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Sample records for atf torsatron

  1. Effects of magnetic field perturbations in the ATF torsatron

    Energy Technology Data Exchange (ETDEWEB)

    Colchin, R.J.; England, A.C.; Isler, R.C.; Murakami, M.; Rasmussen, D.A.; Uckan, T.; Wilgen, J.B. [Oak Ridge National Lab., TN (United States); Aceto, S.C.; Zielinski, J.J. [Rensselaer Polytechnic Inst., Troy, NY (United States)

    1993-10-01

    The effects of errors in the magnetic fields of tokamaks on the plasma are quite different from those in stellarators. In tokamaks, field errors can cause disruptive locked modes through the non-linear evolution of tearing modes acting on initially small error-induced islands. Scaling predictions for these effects indicate that the critical relative field error which can be tolerated becomes smaller as the tokamak size becomes larger. In stellarators, the effect is more benign, as field errors appear only to cause increased plasma transport in the vicinity of islands. Great care has been taken to minimize magnetic field errors in the most recent generation of stellarator-type magnetic plasma traps. In the past six years, several new and sensitive techniques have been developed to detect and map field errors. These methods all rely on the detection of electrons injected along magnetic field lines. During the commissioning of ATF, flux surfaces were mapped using the fluorescent screen technique. Field errors were discovered and traced to uncompensated dipoles in the helical current feeds. Prior to elimination of these errors, plasma discharges indicated centrally peaked plasma profiles. After correction of the uncompensated dipoles, flux surfaces were mapped a second time, and the island widths were found to be greatly reduced. Field errors were then deliberately introduced using a set of perturbation coils that had been added to ATF, and electron-beam mapping of the flux surfaces showed that islands several centimeters in width could easily be created by these coils. After elimination of the error fields, the measured plasma temperature and density profiles were much broader. The field-perturbation coils were then used to produce magnetic field asymmetries, and the measured plasma profiles were again shown to narrow as a result of islands.

  2. Assessment of torsatrons as reactors

    Energy Technology Data Exchange (ETDEWEB)

    Lyon, J.F. (Oak Ridge National Lab., TN (United States)); Painter, S.L. (Australian National Univ., Canberra, ACT (Australia))

    1992-12-01

    Stellarators have significant operational advantages over tokamaks as ignited steady-state reactors because stellarators have no dangerous disruptions and no need for continuous current drive or power recirculated to the plasma, both easing the first wall, blanket, and shield design; less severe constraints on the plasma parameters and profiles; and better access for maintenance. This study shows that a reactor based on the torsatron configuration (a stellarator variant) could also have up to double the mass utilization efficiency (MUE) and a significantly lower cost of electricity (COE) than a conventional tokamak reactor (ARIES-I) for a range of assumptions. Torsatron reactors can have much smaller coil systems than tokamak reactors because the coils are closer to the plasma and they have a smaller cross section (higher average current density because of the lower magnetic field). The reactor optimization approach and the costing and component models are those used in the current stage of the ARIES-I tokamak reactor study. Typical reactor parameters for a 1-GW(e) Compact Torsatron reactor example are major radius R[sub 0] = 6.6-8.8 m, on-axis magnetic field B[sup 0] = 4.8-7.5 T, B[sub max] (on coils) = 16 T, MUE 140-210 kW(e)/tonne, and COE (in constant 1990 dollars) = 67-79 mill/kW(e)h. The results are relatively sensitive to assumptions on the level of confinement improvement and the blanket thickness under the inboard half of the helical windings but relatively insensitive to other assumptions.

  3. ATF2 COMMISSIONING

    CERN Document Server

    Seryi, A; Parker, B; Schulte, D; Delahaye, J P; Tomas, R; Zimmermann, F; Wolski, A; Elsen, E; Sanuki, T; Gianfelice-Wendt, E; Ross, M; Wendt, M; Takahashi, T; Bai, S; Gao, J; Bolzon, B; Geffroy, N; Jeremie, A; Apsimon, R; Burrows, P; Constance, B; Perry, C; Resta-Lopez, J; Swinson, C; Araki, S; Aryshev, A; Hayano, H; Honda, Y; Kubo, K; Kume, T; Kuroda, S; Masuzawa, M; Naito, T; Okugi, T; Sugahara, R; Tauchi, T; Terunuma, N; Urakawa, J; Yokoya, K; Iwashita, Y; Sugimoto, T; Heo, A Y; Kim, E S; Kim, H S; Bambade, P; Renier, Y; Rimbault, C; Huang, J Y; Kim, S H; Park, Y J; Hwang, W H; Blair, G; Boogert, S; Karataev, P; Molloy, S; Amann, J; Bellomo, P; Lam, B; McCormick, D; Nelson, J; Paterson, E; Pivi, M; Raubenheimer, T; Spencer, C; Wang, M H; White, G; Wittmer, W; Woodley, M; Yan, Y; Zhou, F; Angal-Kalinin, D; Jones, J; Lyapin, A; Scarfe, A; Kamiya, Y; Komamiya, S; Oroku, M; Suehara, T; Yamanaka, T

    2010-01-01

    ATF2 is a final-focus test beam line that aims to focus the low-emittance beam from the ATF damping ring to a beam size of about 37 nm, and at the same time to demonstrate nm beam stability, using numerous advanced beam diagnostics and feedback tools. The construction has been finished at the end of 2008 and the beam commissioning of ATF2 has started in December of 2008. ATF2 is constructed and commissioned by ATF international collaborations with strong US, Asian and European participation.

  4. ATF2 Commissioning

    Energy Technology Data Exchange (ETDEWEB)

    Seryi, A.; /SLAC; Christian, G.; /KLTE-ATOMKI; Parker, B.; /BNL; Schulte, D.; Delahaye, J.-P.; Tomas, R.; Zimmermann, F.; /CERN; Wolski, A.; Elsen, E.; /Cockcroft Inst. /DESY; Sanuki, T.; /Tohoku U.; Gianfelice-Wendt, E.; Ross, M.; Wendt, M.; /Fermilab; Takahashi, T.; /Hiroshima U.; Bai, S.; Gao, J.; /Beijing, Inst. High Energy Phys.; Bolzon, B.; Geffroy, N.; Jeremie, A.; /Annecy, LAPP; Apsimon, R.; Burrows, P.; /Oxford U., JAI /Kyoto U., Inst. Chem. Res. /Kyungpook Natl. U. /Orsay, LAL /Phang Accelerator Lab /Royal Holloway, U. of London /SLAC /Daresbury /University Coll. London /Manchester U. /Univ. of Tokyo U.

    2009-10-30

    ATF2 is a final-focus test beam line that aims to focus the low-emittance beam from the ATF damping ring to a beam size of about 37 nm, and at the same time to demonstrate nm beam stability, using numerous advanced beam diagnostics and feedback tools. The construction has been finished at the end of 2008 and the beam commissioning of ATF2 has started in December of 2008. ATF2 is constructed and commissioned by ATF international collaborations with strong US, Asian and European participation.

  5. TOREX-4: a torsatron proof of principle experiment

    Energy Technology Data Exchange (ETDEWEB)

    Politzer, P A; Lidsky, L M; Montgomery, D B

    1979-03-01

    TOREX-4 is a torsatron Proof of Principle experiment designed to simultaneously achieve ntau approx. = to 5 x 10/sup 13/, n approx. = to 5 x 10/sup 14//cm/sup 3/, and T greater than or equal to 1 keV. TOREX-4 is capable of operating without externally driven currents; sufficient neutral beam power to reach betas of 2 to 5% is provided. The unique 4(+2) constant pitch angle winding configuration allows the reliable design of large systems with far greater experimental flexibility than can be achieved in conventional stellarators of comparable size. This will allow investigation of the basic physics questions of the torsatron configuration over a wide range of plasma properties and field configurations without sacrifice of the Proof of Principle goals. (MOW)

  6. ATF2 Proposal

    Energy Technology Data Exchange (ETDEWEB)

    Grishanov, Boris Ivanovich; Logachev, Pavel; Podgorny, Fedor; Telnov, Valery; /Novosibirsk, IYF; Angal-Kalinin, Deepa; Appleby, Robert; Jones, James; Kalinin, Alexander; /Daresbury; Napoly, Olivier; Payet, Jacques; /DAPNIA, Saclay; Braun, Hans-Heinrich; Schulte, Daniel; Zimmermann, Frank; /CERN; Barlow, Roger; Bailey, Ian; Jenner, Leo; Jones, Roger; Kourevlev, German; /Daresbury; Walker, Nick; /DESY; Takahasi, Tohru; /Hiroshima U.; Gao, Jie; /Beijing, Inst. High Energy Phys. /Oxford U. /KEK, Tsukuba /Kyoto U., Inst. Chem. Res.

    2005-08-23

    This document is the first of two volumes describing the ATF2 project. The present volume discusses the technical justification for ATF2 and presents a design description. Since the International Committee for Future Accelerator (ICFA) decision on the choice of technology, a world-wide collaboration on the design of the International Linear Collider (ILC) has rapidly progressed [1]. The formation of the Global Design Effort (GDE) will accelerate the work towards a final design. An important technical challenge is obviously the high gradient acceleration but what is similarly challenging is the collision of extremely small beams of a few nanometer size. The latter challenge has three distinct issues: creating small emittance beams, preserving the emittance during acceleration and transport, and focusing the beams to nanometers. Most studies have been done using computer simulations but many issues still remain that require experimental verification. Accelerator Test Facility (ATF) at KEK was built to create small emittance beams, and succeeded in obtaining an emittance that almost satisfies the ILC requirements [2]. In this proposal we present a project, ATF2, which addresses the focusing of the beam into a nanometer spot. The ATF2 project will extend the extraction beamline of the ATF with an ILC-type final focus system to create a tightly focused, stable beam by making use of the small emittance of the ATF. The layout is shown in Figure 1.1. In the longer term, the ATF2 project would also provide invaluable input for the CLIC design of a future multi-TeV collider.

  7. Plasma engineering analysis of a small torsatron reactor

    Energy Technology Data Exchange (ETDEWEB)

    Lacatski, J.T.; Houlberg, W.A.; Uckan, N.A.

    1985-10-01

    This study examines the plasma physics and reactor engineering feasibility of a small, medium aspect ratio, high-beta, l = 2, D-T torsatron power reactor, based on the magnetic configuration of the Advanced Toroidal Facility, Oak Ridge National Laboratory. Plasma analyses are performed to assess whether confinement in a small, average radius plasma is sufficient to yield an ignited or high-Q driven device. Much of the physics assessment focuses on an evaluation of the radial electric field created by the nonambipolar particle flux. Detailed transport simulations are done with both fixed and self-consistent evolution of the radial electric field. Basic reactor engineering considerations taken into account are neutron wall loading, maximum magnetic field at the helical coils, coil shield thickness, and tritium breeding blanket-shield thickness.

