymidine kinase 1 genes (TK1s) and none for non-TK1 kinases. Four TK1s were identified in the Euryarchaea and one was found in the Crenarcha...

Kinase impact assessment in the landscape of fusion genes that retain kinase domains: a pan-cancer study

Science.gov (United States)

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

Phosphorylation of varicella-zoster virus glycoprotein gpI by mammalian casein kinase II and casein kinase I

International Nuclear Information System (INIS)

Grose, C.; Jackson, W.; Traugh, J.A.

1989-01-01

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 in vitro assay containing [γ- 32 P]ATP. The same glycoprotein was phosphorylated when [ 32 P]GTP was substituted for [ 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

Receptor-interacting protein (RIP) kinase family

OpenAIRE

Zhang, Duanwu; Lin, Juan; Han, Jiahuai

2010-01-01

Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, incl...

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

Science.gov (United States)

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 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.

Protein phosphatases active on acetyl-CoA carboxylase phosphorylated by casein kinase I, casein kinase II and the cAMP-dependent protein kinase

International Nuclear Information System (INIS)

Witters, L.A.; Bacon, G.W.

1985-01-01

The protein phosphatases in rat liver cytosol, active on rat liver acetyl-CoA carboxylase (ACC) phosphorylated by casein kinase I, casein kinase II and the cAMP-dependent protein kinase, have been partially purified by anion-exchange and gel filtration chromatography. The major phosphatase activities against all three substrates copurify through fractionation and appear to be identical to protein phosphatases 2A1 and 2A2. No unique protein phosphatase active on 32 P-ACC phosphorylated by the casein kinases was identified

Receptor-interacting protein (RIP) kinase family

Science.gov (United States)

Zhang, Duanwu; Lin, Juan; Han, Jiahuai

2010-01-01

Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research. PMID:20383176

Tissue-Specific Ablation of Prkar1a Causes Schwannomas by Suppressing Neurofibromatosis Protein Production

Directory of Open Access Journals (Sweden)

Georgette N. Jones

2008-11-01

Full Text Available Signaling events leading to Schwann cell tumor initiation have been extensively characterized in the context of neurofibromatosis (NF. Similar tumors are also observed in patients with the endocrine neoplasia syndrome Carney complex, which results from inactivating mutations in PRKAR1A. Loss of PRKAR1A causes enhanced protein kinase A activity, although the pathways leading to tumorigenesis are not well characterized. Tissue-specific ablation of Prkar1a in neural crest precursor cells (TEC3KO mice causes schwannomas with nearly 80% penetrance by 10 months. These heterogeneous neoplasms were clinically characterized as genetically engineered mouse schwannomas, grades II and III. At the molecular level, analysis of the tumors revealed almost complete loss of both NF proteins, despite the fact that transcript levels were increased, implying posttranscriptional regulation. Although Erk and Akt signaling are typically enhanced in NF-associated tumors, we observed no activation of either of these pathways in TEC3KO tumors. Furthermore, the small G proteins Ras, Rac1, and RhoA are all known to be involved with NF signaling. In TEC3KO tumors, all three molecules showed modest increases in total protein, but only Rac1 showed significant activation. These data suggest that dysregulated protein kinase A activation causes tumorigenesis through pathways that overlap but are distinct from those described in NF tumorigenesis.

A comparative study of night-time enhancement of TEC at a low latitude station on storm and quiet nights including the local time, seasonal and solar activity dependence

Directory of Open Access Journals (Sweden)

K. Unnikrishnan

Full Text Available The main characteristics of night-time enhancements in TEC during magnetic storms are compared with those during quiet nights for different seasons and solar activity conditions at Palehua, a low latitude station during the period 1980–1989. We find that the mean amplitude has both a seasonal and solar activity dependence: in winter, the values are higher for weak storms as compared to those during quiet nights and increase with an increase in solar activity. In summer, the mean amplitude values during weak storms and quiet nights are almost equal. But during equinox, the mean amplitude values for quiet nights are greater than those during weak storms. The mean half-amplitude duration is higher during weak storms as compared to that during quiet nights in summer. However, during winter and equinox, the durations are almost equal for both quiet and weak storm nights. For the mean half-amplitude duration, the quiet night values for all the seasons and equinoctial weak storm values increase with an increase in solar activity. The occurrence frequency (in percent of TEC enhancement during weak storms is greater than during quiet nights for all seasons. The mean amplitude, the mean half-amplitude duration and the occurrence frequency (in percent of TEC enhancement values are higher during major storms as compared to those during quiet nights. The above parameters have their highest values during pre-midnight hours. From the data analysed, this behaviour is true in the case of major storms also.

Key words. Ionosphere (ionospheric disturbances; plasma convection Magnetospheric physics (storms and substorms

Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1)

DEFF Research Database (Denmark)

Dettori, Rosalia; Sonzogni, Silvina; Meyer, Lucas

2009-01-01

of numerous AGC kinases, including the protein kinase C-related protein kinases (PRKs). Here we studied the docking interaction between PDK1 and PRK2 and analyzed the mechanisms that regulate this interaction. In vivo labeling of recombinant PRK2 by (32)P(i) revealed phosphorylation at two sites......, the activation loop and the Z/TM in the C-terminal extension. We provide evidence that phosphorylation of the Z/TM site of PRK2 inhibits its interaction with PDK1. Our studies further provide a mechanistic model to explain different steps in the docking interaction and regulation. Interestingly, we found...... that the mechanism that negatively regulates the docking interaction of PRK2 to the upstream kinase PDK1 is directly linked to the activation mechanism of PRK2 itself. Finally, our results indicate that the mechanisms underlying the regulation of the interaction between PRK2 and PDK1 are specific for PRK2 and do...

Modulatory effects of cAMP and PKC activation on gap junctional intercellular communication among thymic epithelial cells

Directory of Open Access Journals (Sweden)

Neves-dos-Santos Sandra

2010-01-01

Full Text Available Abstract Background We investigated the effects of the signaling molecules, cyclic AMP (cAMP and protein-kinase C (PKC, on gap junctional intercellular communication (GJIC between thymic epithelial cells (TEC. Results Treatment with 8-Br-cAMP, a cAMP analog; or forskolin, which stimulates cAMP production, resulted in an increase in dye transfer between adjacent TEC, inducing a three-fold enhancement in the mean fluorescence of coupled cells, ascertained by flow cytometry after calcein transfer. These treatments also increased Cx43 mRNA expression, and stimulated Cx43 protein accumulation in regions of intercellular contacts. VIP, adenosine, and epinephrine which may also signal through cyclic nucleotides were tested. The first two molecules did not mimic the effects of 8-Br-cAMP, however epinephrine was able to increase GJIC suggesting that this molecule functions as an endogenous inter-TEC GJIC modulators. Stimulation of PKC by phorbol-myristate-acetate inhibited inter-TEC GJIC. Importantly, both the enhancing and the decreasing effects, respectively induced by cAMP and PKC, were observed in both mouse and human TEC preparations. Lastly, experiments using mouse thymocyte/TEC heterocellular co-cultures suggested that the presence of thymocytes does not affect the degree of inter-TEC GJIC. Conclusions Overall, our data indicate that cAMP and PKC intracellular pathways are involved in the homeostatic control of the gap junction-mediated communication in the thymic epithelium, exerting respectively a positive and negative role upon cell coupling. This control is phylogenetically conserved in the thymus, since it was seen in both mouse and human TEC preparations. Lastly, our work provides new clues for a better understanding of how the thymic epithelial network can work as a physiological syncytium.

GPS TEC Fluctuations in the Low and High Latitudes During the 2015 St. Patrick`s Day Storm

Science.gov (United States)

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

Sequence Classification: 890824 [

Lifescience Database Archive (English)

Full Text Available hyphal/invasive growth pathways; cooperates with Tec1p transcription factor to regulate genes specific for invasive growth; Ste12p || http://www.ncbi.nlm.nih.gov/protein/6321876 ... ...ion factor that is activated by a MAP kinase signaling cascade, activates genes involved in mating or pseudo

Purification and characterization of a casein kinase 2-type protein kinase from pea nuclei

Science.gov (United States)

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.

Cocoa Procyanidins Suppress Transformation by Inhibiting Mitogen-activated Protein Kinase Kinase*S⃞

Science.gov (United States)

Kang, Nam Joo; Lee, Ki Won; Lee, Dong Eun; Rogozin, Evgeny A.; Bode, Ann M.; Lee, Hyong Joo; Dong, Zigang

2008-01-01

Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit neoplastic cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 μg/ml and 40 μm, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-κB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 μm) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-κB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and neoplastic cell transformation. PMID:18519570

Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

Science.gov (United States)

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.

Src kinase regulation by phosphorylation and dephosphorylation

International Nuclear Information System (INIS)

Roskoski, Robert

2005-01-01

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, PTPα, PTPε, and PTPλ. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shown 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

The ATLAS tracker strip detector for HL-LHC

CERN Document Server

Cormier, Kyle James Read; The ATLAS collaboration

2016-01-01

As part of the ATLAS upgrades for the High Luminsotiy LHC (HL-LHC) the current ATLAS Inner Detector (ID) will be replaced by a new Inner Tracker (ITk). The ITk will consist of two main components: semi-conductor pixels at the innermost radii, and silicon strips covering larger radii out as far as the ATLAS solenoid magnet including the volume currently occupied by the ATLAS Transition Radiation Tracker (TRT). The primary challenges faced by the ITk are the higher planned read out rate of ATLAS, the high density of charged particles in HL-LHC conditions for which tracks need to be resolved, and the corresponding high radiation doses that the detector and electronics will receive. The ITk strips community is currently working on designing and testing all aspects of the sensors, readout, mechanics, cooling and integration to meet these goals and a Technical Design Report is being prepared. This talk is an overview of the strip detector component of the ITk, highlighting the current status and the road ahead.

The ATLAS tracker strip detector for HL-LHC

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00512833; The ATLAS collaboration

2017-01-01

As part of the ATLAS upgrades for the High Luminsotiy LHC (HL-LHC) the current ATLAS Inner Detector (ID) will be replaced by a new Inner Tracker (ITk). The ITk will consist of two main components: semi-conductor pixels at the innermost radii, and silicon strips covering larger radii out as far as the ATLAS solenoid magnet including the volume currently occupied by the ATLAS Transition Radiation Tracker (TRT). The primary challenges faced by the ITk are the higher planned read out rate of ATLAS, the high density of charged particles in HL-LHC conditions for which tracks need to be resolved, and the corresponding high radiation doses that the detector and electronics will receive. The ITk strips community is currently working on designing and testing all aspects of the sensors, readout, mechanics, cooling and integration to meet these goals and a Technical Design Report is being prepared. This talk is an overview of the strip detector component of the ITk, highlighting the current status and the road ahead.

Structure-function similarities between a plant receptor-like kinase and the human interleukin-1 receptor-associated kinase-4.

Science.gov (United States)

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.

HiTEC: a connectionist model of the interaction between perception and action planning.

Science.gov (United States)

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.

A rice kinase-protein interaction map.

Science.gov (United States)

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.

The spatio-temporal characteristics of the wave structure excited by the solar terminator as deduced from TEC measurements at the global GPS network

Science.gov (United States)

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

Chitin and stress induced protein kinase activation

DEFF Research Database (Denmark)

Kenchappa, Chandra Shekar; Azevedo da Silva, Raquel; Bressendorff, Simon

2017-01-01

The assays described here are pertinent to protein kinase studies in any plant. They include an immunoblot phosphorylation/activation assay and an in-gel activity assay for MAP kinases (MPKs) using the general protein kinase substrate myelin basic protein. They also include a novel in-gel peptide...... substrate assay for Snf1-related kinase family 2 members (SnRK2s). This kinase family-specific assay overcomes some limitations of in-gel assays and permits the identification of different types of kinase activities in total protein extracts....

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

KAUST Repository

Diaz Galicia, Miriam Escarlet

2018-01-01

is then translated into a FRET (Fluorescence Resonance Energy Transfer) signal is here proposed. To this end, DNA constructs for interaction amplification (split kinases), positive controls (intact kinase domains), scaffolding proteins and phosphopeptide - SH2-domain

Receptor Tyrosine Kinases in Drosophila Development

Science.gov (United States)

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

A cGMP kinase mutant with increased sensitivity to the protein kinase inhibitor peptide PKI(5-24).

Science.gov (United States)

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.

ROS and CDPK-like kinase-mediated activation of MAP kinase in rice roots exposed to lead.

Science.gov (United States)

Huang, Tsai-Lien; Huang, Hao-Jen

2008-04-01

Lead (Pb2+) is a cytotoxic metal ion in plants, the mechanism of which is not yet established. The aim of this study is to investigate the signalling pathways that are activated by elevated concentrations of Pb2+ in rice roots. Root growth was stunted and cell death was accelerated when exposed to different dosages of Pb2+ during extended time periods. Using ROS-sensitive dye and Ca2+ indicator, we demonstrated that Pb2+ induced ROS production and Ca2+ accumulation, respectively. In addition, Pb2+ elicited a remarkable increase in myelin basic protein (MBP) kinase activities. By immunoblot and immunoprecipitation analysis, 40- and 42-kDa MBP kinases that were activated by Pb2+ were identified to be mitogen-activated protein (MAP) kinases. Pre-treatment of rice roots with an antioxidant and a NADPH oxidase inhibitor, glutathione (GSH) and diphenylene iodonium (DPI), effectively reduced Pb2+-induced cell death and MAP kinase activation. Moreover, calcium-dependent protein kinase (CDPK) antagonist, W7, attenuated Pb2+-induced cell death and MAP kinase activation. These results suggested that the ROS and CDPK may function in the Pb2+-triggered cell death and MAP kinase signalling pathway in rice roots.

A screen for kinase inhibitors identifies antimicrobial imidazopyridine aminofurazans as specific inhibitors of the Listeria monocytogenes PASTA kinase PrkA.

Science.gov (United States)

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.

CIKS, a connection to Ikappa B kinase and stress-activated protein kinase.

Science.gov (United States)

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.

CIKS, a connection to IκB kinase and stress-activated protein kinase

Science.gov (United States)

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

Kinases Involved in Both Autophagy and Mitosis.

Science.gov (United States)

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.

Kinases Involved in Both Autophagy and Mitosis

Directory of Open Access Journals (Sweden)

Zhiyuan Li

2017-08-01

Full Text Available 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.

Partial purification and characterization of a wortmannin-sensitive and insulin-stimulated protein kinase that activates heart 6-phosphofructo-2-kinase.

OpenAIRE

Deprez, J; Bertrand, L; Alessi, D R; Krause, U; Hue, L; Rider, M H

2000-01-01

A wortmannin-sensitive and insulin-stimulated protein kinase (WISK), which phosphorylates and activates cardiac 6-phosphofructo-2-kinase (PFK-2), was partially purified from perfused rat hearts. Immunoblotting showed that WISK was devoid of protein kinase B (PKB), serum- and glucocorticoid-regulated protein kinase and protein kinase Czeta (PKCzeta). Comparison of the inhibition of WISK, PKCalpha and PKCzeta by different protein kinase inhibitors suggested that WISK was not a member of the PKC...

Distributions of TEC Fluctuations and Losses of Lock Associated with Equatorial Plasma Bubbles

Science.gov (United States)

Nakata, H.; Kikuchi, H.; Tsugawa, T.; Otsuka, Y.; Takano, T.; Shimakura, S.; Shiokawa, K.; Ogawa, T.

2009-12-01

Equatorial plasma bubbles (EPBs) are local depletions of the electron density in the ionosphere. Due to field-aligned irregularities (FAIs) with various spatial scales, EPBs affect wide-band radio waves and cause scintillations in GPS navigation system. Strong scintillation can cause a GPS receiver to lose lock on GPS signals because of rapid variations of signal amplitude and phase, and limit the availability of carrier phase measurements. Since the scintillation is caused by Fresnel diffraction, the spatial scale of FAIs that causes the scintillation of GPS signals is about 2-300 m. Therefore, loss of phase lock (LOL) on GPS signals is a reference of hundred-meter-scale FAIs. As EPBs are also associated with fluctuations of the total electron content (TEC), the enhancement of Rate of TEC change index (ROTI) occurs around EPBs. Assuming that the altitude of the ionosphere is about 400 km, the velocity of the pierce point of the GPS radio wave at the ionospheric altitude is approximately 70 m/s around the zenith. Thus, ROTI averaged during 5 minutes is a reference of ten-kilometer-scale fluctuations. In this study, we analyzed LOL and 5-min. ROTI associated with EPBs to examine the spatial and temporal scales of electron density disturbances associated with EPBs. We selected 11 EPBs from 630-nm airglow images obtained by all-sky imager at Sata, Japan, in 2001. LOL and ROTI are obtained from GPS data from GPS Earth Observation Network (GEONET) of Japan, which consists of more than 1000 GPS receivers. As a result, it is shown that both LOL and the enhancement of ROTI are observed in 8 events out of 11 events. The distributions of LOL are approximately consistent with the areas in which the ionospheric electron density is depleted. The enhancements of ROTI are observed in the vicinities of EPBs. The enhancement of ROTI expands especially in the west side of EPBs. After the EPBs pass through, therefore, LOLs are vanished but the enhancements of ROTI last a while. This

The Insight ToolKit Image Registration Framework

Directory of Open Access Journals (Sweden)

Brian eAvants

2014-04-01

Full Text Available 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 es- tablish new standards in publicly available image registration methodology. ITK4 makes severaladvances 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 com- posite 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 versus 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 tomore easily focus on design/comparison of registration strategies. In total, the ITK4 contribu- tion 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 contextu- alize this work with a reference registration evaluation study with application to pediatric brainlabeling.

Performance of silicon pixel detectors at small track incidence angles for the ATLAS Inner Tracker upgrade

Energy Technology Data Exchange (ETDEWEB)

Viel, Simon, E-mail: sviel@lbl.gov [Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley, CA, United States of America (United States); Banerjee, Swagato [Department of Physics, University of Wisconsin, Madison, WI, United States of America (United States); Brandt, Gerhard; Carney, Rebecca; Garcia-Sciveres, Maurice [Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley, CA, United States of America (United States); Hard, Andrew Straiton; Kaplan, Laser Seymour; Kashif, Lashkar [Department of Physics, University of Wisconsin, Madison, WI, United States of America (United States); Pranko, Aliaksandr [Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley, CA, United States of America (United States); Rieger, Julia [Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley, CA, United States of America (United States); II Physikalisches Institut, Georg-August-Universität, Göttingen (Germany); Wolf, Julian [Physics Division, Lawrence Berkeley National Laboratory and University of California, Berkeley, CA, United States of America (United States); Wu, Sau Lan; Yang, Hongtao [Department of Physics, University of Wisconsin, Madison, WI, United States of America (United States)

2016-09-21

In order to enable the ATLAS experiment to successfully track charged particles produced in high-energy collisions at the High-Luminosity Large Hadron Collider, the current ATLAS Inner Detector will be replaced by the Inner Tracker (ITk), entirely composed of silicon pixel and strip detectors. An extension of the tracking coverage of the ITk to very forward pseudorapidity values is proposed, using pixel modules placed in a long cylindrical layer around the beam pipe. The measurement of long pixel clusters, detected when charged particles cross the silicon sensor at small incidence angles, has potential to significantly improve the tracking efficiency, fake track rejection, and resolution of the ITk in the very forward region. The performance of state-of-the-art pixel modules at small track incidence angles is studied using test beam data collected at SLAC and CERN. - Highlights: • Extended inner pixel barrel layers are proposed for the ATLAS ITk upgrade. • Test beam results at small track incidence angles validate this ATLAS ITk design. • Long pixel clusters are reconstructed with high efficiency at low threshold values. • Excellent angular resolution is achieved using pixel cluster length information.

Performance of silicon pixel detectors at small track incidence angles for the ATLAS Inner Tracker upgrade

International Nuclear Information System (INIS)

Viel, Simon; Banerjee, Swagato; Brandt, Gerhard; Carney, Rebecca; Garcia-Sciveres, Maurice; Hard, Andrew Straiton; Kaplan, Laser Seymour; Kashif, Lashkar; Pranko, Aliaksandr; Rieger, Julia; Wolf, Julian; Wu, Sau Lan; Yang, Hongtao

2016-01-01

In order to enable the ATLAS experiment to successfully track charged particles produced in high-energy collisions at the High-Luminosity Large Hadron Collider, the current ATLAS Inner Detector will be replaced by the Inner Tracker (ITk), entirely composed of silicon pixel and strip detectors. An extension of the tracking coverage of the ITk to very forward pseudorapidity values is proposed, using pixel modules placed in a long cylindrical layer around the beam pipe. The measurement of long pixel clusters, detected when charged particles cross the silicon sensor at small incidence angles, has potential to significantly improve the tracking efficiency, fake track rejection, and resolution of the ITk in the very forward region. The performance of state-of-the-art pixel modules at small track incidence angles is studied using test beam data collected at SLAC and CERN. - Highlights: • Extended inner pixel barrel layers are proposed for the ATLAS ITk upgrade. • Test beam results at small track incidence angles validate this ATLAS ITk design. • Long pixel clusters are reconstructed with high efficiency at low threshold values. • Excellent angular resolution is achieved using pixel cluster length information.

Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids

Energy Technology Data Exchange (ETDEWEB)

Moravcevic, Katarina; Mendrola, Jeannine M.; Schmitz, Karl R.; Wang, Yu-Hsiu; Slochower, David; Janmey, Paul A.; Lemmon, Mark A. (UPENN-MED)

2011-09-28

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 importance 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.

SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1.

Science.gov (United States)

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.

The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling.

Science.gov (United States)

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.

A systematic evaluation of protein kinase a-a-kinase anchoring protein interaction motifs

NARCIS (Netherlands)

Burgers, Pepijn P|info:eu-repo/dai/nl/341566551; van der Heyden, Marcel A G; Kok, Bart; Heck, Albert J R|info:eu-repo/dai/nl/105189332; Scholten, Arjen|info:eu-repo/dai/nl/313939780

2015-01-01

Protein kinase A (PKA) in vertebrates is localized to specific locations in the cell via A-kinase anchoring proteins (AKAPs). The regulatory subunits of the four PKA isoforms (RIα, RIβ, RIIα, and RIIβ) each form a homodimer, and their dimerization domain interacts with a small helical region present

A systematic evaluation of protein kinase A-A-kinase anchoring protein interaction motifs

NARCIS (Netherlands)

Burgers, Pepijn P; van der Heyden, MAG; Kok, Bart; Heck, Albert J R; Scholten, Arjen

2015-01-01

Protein kinase A (PKA) in vertebrates is localized to specific locations in the cell via A-kinase anchoring proteins (AKAPs). The regulatory subunits of the four PKA isoforms (RIα, RIβ, RIIα, and RIIβ) each form a homodimer, and their dimerization domain interacts with a small helical region present

Phosphorylation of nm23/nucleoside diphosphate kinase by casein kinase 2 in vitro

DEFF Research Database (Denmark)

Engel, M; Issinger, O G; Lascu, I

1994-01-01

We have investigated phosphorylation of human nucleoside diphosphate kinase (NDPK) and of homologous NDPK from different species by human casein kinase 2 (CK-2). The human NDPK isotypes A and B were phosphorylated by CK-2 in vitro both when the purified proteins and total lysate of HL-60 leukemia...

Optical power of VCSELs stabilized to 35 ppm/°C without a TEC

Science.gov (United States)

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.

Enterococcus faecalis phosphomevalonate kinase

Science.gov (United States)

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

Muscle phosphorylase kinase deficiency

DEFF Research Database (Denmark)

Preisler, N; Orngreen, M C; Echaniz-Laguna, A

2012-01-01

To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).......To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD)....

Peptide substrates for Rho-associated kinase 2 (Rho-kinase 2/ROCK2.

Directory of Open Access Journals (Sweden)

Jeong-Hun Kang

Full Text Available Peptide substrates sensitive for a certain protein kinase could be important for new-drug development and to understand the mechanism of diseases. Rho-associated kinase (Rho-kinase/ROCK is a serine/threonine kinase, and plays an important part in cardiovascular disease, migration and invasion of tumor cells, and in neurological disorders. The purpose of this study was to find substrates with high affinity and sensitivity for ROCK2. We synthesized 136 peptide substrates from protein substrates for ROCK2 with different lengths and charged peptides. Incorporation of (32P [counts per minute (CPM] for each peptide substrate was determined by the radiolabel assay using [γ-(32P]ATP. When the top five peptide substrates showing high CPMs (R4, R22, R133, R134, and R135 were phosphorylated by other enzymes (PKA, PKCα, and ERK1, R22, R133, and R135 displayed the highest CPM level for ROCK2 compared with other enzymes, whereas R4 and R134 showed similar CPM levels for ROCK2 and PKCα. We hypothesize that R22, R133, and R135 can be useful peptide substrates for ROCK2.

dependent/calmodulin- stimulated protein kinase from moss

Indian Academy of Sciences (India)

Unknown

stimulated protein kinase; CDPK, calmodulin domain-like protein kinase; KM14, 14 amino acid synthetic peptide; .... used were obtained from Sigma Chemical Company, USA, ..... Plant chimeric Ca2+/Calmodulin-dependent protein kinase.

The Pim kinases: new targets for drug development.

Science.gov (United States)

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.

Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.

Science.gov (United States)

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.

Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring

Czech Academy of Sciences Publication Activity Database

Andrs, M.; Kobarecny, J.; Jun, D.; Hodný, Zdeněk; Bartek, Jiří; Kuca, K.

2015-01-01

Roč. 58, č. 1 (2015), s. 41-71 ISSN 0022-2623 R&D Projects: GA MŠk(CZ) CZ.1.07/2.3.00/30.0044 Grant - others:University Hospital Hradec Kralove(CZ) 00179906; Faculty of Military Health Sciences, University of Defence(CZ) SV/FVZ201402 Institutional support: RVO:68378050 Keywords : DEPENDENT PROTEIN-KINASE * STRAND BREAK REPAIR * SELECTIVE PI3K-BETA INHIBITORS * TELANGIECTASIA MUTATED KINASE Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.589, year: 2015

Discovery of 8-Amino-imidazo[1,5- a ]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis

Energy Technology Data Exchange (ETDEWEB)

Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; Gao, Xiaolei; Wang, James; Boga, Sobhana Babu; Alhassan, Abdul-Basit; Yu, Younong; Vaccaro, Henry; Liu, Shilan; Yang, Chundao; Wu, Hao; Cooper, Alan; de Man, Jos; Kaptein, Allard; Maloney, Kevin; Hornak, Viktor; Gao, Ying-Duo; Fischmann, Thierry O.; Raaijmakers, Hans; Vu-Pham, Diep; Presland, Jeremy; Mansueto, My; Xu, Zangwei; Leccese, Erica; Zhang-Hoover, Jie; Knemeyer, Ian; Garlisi, Charles G.; Bays, Nathan; Stivers, Peter; Brandish, Philip E.; Hicks, Alexandra; Kim, Ronald; Kozlowski, Joseph A. (Merck); (WuXi App Tec)

2016-02-11

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-ray 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.

Casein kinase II protein kinase is bound to lamina-matrix and phosphorylates lamin-like protein in isolated pea nuclei

Science.gov (United States)

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.

Contractions activate hormone-sensitive lipase in rat muscle by protein kinase C and mitogen-activated protein kinase

DEFF Research Database (Denmark)

Donsmark, Morten; Langfort, Jozef; Holm, Cecilia

2003-01-01

and contractions. Adrenaline acts via cAMP-dependent protein kinase (PKA). The signalling mediating the effect of contractions is unknown and was explored in this study. Incubated soleus muscles from 70 g male rats were electrically stimulated to perform repeated tetanic contractions for 5 min. The contraction......Intramuscular triacylglycerol is an important energy store and is also related to insulin resistance. The mobilization of fatty acids from this pool is probably regulated by hormone-sensitive lipase (HSL), which has recently been shown to exist in muscle and to be activated by both adrenaline......-induced activation of HSL was abolished by the protein kinase C (PKC) inhibitors bisindolylmaleimide I and calphostin C and reduced 50% by the mitogen-activated protein kinase kinase (MEK) inhibitor U0126, which also completely blocked extracellular signal-regulated kinase (ERK) 1 and 2 phosphorylation. None...

Protocols for the Design of Kinase-focused Compound Libraries.

Science.gov (United States)

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.

Myosin light chain kinase phosphorylation in tracheal smooth muscle

International Nuclear Information System (INIS)

Stull, J.T.; Hsu, L.C.; Tansey, M.G.; Kamm, K.E.

1990-01-01

Purified myosin light chain kinase from smooth muscle is phosphorylated by cyclic AMP-dependent protein kinase, protein kinase C, and the multifunctional calmodulin-dependent protein kinase II. Because phosphorylation in a specific site (site A) by any one of these kinases desensitizes myosin light chain kinase to activation by Ca2+/calmodulin, kinase phosphorylation could play an important role in regulating smooth muscle contractility. This possibility was investigated in 32 P-labeled bovine tracheal smooth muscle. Treatment of tissues with carbachol, KCl, isoproterenol, or phorbol 12,13-dibutyrate increased the extent of kinase phosphorylation. Six primary phosphopeptides (A-F) of myosin light chain kinase were identified. Site A was phosphorylated to an appreciable extent only with carbachol or KCl, agents which contract tracheal smooth muscle. The extent of site A phosphorylation correlated to increases in the concentration of Ca2+/calmodulin required for activation. These results show that cyclic AMP-dependent protein kinase and protein kinase C do not affect smooth muscle contractility by phosphorylating site A in myosin light chain kinase. It is proposed that phosphorylation of myosin light chain kinase in site A in contracting tracheal smooth muscle may play a role in the reported desensitization of contractile elements to activation by Ca2+

Mediator kinase module and human tumorigenesis.

Science.gov (United States)

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.

A framework for classification of prokaryotic protein kinases.

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Nidhi Tyagi

Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSION/SIGNIFICANCE: 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

The PIM kinases in hematological cancers.

Science.gov (United States)

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.

GPS-TEC Observation of Gravity Waves Generated in the Ionosphere During 21 August 2017 Total Solar Eclipse

Science.gov (United States)

Nayak, Chinmaya; Yiǧit, Erdal

2018-01-01

The present work investigates ionospheric effects of the 21 August 2017 total solar eclipse, particularly targeting eclipse-generated gravity waves in the ionosphere. Ionospheric total electron content (TEC) derived from Global Positioning System (GPS) data obtained from a number of stations located both along and across the path of eclipse totality has been utilized for this purpose. Distinct gravity wave-like signatures with wave periods around 20-90 min (with dominant peak at 25-30 min wave period) have been observed at all locations both in the path of totality and away from it. The observed gravity waves are more intense at locations closer to the path of totality, and the wave amplitudes decrease gradually with increasing distance from the path of totality. Our result highlights the manifestation of eclipse-generated waves in the variability of the terrestrial ionosphere.

Measuring Kinase Activity-A Global Challenge.

Science.gov (United States)

Cann, Marissa L; McDonald, Ian M; East, Michael P; Johnson, Gary L; Graves, Lee M

2017-11-01

The kinase enzymes within a cell, known collectively as the kinome, play crucial roles in many signaling pathways, including survival, motility, differentiation, stress response, and many more. Aberrant signaling through kinase pathways is often linked to cancer, among other diseases. A major area of scientific research involves understanding the relationships between kinases, their targets, and how the kinome adapts to perturbations of the cellular system. This review will discuss many of the current and developing methods for studying kinase activity, and evaluate their applications, advantages, and disadvantages. J. Cell. Biochem. 118: 3595-3606, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

Science.gov (United States)

Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

2011-02-10

Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

The NDR kinase scaffold HYM1/MO25 is essential for MAK2 map kinase signaling in Neurospora crassa.

Directory of Open Access Journals (Sweden)

Anne Dettmann

2012-09-01

Full Text Available Cell communication is essential for eukaryotic development, but our knowledge of molecules and mechanisms required for intercellular communication is fragmentary. In particular, the connection between signal sensing and regulation of cell polarity is poorly understood. In the filamentous ascomycete Neurospora crassa, germinating spores mutually attract each other and subsequently fuse. During these tropic interactions, the two communicating cells rapidly alternate between two different physiological states, probably associated with signal delivery and response. The MAK2 MAP kinase cascade mediates cell-cell signaling. Here, we show that the conserved scaffolding protein HYM1/MO25 controls the cell shape-regulating NDR kinase module as well as the signal-receiving MAP kinase cascade. HYM1 functions as an integral part of the COT1 NDR kinase complex to regulate the interaction with its upstream kinase POD6 and thereby COT1 activity. In addition, HYM1 interacts with NRC1, MEK2, and MAK2, the three kinases of the MAK2 MAP kinase cascade, and co-localizes with MAK2 at the apex of growing cells. During cell fusion, the three kinases of the MAP kinase module as well as HYM1 are recruited to the point of cell-cell contact. hym-1 mutants phenocopy all defects observed for MAK2 pathway mutants by abolishing MAK2 activity. An NRC1-MEK2 fusion protein reconstitutes MAK2 signaling in hym-1, while constitutive activation of NRC1 and MEK2 does not. These data identify HYM1 as a novel regulator of the NRC1-MEK2-MAK2 pathway, which may coordinate NDR and MAP kinase signaling during cell polarity and intercellular communication.

Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption

DEFF Research Database (Denmark)

Beck, Halfdan; Nähse-Kumpf, Viola; Larsen, Marie Sofie Yoo

2012-01-01

Activation of oncogenes or inhibition of WEE1 kinase deregulates Cyclin-dependent kinase (CDK) activity and leads to replication stress, however, the underlying mechanism is not understood. We now show that elevation of CDK activity by inhibiting WEE1 kinase rapidly increases initiation of replic......Activation of oncogenes or inhibition of WEE1 kinase deregulates Cyclin-dependent kinase (CDK) activity and leads to replication stress, however, the underlying mechanism is not understood. We now show that elevation of CDK activity by inhibiting WEE1 kinase rapidly increases initiation...... of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted...

Src protein-tyrosine kinase structure and regulation

International Nuclear Information System (INIS)

Roskoski, Robert

2004-01-01

Src and Src-family protein kinases are proto-oncogenes that play key roles in cell morphology, motility, proliferation, and survival. v-Src (a viral protein) is encoded by the chicken oncogene of Rous sarcoma virus, and Src (the cellular homologue) is encoded by a physiological gene, the first of the proto-oncogenes. From the N- to C-terminus, Src contains an N-terminal 14-carbon myristoyl group, a unique segment, an SH3 domain, an SH2 domain, a protein-tyrosine kinase domain, and a C-terminal regulatory tail. The chief phosphorylation sites of Src include tyrosine 416 that results in activation from autophosphorylation and tyrosine 527 that results in inhibition from phosphorylation by C-terminal Src kinase. In the restrained state, the SH2 domain forms a salt bridge with phosphotyrosine 527, and the SH3 domain binds to the kinase domain via a polyproline type II left-handed helix. The SH2 and SH3 domains occur on the backside of the kinase domain away from the active site where they stabilize a dormant enzyme conformation. Protein-tyrosine phosphatases such as PTPα displace phosphotyrosine 527 from the Src SH2 domain and mediate its dephosphorylation leading to Src kinase activation. C-terminal Src kinase consists of an SH3, SH2, and kinase domain; it lacks an N-terminal myristoyl group and a C-terminal regulatory tail. Its X-ray structure has been determined, and the SH2 lobe occupies a position that is entirely different from that of Src. Unlike Src, the C-terminal Src kinase SH2 and SH3 domains stabilize an active enzyme conformation. Amino acid residues in the αD helix near the catalytic loop in the large lobe of C-terminal Src kinase serve as a docking site for the physiological substrate (Src) but not for an artificial substrate (polyGlu 4 Tyr)

Strip detector for the ATLAS detector upgrade for the High-Luminosity LHC

CERN Document Server

Veloce, Laurelle Maria; The ATLAS collaboration

2017-01-01

The ATLAS experiment is currently preparing for an upgrade of the tracking system in the course of the High Luminosity LHC, scheduled for 2025. The expected radiation damage at an integrated luminosity of 3000fb-1 will require the tracking detectors to withstand hadron fluencies to over 1x1016 1 MeV neutron equivalent per cm2. With the addition of increased readout rates, the existing Inner Detector will have to be replaced by an all-silicon Inner Tracker (ITk) with a pixel detector surrounded by a strip detector. The ITk strip detector consists of a four-layer barrel and a forward region composed of six discs on each side of the barrel. The current prototyping phase has resulted in the ITk Strip Detector Technical Design Report (TDR), which starts the pre-production readiness phase at the involved institutes. In this contribution we present the design of the ITk Strip Detector and current status of R&D of various detector components.

Radioimmunoassay of bovine heart protein kinase

International Nuclear Information System (INIS)

Fleischer, N.; Rosen, O.M.; Reichlin, M.

1976-01-01

Immunization of guinea pigs with bovine cardiac cAMP-dependent protein kinase (ATP : protein phosphotransferase, EC 2.7.1.37) resulted in the development of precipitating antibodies to the cAMP-binding subunit of the enzyme. Both the phosphorylated and nonphosphorylated cAMP-binding protein of the protein kinase reacted with the antiserum. A radioimmunoassay was developed that detects 10 ng of holoenzyme and permits measurement of enzyme concentrations in bovine cardiac muscle. Bovine liver, kidney, brain, and skeletal muscle contain protein kinases which are immunologically identical to those found in bovine cardiac muscle. However, the proportion of immunoreactive enzyme activity differed for each tissue. All of the immunologically nonreactive enzyme in skeletal muscle and heart was separable from immunoreactive enzyme by chromatography on DEAE-cellulose. Rat tissues and pig heart contained protein kinase activity that cross reacted immunologically in a nonparallel fashion with bovine cardiac enzyme. These results indicate that cAMP-dependent protein kinases within and between species are immunologically heterogeneous

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

Science.gov (United States)

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

2016-01-01

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

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

Science.gov (United States)

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

2016-04-15

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

Protein kinase inhibitor peptide (PKI): a family of endogenous neuropeptides that modulate neuronal cAMP-dependent protein kinase function.