  8. A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity.

    Science.gov (United States)

    Diring, Jessica; Camuzeaux, Barbara; Donzeau, Mariel; Vigneron, Marc; Rosa-Calatrava, Manuel; Kedinger, Claude; Chatton, Bruno

    2011-01-01

    Alternative splicing and post-translational modifications are processes that give rise to the complexity of the proteome. The nuclear ATF7 and ATF2 (activating transcription factor) are structurally homologous leucine zipper transcription factors encoded by distinct genes. Stress and growth factors activate ATF2 and ATF7 mainly via sequential phosphorylation of two conserved threonine residues in their activation domain. Distinct protein kinases, among which mitogen-activated protein kinases (MAPK), phosphorylate ATF2 and ATF7 first on Thr71/Thr53 and next on Thr69/Thr51 residues respectively, resulting in transcriptional activation. Here, we identify and characterize a cytoplasmic alternatively spliced isoform of ATF7. This variant, named ATF7-4, inhibits both ATF2 and ATF7 transcriptional activities by impairing the first phosphorylation event on Thr71/Thr53 residues. ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, enabling the release of the kinase and ATF7/ATF2 activation. Our data therefore conclusively establish that ATF7-4 is an important cytoplasmic negative regulator of ATF7 and ATF2 transcription factors.

  9. A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Jessica Diring

    Full Text Available Alternative splicing and post-translational modifications are processes that give rise to the complexity of the proteome. The nuclear ATF7 and ATF2 (activating transcription factor are structurally homologous leucine zipper transcription factors encoded by distinct genes. Stress and growth factors activate ATF2 and ATF7 mainly via sequential phosphorylation of two conserved threonine residues in their activation domain. Distinct protein kinases, among which mitogen-activated protein kinases (MAPK, phosphorylate ATF2 and ATF7 first on Thr71/Thr53 and next on Thr69/Thr51 residues respectively, resulting in transcriptional activation. Here, we identify and characterize a cytoplasmic alternatively spliced isoform of ATF7. This variant, named ATF7-4, inhibits both ATF2 and ATF7 transcriptional activities by impairing the first phosphorylation event on Thr71/Thr53 residues. ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, enabling the release of the kinase and ATF7/ATF2 activation. Our data therefore conclusively establish that ATF7-4 is an important cytoplasmic negative regulator of ATF7 and ATF2 transcription factors.

  10. ATF2 Proposal v. 2

    CERN Document Server

    Grishanov, B I; Alabau-Pons, M; Angal-Kalinin, Deepa; Appleby, R; Araki, S; Bailey, I; Bambade, P; Bane, Karl Leopold Freitag; Barlow, R; Blair, G A; Bolzon, B; Boorman, G; Bosco, A; Brachmann, A; Braun, Hans Heinrich; Burrows, P N; Carter, J; Choi, J; Christian, Glenn B; Clarke, C; Dabiri-Khah, A; Dadoun, O; Danagulyan, S; Delerue, N; Dixit, S; Driouichi, C; Elsen E; Gao, J; Geffroy, N; Gronberg, J; Hartin, Anthony F; Hayano, H; Higashi, Y; Himel, T; Honda, Y; Howell, D; Huang, J Y; Iwashita, Y; Jenner, L; Jones, J; Jones, R; Jérémie, A; Kalinin, A; Kanazawa, K; Kang, H S; Karyotakis, Yu; Kim, E S; Kim, S; Komamiya, S; Kourevlev, German Yu; Kubo, K; Kumada, M; Kume, T; Kuriki, M; Kuroda, S; Liu, W; Logatchev, P V; Lyapin, A; Malton, S; Markiewicz, T W; Masuzawa, M; Mihara, T; Miller, D J; Molloy, S; Mtingwa, S; Naito, T; Nan-Phinney, Y; Napoly, O; Nelson, J; Okugi, T; Payet, J; Pei, G X; Pivi, M T F; Podgorny, F; Price, M; Raubenheimer, T O; Reichold, A; Ross, M; Sanuki, T; Schulte, Daniel; Seryi, R A; Solyak, N; Soo Ko In; Spencer, C M; Suehara, T; Sugahara, R; Takahashi, T; Takashi-Boogert, S; Tauchi, T; Telnov, Valery I; Tenenbaum, P G; Terunuma, N; Toge, N; Torrence, E; Urakawa, J; Urner, D; Vogel, V; Walker, N; Wang, J Q; Wendt, M; White, G; Wing, M; Wolski, A; Woodley, M; Yamaoka, H; Yokoya, K; Zimmermann, Frank

    2006-01-01

    For achieving the high luminosity required at the International Linear Collider (ILC), it is critical to focus the beams to nanometer size with the ILC Beam Delivery System (BDS), and to maintain the beam collision with a nanometer-scale stability. To establish the technologies associated with this ultra-high precision beam handling, it has been proposed to implement an ILC-like final focus optics in an extension of the existing extraction beamline of ATF at KEK. The ATF is considered to be the best platform for this exercise, since it provides an adequate ultra-low emittance electron beam in a manner dedicated to the development of ILC. The two major goals for this facility, called ATF2, are : (A) Achievement of a 37 nm beam size, and (B) control of beam position down to 2 nm level. The scientific justification for the ATF2 project and its technical design have been described in Volume 1 of the ATF2 Proposal [1]. We present here Volume 2 of the ATF2 Proposal, in which we present specifics of the construction...

  11. BNL ATF II beamlines design

    Energy Technology Data Exchange (ETDEWEB)

    Fedurin, M. [Brookhaven National Lab. (BNL), Upton, NY (United States); Jing, Y. [Brookhaven National Lab. (BNL), Upton, NY (United States); Stratakis, D. [Brookhaven National Lab. (BNL), Upton, NY (United States); Swinson, C. [Brookhaven National Lab. (BNL), Upton, NY (United States)

    2015-05-03

    The Brookhaven National Laboratory. Accelerator Test Facility (BNL ATF) is currently undergoing a major upgrade (ATF-II). Together with a new location and much improved facilities, the ATF will see an upgrade in its major capabilities: electron beam energy and quality and CO2 laser power. The electron beam energy will be increased in stages, first to 100-150 MeV followed by a further increase to 500 MeV. Combined with the planned increase in CO2 laser power (from 1-100 TW), the ATF-II will be a powerful tool for Advanced Accelerator research. A high-brightness electron beam, produced by a photocathode gun, will be accelerated and optionally delivered to multiple beamlines. Besides the energy range (up to a possible 500 MeV in the final stage) the electron beam can be tailored to each experiment with options such as: small transverse beam size (<10 um), short bunch length (<100 fsec) and, combined short and small bunch options. This report gives a detailed overview of the ATFII capabilities and beamlines configuration.

  12. Configurational effects on low collision plasma confinement in CHS Heliotron/Torsatron

    Energy Technology Data Exchange (ETDEWEB)

    Heyn, M.F.; Kernbichler, W. [Institut fuer Theoretische Physik, Technische Universitaet Graz, Graz (Austria); Kasilov, S.V.; Nemov, V.V.; Pavlichenko, O.S. [Institute of Plasma Physics, NSC KIPT, Kharkov (Ukraine); Matsuoka, K.; Okamura, S. [National Inst. for Fusion Science, Toki, Gifu (Japan)

    2001-01-01

    Multihelicity effects on low collisionality ({approx}1/v) regime of neoclassical transport has been analyzed for full range of magnetic field configurations of CHS Heliotron/Torsatron. Transport coefficients for this regime has been calculated according to an approach developed in the previous paper. It was shown that the drift-orbit-optimized configuration of CHS device investigated in the previous report has the best confinement properties for low collision plasma confinement. (author)

  13. Status of the ATF2 Lattices

    Energy Technology Data Exchange (ETDEWEB)

    Marin, E.; Tomas, R.; /CERN; Bambade, P.; /Orsay, LAL; Okugi, T.; Tauchi, T.; Terunuma, N.; Urakawa, J.; /KEK, Tsukuba; Seryi, A.; /Oxford U., JAI; White, G.; Woodley, M.; /SLAC

    2011-12-09

    The current status for the ATF2 Nominal and Ultra-low {beta}* lattices are presented in this paper. New lattice designs have been obtained in order to minimise the impact of the last interpretation of multipole measurements that have been included into the model. However, the new ATF2 Ultra-low design is not able to recover the expected vertical beam size at the IP with the current magnet distribution. Therefore, different quadrupole sorting have been studied. A significant gain is evident for the ATF2 Ultra-low lattice when sorting the magnets according to the skew-sextupolar components. The ATF2 Nominal lattice is also expected to benefit from the new sorting. Tuning results of the new ATF2 Ultra-low lattice under realistic imperfections are also reported.

  14. Stabilisation of ballooning modes in torsatrons with an externally applied toroidal current

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, W.A. [Ecole Polytechnique Federale, Lausanne (Switzerland). Centre de Recherche en Physique des Plasma (CRPP)

    1996-09-01

    It has been found that ideal ballooning modes can impose very restrictive volume average {beta} limits in torsatrons much below the typical values close to 5% that are required to be economically realisable as reactor systems and it has been shown that externally applied toroidal currents that are peaked can destabilise the Mercier criterion in this type of configuration. We will show here that if the applied currents are hollow, they can stabilise the ballooning modes without triggering Mercier instabilities and as a result raise the limiting {beta}* from 2% to 5%. (author) 3 figs., 10 refs.

  15. Ripple transport in Helical-Axis Advanced Stellarators: A comparison with classical stellarator/torsatrons

    Energy Technology Data Exchange (ETDEWEB)

    Beidler, C.D. [Max-Planck-Institut fuer Plasmaphysik, Garching (Germany); Hitchon, W.N.G. [Wisconsin Univ., Madison, WI (United States). Dept. of Electrical and Computer Engineering

    1995-07-01

    Calculations of the neoclassical transport rates due to particles trapped in the helical ripples of a stellarator`s magnetic field are carried out, based on solutions of the bounceaveraged kinetic equation. These calculations employ a model for the magnetic field strength, B, which is an accurate approximation to the actual B for a wide variety of stellarator-type devices, among which are Helical-Axis Advanced Stellarators (Helias) as well as conventional stellarators and torsatrons. Comparisons are carried out in which it is shown that the Helias concept leads to significant reductions in neoclassical transport rates throughout the entire long-mean-free-path regime, with the reduction being particularly dramatic in the {nu}{sup {minus}1} regime. These findings are confirmed by numerical simulations. Further, it is shown that the behavior of deeply trapped particles in Helias can be fundamentally different from that in classical stellarator/torsatrons; as a consequence, the beneficial effects of a radial electric field on the transport make themselves felt at lower collision frequency than is usual.

  16. Beam halo study on ATF damping ring

    CERN Document Server

    Wang, Dou; Yokoya, Kaoru; Naito, Takashi; Gao, Jie

    2016-01-01

    Halo distribution is a key topic for background study. This paper has developed an analytical method to give an estimation of ATF beam halo distribution. The equilibrium particle distribution of the beam tail in the ATF damping ring is calculated analytically with different emittance and different vacuum degree. The analytical results agree the measurements very well. This is a general method which can be applied to any electron rings.