Science.gov (United States)

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

CZK3, a MAP kinase kinase kinase homolog in Cercospora zeae-maydis, regulates cercosporin biosynthesis, fungal development, and pathogenesis.

Science.gov (United States)

Shim, Won-Bo; Dunkle, Larry D

2003-09-01

The fungus Cercospora zeae-maydis causes gray leaf spot of maize and produces cercosporin, a photosensitizing perylenequinone with toxic activity against a broad spectrum of organisms. However, little is known about the biosynthetic pathway or factors that regulate cercosporin production. Analysis of a cDNA subtraction library comprised of genes that are up-regulated during cercosporin synthesis revealed a sequence highly similar to mitogen-activated protein (MAP) kinases in other fungi. Sequencing and conceptual translation of the full-length genomic sequence indicated that the gene, which we designated CZK3, contains a 4,119-bp open reading frame devoid of introns and encodes a 1,373-amino acid sequence that is highly similar to Wis4, a MAP kinase kinase kinase in Schizosaccharomyces pombe. Targeted disruption of CZK3 suppressed expression of genes predicted to participate in cercosporin biosynthesis and abolished cercosporin production. The disrupted mutants grew faster on agar media than the wild type but were deficient in conidiation and elicited only small chlorotic spots on inoculated maize leaves compared with rectangular necrotic lesions incited by the wild type. Complementation of disruptants with the CZK3 open reading frame and flanking sequences restored wild-type levels of conidiation, growth rate, and virulence as well as the ability to produce cercosporin. The results suggest that cercosporin is a virulence factor in C. zeae-maydis during maize pathogenesis, but the pleiotropic effects of CZK3 disruption precluded definitive conclusions.

The role of the C8 proton of ATP in the catalysis of shikimate kinase and adenylate kinase

Directory of Open Access Journals (Sweden)

Kenyon Colin P

2012-08-01

Full Text Available Abstract 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

Fibronectin phosphorylation by ecto-protein kinase

International Nuclear Information System (INIS)

Imada, Sumi; Sugiyama, Yayoi; Imada, Masaru

1988-01-01

The presence of membrane-associated, extracellular protein kinase (ecto-protein kinase) and its substrate proteins was examined with serum-free cultures of Swiss 3T3 fibroblast. When cells were incubated with [γ- 32 ]ATP for 10 min at 37 degree C, four proteins with apparent molecular weights between 150 and 220 kDa were prominently phosphorylated. These proteins were also radiolabeled by lactoperoxidase catalyzed iodination and were sensitive to mild tryptic digestion, suggesting that they localized on the cell surface or in the extracellular matrix. Phosphorylation of extracellular proteins with [γ- 32 P]ATP in intact cell culture is consistent with the existence of ecto-protein kinase. Anti-fibronectin antibody immunoprecipitated one of the phosphoproteins which comigrated with a monomer and a dimer form of fibronectin under reducing and nonreducing conditions of electrophoresis, respectively. The protein had affinity for gelatin as demonstrated by retention with gelatin-conjugated agarose. This protein substrate of ecto-protein kinase was thus concluded to be fibronectin. The sites of phosphorylation by ecto-protein kinase were compared with those of intracellularly phosphorylated fibronectin by the analysis of radiolabeled amino acids and peptides. Ecto-protein kinase phosphorylated fibronectin at serine and threonine residues which were distinct from the sites of intracellular fibronectin phosphorylation

Protein kinase CK2 in human diseases

DEFF Research Database (Denmark)

Guerra, Barbara; Issinger, Olaf-Georg

2008-01-01

Protein kinase CK2 (formerly referred to as casein kinase II) is an evolutionary conserved, ubiquitous protein kinase. There are two paralog catalytic subunits, i.e. alpha (A1) and alpha' (A2). The alpha and alpha' subunits are linked to two beta subunits to produce a heterotetrameric structure...

Phosphorylation of sites 3 and 2 in rabbit skeletal muscle glycogen synthase by a multifunctional protein kinase (ATP-citrate lyase kinase)

International Nuclear Information System (INIS)

Sheorain, V.S.; Ramakrishna, S.; Benjamin, W.B.; Soderling, T.R.

1985-01-01

A multifunctional protein kinase, purified from rat liver as ATP-citrate lyase kinase, has been identified as a glycogen synthase kinase. This kinase catalyzed incorporation of up to 1.5 mol of and]2number 2 PO 4 /mol of synthase subunit associated with a decrease in the glycogen synthase activity ratio from 0.85 to a value of 0.15. Approximately 65-70% of the 34 PO 4 was incorporated into site 3 and 30-35% into site 2 as determined by reverse phase high performance liquid chromatography. This multifunctional kinase was distinguished from glycogen synthase kinase-3 on the basis of nucleotide and protein substrate specificities. Since the phosphate contents in glycogen synthase of sites 3 and 2 are altered in diabetes and by insulin administration, the possible involvement of the multifunctional kinase was explored. Glycogen synthase purified from diabetic rabbits was phosphorylated in vitro by this multifunctional kinase at only 10% of the rate compared to synthase purified from control rabbits. Treatment of the diabetics with insulin restored the synthase to a form that was readily phosphorylated in vitro

A casein-kinase-2-related protein kinase is tightly associated with the large T antigen of simian virus 40

DEFF Research Database (Denmark)

Götz, C; Koenig, M G; Issinger, O G

1995-01-01

by the addition of protein kinase CK2 suggest that at least one of the T-antigen-associated protein kinases is CK2 or a protein-kinase-CK2-related enzyme. The association of recombinant CK2 with T antigen was strongly confirmed by in vitro binding studies. Experiments with temperature-sensitive SV40-transformed......The simian virus 40 (SV40) large T antigen is a multifunctional protein involved in SV40 cell transformation and lytic virus infection. Some of its activities are regulated by interaction with cellular proteins and/or by phosphorylation of T antigen by various protein kinases. In this study, we...... show that immuno-purified T antigen from SV40-transformed cells and from baculovirus-infected insect cells is tightly associated with a protein kinase that phosphorylates T antigen in vitro. In the presence of heparin or a peptide resembling a protein kinase CK2 recognition site, the phosphorylation...

Exceptional disfavor for proline at the P + 1 position among AGC and CAMK kinases establishes reciprocal specificity between them and the proline-directed kinases.

Science.gov (United States)

Zhu, Guozhi; Fujii, Koichi; Belkina, Natalya; Liu, Yin; James, Michael; Herrero, Juan; Shaw, Stephen

2005-03-18

To precisely regulate critical signaling pathways, two kinases that phosphorylate distinct sites on the same protein substrate must have mutually exclusive specificity. Evolution could assure this by designing families of kinase such as basophilic kinases and proline-directed kinase with distinct peptide specificity; their reciprocal peptide specificity would have to be very complete, since recruitment of substrate allows phosphorylation of even rather poor phosphorylation sites in a protein. Here we report a powerful evolutionary strategy that assures distinct substrates for basophilic kinases (PKA, PKG and PKC (AGC) and calmodulin-dependent protein kinase (CAMK)) and proline-directed kinase, namely by the presence or absence of proline at the P + 1 position in substrates. Analysis of degenerate and non-degenerate peptides by in vitro kinase assays reveals that proline at the P + 1 position in substrates functions as a "veto" residue in substrate recognition by AGC and CAMK kinases. Furthermore, analysis of reported substrates of two typical basophilic kinases, protein kinase C and protein kinase A, shows the lowest occurrence of proline at the P + 1 position. Analysis of crystal structures and sequence conservation provides a molecular basis for this disfavor and illustrate its generality.

Structure of the intact ATM/Tel1 kinase

Science.gov (United States)

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.

Factores que inciden en la evaluación del desempeño docente por los alumnos de nivel superior en la Universidad TecMilenio, campus Ciudad Juárez

Directory of Open Access Journals (Sweden)

Pablo Ayala Hernández

2013-01-01

Full Text Available La evaluación educativa es un proceso sistemático y continuo que considera diversos aspectos del contexto educativo y permite a las instituciones educativas obtener información acerca del aprendizaje de los alumnos, el proceso de enseñanza-aprendizaje, el currículo y la propia institución. La Universidad TecMilenio, al igual que otras instituciones educativas, busca responder a las necesidades educativas que demanda la época actual, a través de un modelo de educación centrado en el alumno que desarrolle su habilidad de autoaprendizaje, reflexión y adaptación a un mundo cambiante y competitivo. Para ello su proyecto educativo se basa en la filosofía constructivista, el presente trabajo de investigación demuestra los factores que intervienen en el proceso de evaluación educativo en el la Universidad TecMilenio mediante un estudio cualitativo, todo con la finalidad de encontrar los sesgos más importantes en la encuesta ECOA y finalmente, que el estudio realizado pueda explotar un cambio en los procesos de evaluación docente en la UTM.

Hybrid and rogue kinases encoded in the genomes of model eukaryotes.

Directory of Open Access Journals (Sweden)

Ramaswamy Rakshambikai

Full Text Available 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.

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

International Nuclear Information System (INIS)

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

2008-01-01

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

Comparative Molecular Dynamics Simulations of Mitogen-Activated Protein Kinase-Activated Protein Kinase 5

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Inger Lindin

2014-03-01

Full Text Available 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.

Non-degradative Ubiquitination of Protein Kinases.

Directory of Open Access Journals (Sweden)

K Aurelia Ball

2016-06-01

Full Text Available 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.

The secret life of kinases: functions beyond catalysis.

LENUS (Irish Health Repository)

Rauch, Jens

2011-10-28

Abstract Protein phosphorylation participates in the regulation of all fundamental biological processes, and protein kinases have been intensively studied. However, while the focus was on catalytic activities, accumulating evidence suggests that non-catalytic properties of protein kinases are essential, and in some cases even sufficient for their functions. These non-catalytic functions include the scaffolding of protein complexes, the competition for protein interactions, allosteric effects on other enzymes, subcellular targeting, and DNA binding. This rich repertoire often is used to coordinate phosphorylation events and enhance the specificity of substrate phosphorylation, but also can adopt functions that do not rely on kinase activity. Here, we discuss such kinase independent functions of protein and lipid kinases focussing on kinases that play a role in the regulation of cell proliferation, differentiation, apoptosis, and motility.

How protein kinases co-ordinate mitosis in animal cells.

Science.gov (United States)

Ma, Hoi Tang; Poon, Randy Y C

2011-04-01

Mitosis is associated with profound changes in cell physiology and a spectacular surge in protein phosphorylation. To accomplish these, a remarkably large portion of the kinome is involved in the process. In the present review, we will focus on classic mitotic kinases, such as cyclin-dependent kinases, Polo-like kinases and Aurora kinases, as well as more recently characterized players such as NIMA (never in mitosis in Aspergillus nidulans)-related kinases, Greatwall and Haspin. Together, these kinases co-ordinate the proper timing and fidelity of processes including centrosomal functions, spindle assembly and microtubule-kinetochore attachment, as well as sister chromatid separation and cytokinesis. A recurrent theme of the mitotic kinase network is the prevalence of elaborated feedback loops that ensure bistable conditions. Sequential phosphorylation and priming phosphorylation on substrates are also frequently employed. Another important concept is the role of scaffolds, such as centrosomes for protein kinases during mitosis. Elucidating the entire repertoire of mitotic kinases, their functions, regulation and interactions is critical for our understanding of normal cell growth and in diseases such as cancers.

Creatine kinase and creatine kinase subunit-B in coronary sinus blood in pacing-induced angina pectoris

DEFF Research Database (Denmark)

Bagger, J P; Ingerslev, J; Heinsvig, E M

1982-01-01

In nine out of 10 patients with angiographic documented coronary artery disease, pacing-induced angina pectoris provoked myocardial production of lactate, whereas no significant release of either creatine kinase or creatine kinase subunit-B to coronary sinus and peripheral venous blood could...

Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways

Science.gov (United States)

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

Calcium-dependent but calmodulin-independent protein kinase from soybean

International Nuclear Information System (INIS)

Harmon, A.C.; Putnam-Evans, C.; Cormier, M.J.

1987-01-01

A calcium-dependent protein kinase activity from suspension-cultured soybean cells (Glycine max L. Wayne) was shown to be dependent on calcium but not calmodulin. The concentrations of free calcium required for half-maximal histone H1 phosphorylation and autophosphorylation were similar (≥ 2 micromolar). The protein kinase activity was stimulated 100-fold by ≥ 10 micromolar-free calcium. When exogenous soybean or bovine brain calmodulin was added in high concentration (1 micromolar) to the purified kinase, calcium-dependent and -independent activities were weakly stimulated (≤ 2-fold). Bovine serum albumin had a similar effect on both activities. The kinase was separated from a small amount of contaminating calmodulin by sodium dodecyl sulfate polyacrylamide gel electrophoresis. After renaturation the protein kinase autophosphorylated and phosphorylated histone H1 in a calcium-dependent manner. Following electroblotting onto nitrocellulose, the kinase bound 45 Ca 2+ in the presence of KCl and MgCl 2 , which indicated that the kinase itself is a high-affinity calcium-binding protein. Also, the mobility of one of two kinase bands in SDS gels was dependent on the presence of calcium. Autophosphorylation of the calmodulin-free kinase was inhibited by the calmodulin-binding compound N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), showing that the inhibition of activity by W-7 is independent of calmodulin. These results show that soybean calcium-dependent protein kinase represents a new class of protein kinase which requires calcium but not calmodulin for activity

Protein kinase CK2 in health and disease: Protein kinase CK2: from structures to insights

DEFF Research Database (Denmark)

Niefind, K; Raaf, J; Issinger, Olaf-Georg

2009-01-01

the critical region of CK2alpha recruitment is pre-formed in the unbound state. In CK2alpha the activation segment - a key element of protein kinase regulation - adapts invariably the typical conformation of the active enzymes. Recent structures of human CK2alpha revealed a surprising plasticity in the ATP......Within the last decade, 40 crystal structures corresponding to protein kinase CK2 (former name 'casein kinase 2'), to its catalytic subunit CK2alpha and to its regulatory subunit CK2beta were published. Together they provide a valuable, yet by far not complete basis to rationalize the biochemical...

Pea DNA topoisomerase I is phosphorylated and stimulated by casein kinase 2 and protein kinase C.

Science.gov (United States)

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.

Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283.

Science.gov (United States)

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.

Field trial of efficacy of the Leish-tec® vaccine against canine leishmaniasis caused by Leishmania infantum in an endemic area with high transmission rates.

Directory of Open Access Journals (Sweden)

Gabriel Grimaldi

Full Text Available 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

From Phosphosites to Kinases

DEFF Research Database (Denmark)

Munk, Stephanie; Refsgaard, Jan C; Olsen, Jesper V

2016-01-01

Kinases play a pivotal role in propagating the phosphorylation-mediated signaling networks in living cells. With the overwhelming quantities of phosphoproteomics data being generated, the number of identified phosphorylation sites (phosphosites) is ever increasing. Often, proteomics investigations...... sequence motifs, mostly based on large scale in vivo and in vitro experiments. The context of the kinase and the phosphorylated proteins in a biological system is equally important for predicting association between the enzymes and substrates, an aspect that is also being tackled with available...

ATLAS Pixel Detector Design For HL-LHC

CERN Document Server

Smart, Ben; The ATLAS collaboration

2016-01-01

The ATLAS Inner Detector will be replaced for the High-Luminosity LHC (HL-LHC) running in 2026. The new Inner Detector will be called the Inner Tracker (ITk). The ITk will cover an extended eta-range: at least to |eta|<3.2, and likely up to |eta|<4.0. The ITk will be an all-Silicon based detector, consisting of a Silicon strip detector outside of a radius of 362mm, and a Silicon pixel detector inside of this radius. Several novel designs are being considered for the ITk pixel detector, to cope with high-eta charged particle tracks. These designs are grouped into 'extended' and 'inclined' design-types. Extended designs have long pixel staves with sensors parallel to the beamline. High-eta particles will therefore hit these sensors at shallow angles, leaving elongated charge clusters. The length of such a charge cluster can be used to estimate the angle of the passing particle. This information can then be used in track reconstruction to improve tracking efficiency and reduce fake rates. Inclined designs ...

Ribosomal S6 Kinase Cooperates with Casein Kinase 2 to Modulate the Drosophila Circadian Molecular Oscillator

Science.gov (United States)

Akten, Bikem; Tangredi, Michelle M.; Jauch, Eike; Roberts, Mary A.; Ng, Fanny; Raabe, Thomas; Jackson, F. Rob

2009-01-01

There is a universal requirement for post-translational regulatory mechanisms in circadian clock systems. Previous work in Drosophila has identified several kinases, phosphatases and an E3 ligase that are critical for determining the nuclear translocation and/or stability of clock proteins. The present study evaluated the function of p90 ribosomal S6 kinase (RSK) in the Drosophila circadian system. In mammals, RSK1 is a light- and clock-regulated kinase known to be activated by the MAPK pathway, but there is no direct evidence that it functions as a component of the circadian system. Here, we show that Drosophila S6KII RNA displays rhythms in abundance, indicative of circadian control. Importantly, an S6KII null mutant exhibits a short-period circadian phenotype that can be rescued by expression of the wild-type gene in clock neurons, indicating a role for S6KII in the molecular oscillator. Peak PER clock protein expression is elevated in the mutant, indicative of enhanced stability, whereas per mRNA level is decreased, consistent with enhanced feedback repression. Gene reporter assays show that decreased S6KII is associated with increased PER repression. Surprisingly, we demonstrate a physical interaction between S6KII and the Casein Kinase 2 regulatory subunit (CK2β), suggesting a functional relationship between the two kinases. In support of such a relationship, there are genetic interactions between S6KII and CK2 mutations, in vivo, which indicate that CK2 activity is required for S6KII action. We propose that the two kinases cooperate within clock neurons to fine-tune circadian period, improving the precision of the clock mechanism. PMID:19144847

PAK4 crystal structures suggest unusual kinase conformational movements.

Science.gov (United States)

Zhang, Eric Y; Ha, Byung Hak; Boggon, Titus J

2018-02-01

In order for protein kinases to exchange nucleotide they must open and close their catalytic cleft. These motions are associated with rotations of the N-lobe, predominantly around the 'hinge region'. We conducted an analysis of 28 crystal structures of the serine-threonine kinase, p21-activated kinase 4 (PAK4), including three newly determined structures in complex with staurosporine, FRAX486, and fasudil (HA-1077). We find an unusual motion between the N-lobe and C-lobe of PAK4 that manifests as a partial unwinding of helix αC. Principal component analysis of the crystal structures rationalizes these movements into three major states, and analysis of the kinase hydrophobic spines indicates concerted movements that create an accessible back pocket cavity. The conformational changes that we observe for PAK4 differ from previous descriptions of kinase motions, and although we observe these differences in crystal structures there is the possibility that the movements observed may suggest a diversity of kinase conformational changes associated with regulation. Protein kinases are key signaling proteins, and are important drug targets, therefore understanding their regulation is important for both basic research and clinical points of view. In this study, we observe unusual conformational 'hinging' for protein kinases. Hinging, the opening and closing of the kinase sub-domains to allow nucleotide binding and release, is critical for proper kinase regulation and for targeted drug discovery. We determine new crystal structures of PAK4, an important Rho-effector kinase, and conduct analyses of these and previously determined structures. We find that PAK4 crystal structures can be classified into specific conformational groups, and that these groups are associated with previously unobserved hinging motions and an unusual conformation for the kinase hydrophobic core. Our findings therefore indicate that there may be a diversity of kinase hinging motions, and that these may

SH2 domains: modulators of nonreceptor tyrosine kinase activity.

Science.gov (United States)

Filippakopoulos, Panagis; Müller, Susanne; Knapp, Stefan

2009-12-01

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation.

TecDEM: A MATLAB Based Toolbox for understanding Tectonics from Digital Elevation Models

Science.gov (United States)

Shahzad, F.; Mahmood, S. A.; Gloaguen, R.

2009-04-01

TecDEM is a MATLAB based tool box for understanding the tectonics from digital elevation models (DEMs) of any area. These DEMs can be derived from data of any spatial resolution (Low, medium and High). In the first step we extract drainage network from the DEMs using flow grid approach. Drainage network is a group of streams having elevation and catchment area information as a function of spatial locations. We implement an array of stream structure to study this drainage network. Knickpoints can be identified on each stream of the drainage network by a graphical user interface and are helpful for understanding stream morphology. Stream profile analysis in steady state condition is applied on all streams to calculate geomorphic parameters and regional uplift rates. Hack index is calculated for all the profiles at a certain interval and over the change of knickpoints. Reports menu of this tool box generates detailed statistics report, complete tabulated report, graphical output of each analyzed stream profile and Hack index profile. All the calculated values are part of stream structure and is saved as .mat file for later use with this tool box. The spatial distribution of geomorphic parameters, uplift rates and knickpoints are exported as a shape files for visualization in professional GIS software. We test this tool box on DEMs from different tectonic settings worldwide and received verifiable results with other studies.

The phosphatidylinositol 3-kinase inhibitor, wortmannin, inhibits insulin-induced activation of phosphatidylcholine hydrolysis and associated protein kinase C translocation in rat adipocytes.

OpenAIRE

Standaert, M L; Avignon, A; Yamada, K; Bandyopadhyay, G; Farese, R V

1996-01-01

We questioned whether phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase C (PKC) function as interrelated signalling mechanisms during insulin action in rat adipocytes. Insulin rapidly activated a phospholipase D that hydrolyses phosphatidylcholine (PC), and this activation was accompanied by increases in diacylglycerol and translocative activation of PKC-alpha and PKC-beta in the plasma membrane. Wortmannin, an apparently specific PI 3-kinase inhibitor, inhibited insulin-stimulat...

Two-site immunoradiometric assay for the MB isoenzyme of creatine kinase

Energy Technology Data Exchange (ETDEWEB)

Willson, V J.C.; Jones, H M; Thompson, R J [Cambridge Univ. (UK). Clinical School

1981-06-18

A two-site immunoradiometric assay for myocardial creatine kinase MB isoenzyme is described. The method utilizes immobilized anti-human creatine kinase BB antibodies and /sup 125/I-labelled anti-human creatine kinase MM antibodies and can specifically detect creatine kinase MB in the presence of approximately 1000-fold excess of creatine kinase MM or BB. Native kinase MB prepared from human heart and creatine kinase MB prepared by hybridisation of purified human creatine kinase MM and creatine kinase BB appeared to react identically in the assay. Serum estimations on patients with suspected myocardial infarction correlated with the presence of MB band on electrophoresis but preliminary results suggest that the two-site immunoradiometric assay may be more sensitive.

Mathematical modelling of ionospheric TEC from Turkish permanent GNSS Network (TPGN) observables during 2009-2017 and predictability of NeQuick and Kriging models

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Ansari, Kutubuddin; Panda, Sampad Kumar; Corumluoglu, Ozsen

2018-03-01

The present study examines 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 years 2009 to 2017. The corresponding vertical TEC (VTEC) predicted by Kriging and NeQuick-2 models are evaluated to realize their efficacy over the country. We studied the diurnal, seasonal and spatial pattern of VTEC variation and tried to estimate by a new mathematical model using the long term of 9 years VTEC data. The diurnal variation of VTEC demonstrates a normal trend with its gradual enhancement from dawn to attain a peak around 09:00-14.00 UT and reaching the minimum level after 22.00 UT. The seasonal behavior of VTEC indicates a strong semi-annual variation of VTEC with maxima in September equinox followed by March equinox and minima in June solstice followed by December solstice. Also, the spatial variation in VTEC depicts a meaningful longitudinal/latitudinal pattern altering with seasons. It decreases longitudinally from the west to the east during March equinox and June solstice increases with latitude. The comparative analysis among the GNSS-VTEC, Kriging, NeQuick and the proposed mathematical model are evaluated with the help one way ANOVA test. The analysis shows that the null hypothesis of the models during storm and quiet days are accepted and suggesting that all models are statistically significantly equivalent from each other. We believe the outcomes from this study would complement towards a relatively better understanding of the lower mid-latitude VTEC variation over the Turkish region and analogous latitudes over the globe.

S -Nitrosylation inhibits the kinase activity of tomato phosphoinositide-dependent kinase 1 (PDK1)

Energy Technology Data Exchange (ETDEWEB)

Liu, Jian-Zhong; Duan, Jicheng; Ni, Min; Liu, Zhen; Qiu, Wen-Li; Whitham, Steven A.; Qian, Wei-Jun

2017-09-29

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 that 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 diverse

Expression and Purification of PI3 Kinase {alpha} and Development of an ATP Depletion and an AlphaScreen PI3 Kinase Activity Assay

DEFF Research Database (Denmark)

Boldyreff, Brigitte; Rasmussen, Tine L; Jensen, Hans H

2008-01-01

Phosphoinositide-3-kinases are important targets for drug development because many proteins in the PI3 kinase signaling pathway are mutated, hyperactivated, or overexpressed in human cancers. Here, the authors coexpressed the human class Ia PI3 kinase p110alpha catalytic domain with an N-terminal....... In parallel, a second assay format using the AlphaScreen technology was optimized to measure PI3 kinase activity. Both assay formats used should be suitable for high-throughput screening for the identification of PI3 kinase inhibitors. (Journal of Biomolecular Screening XXXX:xx-xx)....

Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation.

Science.gov (United States)

Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E M; Jenkins, Jermaine L; Heimiller, Chelsea; Maines, Mahin D

2016-08-01

Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1-3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T(308) before S(473) autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. hBVR and Akt1 coimmunoprecipitated, and in-cell Förster resonance energy transfer (FRET) and glutathione S-transferase pulldown analyses identified Akt1 pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR-activated Akt1 increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR's PDK1 binding (161)RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Akt1 and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Akt1 activation by PDK1.-Miralem, T., Lerner

Protein kinase substrate identification on functional protein arrays

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Zhou Fang

2008-02-01

Full Text Available Abstract Background Over the last decade, kinases have emerged as attractive therapeutic targets for a number of different diseases, and numerous high throughput screening efforts in the pharmaceutical community are directed towards discovery of compounds that regulate kinase function. The emerging utility of systems biology approaches has necessitated the development of multiplex tools suitable for proteomic-scale experiments to replace lower throughput technologies such as mass spectroscopy for the study of protein phosphorylation. Recently, a new approach for identifying substrates of protein kinases has applied the miniaturized format of functional protein arrays to characterize phosphorylation for thousands of candidate protein substrates in a single experiment. This method involves the addition of protein kinases in solution to arrays of immobilized proteins to identify substrates using highly sensitive radioactive detection and hit identification algorithms. Results To date, the factors required for optimal performance of protein array-based kinase substrate identification have not been described. In the current study, we have carried out a detailed characterization of the protein array-based method for kinase substrate identification, including an examination of the effects of time, buffer compositions, and protein concentration on the results. The protein array approach was compared to standard solution-based assays for assessing substrate phosphorylation, and a correlation of greater than 80% was observed. The results presented here demonstrate how novel substrates for protein kinases can be quickly identified from arrays containing thousands of human proteins to provide new clues to protein kinase function. In addition, a pooling-deconvolution strategy was developed and applied that enhances characterization of specific kinase-substrate relationships and decreases reagent consumption. Conclusion Functional protein microarrays are an

A Global Protein Kinase and Phosphatase Interaction Network in Yeast

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Breitkreutz, Ashton; Choi, Hyungwon; Sharom, Jeffrey R.; Boucher, Lorrie; Neduva, Victor; Larsen, Brett; Lin, Zhen-Yuan; Breitkreutz, Bobby-Joe; Stark, Chris; Liu, Guomin; Ahn, Jessica; Dewar-Darch, Danielle; Reguly, Teresa; Tang, Xiaojing; Almeida, Ricardo; Qin, Zhaohui Steve; Pawson, Tony; Gingras, Anne-Claude; Nesvizhskii, Alexey I.; Tyers, Mike

2011-01-01

The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses. PMID:20489023

The Protein Kinase RSK Family - Roles in Prostate Cancer

National Research Council Canada - National Science Library

Lannigan, Deborah

2006-01-01

The Ser/Thr protein kinase p90-kDa ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase but its roles in prostate cancer have not been previously examined...

Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.

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Anshuman Dixit

2009-08-01

Full Text Available Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition

The target landscape of clinical kinase drugs.

Science.gov (United States)

Klaeger, Susan; Heinzlmeir, Stephanie; Wilhelm, Mathias; Polzer, Harald; Vick, Binje; Koenig, Paul-Albert; Reinecke, Maria; Ruprecht, Benjamin; Petzoldt, Svenja; Meng, Chen; Zecha, Jana; Reiter, Katrin; Qiao, Huichao; Helm, Dominic; Koch, Heiner; Schoof, Melanie; Canevari, Giulia; Casale, Elena; Depaolini, Stefania Re; Feuchtinger, Annette; Wu, Zhixiang; Schmidt, Tobias; Rueckert, Lars; Becker, Wilhelm; Huenges, Jan; Garz, Anne-Kathrin; Gohlke, Bjoern-Oliver; Zolg, Daniel Paul; Kayser, Gian; Vooder, Tonu; Preissner, Robert; Hahne, Hannes; Tõnisson, Neeme; Kramer, Karl; Götze, Katharina; Bassermann, Florian; Schlegl, Judith; Ehrlich, Hans-Christian; Aiche, Stephan; Walch, Axel; Greif, Philipp A; Schneider, Sabine; Felder, Eduard Rudolf; Ruland, Juergen; Médard, Guillaume; Jeremias, Irmela; Spiekermann, Karsten; Kuster, Bernhard

2017-12-01

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Casein kinases

DEFF Research Database (Denmark)

Issinger, O G

1993-01-01

The present review on casein kinases focuses mainly on the possible metabolic role of CK-2, with special emphasis on its behavior in pathological tissues. From these data at least three ways to regulate CK-2 activity emerge: (i) CK-2 activity changes during embryogenesis, being high at certain...

c-Jun controls the efficiency of MAP kinase signaling by transcriptional repression of MAP kinase phosphatases

International Nuclear Information System (INIS)

Sprowles, Amy; Robinson, Dan; Wu Yimi; Kung, H.-J.; Wisdom, Ron

2005-01-01

The mammalian JNK signaling pathway regulates the transcriptional response of cells to environmental stress, including UV irradiation. This signaling pathway is composed of a classical MAP kinase cascade; activation results in phosphorylation of the transcription factor substrates c-Jun and ATF2, and leads to changes in gene expression. The defining components of this pathway are conserved in the fission yeast S. pombe, where the genetic studies have shown that the ability of the JNK homolog Spc1 to be activated in response to UV irradiation is dependent on the presence of the transcription factor substrate Atf1. We have used genetic analysis to define the role of c-Jun in activation of the mammalian JNK signaling pathway. Our results show that optimal activation of JNK requires the presence of its transcription factor substrate c-Jun. Mutational analysis shows that the ability of c-Jun to support efficient activation of JNK requires the ability of Jun to bind DNA, suggesting a transcriptional mechanism. Consistent with this, we show that c-Jun represses the expression of several MAP kinase phosphatases. In the absence of c-Jun, the increased expression of MAP kinase phosphatases leads to impaired activation of the ERK, JNK, and p38 MAP kinases after pathway activation. The results show that one function of c-Jun is to regulate the efficiency of signaling by the ERK, p38, and JNK MAP kinases, a function that is likely to affect cellular responses to many different stimuli

Crystal structure of Cryptosporidium parvum pyruvate kinase.

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William J Cook

Full Text Available Pyruvate kinase plays a critical role in cellular metabolism of glucose by serving as a major regulator of glycolysis. This tetrameric enzyme is allosterically regulated by different effector molecules, mainly phosphosugars. In response to binding of effector molecules and substrates, significant structural changes have been identified in various pyruvate kinase structures. Pyruvate kinase of Cryptosporidium parvum is exceptional among known enzymes of protozoan origin in that it exhibits no allosteric property in the presence of commonly known effector molecules. The crystal structure of pyruvate kinase from C. parvum has been solved by molecular replacement techniques and refined to 2.5 Å resolution. In the active site a glycerol molecule is located near the γ-phosphate site of ATP, and the protein structure displays a partially closed active site. However, unlike other structures where the active site is closed, the α6' helix in C. parvum pyruvate kinase unwinds and assumes an extended conformation. In the crystal structure a sulfate ion is found at a site that is occupied by a phosphate of the effector molecule in many pyruvate kinase structures. A new feature of the C. parvum pyruvate kinase structure is the presence of a disulfide bond cross-linking the two monomers in the asymmetric unit. The disulfide bond is formed between cysteine residue 26 in the short N-helix of one monomer with cysteine residue 312 in a long helix (residues 303-320 of the second monomer at the interface of these monomers. Both cysteine residues are unique to C. parvum, and the disulfide bond remained intact in a reduced environment. However, the significance of this bond, if any, remains unknown at this time.

Janus kinase inhibitors: jackpot or potluck?

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Pavithran Keechilat

2012-06-01

Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

Integrating digital topology in image-processing libraries.

Science.gov (United States)

Lamy, Julien

2007-01-01

This paper describes a method to integrate digital topology informations in image-processing libraries. This additional information allows a library user to write algorithms respecting topological constraints, for example, a seed fill or a skeletonization algorithm. As digital topology is absent from most image-processing libraries, such constraints cannot be fulfilled. We describe and give code samples for all the structures necessary for this integration, and show a use case in the form of a homotopic thinning filter inside ITK. The obtained filter can be up to a hundred times as fast as ITK's thinning filter and works for any image dimension. This paper mainly deals of integration within ITK, but can be adapted with only minor modifications to other image-processing libraries.

RhoA/Rho-Kinase in the Cardiovascular System.

Science.gov (United States)

Shimokawa, Hiroaki; Sunamura, Shinichiro; Satoh, Kimio

2016-01-22

Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase-dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system. © 2016 American Heart Association, Inc.

Constitutive Activity in an Ancestral Form of Abl Tyrosine Kinase.

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Saadat U Aleem

Full Text Available The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase that is found in all metazoans, and is ubiquitously expressed in mammalian tissues. The Abl tyrosine kinase plays important roles in the regulation of mammalian cell physiology. Abl-like kinases have been identified in the genomes of unicellular choanoflagellates, the closest relatives to the Metazoa, and in related unicellular organisms. Here, we have carried out the first characterization of a premetazoan Abl kinase, MbAbl2, from the choanoflagellate Monosiga brevicollis. The enzyme possesses SH3, SH2, and kinase domains in a similar arrangement to its mammalian counterparts, and is an active tyrosine kinase. MbAbl2 lacks the N-terminal myristoylation and cap sequences that are critical regulators of mammalian Abl kinase activity, and we show that MbAbl2 is constitutively active. When expressed in mammalian cells, MbAbl2 strongly phosphorylates cellular proteins on tyrosine, and transforms cells much more potently than mammalian Abl kinase. Thus, MbAbl2 appears to lack the autoinhibitory mechanism that tightly constrains the activity of mammalian Abl kinases, suggesting that this regulatory apparatus arose more recently in metazoan evolution.

Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics

International Nuclear Information System (INIS)

Haupt, Armin; Dahl, Andreas; Lappe, Michael; Lehrach, Hans; Gonzalez, Cayetano; Drewes, Gerard; Lange, Bodo MH; Joberty, Gerard; Bantscheff, Marcus; Fröhlich, Holger; Stehr, Henning; Schweiger, Michal R; Fischer, Axel; Kerick, Martin; Boerno, Stefan T

2012-01-01

The heat shock protein 90 (Hsp90) is required for the stability of many signalling kinases. As a target for cancer therapy it allows the simultaneous inhibition of several signalling pathways. However, its inhibition in healthy cells could also lead to severe side effects. This is the first comprehensive analysis of the response to Hsp90 inhibition at the kinome level. We quantitatively profiled the effects of Hsp90 inhibition by geldanamycin on the kinome of one primary (Hs68) and three tumour cell lines (SW480, U2OS, A549) by affinity proteomics based on immobilized broad spectrum kinase inhibitors ('kinobeads'). To identify affected pathways we used the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway classification. We combined Hsp90 and proteasome inhibition to identify Hsp90 substrates in Hs68 and SW480 cells. The mutational status of kinases from the used cell lines was determined using next-generation sequencing. A mutation of Hsp90 candidate client RIPK2 was mapped onto its structure. We measured relative abundances of > 140 protein kinases from the four cell lines in response to geldanamycin treatment and identified many new potential Hsp90 substrates. These kinases represent diverse families and cellular functions, with a strong representation of pathways involved in tumour progression like the BMP, MAPK and TGF-beta signalling cascades. Co-treatment with the proteasome inhibitor MG132 enabled us to classify 64 kinases as true Hsp90 clients. Finally, mutations in 7 kinases correlate with an altered response to Hsp90 inhibition. Structural modelling of the candidate client RIPK2 suggests an impact of the mutation on a proposed Hsp90 binding domain. We propose a high confidence list of Hsp90 kinase clients, which provides new opportunities for targeted and combinatorial cancer treatment and diagnostic applications

The Role of PAS Kinase in PASsing the Glucose Signal

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Julianne H. Grose

2010-06-01

Full Text Available PAS kinase is an evolutionarily conserved nutrient responsive protein kinase that regulates glucose homeostasis. Mammalian PAS kinase is activated by glucose in pancreatic beta cells, and knockout mice are protected from obesity, liver triglyceride accumulation, and insulin resistance when fed a high-fat diet. Yeast PAS kinase is regulated by both carbon source and cell integrity stress and stimulates the partitioning of glucose toward structural carbohydrate biosynthesis. In our current model for PAS kinase regulation, a small molecule metabolite binds the sensory PAS domain and activates the enzyme. Although bona fide PAS kinase substrates are scarce, in vitro substrate searches provide putative targets for exploration.

Growth- and Stress-Induced PASTA Kinase Phosphorylation in Enterococcus faecalis.