  17. Proto-CIRCUS tilted-coil tokamak–torsatron hybrid: Design and construction

    Energy Technology Data Exchange (ETDEWEB)

    Clark, A.W.; Doumet, M.; Hammond, K.C. [Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY 10027 (United States); Kornbluth, Y. [Yeshiva University, New York, NY 10033 (United States); Spong, D.A. [Oak Ridge National Laboratory, Oak Ridge, TN 37830 (United States); Sweeney, R. [Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY 10027 (United States); Volpe, F.A., E-mail: fvolpe@columbia.edu [Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY 10027 (United States)

    2014-11-15

    Highlights: • A tokamak-like device with tilted toroidal field (TF) coils needs less plasma current than a conventional tokamak. • Rotational transform is partly generated by external coils. Device can be considered a tokamak–torsatron hybrid. • We designed and constructed the first device of this type. • Tilted TF coils are interlinked to each other, which helps to reduce aspect ratio of plasma. • This is a six-coil generalization of CNT stellarator, also at Columbia University, which features two interlinked coils. - Abstract: We present the field-line modeling, design, and construction of a prototype circular-coil tokamak–torsatron hybrid called Proto-CIRCUS. The device has a major radius R = 16 cm and minor radius a < 5 cm. The six “toroidal field” coils are planar as in a tokamak, but they are tilted. This, combined with induced or driven plasma current, is expected to generate rotational transform, as seen in field-line tracing and equilibrium calculations. The device is expected to operate at lower plasma current than a tokamak of comparable size and magnetic field, which might have interesting implications for disruptions and steady-state operation. Additionally, the toroidal magnetic ripple is less pronounced than in an equivalent tokamak in which the coils are not tilted. The tilted coils are interlocked, resulting in a relatively low aspect ratio, and can be moved, both radially and in tilt angle, between discharges. This capability will be exploited for detailed comparisons between calculations and field-line mapping measurements. Such comparisons will reveal whether this relatively simple concept can generate the expected rotational transform.

  18. ATF3 inhibits PPARγ-stimulated transactivation in adipocyte cells

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Min-Kyung; Jung, Myeong Ho, E-mail: jung0603@pusan.ac.kr

    2015-01-02

    Highlights: • ATF3 inhibits PPARγ-stimulated transcriptional activation. • ATF3 interacts with PPARγ. • ATF3 suppresses p300-mediated transcriptional coactivation. • ATF3 decreases the binding of PPARγ and recruitment of p300 to PPRE. - Abstract: Previously, we reported that activating transcription factor 3 (ATF3) downregulates peroxisome proliferator activated receptor (PPARγ) gene expression and inhibits adipocyte differentiation in 3T3-L1 cells. Here, we investigated another role of ATF3 on the regulation of PPARγ activity. ATF3 inhibited PPARγ-stimulated transactivation of PPARγ responsive element (PPRE)-containing reporter or GAL4/PPARγ chimeric reporter. Thus, ATF3 effectively repressed rosiglitazone-stimulated expression of adipocyte fatty acid binding protein (aP2), PPARγ target gene, in 3T3-L1 cells. Coimmunoprecipitation and GST pulldown assay demonstrated that ATF3 interacted with PPARγ. Accordingly, ATF3 prevented PPARγ from binding to PPRE on the aP2 promoter. Furthermore, ATF3 suppressed p300-mediated transcriptional coactivation of PPRE-containing reporter. Chromatin immunoprecipitation assay showed that overexpression of ATF3 blocked both binding of PPARγ and recruitment of p300 to PPRE on aP2 promoter induced by rosiglitazone treatment in 3T3-L1 cells. Taken together, these results suggest that ATF3 interacts with PPARγ and represses PPARγ-mediated transactivation through suppression of p300-stimulated coactivation in 3T3-L1 cells, which may play a role in inhibition of adipocyte differentiation.

  19. ATF2 tests and CLIC IR study

    CERN Document Server

    Angal-Kalinin, D; Jones, J; Scarfe, A; Tygier, S

    2013-01-01

    This task covered three separate subtasks dealing with ILC and CLIC beam delivery system and Interaction region studies as well as testing the tuning procedures at ATF2 final focus test facility. The proposed local chromaticity correction final focus system for both ILC as well as CLIC is being tested experimentally for the first time at ATF2, various tuning procedures have been applied to study the applicability of various procedures to the ILC and CLIC to optimize the interaction region. The CLIC IR region was studied in detail, and the impact and mitigation of CLIC detector solenoid effects on the beam orbit, coupling and extraction have been considered. The work programme of this task concentrated on central region integration of the ILC following the design changes proposed during the technical design phase of the ILC, participation in ATF2 beam tuning studies and CLIC interaction region studies.

  20. ATF3 represses PPARγ expression and inhibits adipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Min-Kyung; Jung, Myeong Ho, E-mail: jung0603@pusan.ac.kr

    2014-11-07

    Highlights: • ATF3 decrease the expression of PPARγ and its target gene in 3T3-L1 adipocytes. • ATF3 represses the promoter activity of PPARγ2 gene. • ATF/CRE (−1537/−1530) is critical for ATF3-mediated downregulation of PPARγ. • ATF3 binds to the promoter region containing the ATF/CRE. • ER stress inhibits adipocyte differentiation through downregulation of PPARγ by ATF3. - Abstract: Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of −2.6 Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5′ deleted-reporters showed that ATF3 repressed the activity of −2037 bp promoter, whereas it did not affect the activity of −1458 bp promoter, suggesting that ATF3 responsive element is located between the −2037 and −1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5′-TGACGTTT-3′) between −1537 and −1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated

  1. Analysis list: ATF7IP [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ATF7IP Epidermis + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/ATF7IP....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/ATF7IP.5.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/hg19/target/ATF7IP.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/ATF7IP.Epidermis.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Epidermis.gml ...

  2. Analysis list: Atf7ip [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Atf7ip Pluripotent stem cell + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Atf7ip....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Atf7ip.5.tsv http://dbarchive.biosc...iencedbc.jp/kyushu-u/mm9/target/Atf7ip.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Atf7ip.Plurip...otent_stem_cell.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Pluripotent_stem_cell.gml ...

  3. Proto-CIRCUS Tilted-Coil Tokamak-Torsatron Hybrid: Design and Construction

    CERN Document Server

    Clark, A W; Hammond, K C; Kornbluth, Y; Spong, D A; Sweeney, R; Volpe, F A

    2014-01-01

    We present the field-line modeling, design and construction of a prototype circular-coil tokamak-torsatron hybrid called Proto-CIRCUS. The device has a major radius R = 16 cm and minor radius a < 5 cm. The six "toroidal field" coils are planar as in a tokamak, but they are tilted. This, combined with induced or driven plasma current, is expected to generate rotational transform, as seen in field-line tracing and equilibrium calculations. The device is expected to operate at lower plasma current than a tokamak of comparable size and magnetic field, which might have interesting implications for disruptions and steady-state operation. Additionally, the toroidal magnetic ripple is less pronounced than in an equivalent tokamak in which the coils are not tilted. The tilted coils are interlocked, resulting in a relatively low aspect ratio, and can be moved, both radially and in tilt angle, between discharges. This capability will be exploited for detailed comparisons between calculations and field-line mapping me...

  4. A Superconducting Magnet Upgrade of the ATF2 Final Focus

    Energy Technology Data Exchange (ETDEWEB)

    Parker B.; Anerella M.; Escallier J.; He P.; Jain A.; Marone A.; Wanderer P.; Wu K.C.; Hauviller C.; Marin E.; Tomas R.; Zimmermann F.; Bolzon B.; Jeremie A.; Kimura N.; Kubo K.; Kume T.; Kuroda S.; Okugi T.; Tauchi T.; Terunuma N.; Tomaru T.; Tsuchiya K.; Urakawa J.; Yamamoto A.; Bambabe P.; Coe P.; Urner D.; Seryi A.; Spencer C.; White G.

    2010-05-23

    The ATF2 facility at KEK is a proving ground for linear collider technology with a well instrumented extracted beam line and Final Focus (FF). The primary ATF2 goal is to demonstrate the extreme beam demagnification and spot stability needed for a linear collider FF. But the ATF2 FF uses water cooled magnets and the ILC baseline has a superconducting (SC) FF. We plan to upgrade ATF2 and replace some of the warm FF magnets with SC FF magnets. The ATF2 SC magnets, like the ILC FF, will made via direct wind construction. ATF2 coil winding is in progress at BNL and warm magnetic measurements indicate we have achieved good field quality. Studies indicate that having ATF2 FF magnets with larger aperture and better field quality should allow reducing the ATF2 FF beta function for study of focusing regimes relevant to CLIC. The ATF2 magnet cryostat will have laser view ports for directly monitoring cold mass movement. We plan to make stability measurements at BNL and KEK to relate ATF2 FF magnet performance to that of a full length ILC QD0 R and D FF prototype under construction at BNL.

  5. A Superconducting Magnet Upgrade of the ATF2 Final Focus

    Energy Technology Data Exchange (ETDEWEB)

    Parker, Brett; /Brookhaven; Anerella, Michael; /Brookhaven; Escallier, John; /Brookhaven; He, Ping; /Brookhaven; Jain, Animesh; /Brookhaven; Marone, Andrew; /Brookhaven; Wanderer, Peter; /Brookhaven; Wu, Kuo-Chen; /Brookhaven; Bambade, Philip; /Orsay, LAL; Bolzon, Benoit; /Annecy, LAPP; Jeremie, Andrea; /Annecy, LAPP; Coe, Paul; /Oxford U.; Urner, David /Oxford U.; Hauviller, Claude; /CERN; Marin, Eduardo; /CERN; Tomas, Rogelio; /CERN; Zimmermann, Frank; /CERN; Kimura, Nobuhiro; /KEK, Tsukuba; Kubo, Kiyoshi; /KEK, Tsukuba; Kume, Tatsuya /KEK, Tsukuba; Kuroda, Shigeru; /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /KEK, Tsukuba /SLAC /SLAC /SLAC

    2012-07-05

    The ATF2 facility at KEK is a proving ground for linear collider technology with a well instrumented extracted beam line and Final Focus (FF). The primary ATF2 goal is to demonstrate the extreme beam demagnification and spot stability needed for a linear collider FF. But the ATF2 FF uses water cooled magnets and the ILC baseline has a superconducting (SC) FF. We plan to upgrade ATF2 and replace some of the warm FF magnets with SC FF magnets. The ATF2 SC magnets, like the ILC FF, will made via direct wind construction. ATF2 coil winding is in progress at BNL and warm magnetic measurements indicate we have achieved good field quality. Studies indicate that having ATF2 FF magnets with larger aperture and better field quality should allow reducing the ATF2 FF beta function for study of focusing regimes relevant to CLIC. The ATF2 magnet cryostat will have laser view ports for directly monitoring cold mass movement. We plan to make stability measurements at BNL and KEK to relate ATF2 FF magnet performance to that of a full length ILC QD0 R&D FF prototype under construction at BNL.

  6. A superconducting magnet upgrade of the ATF2 final focus

    CERN Document Server

    Parker, B; Escallier, J; He, P; Jain, P; Marone, A; Wanderer, P; Wu, KC; Hauviller, C; Marin, E; Tomas, R; Zimmermann, F; Bolzon, B; Jeremie, A; Kimura, N; Kubo, K; Kume, T; Kuroda, S; Okugi, T; Tauchi, T; Terunuma, N; Tomaru, T; Tsuchiya, K; Urakawa, J; Yamamoto, A; Bambade, P; Coe, P; Urner, D; Seryi, A; Spencer, C; White, G

    2010-01-01

    The ATF2 facility at KEK is a proving ground for linear collider technology with a well instrumented extracted beam line and Final Focus (FF). The primary ATF2 goal is to demonstrate the extreme beam demagnification and spot stability needed for a linear collider FF [1]. But the ATF2 FF uses water cooled magnets and the ILC baseline has a superconducting (SC) FF [2]. We plan to upgrade ATF2 and replace some of the warm FF magnets with SC FF magnets. The ATF2 SC magnets, like the ILC FF, will made via direct wind construction [3]. ATF2 coil winding is in progress at BNL and warm magnetic measurements indicate we have achieved good field quality. Studies indicate that having ATF2 FF magnets with larger aperture and better field quality should allow reducing the ATF2 FF beta function for study of focusing regimes relevant to CLIC [4]. The ATF2 magnet cryostat will have laser view ports for directly monitoring cold mass movement. We plan to make stability measurements at BNL and KEK to relate ATF2 FF magnet perfo...