Science.gov (United States)

Labbe, Benjamin D; Kristich, Christopher J

2017-11-01

Transmembrane Ser/Thr kinases containing extracellular PASTA domains are ubiquitous among Actinobacteria and Firmicutes Such PASTA kinases regulate critical processes, including antibiotic resistance, cell division, toxin production, and virulence, and are essential for viability in certain organisms. Based on in vitro studies with purified extracellular and intracellular fragments of PASTA kinases, a model for signaling has been proposed, in which the extracellular PASTA domains bind currently undefined ligands (typically thought to be peptidoglycan, or fragments thereof) to drive kinase dimerization, which leads to enhanced kinase autophosphorylation and enhanced phosphorylation of substrates. However, this model has not been rigorously tested in vivo Enterococcus faecalis is a Gram-positive intestinal commensal and major antibiotic-resistant opportunistic pathogen. In E. faecalis , the PASTA kinase IreK drives intrinsic resistance to cell wall-active antimicrobials, suggesting that such antimicrobials may trigger IreK signaling. Here we show that IreK responds to cell wall stress in vivo by enhancing its phosphorylation and that of a downstream substrate. This response requires both the extracellular PASTA domains and specific phosphorylatable residues in the kinase domain. Thus, our results provide in vivo evidence, with an intact full-length PASTA kinase in its native physiological environment, that supports the prevailing model of PASTA kinase signaling. In addition, we show that IreK responds to a signal associated with growth and/or cell division, in the absence of cell wall-active antimicrobials. Surprisingly, the ability of IreK to respond to growth and/or division does not require the extracellular PASTA domains, suggesting that IreK monitors multiple parameters for sensory input in vivo IMPORTANCE Transmembrane Ser/Thr kinases containing extracellular PASTA domains are ubiquitous among Actinobacteria and Firmicutes and regulate critical processes. The

Diacylglycerol kinase regulation of protein kinase D during oxidative stress-induced intestinal cell injury

International Nuclear Information System (INIS)

Song Jun; Li Jing; Mourot, Joshua M.; Mark Evers, B.; Chung, Dai H.

2008-01-01

We recently demonstrated that protein kinase D (PKD) exerts a protective function during oxidative stress-induced intestinal epithelial cell injury; however, the exact role of DAG kinase (DGK)ζ, an isoform expressed in intestine, during this process is unknown. We sought to determine the role of DGK during oxidative stress-induced intestinal cell injury and whether DGK acts as an upstream regulator of PKD. Inhibition of DGK with R59022 compound or DGKζ siRNA transfection decreased H 2 O 2 -induced RIE-1 cell apoptosis as measured by DNA fragmentation and increased PKD phosphorylation. Overexpression of kinase-dead DGKζ also significantly increased PKD phosphorylation. Additionally, endogenous nuclear DGKζ rapidly translocated to the cytoplasm following H 2 O 2 treatment. Our findings demonstrate that DGK is involved in the regulation of oxidative stress-induced intestinal cell injury. PKD activation is induced by DGKζ, suggesting DGK is an upstream regulator of oxidative stress-induced activation of the PKD signaling pathway in intestinal epithelial cells

Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4

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Agarwala Usha

2011-06-01

Full Text Available Abstract Background Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6 are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and overexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. Results A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP. An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. Conclusion These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with

Involvement of protein kinase B and mitogen-activated protein kinases in experimental normothermic liver ischaemia-reperfusion injury.

Science.gov (United States)

Cursio, R; Filippa, N; Miele, C; Van Obberghen, E; Gugenheim, J

2006-06-01

This study evaluated the role of protein kinase B (PKB), phosphatidylinositol 3-kinase (PI3-K), Bcl-2-associated death protein (BAD) and mitogen-activated protein kinases (MAPKs) in normothermic ischaemia-reperfusion (IR)-induced apoptosis in rat liver. Rats were divided into two groups that received either phosphate-buffered saline (control) or the caspase inhibitor Z-Asp-2,6-dichorobenzoyloxymethylketone (Z-Asp-cmk), injected intravenously 2 min before the induction of 120 min of normothermic liver ischaemia. Liver apoptosis was assessed by the terminal deoxyribonucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) method. PI3-K, PKB, BAD and MAPK activities were measured in ischaemic and non-ischaemic lobes at various times after reperfusion. The number of TUNEL-positive cells was significantly decreased after pretreatment with Z-Asp-cmk. In controls, PI3-K and PKB activities and BAD phosphorylation were inhibited in ischaemic liver lobes. The MAPKs (extracellular signal-regulated kinases, c-Jun N-terminal kinase and p38) showed different patterns of activation during IR. PKB activity was not modified by pretreatment with Z-Asp-cmk. Induction of apoptosis during IR liver injury might be triggered by inactivation of the antiapoptotic PI3-K-PKB pathway and activation of the proapoptotic MAPKs. Copyright (c) 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Stimulation of casein kinase II by epidermal growth factor: Relationship between the physiological activity of the kinase and the phosphorylation state of its beta subunit

International Nuclear Information System (INIS)

Ackerman, P.; Osheroff, N.; Glover, C.V.C.

1990-01-01

To determine relationships between the hormonal activation of casein kinase II and its phosphorylation state, epidermal growth factor (EGF)-treated and EGF-naive human A-431 carcinoma cells were cultured in the presence of [ 32 P]orthophosphate. Immunoprecipitation experiments indicated that casein kinase II in the cytosol of EGF-treated cells contained approximately 3-fold more incorporated [ 32 P]phosphate than did its counterpart in untreated cells. Levels of kinase phosphorylation paralleled levels of kinase activity over a wide range of EGF concentrations as well as over a time course of hormone action. Approximately 97% of the incorporated [ 32 P]phosphate was found in the β subunit of casein kinase II. Both activated and hormone-naive kinase contained radioactive phosphoserine and phosphothreonine but no phosphotyronsine. On the basis of proteolytic mapping experiments, EGF treatment of A-431 cells led to an increase in the average [ 32 P]phosphate content (i.e., hyperphosphorylation) of casein kinase II β subunit peptides which were modified prior to hormone treatment. Finally, the effect of alkaline phosphatase on the reaction kinetics of activated casein kinase II indicated that hormonal stimulation of the kinase resulted from the increase in its phosphorylation state

Crystal structure of human protein kinase CK2

DEFF Research Database (Denmark)

Niefind, K; Guerra, B; Ermakowa, I

2001-01-01

The crystal structure of a fully active form of human protein kinase CK2 (casein kinase 2) consisting of two C-terminally truncated catalytic and two regulatory subunits has been determined at 3.1 A resolution. In the CK2 complex the regulatory subunits form a stable dimer linking the two catalyt...... as a docking partner for various protein kinases. Furthermore it shows an inter-domain mobility in the catalytic subunit known to be functionally important in protein kinases and detected here for the first time directly within one crystal structure.......The crystal structure of a fully active form of human protein kinase CK2 (casein kinase 2) consisting of two C-terminally truncated catalytic and two regulatory subunits has been determined at 3.1 A resolution. In the CK2 complex the regulatory subunits form a stable dimer linking the two catalytic...... subunits, which make no direct contact with one another. Each catalytic subunit interacts with both regulatory chains, predominantly via an extended C-terminal tail of the regulatory subunit. The CK2 structure is consistent with its constitutive activity and with a flexible role of the regulatory subunit...

Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism

DEFF Research Database (Denmark)

Ard, Ryan; Mulatz, Kirk; Abramovici, Hanan

2012-01-01

, but the underlying mechanisms are unclear. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phosphorylation of RhoGDI on Ser-101/174. Similarly, phosphorylation of RhoGDI on Ser-34 by protein kinase Cα (PKCα......GDI and was required for efficient interaction of PKCα and RhoA. DGKζ-null fibroblasts had condensed F-actin bundles and altered focal adhesion distribution, indicative of aberrant RhoA signaling. Two targets of the RhoA effector ROCK showed reduced phosphorylation in DGKζ-null cells. Collectively our findings suggest...

Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae.

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Qiu, Yixuan; Hassaninasab, Azam; Han, Gil-Soo; Carman, George M

2016-12-16

In the yeast Saccharomyces cerevisiae, Dgk1 diacylglycerol (DAG) kinase catalyzes the CTP-dependent phosphorylation of DAG to form phosphatidic acid (PA). The enzyme in conjunction with Pah1 PA phosphatase controls the levels of PA and DAG for the synthesis of triacylglycerol and membrane phospholipids, the growth of the nuclear/endoplasmic reticulum membrane, and the formation of lipid droplets. Little is known about how DAG kinase activity is regulated by posttranslational modification. In this work, we examined the phosphorylation of Dgk1 DAG kinase by casein kinase II (CKII). When phosphate groups were globally reduced using nonspecific alkaline phosphatase, Triton X-100-solubilized membranes from DGK1-overexpressing cells showed a 7.7-fold reduction in DAG kinase activity; the reduced enzyme activity could be increased 5.5-fold by treatment with CKII. Dgk1(1-77) expressed heterologously in Escherichia coli was phosphorylated by CKII on a serine residue, and its phosphorylation was dependent on time as well as on the concentrations of CKII, ATP, and Dgk1(1-77). We used site-specific mutagenesis, coupled with phosphorylation analysis and phosphopeptide mapping, to identify Ser-45 and Ser-46 of Dgk1 as the CKII target sites, with Ser-46 being the major phosphorylation site. In vivo, the S46A and S45A/S46A mutations of Dgk1 abolished the stationary phase-dependent stimulation of DAG kinase activity. In addition, the phosphorylation-deficient mutations decreased Dgk1 function in PA production and in eliciting pah1Δ phenotypes, such as the expansion of the nuclear/endoplasmic reticulum membrane, reduced lipid droplet formation, and temperature sensitivity. This work demonstrates that the CKII-mediated phosphorylation of Dgk1 regulates its function in the production of PA. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae*

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Qiu, Yixuan; Hassaninasab, Azam; Han, Gil-Soo; Carman, George M.

2016-01-01

In the yeast Saccharomyces cerevisiae, Dgk1 diacylglycerol (DAG) kinase catalyzes the CTP-dependent phosphorylation of DAG to form phosphatidic acid (PA). The enzyme in conjunction with Pah1 PA phosphatase controls the levels of PA and DAG for the synthesis of triacylglycerol and membrane phospholipids, the growth of the nuclear/endoplasmic reticulum membrane, and the formation of lipid droplets. Little is known about how DAG kinase activity is regulated by posttranslational modification. In this work, we examined the phosphorylation of Dgk1 DAG kinase by casein kinase II (CKII). When phosphate groups were globally reduced using nonspecific alkaline phosphatase, Triton X-100-solubilized membranes from DGK1-overexpressing cells showed a 7.7-fold reduction in DAG kinase activity; the reduced enzyme activity could be increased 5.5-fold by treatment with CKII. Dgk1(1–77) expressed heterologously in Escherichia coli was phosphorylated by CKII on a serine residue, and its phosphorylation was dependent on time as well as on the concentrations of CKII, ATP, and Dgk1(1–77). We used site-specific mutagenesis, coupled with phosphorylation analysis and phosphopeptide mapping, to identify Ser-45 and Ser-46 of Dgk1 as the CKII target sites, with Ser-46 being the major phosphorylation site. In vivo, the S46A and S45A/S46A mutations of Dgk1 abolished the stationary phase-dependent stimulation of DAG kinase activity. In addition, the phosphorylation-deficient mutations decreased Dgk1 function in PA production and in eliciting pah1Δ phenotypes, such as the expansion of the nuclear/endoplasmic reticulum membrane, reduced lipid droplet formation, and temperature sensitivity. This work demonstrates that the CKII-mediated phosphorylation of Dgk1 regulates its function in the production of PA. PMID:27834677

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

Science.gov (United States)

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

2015-10-01

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

A two-site immunoradiometric assay for the MB isoenzyme of creatine kinase

International Nuclear Information System (INIS)

Willson, V.J.C.; Jones, H.M.; Thompson, R.J.

1981-01-01

A two-site immunoradiometric assay for myocardial creatine kinase MB isoenzyme is described. The method utilizes immobilized anti-human creatine kinase BB antibodies and 125 I-labelled anti-human creatine kinase MM antibodies and can specifically detect creatine kinase MB in the presence of approximately 1000-fold excess of creatine kinase MM or BB. Native kinase MB prepared from human heart and creatine kinase MB prepared by hybridisation of purified human creatine kinase MM and creatine kinase BB appeared to react identically in the assay. Serum estimations on patients with suspected myocardial infarction correlated with the presence of MB band on electrophoresis but preliminary results suggest that the two-site immunoradiometric assay may be more sensitive. (Auth.)

Kinome profiling of Arabidopsis using arrays of kinase consensus substrates

Directory of Open Access Journals (Sweden)

Pieterse Corné MJ

2007-02-01

Full Text Available Abstract Background Kinome profiling aims at the parallel analysis of kinase activities in a cell. Novel developed arrays containing consensus substrates for kinases are used to assess those kinase activities. The arrays described in this paper were already used to determine kinase activities in mammalian systems, but since substrates from many organisms are present we decided to test these arrays for the determination of kinase activities in the model plant species Arabidopsis thaliana. Results Kinome profiling using Arabidopsis cell extracts resulted in the labelling of many consensus peptides by kinases from the plant, indicating the usefulness of this kinome profiling tool for plants. Method development showed that fresh and frozen plant material could be used to make cell lysates containing active kinases. Dilution of the plant extract increased the signal to noise ratio and non-radioactive ATP enhances full development of spot intensities. Upon infection of Arabidopsis with an avirulent strain of the bacterial pathogen Pseudomonas syringae pv. tomato, we could detect differential kinase activities by measuring phosphorylation of consensus peptides. Conclusion We show that kinome profiling on arrays with consensus substrates can be used to monitor kinase activities in plants. In a case study we show that upon infection with avirulent P. syringae differential kinase activities can be found. The PepChip can for example be used to purify (unknown kinases that play a role in P. syringae infection. This paper shows that kinome profiling using arrays of consensus peptides is a valuable new tool to study signal-transduction in plants. It complements the available methods for genomics and proteomics research.

Roles of Apicomplexan protein kinases at each life cycle stage.

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Kato, Kentaro; Sugi, Tatsuki; Iwanaga, Tatsuya

2012-06-01

Inhibitors of cellular protein kinases have been reported to inhibit the development of Apicomplexan parasites, suggesting that the functions of protozoan protein kinases are critical for their life cycle. However, the specific roles of these protein kinases cannot be determined using only these inhibitors without molecular analysis, including gene disruption. In this report, we describe the functions of Apicomplexan protein kinases in each parasite life stage and the potential of pre-existing protein kinase inhibitors as Apicomplexan drugs against, mainly, Plasmodium and Toxoplasma. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The phosphatidylinositol 3-kinase inhibitor, wortmannin, inhibits insulin-induced activation of phosphatidylcholine hydrolysis and associated protein kinase C translocation in rat adipocytes.

Science.gov (United States)

Standaert, M L; Avignon, A; Yamada, K; Bandyopadhyay, G; Farese, R V

1996-02-01

We questioned whether phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase C (PKC) function as interrelated signalling mechanisms during insulin action in rat adipocytes. Insulin rapidly activated a phospholipase D that hydrolyses phosphatidylcholine (PC), and this activation was accompanied by increases in diacylglycerol and translocative activation of PKC-alpha and PKC-beta in the plasma membrane. Wortmannin, an apparently specific PI 3-kinase inhibitor, inhibited insulin-stimulated, phospholipase D-dependent PC hydrolysis and subsequent translocation of PKC-alpha and PKC-beta to the plasma membrane. Wortmannin did not inhibit PKC directly in vitro, or the PKC-dependent effects of phorbol esters on glucose transport in intact adipocytes. The PKC inhibitor RO 31-8220 did not inhibit PI 3-kinase directly or its activation in situ by insulin, but inhibited both insulin-stimulated and phorbol ester-stimulated glucose transport. Our findings suggest that insulin acts through PI 3-kinase to activate a PC-specific phospholipase D and causes the translocative activation of PKC-alpha and PKC-beta in plasma membranes of rat adipocytes.

Purification and characterization of a thylakoid protein kinase

International Nuclear Information System (INIS)

Coughlan, S.J.; Hind, G.

1986-01-01

Control of state transitions in the thylakoid by reversible phosphorylation of the light-harvesting chlorophyll a/b protein complex of photosystem II (LHC-II) is modulated by a kinase. The kinase catalyzing this phosphorylation is associated with the thylakoid membrane, and is regulated by the redox state of the plastoquinone pool. The isolation and partial purification from spinach thylakoids of two protein kinases (CPK1, CPK2) of apparent molecular masses 25 kDa and 38 kDa has been reported. Neither enzyme utilizes isolated LHC-II as a substrate. The partial purification of a third protein kinase (LHCK) which can utilize both lysine-rich histones (IIIs and Vs) and isolated LHC-II as substrate has now been purified to homogeneity and characterized by SDS-polyacrylamide gel electrophoresis as a 64 kDa peptide. From a comparison of the two isolation procedures we have concluded that CPK1 is indeed a protein kinase, but has a lower specific activity than that of LHCK. 8 refs., 4 figs

Janus Associated Kinases Inhibitors in the Pharmacological Thera

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Daniela Santos1

2017-01-01

Full Text Available Janus associated kinases inhibitors are a new strategy for the treatment of different clinical conditions like immunologic, inflammatory and oncology disorders. The aim of this study was to perform a review of all Janus associated kinases inhibitors available in national and international pharmaceutical market, their therapeutic indications and adverse effects, and the potential indications for investigation of those already available in the pharmaceutical market. It was also performed a review of the main new Janus associated kinases inhibitors that are still in clinical research. A literature review was conducted by consulting the summary of product characteristics of Janus associated kinases inhibitors available in the pharmaceutical market and a research in the bibliographic database PubMed using the terms «JAK inhibitors», «Janus associated kinases inhibitors» and «Janus kinases inhibitors». Ninety-five publications were included in the present review, published from January 2014 to January 2015. Drug databases of the European Medicines Agency and United States Food and Drug Administration were also consulted to search for Janus associated kinases inhibitors authorized in clinical practice. Currently, ruxolitinib and tofacitinib are available in the pharmaceutical market and oclatinib is approved as a veterinary medicinal product. Both drugs approved for human use have major adverse effects at hematological and immunological levels, which enhance the importance of the pharmacist’s role in the monitoring of patients involved in these treatments. However, several molecules are in pre-clinical and clinical studies trying to prove its potential in the treatment of several immunologic, inflammatory and oncology disorders. Thus, it is still necessary to deepen the knowledge in this area in order to overcome the risks of therapy with these agents. These risks weighed against the benefits of its clinical use have compromised the progress of

Discovery of inhibitors of bacterial histidine kinases

NARCIS (Netherlands)

Velikova, N.R.

2014-01-01

Discovery of Inhibitors of Bacterial Histidine Kinases Summary

The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

Protein Kinases in Shaping Plant Architecture.

Science.gov (United States)

Wu, Juan; Wang, Bo; Xin, Xiaoyun; Ren, Dongtao

2018-02-13

Plant architecture, the three-dimensional organization of the plant body, includes the branching pattern and the size, shape, and position of organs. Plant architecture is genetically controlled and is influenced by environmental conditions. The regulations occur at most of the stages from the first division of the fertilized eggs to the final establishment of plant architecture. Among the various endogenous regulators, protein kinases and their associated signaling pathways have been shown to play important roles in regulating the process of plant architecture establishment. In this review, we summarize recent progress in the understanding of the mechanisms by which plant architecture formation is regulated by protein kinases, especially mitogen-activated protein kinase (MAPK). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Characterization of cyclin-dependent kinases and Cdc2/Cdc28 kinase subunits in Trichomonas vaginalis.

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Amador, Erick; López-Pacheco, Karla; Morales, Nataly; Coria, Roberto; López-Villaseñor, Imelda

2017-04-01

Cyclin-dependent kinases (CDKs) have important roles in regulating key checkpoints between stages of the cell cycle. Their activity is tightly regulated through a variety of mechanisms, including through binding with cyclin proteins and the Cdc2/Cdc28 kinase subunit (CKS), and their phosphorylation at specific amino acids. Studies of the components involved in cell cycle control in parasitic protozoa are limited. Trichomonas vaginalis is the causative agent of trichomoniasis in humans and is therefore important in public health; however, some of the basic biological processes used by this organism have not been defined. Here, we characterized proteins potentially involved in cell cycle regulation in T. vaginalis. Three genes encoding protein kinases were identified in the T. vaginalis genome, and the corresponding recombinant proteins (TvCRK1, TvCRK2, TvCRK5) were studied. These proteins displayed similar sequence features to CDKs. Two genes encoding CKSs were also identified, and the corresponding recombinant proteins were found to interact with TvCRK1 and TvCRK2 by a yeast two-hybrid system. One putative cyclin B protein from T. vaginalis was found to bind to and activate the kinase activities of TvCRK1 and TvCRK5, but not TvCRK2. This work is the first characterization of proteins involved in cell cycle control in T. vaginalis.

Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.

Science.gov (United States)

Stavenger, Robert A; Cui, Haifeng; Dowdell, Sarah E; Franz, Robert G; Gaitanopoulos, Dimitri E; Goodman, Krista B; Hilfiker, Mark A; Ivy, Robert L; Leber, Jack D; Marino, Joseph P; Oh, Hye-Ja; Viet, Andrew Q; Xu, Weiwei; Ye, Guosen; Zhang, Daohua; Zhao, Yongdong; Jolivette, Larry J; Head, Martha S; Semus, Simon F; Elkins, Patricia A; Kirkpatrick, Robert B; Dul, Edward; Khandekar, Sanjay S; Yi, Tracey; Jung, David K; Wright, Lois L; Smith, Gary K; Behm, David J; Doe, Christopher P; Bentley, Ross; Chen, Zunxuan X; Hu, Erding; Lee, Dennis

2007-01-11

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

Partial contribution of Rho-kinase inhibition to the bioactivity of Ganoderma lingzhi and its isolated compounds: insights on discovery of natural Rho-kinase inhibitors.

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Amen, Yhiya; Zhu, Qinchang; Tran, Hai-Bang; Afifi, Mohamed S; Halim, Ahmed F; Ashour, Ahmed; Shimizu, Kuniyoshi

2017-04-01

Recent studies identified Rho-kinase enzymes (ROCK-I and ROCK-II) as important targets that are involved in a variety of diseases. Synthetic Rho-kinase inhibitors have emerged as potential therapeutic agents to treat disorders such as hypertension, stroke, cancer, diabetes, glaucoma, etc. Our study is the first to screen the total ethanol extract of the medicinal mushroom Ganoderma lingzhi with thirty-five compounds for Rho-kinase inhibitory activity. Moreover, a molecular binding experiment was designed to investigate the binding affinity of the compounds at the active sites of Rho-kinase enzymes. The structure-activity relationship analysis was investigated. Our results suggest that the traditional uses of G. lingzhi might be in part due to the ROCK-I and ROCK-II inhibitory potential of this mushroom. Structure-activity relationship studies revealed some interesting features of the lanostane triterpenes that potentiate their Rho-kinase inhibition. These findings would be helpful for further studies on the design of Rho-kinase inhibitors from natural sources and open the door for contributions from other researchers for optimizing the development of natural Rho-kinase inhibitors.

Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery

Directory of Open Access Journals (Sweden)

Gennady Verkhivker

2013-11-01

Full Text Available A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4 kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock kinase from the system during client loading (release stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.

Low latitude ionospheric TEC responses to dynamical complexity quantifiers during transient events over Nigeria

Science.gov (United States)

Ogunsua, Babalola

2018-04-01

In this study, the values of chaoticity and dynamical complexity parameters for some selected storm periods in the year 2011 and 2012 have been computed. This was done using detrended TEC data sets measured from Birnin-Kebbi, Torro and Enugu global positioning system (GPS) receiver stations in Nigeria. It was observed that the significance of difference (SD) values were mostly greater than 1.96 but surprisingly lower than 1.96 in September 29, 2011. The values of the computed SD were also found to be reduced in most cases just after the geomagnetic storm with immediate recovery a day after the main phase of the storm while the values of Lyapunov exponent and Tsallis entropy remains reduced due to the influence of geomagnetic storms. It was also observed that the value of Lyapunov exponent and Tsallis entropy reveals similar variation pattern during storm period in most cases. Also recorded surprisingly were lower values of these dynamical quantifiers during the solar flare event of August 8th and 9th of the year 2011. The possible mechanisms responsible for these observations were further discussed in this work. However, our observations show that the ionospheric effects of some other possible transient events other than geomagnetic storms can also be revealed by the variation of chaoticity and dynamical complexity.

Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.

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Jauch, Ralf; Cho, Min-Kyu; Jäkel, Stefan; Netter, Catharina; Schreiter, Kay; Aicher, Babette; Zweckstetter, Markus; Jäckle, Herbert; Wahl, Markus C

2006-09-06

Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily.

Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase

DEFF Research Database (Denmark)

Sayed, M; Kim, S O; Salh, B S

2000-01-01

Protein kinase CK2 has been implicated in the regulation of a wide range of proteins that are important in cell proliferation and differentiation. Here we demonstrate that the stress signaling agents anisomycin, arsenite, and tumor necrosis factor-alpha stimulate the specific enzyme activity of CK2...... in the human cervical carcinoma HeLa cells by up to 8-fold, and this could be blocked by the p38 MAP kinase inhibitor SB203580. We show that p38alpha MAP kinase, in a phosphorylation-dependent manner, can directly interact with the alpha and beta subunits of CK2 to activate the holoenzyme through what appears...

Mechanism of polyphosphate kinase from Propionibacterium shermanii

International Nuclear Information System (INIS)

Robinson, N.A.

1986-01-01

Polyphosphate kinase, which catalyzes the reaction shown below, is one of two enzymes which have been reported to catalyze the synthesis of polyphosphate. Purification performed by ammonium sulfate precipitation (0-40% fraction) was followed by chromatography. The enzyme represents 70% of the protein in the hydroxylapatite pool and is stable at this level of purity. The subunit molecular weight was determined by SDS polyacrylamide gel analysis, (83,000 +/- 3000), nondenaturing polyacrylamide gel electrophoresis, (80,000 and 86,000 daltons), gel filtration (Biogel A 0.5m column was 85,000 +/- 4000.) Polyphosphate kinase appears to be a monomeric enzyme of ∼83,000 daltons. Four assays were developed for polyphosphate kinase. Basic proteins such as polylysine stimulate the synthesis of polyphosphate, these proteins cause precipitation of polyphosphate kinase from relatively impure enzyme extracts: Synthesized polyphosphate interacts noncovalently with the basic protein-enzyme precipitate. Efficient synthesis of polyphosphate requires the addition of either phosphate or short chain polyphosphate. Synthesis did occur at 1/10 the rate when neither of these two compounds were included. Initiation, elongation, and termination events of polyphosphate synthesis were examined. Short chain polyphosphate acts as a primer, with [ 32 P] short-chain polyphosphate incorporation into long chain polyphosphate by the kinase

A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity.

Science.gov (United States)

Kim, Dennis H; Feinbaum, Rhonda; Alloing, Geneviève; Emerson, Fred E; Garsin, Danielle A; Inoue, Hideki; Tanaka-Hino, Miho; Hisamoto, Naoki; Matsumoto, Kunihiro; Tan, Man-Wah; Ausubel, Frederick M

2002-07-26

A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1, which encodes a mitogen-activated protein (MAP) kinase kinase, and nsy-1, which encodes a MAP kinase kinase kinase. RNA interference assays and biochemical analysis established that a p38 ortholog, pmk-1, functions as the downstream MAP kinase required for pathogen defense. These data suggest that this MAP kinase signaling cassette represents an ancient feature of innate immune responses in evolutionarily diverse species.

The Roles of Protein Kinases in Learning and Memory

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Giese, Karl Peter; Mizuno, Keiko

2013-01-01

In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate…

Telocinobufagin inhibits the epithelial-mesenchymal transition of breast cancer cells through the phosphoinositide 3-kinase/protein kinase B/extracellular signal-regulated kinase/Snail signaling pathway.

Science.gov (United States)

Gao, Yuxue; Shi, Lihong; Cao, Zhen; Zhu, Xuetao; Li, Feng; Wang, Ruyan; Xu, Jinyuan; Zhong, Jinyi; Zhang, Baogang; Lu, Shijun

2018-05-01

Telocinobufagin (TBG), an active ingredient of Venenumbufonis , exhibits an immunomodulatory activity. However, its antimetastatic activity in breast cancer remains unknown. The present study investigated whether TBG prevents breast cancer metastasis and evaluated its regulatory mechanism. TBG inhibited the migration and invasion of 4T1 breast cancer cells. Furthermore, TBG triggered the collapse of F-actin filaments in breast cancer. The epithelial-mesenchymal transition (EMT) markers, vimentin and fibronectin, were downregulated following TBG treatment. However, E-cadherin was upregulated following TBG treatment. Snail, a crucial transcriptional factor of EMT, was downregulated following TBG treatment. Signaling pathway markers, including phosphorylated protein kinase B (P-Akt), p-mechanistic target of rapamycin (mTOR) and p-extracellular signal-regulated kinase (ERK), were decreased following TBG treatment. The same results were obtained from in vivo experiments. In conclusion, in vitro and in vivo experiments reveal that TBG inhibited migration, invasion and EMT via the phosphoinositide 3-kinase (PI3K)/Akt/ERK/Snail signaling pathway in breast cancer.

Profiling bacterial kinase activity using a genetic circuit

DEFF Research Database (Denmark)

van der Helm, Eric; Bech, Rasmus; Lehning, Christina Eva

Phosphorylation is a post-translational modification that regulates the activity of several key proteins in bacteria and eukaryotes. Accordingly, a variety of tools has been developed to measure kinase activity. To couple phosphorylation to an in vivo fluorescent readout we used the Bacillus...... subtilis kinase PtkA, transmembrane activator TkmA and the repressor FatR to construct a genetic circuit in E. coli. By tuning the repressor and kinase expression level at the same time, we were able to show a 4.2-fold increase in signal upon kinase induction. We furthermore validated that the previously...... reported FatR Y45E mutation1 attenuates operator repression. This genetic circuit provides a starting point for computational protein design and a metagenomic library-screening tool....

p21-activated Kinase1(PAK1) can promote ERK activation in a kinase independent manner

DEFF Research Database (Denmark)

Wang, Zhipeng; Fu, Meng; Wang, Lifeng

2013-01-01

204) although phosphorylation of b-Raf (Ser445) and c-Raf (Ser 338) remained unchanged. Furthermore, increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1, PAK1 and Mek1, independent of the kinase activity of PAK1. These data suggest that PAK1 can stimulate...... MEK activity in a kinase independent manner, probably by serving as a scaffold to facilitate interaction of c-Raf....

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

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

2015-01-20

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

Tyrosine kinase, aurora kinase and leucine aminopeptidase as attractive drug targets in anticancer therapy - characterisation of their inhibitors.

Science.gov (United States)

Ziemska, Joanna; Solecka, Jolanta

Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.

Kinase inhibition by the Jamaican ball moss, Tillandsia recurvata L.

Science.gov (United States)

Lowe, Henry I C; Watson, Charah T; Badal, Simone; Toyang, Ngeh J; Bryant, Joseph

2012-10-01

This research was undertaken in order to investigate the inhibitory potential of the Jamaican ball moss, Tillandsia recurvata against several kinases. The inhibition of these kinases has emerged as a potential solution to restoring the tight regulation of normal cellular growth, the loss of which leads to cancer cell formation. Kinase inhibition was investigated using competition binding (to the ATP sites) assays, which have been previously established and authenticated. Four hundred and fifty one kinases were tested against the Jamaican ball moss extract and a dose-response was tested on 40 kinases, which were inhibited by more than 35% compared to the control. Out of the 40 kinases, the Jamaican ball moss selectively inhibited 5 (CSNK2A2, MEK5, GAK, FLT and DRAK1) and obtained Kd(50)s were below 20 μg/ml. Since MEK5 and GAK kinases have been associated with aggressive prostate cancer, the inhibitory properties of the ball moss against them, coupled with its previously found bioactivity towards the PC-3 cell line, makes it promising in the arena of drug discovery towards prostate cancer.

The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions.

Science.gov (United States)

Santafé, Manel M; Garcia, Neus; Tomàs, Marta; Obis, Teresa; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

2014-02-21

We conducted an electrophysiological study of the functional link between the tropomyosin-related kinase B (trkB) receptor signaling mechanism and serine-threonine kinases, both protein kinase C (PKC) and protein kinase A (PKA). We describe their coordinated role in transmitter release at the neuromuscular junction (NMJ) of the Levator auris longus muscle of the adult mouse. The trkB receptor normally seems to be coupled to stimulate ACh release because inhibiting the trkB receptor with K-252a results in a significant reduction in the size of EPPs. We found that the intracellular PKC pathway can operate as in basal conditions (to potentiate ACh release) without the involvement of the trkB receptor function, although the trkB pathway needs an operative PKC pathway if it is to couple to the release mechanism and potentiate it. To actively stimulate PKA (which also results in ACh release potentiation), the operativity of trkB is a necessary condition, and one effect of trkB may be PKA stimulation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.

Science.gov (United States)

Gajiwala, Ketan S; Grodsky, Neil; Bolaños, Ben; Feng, Junli; Ferre, RoseAnn; Timofeevski, Sergei; Xu, Meirong; Murray, Brion W; Johnson, Ted W; Stewart, Al

2017-09-22

The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Transphosphorylation of E. coli proteins during production of recombinant protein kinases provides a robust system to characterize kinase specificity

Science.gov (United States)

Protein kinase specificity is of fundamental importance to pathway regulation and signal transduction. Here, we report a convenient system to monitor the activity and specificity of recombinant protein kinases expressed in E.coli. We apply this to the study of the cytoplasmic domain of the plant rec...

Dominant negative selection of vaccinia virus using a thymidine kinase/thymidylate kinase fusion gene and the prodrug azidothymidine

International Nuclear Information System (INIS)

Holzer, Georg W.; Mayrhofer, Josef; Gritschenberger, Werner; Falkner, Falko G.

2005-01-01

The Escherichia coli thymidine kinase/thymidylate kinase (tk/tmk) fusion gene encodes an enzyme that efficiently converts the prodrug 3'-azido-2',3'-dideoxythymidine (AZT) into its toxic triphosphate derivative, a substance which stops DNA chain elongation. Integration of this marker gene into vaccinia virus that normally is not inhibited by AZT allowed the establishment of a powerful selection procedure for recombinant viruses. In contrast to the conventional vaccinia thymidine kinase (tk) selection that is performed in tk-negative cell lines, AZT selection can be performed in normal (tk-positive) cell lines. The technique is especially useful for the generation of replication-deficient vaccinia viruses and may also be used for gene knock-out studies of essential vaccinia genes

Quantitative and Dynamic Imaging of ATM Kinase Activity.

Science.gov (United States)

Nyati, Shyam; Young, Grant; Ross, Brian Dale; Rehemtulla, Alnawaz

2017-01-01

Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase critical to the cellular DNA-damage response, including DNA double-strand breaks (DSBs). ATM activation results in the initiation of a complex cascade of events facilitating DNA damage repair, cell cycle checkpoint control, and survival. Traditionally, protein kinases have been analyzed in vitro using biochemical methods (kinase assays using purified proteins or immunological assays) requiring a large number of cells and cell lysis. Genetically encoded biosensors based on optical molecular imaging such as fluorescence or bioluminescence have been developed to enable interrogation of kinase activities in live cells with a high signal to background. We have genetically engineered a hybrid protein whose bioluminescent activity is dependent on the ATM-mediated phosphorylation of a substrate. The engineered protein consists of the split luciferase-based protein complementation pair with a CHK2 (a substrate for ATM kinase activity) target sequence and a phospho-serine/threonine-binding domain, FHA2, derived from yeast Rad53. Phosphorylation of the serine residue within the target sequence by ATM would lead to its interaction with the phospho-serine-binding domain, thereby preventing complementation of the split luciferase pair and loss of reporter activity. Bioluminescence imaging of reporter expressing cells in cultured plates or as mouse xenografts provides a quantitative surrogate for ATM kinase activity and therefore the cellular DNA damage response in a noninvasive, dynamic fashion.

Can a Proper T-Cell Development Occur in an Altered Thymic Epithelium? Lessons From EphB-Deficient Thymi

Directory of Open Access Journals (Sweden)

Juan José Muñoz

2018-04-01

Full Text Available For a long time, the effects of distinct Eph tyrosine kinase receptors and their ligands, ephrins on the structure, immunophenotype, and development of thymus and their main cell components, thymocytes (T and thymic epithelial cells (TECs, have been studied. In recent years, the thymic phenotype of mutant mice deficient in several Ephs and ephrins B has been determined. Remarkably, thymic stroma in these animals exhibits important defects that appear early in ontogeny but little alterations in the proportions of distinct lymphoid cell populations. In the present manuscript, we summarize and extend these results discussing possible mechanisms governing phenotypical and functional thymocyte maturation in an absence of the critical T–TEC interactions, concluding that some signaling mediated by key molecules, such as MHCII, CD80, β5t, Aire, etc. could be sufficient to enable a proper maturation of thymocytes, independently of morphological alterations affecting thymic epithelium.

Auxin efflux by PIN-FORMED proteins is activated by two different protein kinases, D6 PROTEIN KINASE and PINOID

KAUST Repository

Zourelidou, Melina; Absmanner, Birgit; Weller, Benjamin; Barbosa, Inê s CR; Willige, Bjö rn C; Fastner, Astrid; Streit, Verena; Port, Sarah A; Colcombet, Jean; de la Fuente van Bentem, Sergio; Hirt, Heribert; Kuster, Bernhard; Schulze, Waltraud X; Hammes, Ulrich Z; Schwechheimer, Claus

2014-01-01

The development and morphology of vascular plants is critically determined by synthesis and proper distribution of the phytohormone auxin. The directed cell-to-cell distribution of auxin is achieved through a system of auxin influx and efflux transporters. PIN-FORMED (PIN) proteins are proposed auxin efflux transporters, and auxin fluxes can seemingly be predicted based on the-in many cells-asymmetric plasma membrane distribution of PINs. Here, we show in a heterologous Xenopus oocyte system as well as in Arabidopsis thaliana inflorescence stems that PIN-mediated auxin transport is directly activated by D6 PROTEIN KINASE (D6PK) and PINOID (PID)/WAG kinases of the Arabidopsis AGCVIII kinase family. At the same time, we reveal that D6PKs and PID have differential phosphosite preferences. Our study suggests that PIN activation by protein kinases is a crucial component of auxin transport control that must be taken into account to understand auxin distribution within the plant.