  7. Analysis list: ATF4 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ATF4 Blood,Others + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/ATF4.1.tsv http:...//dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/ATF4.5.tsv http://dbarchive.biosciencedbc.jp/...kyushu-u/hg19/target/ATF4.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/ATF4.Blood.tsv,http://...dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/ATF4.Others.tsv http://dbarchive.bi...osciencedbc.jp/kyushu-u/hg19/colo/Blood.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Others.gml ...

  8. ATF2 Ultra-Low IP Betas Proposal

    CERN Document Server

    Bambade, P; Bai, S; Braun, H; Delahaye, J P; Marin, E; Schulte, D; Tomás, R; Zimmermann, F; Gao, J; Wang, D; Zhu, XW; Honda, Y; Kuroda, S; Okugi, T; Tauchi, T; Terunuma, N; Urakawa, J; Seryi, A; White, G; Woodley, M; Angal-Kalinin, D; Jones, J; Scarfe, A

    2010-01-01

    The CLIC Final Focus System has considerably larger chromaticity than those of ILC and its scaled test machine ATF2. We propose to reduce the IP betas of ATF2 to reach a CLIC-like chromaticity. This would also allow to study the FFS tuning difficulty as function of the IP beam spot size. Both the ILC and CLIC projects will largely benefit from the ATF2 experience at these ultra-low IP betas.

  9. The Recent Results of the ATF

    CERN Document Server

    Urakawa, J; Ross, M

    2003-01-01

    This report describes the recent results of the beam commissioning of the ATF at KEK. Recent progress on the studies on production of low emittance beam, multi-bunch beam operation and development on beam instrumentation are discussed. So far, a horizontal emittance of 1.7 +- 0.3 nm was measured with wire-scanners in the extraction line and with the horizontal spatial coherence using an SR interferometer. In addition, a vertical emittance of 15 +- 7.5 pm was measured with a laser wire and the SR interferometer in the ring and 5 wire scanners.

  10. Mineral trioxide aggregate induces osteoblastogenesis via Atf6

    Directory of Open Access Journals (Sweden)

    Toyonobu Maeda

    2015-06-01

    Full Text Available Mineral trioxide aggregate (MTA has been recommended for various uses in endodontics. To understand the effects of MTA on alveolar bone, we examined whether MTA induces osteoblastic differentiation using MC3T3-E1 cells. MTA enhanced mineralization concomitant with alkaline phosphatase activity in a dose- and time-dependent manner. MTA increased production of collagens (Type I and Type III and matrix metalloproteinases (MMP-9 and MMP-13, suggesting that MTA affects bone matrix remodeling. MTA also induced Bglap (osteocalcin but not Bmp2 (bone morphogenetic protein-2 mRNA expression. We observed induction of Atf6 (activating transcription factor 6, an endoplasmic reticulum (ER stress response transcription factor mRNA expression and activation of Atf6 by MTA treatment. Forced expression of p50Atf6 (active form of Atf6 markedly enhanced Bglap mRNA expression. Chromatin immunoprecipitation assay was performed to investigate the increase in p50Atf6 binding to the Bglap promoter region by MTA treatment. Furthermore, knockdown of Atf6 gene expression by introduction of Tet-on Atf6 shRNA expression vector abrogated MTA-induced mineralization. These results suggest that MTA induces in vitro osteoblastogenesis through the Atf6–osteocalcin axis as ER stress signaling. Therefore, MTA in endodontic treatment may affect alveolar bone healing in the resorbed region caused by pulpal infection.

  11. Coupling Measurements in ATF2 Extraction Line

    Energy Technology Data Exchange (ETDEWEB)

    Rimbault, Cecile; /Orsay, LAL; Kuroda, Shigeru; /KEK, Tsukuba; Tauchi, Toshiaki; /KEK, Tsukuba; Terunuma, Nobuhiro; /KEK, Tsukuba; White, Glen; /SLAC; Woodley, Mark; /SLAC

    2012-06-29

    The purpose of ATF2 is to deliver a beam with stable very small spotsizes as required for future linear colliders such as ILC or CLIC. To achieve that, precise controls of aberrations such as dispersion and coupling are necessary. Theoretically, the complete reconstruction of the beam matrix is possible from the measurements of horizontal, vertical and tilted beam sizes, combining skew quadrupole scans at several wire-scanner positions. Such measurements were performed in the extraction line (EXT) of ATF2 in May 2009. We present analysis results attempting to resolve the 4 x 4 beam matrix. We aimed to reconstruct the full beam matrix using only skew quadrupole scans at different EXT wire-scanner locations, with measurements of horizontal, vertical and two tilted beam size projections. Checking the coherence of the {sigma}{sub 13} reconstruction from the {sigma}{sub 80{sup o}} and the {sigma}{sub 100{sup o}} measurements was essential to perform this analysis. We have shown that reconstruction of the coupling element can not be performed independantly of the 4 x 4 diagonal ones since it leads to unphysical results. A more accurate and automatisable method was find, leading to physical beam matrix reconstruction, compatible with the measurements. Another analysis should be performed based on a larger number of data sets to minimise statistical errors.

  12. Micron size laser-wire system at the ATF extraction line, recent results and ATF-II upgrade

    Energy Technology Data Exchange (ETDEWEB)

    Aryshev, A., E-mail: alar@post.kek.j [John Adams Institute at Royal Holloway, Egham, Surrey TW20 0EX (United Kingdom); Blair, G.A.; Boogert, S.T.; Boorman, G.; Bosco, A. [John Adams Institute at Royal Holloway, Egham, Surrey TW20 0EX (United Kingdom); Corner, L. [John Adams Institute at Oxford University, Nuclear and Astrophysics Laboratory, Keble Road, Oxford OX1 3RH (United Kingdom); Deacon, L. [John Adams Institute at Royal Holloway, Egham, Surrey TW20 0EX (United Kingdom); Delerue, N.; Foster, B.; Gannaway, F. [John Adams Institute at Oxford University, Nuclear and Astrophysics Laboratory, Keble Road, Oxford OX1 3RH (United Kingdom); Hayano, H. [KEK, 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan); Howell, D. [John Adams Institute at Oxford University, Nuclear and Astrophysics Laboratory, Keble Road, Oxford OX1 3RH (United Kingdom); Karataev, P. [John Adams Institute at Royal Holloway, Egham, Surrey TW20 0EX (United Kingdom); Nevay, L.; Newman, M.; Senanayake, R. [John Adams Institute at Oxford University, Nuclear and Astrophysics Laboratory, Keble Road, Oxford OX1 3RH (United Kingdom); Terunuma, N.; Urakawa, J. [KEK, 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan); Walczak, R. [John Adams Institute at Oxford University, Nuclear and Astrophysics Laboratory, Keble Road, Oxford OX1 3RH (United Kingdom)

    2010-11-01

    The KEK Accelerator test facility (ATF) extraction line laser-wire system has been upgraded last year allowing the measurement of micron scale transverse size electron beams. The last measurements using the upgraded system from recent operation at the ATF are presented, demonstrating raw measurements of order 3{mu}m RMS. The main component contributions to this measurement are also discussed.

  13. Micron size laser-wire system at the ATF extraction line, recent results and ATF-II upgrade

    Science.gov (United States)

    Aryshev, A.; Blair, G. A.; Boogert, S. T.; Boorman, G.; Bosco, A.; Corner, L.; Deacon, L.; Delerue, N.; Foster, B.; Gannaway, F.; Hayano, H.; Howell, D.; Karataev, P.; Nevay, L.; Newman, M.; Senanayake, R.; Terunuma, N.; Urakawa, J.; Walczak, R.

    2010-11-01

    The KEK Accelerator test facility (ATF) extraction line laser-wire system has been upgraded last year allowing the measurement of micron scale transverse size electron beams. The last measurements using the upgraded system from recent operation at the ATF are presented, demonstrating raw measurements of order 3 μm RMS. The main component contributions to this measurement are also discussed.

  14. Flavour formation in fungi: characterisation of KlAtf, the Kluyveromyces lactis orthologue of the Saccharomyces cerevisiae alcohol acetyltransferases Atf1 and Atf2.

    Science.gov (United States)

    Van Laere, Stijn D M; Saerens, Sofie M G; Verstrepen, Kevin J; Van Dijck, Patrick; Thevelein, Johan M; Delvaux, Freddy R

    2008-04-01

    Volatile aroma-active esters are responsible for the fruity character of fermented alcoholic beverages, such as beer and wine. In the brewers' yeast Saccharomyces cerevisiae, the major part of these esters is formed by two alcohol acetyltransferases, Atf1 and Atf2. In this paper, the existence of orthologues of these S. cerevisiae alcohol acetyltransferases in several ascomycetous fungi was investigated. Bioinformatic analysis of sequenced fungal genomes revealed the presence of multiple orthologues. The Saccharomyces sensu stricto yeasts all have two genes coding for orthologues. More distantly related fungi like Saccharomyces castelii, Candida glabrata, Kluyveromyces waltii and Kluyveromyces lactis have only one orthologue in their genome. The homology between the identified proteins and the S. cerevisiae alcohol acetyltransferases suggests a role for these orthologues in the aroma-active ester formation. To verify this, the K. lactis orthologue KlAtf was cloned and expressed in S. cerevisiae. Gas chromatographic analysis of small-scale fermentations with the transformant strains showed that, while S. cerevisiae ATF1 overexpression resulted in a substantial increase in acetate ester levels, S. cerevisiae ATF2 and K. lactis ATF overexpression only caused a moderate increase in acetate esters. This study is the first report of the presence of an ester synthesis gene in K. lactis.

  15. Characteristics of the three-half-turn-antenna-driven RF discharge in the Uragan-3M torsatron

    Energy Technology Data Exchange (ETDEWEB)

    Grigor’eva, L. I.; Chechkin, V. V., E-mail: chechkin@ipp.kharkov.ua; Moiseenko, V. E.; Grekov, D. L.; Pavlichenko, R. O.; Lozin, A. V.; Tarasov, I. K.; Kulaga, A. Ye.; Zamanov, N. V.; Tretiak, K. K.; Kozulya, M. M.; Beletskii, A. A.; Kasilov, A. A.; Mironov, Yu. K.; Romanov, V. S.; Voitsenya, V. S. [National Science Center Kharkiv Institute of Physics and Technology, Institute of Plasma Physics (Ukraine)

    2015-12-15

    In the ℓ = 3 Uragan-3M torsatron hydrogen plasma is produced by RF fields in the Alfvén range of frequencies (ω ≤ ω{sub ci}). The initial (target) plasma with the line-averaged density of units 10{sup 12} cm{sup −3} is produced by a frame antenna with a broad spectrum of generated parallel wavenumbers. After this, to heat the plasma and bring its density to ∼10{sup 13} cm{sup –3}, another, shorter wavelength three-half-turn antenna with large transverse currents is used. The behavior of the density, electron temperature, and loss of the plasma supported by the three-half-turn antenna is studied depending on the RF power fed to the antenna and initial values of the density and electron temperature supplied by the frame antenna.

  16. CAVITY BEAM POSITION MONITOR SYSTEM FOR ATF2

    CERN Document Server

    Boogert, S T; Cullinan, F; Joshi, N; Lyapin, A; Aryshev, A; Honda, Y; Naito, T; Terunuma, N; Urakara, J; Heo, A; Kim, E-S; Kim, Y I; McCormick, D; Frisch, J; Nelson, J; Smith, T; White, G R

    2011-01-01

    The Accelerator Test Facility 2 (ATF2) in KEK, Japan, is a prototype scaled demonstrator system for the final focus required for a future high energy lepton linear collider. The ATF2 beam-line is instrumented with a total of 41 high resolution C and S band resonant cavity beam position monitors (BPM) with associated mixer electronics and digitisers. In addition 4 high resolution BPMs have been recently installed at the interaction point, we briefly describe the first operational experience of these cavities in the ATF2 beam-line. The current status of the overall BPM system is also described, with a focus on operational techniques and performance.

  17. ATF3 suppresses ESCC via downregulation of ID1

    Science.gov (United States)

    Li, Jian; Yang, Zishan; Chen, Zhiuguo; Bao, Yonghua; Zhang, Huijuan; Fang, Xinhui; Yang, Wancai

    2016-01-01

    Esophageal cancer is one of the most prevalent forms of cancer and has a particularly high mortality rate due to early metastasis; however, the underlying mechanisms of its formation and progression remain unclear. The present study performed immunohistochemical analysis and observed that the expression of activating transcription factor 3 (ATF3) was reduced in esophageal squamous cell carcinoma (ESCC) in comparison with non-tumor adjacent tissues. By contrast, inhibitor of DNA binding 1 (ID1) was overexpressed in ESCC tissues, demonstrating an inverse correlation with ATF3 (P<0.01). In ESCC EC109 and KYSE450 cells lines, transfection with an ATF3-overexpression plasmid resulted in the inhibition of cell proliferation, motility and migration, which was associated with the induction of E-cadherin expression and inhibition of cyclin D1 and Twist. Notably, ATF3 exerted an inverse regulatory interaction with ID1. The results of the present study provide additional evidence of the tumor suppressive features of ATF3 and demonstrate a novel mechanism of ATF3-mediated inhibition of cancer metastasis in esophageal cancer. PMID:27602100

  18. Micron Size Laser-Wire System at the ATF Extraction Line, Recent Results and ATF-II Upgrade

    CERN Document Server

    Blair, G A; Boorman, G; Bosco, A; Deacon, L; Karataev, P; Howell, D; Nevay, L J; Corner, L; Delerue, N; Foster, B; Gannaway, F; Newman, M; Senanayake, R; Walczak, R; Hayano, H; Aryshev, A; Terunuma, N; Urakawa, J

    2010-01-01

    The KEK Accelerator test facility (ATF) extraction line laser-wire system has been upgraded last year allowing the measurement of micron scale transverse size electron beams. The most recent measurements using the upgraded system are presented. The ATF-II extraction line design call for the major upgrade of the existing laser-wire system. We report on the hardware upgrades, including the major hardware upgrades to the laser transport, the laser beam diagnostics line, and the mechanical control systems.

  19. Design and high order optimization of the ATF2 lattices

    CERN Document Server

    Marin, E; Woodley, M; Kubo, K; Okugi, T; Tauchi, T; Urakawa, J; Tomas, R

    2013-01-01

    The next generation of future linear colliders (LC) demands nano-meter beam sizes at the interaction point (IP) in order to reach the required luminosity. The final focus system (FFS) of a LC is meant to deliver such small beam sizes. The Accelerator Test Facility (ATF) aims to test the feasibility of the new local chromaticity correction scheme which the future LCs are based on. To this end the ATF2 nominal and ultra-low beta* lattices are design to vertically focus the beam at the IP to 37nm and 23nm, respectively if error-free lattices are considered. However simulations show that the measured field errors of the ATF2 magnets preclude to reach the mentioned spot sizes. This paper describes the optimization of high order aberrations of the ATF2 lattices in order to minimize the detrimental effect of the measured multipole components for both ATF2 lattices. Specifically three solutions are studied, the replacement of the last focusing quadrupole (QF1FF), insertion of octupole magnets and optics modification....

  20. Design of multichord Hα detector arrays for the U-3M torsatron and identification of rotating plasma perturbations

    Science.gov (United States)

    Dreval, M. B.; Shapoval, A. M.; Ozherelyev, F. I.; Makhov, M. M.

    2016-07-01

    An Hα camera has been designed and installed in the U-3M torsatron for spatially and temporally resolved measurements. This device provides fast measurements of the emission brightness profile in the noisy environment of the radio frequency (RF) heated plasma. Unusual topology of diagnostics and the data acquisition system are applied. All the system components, including digitizers, are assembled in a single unit. It allows the suppression of a low-frequency electromagnetic interference by eliminating the ground loops. And the suppression of RF noises is achieved by eliminating the signal interface cables and digital interface cables in the design. The Wi-Fi interface is used to prevent a ground loop in the data transfer stage. The achieved sensitivity of our diagnostics is high enough for measuring the Hα emission from the low-density (ne ≈ (1-2)ṡ1010 cm-3) plasma with a temporal resolution of about 20 μs in the noisy environment. Different types of Hα emission fluctuations within the frequency range of 1-5 kHz and poloidal mode numbers m = 0 and m = 5 have been observed in U-3M. A simple technique of the line-of-sight data analysis, based on the U-3M magnetic surface asymmetry, is proposed and used for the spatial localization of the rotating mode and for the determination of mode numbers and its poloidal rotation direction using a single Hα array.

  1. Testing of a pulsed He supersonic beam for plasma edge diagnostic in the TJ-IU torsatron

    Science.gov (United States)

    Tabarés, F. L.; Tafalla, D.; Herrero, V.; Tanarro, I.

    1997-02-01

    A new, compact atomic beam source based on the supersonic expansion of He has been developed for application as a plasma edge diagnostic. The beam is produced from a pulsed valve with a duration between 0.2 to 2 ms and a nominal repetition rate 10 and a divergence of ± 1° have been achieved at stagnation pressures below 2 bar. The diagnostic has been tested in ECRH plasmas on the TJ-IU torsatron, representing the first application of a supersonic beam to plasma characterization, to our knowledge. Operational conditions which minimized the total amount of He injected into the plasma were chosen. Non-perturbative injection conditions in the low density plasmas could be obtained at local He densities of ⋍ 1 × 10 11 cm -3 and a beam diameter < 1 cm. Due to the relatively low electron density of the ECRH plasmas, and to the good penetration characteristics of the supersonic He beam, the diagnostic could be used up to fairly low values of the normalized plasma minor radius, {r}/{a} (a = 12 cm) . Details of the optimization of the atomic beam diagnostics and typical results for steady state conditions in the TJ-IU plasmas are presented.

  2. Testing of a pulsed He supersonic beam for plasma edge diagnostic in the TJ-IU torsatron

    Energy Technology Data Exchange (ETDEWEB)

    Tabares, F.L. [Association EURATOM/CIEMAT, Madrid (Spain); Tafalla, D. [Association EURATOM/CIEMAT, Madrid (Spain); Herrero, V. [Instituto de Estructura de la Materia, CSIC, 28006 Madrid (Spain); Tanarro, I. [Instituto de Estructura de la Materia, CSIC, 28006 Madrid (Spain)

    1997-02-01

    A new, compact atomic beam source based on the supersonic expansion of He has been developed for application as a plasma edge diagnostic. The beam is produced from a pulsed valve with a duration between 0.2 to 2 ms and a nominal repetition rate <500 Hz. A terminal speed ratio >10 and a divergence of {+-}1 have been achieved at stagnation pressures below 2 bar. The diagnostic has been tested in ECRH plasmas on the TJ-IU torsatron, representing the first application of a supersonic beam to plasma characterization, to our knowledge. Operational conditions which minimized the total amount of He injected into the plasma were chosen. Non-perturbative injection conditions in the low density plasmas could be obtained at local He densities of {approx_equal}1 x 10{sup 11} cm{sup -3} and a beam diameter <1 cm. Due to the relatively low electron density of the ECRH plasmas, and to the good penetration characteristics of the supersonic He beam, the diagnostic could be used up to fairly low values of the normalized plasma minor radius, r/a (a=12 cm). Details of the optimization of the atomic beam diagnostics and typical results for steady state conditions in the TJ-IU plasmas are presented. (orig.).

  3. Transforming growth factor-beta1 regulation of ATF-3 and identification of ATF-3 target genes in breast cancer cells.

    Science.gov (United States)

    Kwok, Sukyee; Rittling, Susan R; Partridge, Nicola C; Benson, Chellakkan S; Thiyagaraj, Mayuranathan; Srinivasan, Narasimhan; Selvamurugan, Nagarajan

    2009-10-01

    Transforming growth factor-beta1 (TGF-beta1) is a crucial molecule for stimulation of breast cancer invasion and formation of bone metastases. The molecular mechanisms of how TGF-beta1 mediates these effects have yet to be completely determined. We have found that activating transcription factor-3 (ATF-3) is strongly stimulated and its level is sustained by TGF-beta1 in highly invasive and metastatic human breast cancer (MDA-MB231) and in mouse mammary pad tumor cells (r3T). ATF-3 is also overexpressed in human primary breast cancer tissue. Overexpression of ATF-3 increased normal human mammary epithelial cell number and DNA synthesis suggesting a role for ATF-3 in cell proliferation. The functional role of ATF-3 in breast cancer progression was determined by the RNA interference technique. Knockdown of ATF-3 by ATF-3 shRNA in MDA-MB231 cells decreased expression of cell cycle gene, cyclin A1 in MDA-MB231 cells. ATF-3 shRNA also decreased expression of an invasive and metastatic gene, matrix metalloproteinase-13 (MMP-13; collagenase-3) in these cells. Chromatin immunoprecipitation experiments identified the direct physical interaction of ATF-3 protein on the human MMP-13 promoter. Thus, the dysregulation of ATF-3 by TGF-beta1 is likely to activate cyclin A1 and MMP-13 genes in breast cancer cells and that would be key to the subsequent cancer cell invasion and metastasis.

  4. A role for ATF2 in regulating MITF and melanoma development.

    Directory of Open Access Journals (Sweden)

    Meera Shah

    2010-12-01

    Full Text Available The transcription factor ATF2 has been shown to attenuate melanoma susceptibility to apoptosis and to promote its ability to form tumors in xenograft models. To directly assess ATF2's role in melanoma development, we crossed a mouse melanoma model (Nras(Q61K::Ink4a⁻/⁻ with mice expressing a transcriptionally inactive form of ATF2 in melanocytes. In contrast to 7/21 of the Nras(Q61K::Ink4a⁻/⁻ mice, only 1/21 mice expressing mutant ATF2 in melanocytes developed melanoma. Gene expression profiling identified higher MITF expression in primary melanocytes expressing transcriptionally inactive ATF2. MITF downregulation by ATF2 was confirmed in the skin of Atf2⁻/⁻ mice, in primary human melanocytes, and in 50% of human melanoma cell lines. Inhibition of MITF transcription by MITF was shown to be mediated by ATF2-JunB-dependent suppression of SOX10 transcription. Remarkably, oncogenic BRAF (V600E-dependent focus formation of melanocytes on soft agar was inhibited by ATF2 knockdown and partially rescued upon shMITF co-expression. On melanoma tissue microarrays, a high nuclear ATF2 to MITF ratio in primary specimens was associated with metastatic disease and poor prognosis. Our findings establish the importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression.