Auxin efflux by PIN-FORMED proteins is activated by two different protein kinases, D6 PROTEIN KINASE and PINOID

KAUST Repository

Zourelidou, Melina

2014-06-19

The development and morphology of vascular plants is critically determined by synthesis and proper distribution of the phytohormone auxin. The directed cell-to-cell distribution of auxin is achieved through a system of auxin influx and efflux transporters. PIN-FORMED (PIN) proteins are proposed auxin efflux transporters, and auxin fluxes can seemingly be predicted based on the-in many cells-asymmetric plasma membrane distribution of PINs. Here, we show in a heterologous Xenopus oocyte system as well as in Arabidopsis thaliana inflorescence stems that PIN-mediated auxin transport is directly activated by D6 PROTEIN KINASE (D6PK) and PINOID (PID)/WAG kinases of the Arabidopsis AGCVIII kinase family. At the same time, we reveal that D6PKs and PID have differential phosphosite preferences. Our study suggests that PIN activation by protein kinases is a crucial component of auxin transport control that must be taken into account to understand auxin distribution within the plant.

Kinase detection with gallium nitride based high electron mobility transistors.

Science.gov (United States)

Makowski, Matthew S; Bryan, Isaac; Sitar, Zlatko; Arellano, Consuelo; Xie, Jinqiao; Collazo, Ramon; Ivanisevic, Albena

2013-07-01

A label-free kinase detection system was fabricated by the adsorption of gold nanoparticles functionalized with kinase inhibitor onto AlGaN/GaN high electron mobility transistors (HEMTs). The HEMTs were operated near threshold voltage due to the greatest sensitivity in this operational region. The Au NP/HEMT biosensor system electrically detected 1 pM SRC kinase in ionic solutions. These results are pertinent to drug development applications associated with kinase sensing.

Diversity, classification and function of the plant protein kinase superfamily

OpenAIRE

Lehti-Shiu, Melissa D.; Shiu, Shin-Han

2012-01-01

Eukaryotic protein kinases belong to a large superfamily with hundreds to thousands of copies and are components of essentially all cellular functions. The goals of this study are to classify protein kinases from 25 plant species and to assess their evolutionary history in conjunction with consideration of their molecular functions. The protein kinase superfamily has expanded in the flowering plant lineage, in part through recent duplications. As a result, the flowering plant protein kinase r...

Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation.

Science.gov (United States)

Zhou, Haoming; Wang, Han; Ni, Ming; Yue, Shi; Xia, Yongxiang; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

2018-02-13

Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo. We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model. Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection

The role of p38 MAP kinase and c-Jun N-terminal protein kinase signaling in the differentiation and apoptosis of immortalized neural stem cells

International Nuclear Information System (INIS)

Yang, Se-Ran; Cho, Sung-Dae; Ahn, Nam-Shik; Jung, Ji-Won; Park, Joon-Suk; Jo, Eun-Hye; Hwang, Jae-Woong; Kim, Sung-Hoon; Lee, Bong-Hee; Kang, Kyung-Sun; Lee, Yong-Soon

2005-01-01

The two distinct members of the mitogen-activated protein (MAP) kinase family c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, play an important role in central nervous system (CNS) development and differentiation. However, their role and functions are not completely understood in CNS. To facilitate in vitro study, we have established an immortal stem cell line using SV40 from fetal rat embryonic day 17. In these cells, MAP kinase inhibitors (SP600125, SB202190, and PD98059) were treated for 1, 24, 48, and 72 h to examine the roles of protein kinases. Early inhibition of JNK did not alter phenotypic or morphological changes of immortalized cells, however overexpression of Bax and decrease of phosphorylated AKT was observed. The prolonged inhibition of JNK induced polyploidization of immortalized cells, and resulted in differentiation and inhibition of cell proliferation. Moreover, JNK and p38 MAP kinase but not ERK1/2 was activated, and p21, p53, and Bax were overexpressed by prolonged inhibition of JNK. These results indicate that JNK and p38 MAP kinase could play dual roles on cell survival and apoptosis. Furthermore, this established cell line could facilitate study of the role of JNK and p38 MAP kinase on CNS development or differentiation/apoptosis

Structural analysis of the Csk homologous kinase CHK

International Nuclear Information System (INIS)

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

2003-01-01

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

Interleukin-1 beta induced synthesis of protein kinase C-delta and protein kinase C-epsilon in EL4 thymoma cells: possible involvement of phosphatidylinositol 3-kinase.

Science.gov (United States)

Varley, C L; Royds, J A; Brown, B L; Dobson, P R

2001-01-01

We present evidence here that the proinflammatory cytokine, interleukin-1 beta (IL-1 beta) stimulates a significant increase in protein kinase C (PKC)-epsilon and PKC-delta protein levels and increases PKC-epsilon, but not PKC-delta, transcripts in EL4 thymoma cells. Incubation of EL4 cells with IL-1 beta induced protein synthesis of PKC-epsilon (6-fold increase) by 7 h and had a biphasic effect on PKC-delta levels with peaks at 4 h (2-fold increase) and 24 h (4-fold increase). At the level of mRNA, PKC-epsilon, but not PKC-delta levels, were induced after incubation of EL4 cells with IL-1 beta. The signalling mechanisms utilized by IL-1 beta to induce the synthesis of these PKC isoforms were investigated. Two phosphatidylinositol (PI) 3-kinase-specific inhibitors, wortmannin and LY294002, inhibited IL-1 beta-induced synthesis of PKC-epsilon. However, the PI 3-kinase inhibitors had little effect on the IL-1 beta-induced synthesis of PKC-delta in these cells. Our results indicate that IL-1 beta induced both PKC-delta and PKC-epsilon expression over different time periods. Furthermore, our evidence suggests that IL-1 beta induction of PKC-epsilon, but not PKC-delta, may occur via the PI 3-kinase pathway. Copyright 2001 S. Karger AG, Basel

Structure of Human G Protein-Coupled Receptor Kinase 2 in Complex with the Kinase Inhibitor Balanol

Energy Technology Data Exchange (ETDEWEB)

Tesmer, John J.G.; Tesmer, Valerie M.; Lodowski, David T.; Steinhagen, Henning; Huber, Jochen (Sanofi); (Michigan); (Texas)

2010-07-19

G protein-coupled receptor kinase 2 (GRK2) is a pharmaceutical target for the treatment of cardiovascular diseases such as congestive heart failure, myocardial infarction, and hypertension. To better understand how nanomolar inhibition and selectivity for GRK2 might be achieved, we have determined crystal structures of human GRK2 in complex with G{beta}{gamma} in the presence and absence of the AGC kinase inhibitor balanol. The selectivity of balanol among human GRKs is assessed.

Prevención de la adicción a videojuegos: eficacia de las técnicas de control de la impulsividad en el programa PrevTec 3.1

OpenAIRE

Marco Puche, Clara

2013-01-01

Participaron 1.1106 alumnos de Educación Primaria y Secundaria de 13 centros educativos de la ciudad de Valencia y su área metropolitana. Se aplicó un diseño mixto o de medidas parcialmente repetidas, con una variable intra-sujeto –momento de medida- y una variable entre-sujetos –un grupo recibió las sesiones del programa PrevTec 3.1 (tradicional), otro recibió el programa con técnicas de control de la impulsividad adicionales, y un tercer grupo conformó el grupo en lista de espera-. Las ...

Mycosporine-Like Amino Acids Promote Wound Healing through Focal Adhesion Kinase (FAK and Mitogen-Activated Protein Kinases (MAP Kinases Signaling Pathway in Keratinocytes

Directory of Open Access Journals (Sweden)

Yun-Hee Choi

2015-11-01

Full Text Available Mycosporine-like amino acids (MAAs are secondary metabolites found in diverse marine, freshwater, and terrestrial organisms. Evidence suggests that MAAs have several beneficial effects on skin homeostasis such as protection against UV radiation and reactive oxygen species (ROS. In addition, MAAs are also involved in the modulation of skin fibroblasts proliferation. However, the regulatory function of MAAs on wound repair in human skin is not yet clearly elucidated. To investigate the roles of MAAs on the wound healing process in human keratinocytes, three MAAs, Shinorine (SH, Mycosporine-glycine (M-Gly, and Porphyra (P334 were purified from Chlamydomonas hedlyei and Porphyra yezoensis. We found that SH, M-Gly, and P334 have significant effects on the wound healing process in human keratinocytes and these effects were mediated by activation of focal adhesion kinases (FAK, extracellular signal-regulated kinases (ERK, and c-Jun N-terminal kinases (JNK. These results suggest that MAAs accelerate wound repair by activating the FAK-MAPK signaling pathways. This study also indicates that MAAs can act as a new wound healing agent and further suggests that MAAs might be a novel biomaterial for wound healing therapies.

Mycosporine-Like Amino Acids Promote Wound Healing through Focal Adhesion Kinase (FAK) and Mitogen-Activated Protein Kinases (MAP Kinases) Signaling Pathway in Keratinocytes

Science.gov (United States)

Choi, Yun-Hee; Yang, Dong Joo; Kulkarni, Atul; Moh, Sang Hyun; Kim, Ki Woo

2015-01-01

Mycosporine-like amino acids (MAAs) are secondary metabolites found in diverse marine, freshwater, and terrestrial organisms. Evidence suggests that MAAs have several beneficial effects on skin homeostasis such as protection against UV radiation and reactive oxygen species (ROS). In addition, MAAs are also involved in the modulation of skin fibroblasts proliferation. However, the regulatory function of MAAs on wound repair in human skin is not yet clearly elucidated. To investigate the roles of MAAs on the wound healing process in human keratinocytes, three MAAs, Shinorine (SH), Mycosporine-glycine (M-Gly), and Porphyra (P334) were purified from Chlamydomonas hedlyei and Porphyra yezoensis. We found that SH, M-Gly, and P334 have significant effects on the wound healing process in human keratinocytes and these effects were mediated by activation of focal adhesion kinases (FAK), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinases (JNK). These results suggest that MAAs accelerate wound repair by activating the FAK-MAPK signaling pathways. This study also indicates that MAAs can act as a new wound healing agent and further suggests that MAAs might be a novel biomaterial for wound healing therapies. PMID:26703626

AGC kinases, mechanisms of regulation ‎and innovative drug development.

Science.gov (United States)

Leroux, Alejandro E; Schulze, Jörg O; Biondi, Ricardo M

2018-02-01

The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Germinal Center Kinases SmKIN3 and SmKIN24 Are Associated with the Sordaria macrospora Striatin-Interacting Phosphatase and Kinase (STRIPAK) Complex.

Science.gov (United States)

Frey, Stefan; Reschka, Eva J; Pöggeler, Stefanie

2015-01-01

The striatin-interacting phosphatase and kinase (STRIPAK) complex is composed of striatin, protein phosphatase PP2A and protein kinases that regulate development in animals and fungi. In the filamentous ascomycete Sordaria macrospora, it is required for fruiting-body development and cell fusion. Here, we report on the presence and function of STRIPAK-associated kinases in ascomycetes. Using the mammalian germinal center kinases (GCKs) MST4, STK24, STK25 and MINK1 as query, we identified the two putative homologs SmKIN3 and SmKIN24 in S. macrospora. A BLASTP search revealed that both kinases are conserved among filamentous ascomycetes. The physical interaction of the striatin homolog PRO11 with SmKIN3 and SmKIN24 were verified by yeast two-hybrid (Y2H) interaction studies and for SmKIN3 by co-Immunoprecipitation (co-IP). In vivo localization found that both kinases were present at the septa and deletion of both Smkin3 and Smkin24 led to abnormal septum distribution. While deletion of Smkin3 caused larger distances between adjacent septa and increased aerial hyphae, deletion of Smkin24 led to closer spacing of septa and to sterility. Although phenotypically distinct, both kinases appear to function independently because the double-knockout strain ΔSmkin3/ΔSmkin24 displayed the combined phenotypes of each single-deletion strain.

Germinal Center Kinases SmKIN3 and SmKIN24 Are Associated with the Sordaria macrospora Striatin-Interacting Phosphatase and Kinase (STRIPAK Complex.

Directory of Open Access Journals (Sweden)

Stefan Frey

Full Text Available The striatin-interacting phosphatase and kinase (STRIPAK complex is composed of striatin, protein phosphatase PP2A and protein kinases that regulate development in animals and fungi. In the filamentous ascomycete Sordaria macrospora, it is required for fruiting-body development and cell fusion. Here, we report on the presence and function of STRIPAK-associated kinases in ascomycetes. Using the mammalian germinal center kinases (GCKs MST4, STK24, STK25 and MINK1 as query, we identified the two putative homologs SmKIN3 and SmKIN24 in S. macrospora. A BLASTP search revealed that both kinases are conserved among filamentous ascomycetes. The physical interaction of the striatin homolog PRO11 with SmKIN3 and SmKIN24 were verified by yeast two-hybrid (Y2H interaction studies and for SmKIN3 by co-Immunoprecipitation (co-IP. In vivo localization found that both kinases were present at the septa and deletion of both Smkin3 and Smkin24 led to abnormal septum distribution. While deletion of Smkin3 caused larger distances between adjacent septa and increased aerial hyphae, deletion of Smkin24 led to closer spacing of septa and to sterility. Although phenotypically distinct, both kinases appear to function independently because the double-knockout strain ΔSmkin3/ΔSmkin24 displayed the combined phenotypes of each single-deletion strain.

Reflexões sobre mediação pedagógica em programas de formação a distância (e-TEC Brasil)

OpenAIRE

Queiroz, Magali Aparecida Mendes; IFTM- Instituto Federal de Educação Ciência e Tecnologia do Triângulo Mineiro

2012-01-01

Resumo: A educação a distância é hoje uma realidade, não só em cursos de nível superior, mas também em nível médio como é o caso do Programa Escola Técnica Aberta do Brasil (e-TEC Brasil), do Ministério da Educação. Este artigo faz uma análise sobre a mediação pedagógica nesta modalidade de ensino no tocante ao papel do professor frente a este novo paradigma e a sua abrangência social e educacional. As reflexões teóricas fundamentam-se em Lima (2007), Behrens (2000), Moran (2003), Lévy (2000)...

Deoxyribonucleoside kinases in mitochondrial DNA depletion.

Science.gov (United States)

Saada-Reisch, Ann

2004-10-01

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a heterogeneous group of mitochondrial disorders, manifested by a decreased mtDNA copy number and respiratory chain dysfunction. Primary MDS are inherited autosomally and may affect a single organ or multiple tissues. Mutated mitochondrial deoxyribonucleoside kinases; deoxyguanosine kinase (dGK) and thymidine kinase 2 (TK2), were associated with the hepatocerebral and myopathic forms of MDS respectively. dGK and TK2 are key enzymes in the mitochondrial nucleotide salvage pathway, providing the mitochondria with deoxyribonucleotides (dNP) essential for mtDNA synthesis. Although the mitochondrial dNP pool is physically separated from the cytosolic one, dNP's may still be imported through specific transport. Non-replicating tissues, where cytosolic dNP supply is down regulated, are thus particularly vulnerable to dGK and TK2 deficiency. The overlapping substrate specificity of deoxycytidine kinase (dCK) may explain the relative sparing of muscle in dGK deficiency, while low basal TK2 activity render this tissue susceptible to TK2 deficiency. The precise pathophysiological mechanisms of mtDNA depletion due to dGK and TK2 deficiencies remain to be determined, though recent findings confirm that it is attributed to imbalanced dNTP pools.

The 'retro-design' concept for novel kinase inhibitors.

Science.gov (United States)

Müller, Gerhard; Sennhenn, Peter C; Woodcock, Timothy; Neumann, Lars

2010-07-01

Protein kinases are among the most attractive therapeutic targets for a broad range of diseases. This feature review highlights and classifies the main design principles employed to generate active and selective kinase inhibitors. In particular, emphasis is focused on a fragment-based lead-generation approach, which constitutes a novel design method for developing type II kinase inhibitors with distinct binding kinetic attributes. This 'retro-design' strategy relies on a customized fragment library, and contrasts the traditional approach used in the design of type II inhibitors.

A chimeric cyclic interferon-α2b peptide induces apoptosis by sequential activation of phosphatidylinositol 3-kinase, protein kinase Cδ and p38 MAP kinase.

Science.gov (United States)

Blank, V C; Bertucci, L; Furmento, V A; Peña, C; Marino, V J; Roguin, L P

2013-06-10

We have previously demonstrated that tyrosine phosphorylation of STAT1/3 and p38 mitogen-activated protein kinase (p38 MAPK) activation are involved in the apoptotic response triggered by a chimeric cyclic peptide of the interferon-α2b (IFN-α2b) in WISH cells. Since the peptide also induced serine phosphorylation of STAT proteins, in the present study we examined the kinase involved in serine STAT1 phosphorylation and the signaling effectors acting upstream such activation. We first found that p38 MAPK is involved in serine STAT1 phosphorylation, since a reduction of phophoserine-STAT1 levels was evident after incubating WISH cells with cyclic peptide in the presence of a p38 pharmacological inhibitor or a dominant-negative p38 mutant. Next, we demonstrated that the peptide induced activation of protein kinase Cδ (PKCδ). Based on this finding, the role of this kinase was then evaluated. After incubating WISH cells with a PKCδ inhibitor or after decreasing PKCδ expression levels by RNA interference, both peptide-induced serine STAT1 and p38 phosphorylation levels were significantly decreased, indicating that PKCδ functions as an upstream regulator of p38. We also showed that PKCδ and p38 activation stimulated by the peptide was inhibited by a specific pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) or by a dominant-negative p85 PI3K-regulatory subunit, suggesting that PI3K is upstream in the signaling cascade. In addition, the role of PI3K and PKCδ in cyclic peptide-induced apoptosis was examined. Both signaling effectors were found to regulate the antiproliferative activity and the apoptotic response triggered by the cyclic peptide in WISH cells. In conclusion, we herein demonstrated that STAT1 serine phosphorylation is mediated by the sequential activation of PI3K, PKCδ and p38 MAPK. This signaling cascade contributes to the antitumor effect induced by the chimeric IFN-α2b cyclic peptide in WISH cells. Copyright © 2013 Elsevier Inc

Creatine kinase activity is associated with blood pressure

NARCIS (Netherlands)

Brewster, Lizzy M.; Mairuhu, Gideon; Bindraban, Navin R.; Koopmans, Richard P.; Clark, Joseph F.; van Montfrans, Gert A.