  5. p38beta2-mediated phosphorylation and sumoylation of ATF7 are mutually exclusive.

    Science.gov (United States)

    Camuzeaux, Barbara; Diring, Jessica; Hamard, Pierre-Jacques; Oulad-Abdelghani, Mustapha; Donzeau, Mariel; Vigneron, Marc; Kedinger, Claude; Chatton, Bruno

    2008-12-26

    The ubiquitous activating transcription factor (ATF) 7 binds as a homodimer to the cAMP response element/TPA response element motifs present in the promoters of its target genes. ATF7 is homologous to ATF2 and heterodimerizes with Jun or Fos proteins, modulating their DNA-binding specificities. We previously demonstrated that TAF12, a component of the TFIID general transcription factor, mediates ATF7 transcriptional activity through direct interactions between the two proteins. By contrast, ATF7, but not ATF2, is modified in vivo by sumoylation, which restricts its subcellular localization, thereby inhibiting its transcriptional activity. In the present study, we dissect the mechanism of this functional switch. We characterized the multisite phosphorylation of the ATF7 activation domain and identified one of the involved kinase, p38beta2 mitogen-activated protein kinase. In addition, we show that epidermal growth factor treatment results in a two-step modification mechanism of ATF7 activation domain. The Thr53 residue is phosphorylated first by a presently unknown kinase, allowing p38beta2 mitogen-activated protein kinase to modify the Thr51 residue, excluding the sumoylation of ATF7 protein. The resulting activation of transcription is related to an increased association of TAF12 with this phosphorylated form of ATF7. Our data therefore conclusively establish that sumoylation and phosphorylation of ATF7 are two antagonistic posttranslational modifications.

  6. Identification of ATF2 as a transcriptional regulator of renin gene.

    Science.gov (United States)

    Desch, Michael; Hackmayer, Gerit; Todorov, Vladimir T

    2012-01-01

    The cAMP response element (enhCRE) in the distal enhancer regulatory region of renin gene is believed to play a major role in the control of renin transcription. enhCRE binds the CRE-binding protein (CREB), which is the main transcription factor target of cAMP signaling. Using the mouse renin-producing cell line As4.1 we found that activating transcription factor-2 (ATF2) also binds to enhCRE. N-terminal phosphorylation of ATF2, which controls its transactivation, is associated with downregulation of renin gene expression by the cytokine tumor necrosis factor-α (TNFα). The ubiquitin proteasome inhibitor MG132 also phosphorylates ATF2 and inhibits renin expression. Knockdown of ATF2 attenuated the suppression of renin gene expression by MG132, thus demonstrating that ATF2 mediates the inhibitory effect of MG132. In addition, MG132 increased the DNA-binding of ATF2 as well as the ratio of bound ATF2 to CREB. Using ATF2- and CREB-Gal4 fusion protein constructs coupled with luciferase reporter system we showed that ATF2 has a weaker transactivating capacity than CREB. These data suggest that ATF2 represses renin expression by drifting the transcriptional control of renin gene away from CREB. Accordingly, TNFα completely abrogated the cAMP-dependent stimulation of renin gene expression.

  7. Identification and characterization of a mitochondrial unfolded protein response transcription factor ATFS-1 in Litopenaeus vannamei.

    Science.gov (United States)

    Chen, Yong-Gui; Yue, Hai-Tao; Zhang, Ze-Zhi; Yuan, Feng-Hua; Bi, Hai-Tao; Yuan, Kai; Weng, Shao-Ping; He, Jian-Guo; Chen, Yi-Hong

    2016-07-01

    A mitochondrial specific stress response termed mitochondrial unfolded protein response (UPR(mt)) is activated in responding to disturbance of protein homeostasis in mitochondria. The activating transcription factor associated with stress-1 (designated as ATFS-1) is the key regulator of UPR(mt). To investigating the roles of ATFS-1 (LvATFS-1) in Litopenaeus vannamei mitochondrial stress remission and immunity, it's full length cDNA was cloned. The open reading frame of LvATFS-1 was 1, 557 bp in length, deducing to a 268 amino acids protein. LvATFS-1 was highly expressed in muscle, hemocytes and eyestalk. Subcellular location assays showed that N-terminal of LvATFS-1 contained a mitochondrial targeting sequence, which could directed the fused EGFP located to mitochondria. And the C-terminal of LvATFS-1, which had a nuclear localization signal, expressed in nucleus. The in vitro experiments verified that LvATFS-1 could reduced the level of intracellular reactive oxygen species (ROS). And results of real-time RT-PCR indicated that LvATFS-1 might scavenge excess ROS via ROS-eliminating genes regulation. Reporter gene assays showed that LvATFS-1 could upregulated the expression of the antimicrobial peptide genes in Drosophila Schneider 2 cells. Results of real-time RT-PCR showed that Vibrio alginolyticus or white spot syndrome virus (WSSV) infection induced the expression of LvATFS-1. And knocked-down LvATFS-1 by RNAi resulted in a higher cumulative mortality of L. vannamei upon V. alginolyticus or WSSV infection. These results suggested that LvATFS-1 not only rolled in mitochondrial specific stress responding, but also important for L. vannamei immunologic defence.

  8. Detect ground motion effects on the trajectory at ATF2

    CERN Document Server

    Rénier, Yves; Garcia, Rogelio

    2011-01-01

    The Accelerator Test Facility 2 (ATF2) commissioning group aims to demonstrate the feasibility of the Beam Delivery System (BDS) of the next linear colliders (ILC and CLIC) as well as to define and to test the tunning methods. As the design vertical beam sizes of the linear colliders are about few nanometers, the stability of the trajectory as well as the control of the aberrations are very critical. The magnet displacements induced by ground motion are large enough for CLIC to perturb the beam stability above requirements. It is planned to measure the displacement of the magnets and implement a feed-forward correcting the effects on the beam trajectory with correctors (dipoles). This article studies the possibility to detect ground motion effects on the beam trajectory at ATF2. Characteristics of the ground motion at ATF2 are presented, the effects of the magnet displacements on the beam trajectory are simulated and an algorithm predicting the induced trajectory fluctuations is evaluated. After the estimated...

  9. Study of Abnormal Vertical Emittance Growth in ATF Extraction Line

    Energy Technology Data Exchange (ETDEWEB)

    Alabau, M.; Faus-Golfe, A.; /Valencia U., IFIC; Alabau, M.; Bambade, P.; Brossard, J.; Le Meur, G.; Rimbault, C.; Touze, F.; /Orsay, LAL; Angal-Kalinin, D.; Jones, J.K.; /Daresbury; Appleby, R.; Scarfe, A.; /Manchester U.; Kuroda, S.; /KEK, Tsukuba; White, G.R.; Woodley, M.; /SLAC; Zimmermann, F.; /CERN

    2011-11-04

    Since several years, the vertical beam emittance measured in the Extraction Line (EXT) of the Accelerator Test Facility (ATF) at KEK, that will transport the electron beam from the ATF Damping Ring (DR) to the future ATF2 Final Focus beam line, is significantly larger than the emittance measured in the DR itself, and there are indications that it grows rapidly with increasing beam intensity. This longstanding problem has motivated studies of possible sources of this anomalous emittance growth. One possible contribution is non-linear magnetic fields in the extraction region experimented by the beam while passing off-axis through magnets of the DR during the extraction process. In this paper, simulations of the emittance growth are presented and compared to observations. These simulations include the effects of predicted non-linear field errors in the shared DR magnets and orbit displacements from the reference orbit in the extraction region. Results of recent measurements using closed orbit bumps to probe the relation between the extraction trajectory and the anomalous emittance growth are also presented.

  10. ATF4 is involved in the regulation of simulated microgravity induced integrated stress response

    Science.gov (United States)

    Li, Yingxian; Li, Qi; Wang, Xiaogang; Sun, Qiao; Wan, Yumin; Li, Yinghui; Bai, Yanqiang

    Objective: Many important metabolic and signaling pathways have been identified as being affected by microgravity, thereby altering cellular functions such as proliferation, differentiation, maturation and cell survival. It has been demonstrated that microgravity could induce all kinds of stress response such as endoplasmic reticulum stress and oxidative stress et al. ATF4 belongs to the ATF/CREB family of basic region leucine zipper transcription factors. ATF4 is induced by stress signals including anoxia/hypoxia, ER stress, amino acid deprivation and oxidative stress. ATF4 regulates the expression of genes involved in oxidative stress, amino acid synthesis, differentiation, metastasis and angiogenesis. The aim of this study was to examine the changes of ATF4 under microgravity, and to investigate the role of ATF4 in microgravity induced stress. MethodsMEF cells were cultured in clinostat to simulate microgravity. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to examine mRNA and protein levels of ATF4 expression under simulated microgravity in MEF cells. ROS levels were measured with the use of the fluorescent signal H2DCF-DA. GFP-XBP1 stably transfected cell lines was used to detect the extent of ER stress under microgravity by the intensity of GFP. Dual luciferase reporter assay was used to detect the activity of ATF4. Co-immunoprecipitation was performed to analyze protein interaction. Results: ATF4 protein levels in MEF cells increased under simulated microgravity. However, ATF4 mRNA levels were consistent. XBP1 splicing can be induced due to ER stress caused by simulated microgravity. At the same time, ROS levels were also increased. Increased ATF4 could promote the expression of CHOP, which is responsible for cell apoptosis. ATF4 also play an important role in cellular anti-oxidant stress. In ATF4 -/-MEF cells, the ROS levels after H2O2 treatment were obviously higher than that of wild type cells. HDAC4 was

  11. Pressure drop – flow characteristic investigations of ATF filter in automatic transmissions (AT of cars

    Directory of Open Access Journals (Sweden)

    Tadeusz Dziubak

    2014-12-01

    Full Text Available [b]Abstract[/b]. Potentials effects of pressure drop-flow characteristics of ATF filter on the hydraulic pumps are discussed. Draft device to investigations pressure drop-flow characteristics of ATF filter used in automatic transmissions constructed based on SAE J2312 standard is presented. Method of investigation pressure drop-flow characteristics of ATF filter used in automatic transmission is presented. The results of investigation pressure drop-flow characteristics Δp = f(QV of two types ATF filter (metal mesh and filter cloth in two technical conditions (at the beginning of the operation and after are presented and analyzed.[b]Keywords[/b]: AT — automatic transmissions, ATF — automatic transmission fluid, ATF filter, pressure drop-flow characteristic

  12. A functional interaction between ATF7 and TAF12 that is modulated by TAF4.

    Science.gov (United States)

    Hamard, Pierre-Jacques; Dalbies-Tran, Rozenn; Hauss, Charlotte; Davidson, Irwin; Kedinger, Claude; Chatton, Bruno

    2005-05-12

    The ATF7 proteins, which are members of the cyclic AMP responsive binding protein (CREB)/activating transcription factor (ATF) family of transcription factors, display quite versatile properties: they can interact with the adenovirus E1a oncoprotein, mediating part of its transcriptional activity; they heterodimerize with the Jun, Fos or related transcription factors, likely modulating their DNA-binding specificity; they also recruit to the promoter a stress-induced protein kinase (JNK2). In the present study, we investigate the functional relationships of ATF7 with hsTAF12 (formerly hsTAF(II)20/15), which has originally been identified as a component of the general transcription factor TFIID. We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7. In support of this conclusion, chromatin immunoprecipitation experiments confirm the interaction of ATF7 with TAF12 on an ATF7-responsive promoter, in the absence of any artificial overexpression of both proteins. We also show that the TAF12-dependent transcriptional activation is competitively inhibited by TAF4. Although both TAF12 isoforms (TAF12-1 and -2, formerly TAF(II)20 and TAF(II)15) interact with the ATF7 activation region through their histone-fold domain, only the largest, hsTAF12-1, mediates transcriptional activation through its N-terminal region.

  13. Improved antibody production in Chinese hamster ovary cells by ATF4 overexpression

    OpenAIRE

    Haredy, AM; Nishizawa, A.; Honda, K.; T. Ohya; Ohtake, H; Omasa, T

    2013-01-01

    To improve antibody production in Chinese hamster ovary (CHO) cells, the humanized antibody-producing CHO DP-12-SF cell line was transfected with the gene encoding activating transcription factor 4 (ATF4), a central factor in the unfolded protein response. Overexpression of ATF4 significantly enhanced the production of antibody in the CHO DP-12-SF cell line. The specific IgG production rate of in the ATF4-overexpressing CHO-ATF4-16 cells was approximately 2.4 times that of the parental host c...

  14. Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

    DEFF Research Database (Denmark)

    Kristensen, Hans-Ulrik Svejstrup; Epanchintsev, Alexey; Rauschendorf, Marc-Alexander;

    2013-01-01

    RNA restarts on the arrival of RNA polymerase II and CSB and the subsequent release of ATF3 from its cAMP response element/ATF target site. In CSB-deficient cells ATF3 remains bound to the promoter, thereby preventing the arrival of polymerase II and the restart of transcription. Silencing of ATF3, as well......, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis in CSB-deficient cells, transcription was restored rapidly in normal cells. There the synthesis of DHFR m...

  15. High resolution upgrade of the ATF damping ring BPM system

    Energy Technology Data Exchange (ETDEWEB)

    Terunuma, N.; Urakawa, J.; /KEK, Tsukuba; Frisch, J.; May, J.; McCormick, D.; Nelson, J.; Seryi, A.; Smith, T.; Woodley, M.; /SLAC; Briegel, C.; Dysert, R.; /Fermilab

    2008-05-01

    A beam position monitor (BPM) upgrade at the KEK Accelerator Test Facility (ATF) damping ring has been accomplished in its first stage, carried out by a KEK/FNAL/SLAC collaboration under the umbrella of the global ILC R&D effort. The upgrade consists of a high resolution, high reproducibility read-out system, based on analog and digital downconversion techniques, digital signal processing, and also tests a new automatic gain error correction schema. The technical concept and realization, as well as preliminary results of beam studies are presented.

  16. ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease.

    Science.gov (United States)

    Watson, Gregory; Ronai, Ze'ev; Lau, Eric

    2017-02-15

    Stringent transcriptional regulation is crucial for normal cellular biology and organismal development. Perturbations in the proper regulation of transcription factors can result in numerous pathologies, including cancer. Thus, understanding how transcription factors are regulated and how they are dysregulated in disease states is key to the therapeutic targeting of these factors and/or the pathways that they regulate. Activating transcription factor 2 (ATF2) has been studied in a number of developmental and pathological conditions. Recent findings have shed light on the transcriptional, post-transcriptional, and post-translational regulatory mechanisms that influence ATF2 function, and thus, the transcriptional programs coordinated by ATF2. Given our current knowledge of its multiple levels of regulation and function, ATF2 represents a paradigm for the mechanistic complexity that can regulate transcription factor function. Thus, increasing our understanding of the regulation and function of ATF2 will provide insights into fundamental regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into a genomic response through transcription factors. Characterization of ATF2 dysfunction in the context of pathological conditions, particularly in cancer biology and response to therapy, will be important in understanding how pathways controlled by ATF2 or other transcription factors might be therapeutically exploited. In this review, we provide an overview of the currently known upstream regulators and downstream targets of ATF2.

  17. Improved antibody production in Chinese hamster ovary cells by ATF4 overexpression.

    Science.gov (United States)

    Haredy, Ahmad M; Nishizawa, Akitoshi; Honda, Kohsuke; Ohya, Tomoshi; Ohtake, Hisao; Omasa, Takeshi

    2013-12-01

    To improve antibody production in Chinese hamster ovary (CHO) cells, the humanized antibody-producing CHO DP-12-SF cell line was transfected with the gene encoding activating transcription factor 4 (ATF4), a central factor in the unfolded protein response. Overexpression of ATF4 significantly enhanced the production of antibody in the CHO DP-12-SF cell line. The specific IgG production rate of in the ATF4-overexpressing CHO-ATF4-16 cells was approximately 2.4 times that of the parental host cell line. Clone CHO-ATF4-16 did not show any change in growth rate compared with the parental cells or mock-transfected CHO-DP12-SF cells. The expression levels of mRNAs encoding both the antibody heavy and light chains in the CHO-ATF4-16 clone were analyzed. This analysis showed that ATF4 overexpression improved the total production and specific production rate of antibody without affecting the mRNA transcription level. These results indicate that ATF4 overexpression is a promising method for improving recombinant IgG production in CHO cells.

  18. The atf2 gene is involved in triacylglycerol biosynthesis and accumulation in the oleaginous Rhodococcus opacus PD630.

    Science.gov (United States)

    Hernández, Martín A; Arabolaza, Ana; Rodríguez, Eduardo; Gramajo, Hugo; Alvarez, Héctor M

    2013-03-01

    Rhodococcus opacus PD630 is an oleaginous bacterium able to accumulate large amounts of triacylglycerols (TAG) in different carbon sources. The last reaction for TAG biosynthesis is catalyzed by the bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase (WS/DGAT) enzymes encoded by atf genes. R. opacus PD630 possesses at least 17 putative atf homologous genes in its genome, but only atf1 and atf2 exhibited a significant DGAT activity when expressed in E. coli, as revealed in a previous study. The contribution of atf1 gene to TAG accumulation by strain PD630 has been demonstrated previously, although additional Atfs may also contribute to lipid accumulation, since the atf1-disrupted mutant is still able to produce significant amounts of TAG (Alvarez et al., Microbiology 154:2327-2335, 2008). In this study, we investigated the in vivo role of atf2 gene in TAG accumulation by R. opacus PD630 by using different genetic strategies. The atf2-disrupted mutant exhibited a decrease in TAG accumulation (up to 25-30 %, w/w) and an approximately tenfold increase in glycogen formation in comparison with the wild-type strain. Surprisingly, in contrast to single mutants, a double mutant generated by the disruption of atf1 and atf2 genes only showed a very low effect in TAG and in glycogen accumulation under lipid storage conditions. Overexpression of atf1 and atf2 genes in strain PD630 promoted an increase of approximately 10 % (w/w) in TAG accumulation, while heterologous expression of atf2 gene in Mycobacterium smegmatis caused an increase in TAG accumulation during cultivation in nitrogen-rich media. This study demonstrated that, in addition to atf1 gene, atf2 is actively involved in TAG accumulation by the oleaginous R. opacus PD630.

  19. 75 FR 47254 - Elimination of Firearms Transaction Record, ATF Form 4473 (Low Volume) (2008R-21P)

    Science.gov (United States)

    2010-08-05

    ... Transaction Record, ATF Form 4473 (Low Volume) (2008R-21P) AGENCY: Bureau of Alcohol, Tobacco, Firearms, and... (ATF) by eliminating the Firearms Transaction Record, ATF Form 4473 (Low Volume (LV)), Parts I and II...) Part I, Firearms Transaction Record Part I--Low Volume--Over-The-Counter, or Form 4473 (LV) Part...

  20. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis

    Directory of Open Access Journals (Sweden)

    Thames Howard D

    2008-09-01

    Full Text Available Abstract Background Overexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5 promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas. CK5 is known to be expressed in myoepithelial cells of the mammary gland, suggesting the possibility that transgenic BK5.ATF3 mice may exhibit mammary gland phenotypes. Methods Mammary glands from nulliparous mice in our BK5.ATF3 colony, both non-transgenic and transgenic, were examined for anomalies by histopathology and immunohistochemistry. Nulliparous and biparous female mice were observed for possible mammary tumor development, and suspicious masses were analyzed by histopathology and immunohistochemistry. Human breast tumor samples, as well as normal breast tissue, were similarly analyzed for ATF3 expression. Results Transgenic BK5.ATF3 mice expressed nuclear ATF3 in the basal layer of the mammary ductal epithelium, and often developed squamous metaplastic lesions in one or more mammary glands by 25 weeks of age. No progression to malignancy was seen in nulliparous BK5.ATF3 or non-transgenic mice held for 16 months. However, biparous BK5.ATF3 mice developed mammary carcinomas with squamous metaplasia between 6 months and one year of age, reaching an incidence of 67%. Cytokeratin expression in the tumors was profoundly disturbed, including expression of CK5 and CK8 (characteristic of basal and luminal cells, respectively throughout the epithelial component of the tumors, CK6 (potentially a stem cell marker, CK10 (a marker of interfollicular epidermal differentiation, and mIRSa2 and mIRSa3.1 (markers of the inner root sheath of hair follicles. Immunohistochemical studies indicated that a subset of human breast tumors exhibit high levels of nuclear ATF3 expression. Conclusion Overexpression of ATF3 in CK5

  1. Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.

    Directory of Open Access Journals (Sweden)

    Julien Ackermann

    Full Text Available The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.

  2. Integrative decomposition procedure and Kappa statistics set up ATF2 ion binding module in malignant pleural mesothelioma (MPM)

    Institute of Scientific and Technical Information of China (English)

    Ying SUN; Lin WANG; Lei LIU

    2008-01-01

    Activating transcription factor 2 (ATF2) is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors. However, the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma (MPM) has never been addressed. In this study, by using GRNInfer and GVedit based on linear pro-gramming and a decomposition procedure, with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM, we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ, C20orf31, NME2, PLOD2, RNF10, and RNASEH1, upstream RNF10 and PLOD2 activation to ATF2, upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues. Remarkably, our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM. Importantly, the ATF2 ion-mediated DNA binding module reflects 'mutual' positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes. It may be useful for developing novel prognostic markers and therapeutic targets in MPM.

  3. The loss of activating transcription factor 4 (ATF4) reduces bone toughness and fracture toughness.

    Science.gov (United States)

    Makowski, Alexander J; Uppuganti, Sasidhar; Wadeer, Sandra A; Whitehead, Jack M; Rowland, Barbara J; Granke, Mathilde; Mahadevan-Jansen, Anita; Yang, Xiangli; Nyman, Jeffry S

    2014-05-01

    Even though age-related changes to bone tissue affecting fracture risk are well characterized, only a few matrix-related factors have been identified as important to maintaining fracture resistance. As a gene critical to osteoblast differentiation, activating transcription factor 4 (ATF4) is possibly one of these important factors. To test the hypothesis that the loss of ATF4 affects the fracture resistance of bone beyond bone mass and structure, we harvested bones from Atf4+/+ and Atf4-/- littermates at 8 and 20 weeks of age (n≥9 per group) for bone assessment across several length scales. From whole bone mechanical tests in bending, femurs from Atf4-/- mice were found to be brittle with reduced toughness and fracture toughness compared to femurs from Atf4+/+ mice. However, there were no differences in material strength and in tissue hardness, as determined by nanoindentation, between the genotypes, irrespective of age. Tissue mineral density of the cortex at the point of loading as determined by micro-computed tomography was also not significantly different. However, by analyzing local composition by Raman Spectroscopy (RS), bone tissue of Atf4-/- mice was found to have higher mineral to collagen ratio compared to wild-type tissue, primarily at 20 weeks of age. From RS analysis of intact femurs at 2 orthogonal orientations relative to the polarization axis of the laser, we also found that the organizational-sensitive peak ratio, ν1Phosphate per Amide I, changed to a greater extent upon bone rotation for Atf4-deficient tissue, implying bone matrix organization may contribute to the brittleness phenotype. Target genes of ATF4 activity are not only important to osteoblast differentiation but also in maintaining bone toughness and fracture toughness.