2006-01-01

BACKGROUND: We previously hypothesized that high activity of creatine kinase, the central regulatory enzyme of energy metabolism, facilitates the development of high blood pressure. Creatine kinase rapidly provides adenosine triphosphate to highly energy-demanding processes, including cardiovascular

A Stabilized Demethoxyviridin Derivative Inhibits PI3 kinase

Science.gov (United States)

Yuan, Hushan; Pupo, Monica T.; Blois, Joe; Smith, Adam; Weissleder, Ralph; Clardy, Jon; Josephson, Lee

2009-01-01

The viridins like demethoxyviridin (Dmv) and wortmannin (Wm) are nanomolar inhibitors of the PI3 kinases, a family of enzymes that play key roles in a host of regulatory processes. Central to the use of these compounds to investigate the role of PI3 kinase in biological systems, or as scaffolds for drug development, are the interrelated issues of stability, chemical reactivity, and bioactivity as inhibitors of PI3 kinase. We found that Dmv was an even more potent inhibitor of PI3 kinase than Wm. However, Dmv was notably less stable than Wm in PBS, with a half-life of 26 min vs Wm’s half-life of 3470 min. Dmv, like Wm, disappeared in culture media with a half-life of less than 1 min. To overcome Dmv’s instability, it was esterified at the C1 position, and then reacted with glycine at the C20 position. The resulting Dmv derivative, termed SA-DmvC20-Gly had a half-life of 218 min in PBS and 64 min in culture media. SA-DmvC20-Gly underwent an exchange reaction at the C20 position with N-acetyl lysine in a manner similar to a WmC20 derivative, WmC20-Proline. SA-DmvC20-Gly inhibited PI3 kinase with an IC50 of 44 nM, compared to Wm’s IC50 of 12 nM. These results indicate that the stability of Dmv can be manipulated by reactions at the C1 and C20 positions, while substantially maintaining its ability to inhibit PI3 kinase. Our results indicate it may be possible to obtain stabilized Dmv derivatives for use as PI3 kinase inhibitors in biological systems. PMID:19523825

Geomagnetic storm effects in ionospheric TEC at an euatorial station: contribution of EXB drifts and meridional neutral winds

International Nuclear Information System (INIS)

Dabas, R.S.; Jain, A.R.

1985-01-01

Storm-time variations in TEC measurements at the Indian station Ootacamund with IEC data for four stations in the anomaly region. Variations in Nsub(T)(OOTY) are found to be smaller compared to those observed at anomaly stations. The equatorial electrojet control of Nsub(T)(OOTY) is weaker compared to that of Nsub(m)F2. This result and absence of midday biteout in Nsub(T)(OOTY) are interpreted in terms of plasma exchange between ionosphere and plasmasphere which, to some extent, compensates the loss of plasma in the column due to E x B drifts. The anomaly depth is found to be well correlated with the electrojet strength. It is also noticed that for the same anomaly is weaker on a storm day than for quiet days. This is interpreted in terms of converging equatorward meridional winds. Thus, ionosphere-plasmasphere plasma exchange and, during disturbed period, the converging equatorward meridional winds also have significant effects on the distribution of ionization at these latitudes though the E x B drifts are most important in affecting the ionization distribution at low latitudes. (author)

Role of nongenomic activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase 1/2 pathways in 1,25D3-mediated apoptosis in squamous cell carcinoma cells.

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Kong, Rui-Xian; Trump, Donald L; Johnson, Candace S

2006-08-15

Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1 alpha,25-dihydroxyvitamin D(3) (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V-positive cells and increased sub-G(1) population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells.

Protein kinase A regulatory subunit distribution in medulloblastoma

International Nuclear Information System (INIS)

Mucignat-Caretta, Carla; Denaro, Luca; Redaelli, Marco; D'Avella, Domenico; Caretta, Antonio

2010-01-01

Previous studies showed a differential distribution of the four regulatory subunits of cAMP-dependent protein kinases inside the brain, that changed in rodent gliomas: therefore, the distribution of these proteins inside the brain can give information on the functional state of the cells. Our goal was to examine human brain tumors to provide evidence for a differential distribution of protein kinase A in different tumors. The distribution of detergent insoluble regulatory (R1 and R2) and catalytic subunits of cAMP dependent kinases was examined in pediatric brain tumors by immunohistochemistry and fluorescent cAMP analogues binding. R2 is organized in large single dots in medulloblastomas, while it has a different appearance in other tumors. Fluorescent cAMP labelling was observed only in medulloblastoma. A different distribution of cAMP dependent protein kinases has been observed in medulloblastoma

Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells.

Science.gov (United States)

Evans, Robert; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Keats, Jonathan; Maxwell, Christopher; Perry, Troy; Chau, Heidi; Belch, Andrew; Pilarski, Linda; Reiman, Tony

2008-03-01

The expression of RHAMM and other centrosome-associated genes are known to correlate with the extent of centrosome amplification in multiple myeloma, and with poor prognosis. RHAMM has a significant interaction with TPX2, a protein which regulates the localization and action of Aurora A kinase (AURKA) at the spindle poles. AURKA is known to be a central determinant of centrosome and spindle function and is a target for cancer therapy. Given these observations, we investigated the role of Aurora kinases as therapeutic targets in myeloma. Here we report that AURKA is expressed ubiquitously in myeloma, to varying degrees, in both cell lines and patients' bone marrow plasma cells. siRNA targeting AURKA induces apoptotic cell death in myeloma cell lines. The Aurora kinase inhibitor VE-465 also induces apoptosis and death in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. The phenotype of myeloma cells treated with VE-465 is consistent with published reports on the effects of Aurora kinase inhibition. Aurora kinase inhibitors should be pursued as potential treatments for myeloma.

LmxMPK4, an essential mitogen-activated protein kinase of Leishmania mexicana is phosphorylated and activated by the STE7-like protein kinase LmxMKK5

DEFF Research Database (Denmark)

John von Freyend, Simona; Rosenqvist, Heidi; Fink, Annette

2010-01-01

The essential mitogen-activated protein kinase (MAP kinase), LmxMPK4, of Leishmania mexicana is minimally active when purified following recombinant expression in Escherichia coli and was therefore unsuitable for drug screening until now. Using an E. coli protein co-expression system we identified...... LmxMKK5, a STE7-like protein kinase from L. mexicana, which phosphorylates and activates recombinant LmxMPK4 in vitro. LmxMKK5 is comprised of 525 amino acids and has a calculated molecular mass of 55.9kDa. The co-expressed, purified LmxMPK4 showed strong phosphotransferase activity in radiometric...... kinase assays and was confirmed by immunoblot and tandem mass spectrometry analyses to be phosphorylated on threonine 190 and tyrosine 192 of the typical TXY MAP kinase activation motif. The universal protein kinase inhibitor staurosporine reduced the phosphotransferase activity of co...

Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.

Science.gov (United States)

Roskoski, Robert

2005-11-11

Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of

Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation

OpenAIRE

Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E. M.; Jenkins, Jermaine L.; Heimiller, Chelsea; Maines, Mahin D.

2016-01-01

Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1–3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T308 before S473 autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present ...

Using GPS TEC measurements to probe ionospheric spatial spectra at mid-latitudes

Science.gov (United States)

Lay, E. H.; Parker, P. A.; Light, M. E.; Carrano, C. S.; Debchoudhury, S.; Haaser, R. A.

2017-12-01

The physics of how random ionospheric structure causes signal degradation is well understood as weak forward scattering through an effective diffraction grating created by plasma irregularities in the ionosphere. However, the spatial scale spectrum of those irregularities required for input into scintillation models and models of traveling ionospheric disturbances is poorly characterized, particularly at the kilometer to tens of kilometer scale lengths important for very-high-frequency (VHF) scintillation prediction. Furthermore, the majority of characterization studies have been performed in low-latitude or high-latitude regions where geomagnetic activity dominates the physical processes. At mid-latitudes, tropospheric and geomagnetic phenomena compete in disturbing the ionosphere, and it is not well understood how these multiple sources affect the drivers that influence the spatial spectrum. In this study, we are interested in mid-latitude electron density irregularities on the order of 10s of kilometers that would affect VHF signals. Data from the GPS networks Japan GEONET and the Plate Boundary Observatory (PBO, UNAVCO) in the western United States were analyzed for this study. Japan GEONET is a dense network of GPS receivers (station spacing of tens of km), with fairly evenly spaced positions over all of Japan. The PBO, on the other hand, has several pockets of extremely dense coverage (station spacing within a few km), but is less dense on average. We analyze a day with a large solar storm (2015/03/17, St. Patrick's Day Storm) to allow high scintillation potential at mid-latitudes, a day with low geomagnetic activity and low thunderstorm activity (2016/01/31), and a day with low geomagnetic activity and high thunderstorm activity (2015/08/02). We then perform two-dimensional spatial analyses on the TEC data from these two networks on scale lengths of 20 to 200 km to infer the spatial scale spectra.

PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.

Science.gov (United States)

Deng, Youping; Xu, Hu; Riedel, Heimo

2007-02-15

The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.

Effects of phorbol ester on mitogen-activated protein kinase kinase activity in wild-type and phorbol ester-resistant EL4 thymoma cells.

Science.gov (United States)

Gause, K C; Homma, M K; Licciardi, K A; Seger, R; Ahn, N G; Peterson, M J; Krebs, E G; Meier, K E

1993-08-05

Phorbol ester-sensitive and -resistant EL4 thymoma cell lines differ in their ability to activate mitogen-activated protein kinase (MAPK) in response to phorbol ester. Treatment of wild-type EL4 cells with phorbol ester results in the rapid activations of MAPK and pp90rsk kinase, a substrate for MAPK, while neither kinase is activated in response to phorbol ester in variant EL4 cells. This study examines the activation of MAPK kinase (MAPKK), an activator of MAPK, in wild-type and variant EL4 cells. Phosphorylation of a 40-kDa substrate, identified as MAPK, was observed following in vitro phosphorylation reactions using cytosolic extracts or Mono Q column fractions prepared from phorbol ester-treated wild-type EL4 cells. MAPKK activity coeluted with a portion of the inactive MAPK upon Mono Q anion-exchange chromatography, permitting detection of the MAPKK activity in fractions containing both kinases. This MAPKK activity was present in phorbol ester-treated wild-type cells, but not in phorbol ester-treated variant cells or in untreated wild-type or variant cells. The MAPKK from wild-type cells was able to activate MAPK prepared from either wild-type or variant cells. MAPKK activity could be stimulated in both wildtype and variant EL4 cells in response to treatment of cells with okadaic acid. These results indicate that the failure of variant EL4 cells to activate MAP kinase in response to phorbol ester is due to a failure to activate MAPKK. Therefore, the step that confers phorbol ester resistance to variant EL4 cells lies between the activation of protein kinase C and the activation of MAPKK.

Synapses of Amphids Defective (SAD-A) Kinase Promotes Glucose-stimulated Insulin Secretion through Activation of p21-activated Kinase (PAK1) in Pancreatic β-Cells*

Science.gov (United States)

Nie, Jia; Sun, Chao; Faruque, Omar; Ye, Guangming; Li, Jia; Liang, Qiangrong; Chang, Zhijie; Yang, Wannian; Han, Xiao; Shi, Yuguang

2012-01-01

The p21-activated kinase-1 (PAK1) is implicated in regulation of insulin exocytosis as an effector of Rho GTPases. PAK1 is activated by the onset of glucose-stimulated insulin secretion (GSIS) through phosphorylation of Thr-423, a major activation site by Cdc42 and Rac1. However, the kinase(s) that phosphorylates PAK1 at Thr-423 in islet β-cells remains elusive. The present studies identified SAD-A (synapses of amphids defective), a member of AMP-activated protein kinase-related kinases exclusively expressed in brain and pancreas, as a key regulator of GSIS through activation of PAK1. We show that SAD-A directly binds to PAK1 through its kinase domain. The interaction is mediated by the p21-binding domain (PBD) of PAK1 and requires both kinases in an active conformation. The binding leads to direct phosphorylation of PAK1 at Thr-423 by SAD-A, triggering the onset of GSIS from islet β-cells. Consequently, ablation of PAK1 kinase activity or depletion of PAK1 expression completely abolishes the potentiating effect of SAD-A on GSIS. Consistent with its role in regulating GSIS, overexpression of SAD-A in MIN6 islet β-cells significantly stimulated cytoskeletal remodeling, which is required for insulin exocytosis. Together, the present studies identified a critical role of SAD-A in the activation of PAK1 during the onset of insulin exocytosis. PMID:22669945

Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic β-Cells.

Science.gov (United States)

Nie, Jia; Sun, Chao; Faruque, Omar; Ye, Guangming; Li, Jia; Liang, Qiangrong; Chang, Zhijie; Yang, Wannian; Han, Xiao; Shi, Yuguang

2012-07-27

The p21-activated kinase-1 (PAK1) is implicated in regulation of insulin exocytosis as an effector of Rho GTPases. PAK1 is activated by the onset of glucose-stimulated insulin secretion (GSIS) through phosphorylation of Thr-423, a major activation site by Cdc42 and Rac1. However, the kinase(s) that phosphorylates PAK1 at Thr-423 in islet β-cells remains elusive. The present studies identified SAD-A (synapses of amphids defective), a member of AMP-activated protein kinase-related kinases exclusively expressed in brain and pancreas, as a key regulator of GSIS through activation of PAK1. We show that SAD-A directly binds to PAK1 through its kinase domain. The interaction is mediated by the p21-binding domain (PBD) of PAK1 and requires both kinases in an active conformation. The binding leads to direct phosphorylation of PAK1 at Thr-423 by SAD-A, triggering the onset of GSIS from islet β-cells. Consequently, ablation of PAK1 kinase activity or depletion of PAK1 expression completely abolishes the potentiating effect of SAD-A on GSIS. Consistent with its role in regulating GSIS, overexpression of SAD-A in MIN6 islet β-cells significantly stimulated cytoskeletal remodeling, which is required for insulin exocytosis. Together, the present studies identified a critical role of SAD-A in the activation of PAK1 during the onset of insulin exocytosis.

Structural basis for substrate specificities of cellular deoxyribonucleoside kinases

DEFF Research Database (Denmark)

Johansson, K.; Ramaswamy, S.; Ljungcrantz, C.

2001-01-01

Deoxyribonucleoside kinases phosphorylate deoxyribonucleosides and activate a number of medically important nucleoside analogs. Here we report the structure of the Drosophila deoxyribonucleoside kinase with deoxycytidine bound at the nucleoside binding site and that of the human deoxyguanosine ki......; this is apparently due to the presence of Arg 118, which provides favorable hydrogen bonding interactions with the substrate. The two new structures provide an explanation for the substrate specificity of cellular deoxyribonucleoside kinases....

SH2 domains: modulators of nonreceptor tyrosine kinase activity

OpenAIRE

Filippakopoulos, Panagis; Müller, Susanne; Knapp, Stefan

2009-01-01

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed ...

Interactions between Casein kinase Iepsilon (CKIepsilon and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity.

Directory of Open Access Journals (Sweden)

Caroline Lund Dahlberg

Full Text Available Members of the Casein Kinase I (CKI family of serine/threonine kinases regulate diverse biological pathways. The seven mammalian CKI isoforms contain a highly conserved kinase domain and divergent amino- and carboxy-termini. Although they share a preferred target recognition sequence and have overlapping expression patterns, individual isoforms often have specific substrates. In an effort to determine how substrates recognize differences between CKI isoforms, we have examined the interaction between CKIepsilon and two substrates from different signaling pathways.CKIepsilon, but not CKIalpha, binds to and phosphorylates two proteins: Period, a transcriptional regulator of the circadian rhythms pathway, and Disheveled, an activator of the planar cell polarity pathway. We use GST-pull-down assays data to show that two key residues in CKIalpha's kinase domain prevent Disheveled and Period from binding. We also show that the unique C-terminus of CKIepsilon does not determine Dishevelled's and Period's preference for CKIepsilon nor is it essential for binding, but instead plays an auxillary role in stabilizing the interactions of CKIepsilon with its substrates. We demonstrate that autophosphorylation of CKIepsilon's C-terminal tail prevents substrate binding, and use mass spectrometry and chemical crosslinking to reveal how a phosphorylation-dependent interaction between the C-terminal tail and the kinase domain prevents substrate phosphorylation and binding.The biochemical interactions between CKIepsilon and Disheveled, Period, and its own C-terminus lead to models that explain CKIepsilon's specificity and regulation.

Oral protein kinase c β inhibition using ruboxistaurin

DEFF Research Database (Denmark)

Aiello, Lloyd Paul; Vignati, Louis; Sheetz, Matthew J

2011-01-01

To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2 ruboxi...

Intramolecular Crosstalk between Catalytic Activities of Receptor Kinases

KAUST Repository

Kwezi, Lusisizwe

2018-01-22

Signal modulation is important for the growth and development of plants and this process is mediated by a number of factors including physiological growth regulators and their associated signal transduction pathways. Protein kinases play a central role in signaling, including those involving pathogen response mechanisms. We previously demonstrated an active guanylate cyclase (GC) catalytic center in the brassinosteroid insensitive receptor (AtBRI1) within an active intracellular kinase domain resulting in dual enzymatic activity. Here we propose a novel type of receptor architecture that is characterized by a functional GC catalytic center nested in the cytosolic kinase domain enabling intramolecular crosstalk. This may be through a cGMP-AtBRI1 complex forming that may induce a negative feedback mechanism leading to desensitisation of the receptor, regulated through the cGMP production pathway. We further argue that the comparatively low but highly localized cGMP generated by the GC in response to a ligand is sufficient to modulate the kinase activity. This type of receptor therefore provides a molecular switch that directly and/or indirectly affects ligand dependent phosphorylation of downstream signaling cascades and suggests that subsequent signal transduction and modulation works in conjunction with the kinase in downstream signaling.

Intramolecular Crosstalk between Catalytic Activities of Receptor Kinases

KAUST Repository

Kwezi, Lusisizwe; Wheeler, Janet I; Marondedze, Claudius; Gehring, Christoph A; Irving, Helen R

2018-01-01

Signal modulation is important for the growth and development of plants and this process is mediated by a number of factors including physiological growth regulators and their associated signal transduction pathways. Protein kinases play a central role in signaling, including those involving pathogen response mechanisms. We previously demonstrated an active guanylate cyclase (GC) catalytic center in the brassinosteroid insensitive receptor (AtBRI1) within an active intracellular kinase domain resulting in dual enzymatic activity. Here we propose a novel type of receptor architecture that is characterized by a functional GC catalytic center nested in the cytosolic kinase domain enabling intramolecular crosstalk. This may be through a cGMP-AtBRI1 complex forming that may induce a negative feedback mechanism leading to desensitisation of the receptor, regulated through the cGMP production pathway. We further argue that the comparatively low but highly localized cGMP generated by the GC in response to a ligand is sufficient to modulate the kinase activity. This type of receptor therefore provides a molecular switch that directly and/or indirectly affects ligand dependent phosphorylation of downstream signaling cascades and suggests that subsequent signal transduction and modulation works in conjunction with the kinase in downstream signaling.