  4. Scenarios for the ATF2 Ultra-Low Betas Proposal

    Energy Technology Data Exchange (ETDEWEB)

    Marin, Eduardo; /CERN; Tomas, Rogelio; /CERN; Bambade, Philip; /Orsay, LAL; Kuroda, Shigeru; /KEK, Tsukuba; Okugi, Toshiyuki; /KEK, Tsukuba; Tauchi, Toshiaki; /KEK, Tsukuba; Terunuma, Nobuhiro; /KEK, Tsukuba; Urakawa, Junji; /KEK, Tsukuba; Parker, Brett; /Brookhaven; Seryi, Andrei; /SLAC; White, Glen; /SLAC; Woodley, Mark; /SLAC

    2012-06-29

    The current ATF2 Ultra-Low beta proposal was designed to achieve 20nm vertical IP beam size without considering the multipolar components of the FD magnets. In this paper we describe different scenarios that avoid the detrimental effect of these multipolar errors to the beam size at the interaction point (IP). The simplest approach consists in modifying the optics, but other solutions are studied as the introduction of super-conducting wigglers to reduce the emittance or the replacement of the normal-conducting focusing quadrupole in the Final Doublet (NC-QF1FF) with a super-conducting quadrupole one (SC-QF1FF). These are fully addressed in the paper.

  5. Specifications of the octupole magnets required for the ATF2 ultra-low ß* lattice

    Energy Technology Data Exchange (ETDEWEB)

    Marin, E.; /SLAC; Modena, M.; /CERN; Tauchi, T.; Terunuma, N.; /KEK, Tsukuba; Tomas, R.; /CERN; White, G.R.; /SLAC

    2014-05-28

    The Accelerator Test Facility 2 (ATF2) aims to test the novel chromaticity correction for higher chromaticity lattices as the one of CLIC. To this end the ATF2 ultra-low ß* lattice is designed to vertically focus the beam at the focal point or usually referred to as interaction point (IP), down to 23 nm. However when the measured multipole components of the ATF2 magnets are considered in the simulations, the evaluated spot sizes at the IP are well above the design value. The designed spot size is effectively recovered by inserting a pair of octupole magnets. In this note we address the technical specifications required for these octupole magnets.

  6. ATF CO{sub 2} laser system upgrade to terawatt peak power

    Energy Technology Data Exchange (ETDEWEB)

    Pogorelsky, I.V.

    1995-05-01

    This document describes the proposed upgrade of the 10-GW peak power 50-ps CO{sub 2} laser presently operational at the ATF to the 1 TW level at a shorter, 3--10 ps, pulse duration. The approach adopted is based on state of the art CO{sub 2} laser technology and an experience gained in the course of the ATF laser design and application for the laser accelerator experiment. The proposed upgrade is an economical way for the ATF to become in a short time among leading users facilities available for next generation ({ge} 100 MeV) laser accelerator studies.

  7. ATF3 expression is induced by low glucose in pancreatic α and β cells and regulates glucagon but not insulin gene transcription.

    Science.gov (United States)

    Lee, Yong-Soo; Kobayashi, Masaki; Kikuchi, Osamu; Sasaki, Tsutomu; Yokota-Hashimoto, Hiromi; Susanti, Vina Yanti; Ido Kitamura, Yukari; Kitamura, Tadahiro

    2014-01-01

    The pancreas is critical for maintaining glucose homeostasis. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. There are major discrepancies in previous reports on pancreatic ATF3; therefore, its role in the pancreas is unclear. To better elucidate the role of ATF3 in the pancreas, we conducted in vitro studies using pancreatic α and β cell lines, and also evaluated the use of ATF3 antibodies for immunohistochemistry. We determined ATF3 expression was increased by low glucose and decreased by high glucose in both αTC-1.6 and βTC3 cells. We also showed that adenovirus-mediated ATF3 overexpression increased glucagon promoter activity and glucagon mRNA levels in αTC-1.6 cells; whereas, it had no effect on insulin promoter activity and insulin mRNA levels in βTC3 cells. Although immunostaining with the C-19 ATF3 antibody demonstrated predominant expression in α cells rather than β cells, ATF3 staining was still detected in ATF3 knockout mice as clearly as in control mice. On the other hand, another ATF3 antibody (H-90) detected ATF3 in both α cells and β cells, and was clearly diminished in ATF3 knockout mice. These results indicate that previous discrepancies in ATF3 expression patterns in the pancreas were caused by the varying specificities of the ATF3 antibodies used, and that ATF3 is actually expressed in both α cells and β cells.

  8. ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells

    Directory of Open Access Journals (Sweden)

    Ohshima Koichi

    2011-03-01

    Full Text Available Abstract Background Adult T-cell leukemia (ATL is an aggressive malignancy of CD4+ T-cells caused by human T-cell leukemia virus type 1 (HTLV-1. The HTLV-1 bZIP factor (HBZ gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3 as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known. Results Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR, doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2 and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ. Conclusions Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system.

  9. Sumoylation delays the ATF7 transcription factor subcellular localization and inhibits its transcriptional activity.

    Science.gov (United States)

    Hamard, Pierre-Jacques; Boyer-Guittaut, Michaël; Camuzeaux, Barbara; Dujardin, Denis; Hauss, Charlotte; Oelgeschläger, Thomas; Vigneron, Marc; Kedinger, Claude; Chatton, Bruno

    2007-01-01

    Over the past few years, small ubiquitin-like modifier (SUMO) modification has emerged as an important regulator of diverse pathways and activities including protein localization and transcriptional regulation. We identified a consensus sumoylation motif (IKEE), located within the N-terminal activation domain of the ATF7 transcription factor and thus investigated the role of this modification. ATF7 is a ubiquitously expressed transcription factor, homologous to ATF2, that binds to CRE elements within specific promoters. This protein is able to heterodimerize with Jun or Fos proteins and its transcriptional activity is mediated by interaction with TAF12, a subunit of the general transcription factor TFIID. In the present article, we demonstrate that ATF7 is sumoylated in vitro (using RanBP2 as a E3-specific ligase) and in vivo. Moreover, we show that ATF7 sumoylation affects its intranuclear localization by delaying its entry into the nucleus. Furthermore, SUMO conjugation inhibits ATF7 transactivation activity by (i) impairing its association with TAF12 and (ii) blocking its binding-to-specific sequences within target promoters.

  10. Atf6 plays protective and pathologic roles in fatty liver disease due to endoplasmic reticulum stress

    Science.gov (United States)

    Cinaroglu, Ayca; Gao, Chuan; Imrie, Dru; Sadler, Kirsten C.

    2011-01-01

    Many etiologies of fatty liver disease (FLD) are associated with hyper-activation of one of the three pathways that comprise the unfolded protein response (UPR), a harbinger of endoplasmic reticulum (ER) stress. The UPR is mediated by pathways initiated by PERK, IRE1a/XBP1and ATF6, and each of these pathways have been implicated as either protective or pathological in FLD. We use zebrafish with FLD and hepatic ER stress to explore the relationship between Atf6 and steatosis. Mutation of the foie gras (foigr) gene causes FLD and hepatic ER stress. Prolonged treatment of wild-type larvae with a dose of tunicamycin that causes chronic ER stress phenocopies foigr. In contrast, acute exposure to a high dose of tunicamycin robustly activates the UPR but is less effective at inducing steatosis. The Srebp transcription factors are not required for steatosis in any of these models. Instead, depleting larvae of active Atf6 either through mbtps1 mutation or atf6 morpholino injection protects against steatosis caused by chronic ER stress whereas it exacerbates steatosis caused by acute tunicamycin treatment. Conclusion ER stress causes FLD. Loss of Atf6 prevents steatosis caused by chronic ER stress but can also potentiate steatosis caused by acute ER stress. This demonstrates that Atf6 can play both protective and pathological roles in FLD. PMID:21538441

  11. Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response.

    Science.gov (United States)

    Fawcett, T W; Martindale, J L; Guyton, K Z; Hai, T; Holbrook, N J

    1999-01-01

    Gadd153, also known as chop, encodes a member of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family and is transcriptionally activated by cellular stress signals. We recently demonstrated that arsenite treatment of rat pheochromocytoma PC12 cells results in the biphasic induction of Gadd153 mRNA expression, controlled in part through binding of C/EBPbeta and two uncharacterized protein complexes to the C/EBP-ATF (activating transcription factor) composite site in the Gadd153 promoter. In this report, we identified components of these additional complexes as two ATF/CREB (cAMP-responsive-element-binding protein) transcription factors having differential binding activities dependent upon the time of arsenite exposure. During arsenite treatment of PC12 cells, we observed enhanced binding of ATF4 to the C/EBP-ATF site at 2 h as Gadd153 mRNA levels increased, and enhanced binding of ATF3 complexes at 6 h as Gadd153 expression declined. We further demonstrated that ATF4 activates, while ATF3 represses, Gadd153 promoter activity through the C/EBP-ATF site. ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter. Our results suggest that numerous members of the ATF/CREB family are involved in the cellular stress response, and that regulation of stress-induced biphasic Gadd153 expression in PC12 cells involves the ordered, sequential binding of multiple transcription factor complexes to the C/EBP-ATF composite site. PMID:10085237

  12. ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression.

    Science.gov (United States)

    Schaeffer, Etienne; Vigneron, Marc; Sibler, Annie-Paule; Oulad-Abdelghani, Mustapha; Chatton, Bruno; Donzeau, Mariel

    2015-01-01

    The transcription factor ATF7 undergoes multiple post-translational modifications, each of which has distinct effects upon ATF7 function. Here, we show that ATF7 phosphorylation on residue Thr112 exclusively occurs during mitosis, and that ATF7 is excluded from the condensed chromatin. Both processes are CDK1/cyclin B dependent. Using a transduced neutralizing monoclonal antibody directed against the Thr112 epitope in living cells, we could demonstrate that Thr112 phosphorylation protects endogenous ATF7 protein from degradation, while it has no effect on the displacement of ATF7 from the condensed chromatin. The crucial role of Thr112 phosphorylation in stabilizing ATF7 protein during mitosis was confirmed using phospho-mimetic and phospho-deficient mutants. Finally, silencing ATF7 by CRISPR/Cas9 technology leads to a decrease of cyclin D1 protein expression levels. We propose that mitotic stabilized ATF7 protein re-localizes onto chromatin at the end of telophase and contributes to induce the cyclin D1 gene expression.

  13. ATF6 as a Transcription Activator of the Endoplasmic Reticulum Stress Element: Thapsigargin Stress-Induced Changes and Synergistic Interactions with NF-Y and YY1

    OpenAIRE

    Li, Mingqing; Baumeister, Peter; Roy, Binayak; Phan, Trevor; Foti, Dolly; Luo, Shengzhan; Lee, Amy S.

    2000-01-01

    ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER calcium depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress-induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane ...

  14. Design of bunch compressing system with suppression of coherent synchrotron radiation for ATF upgrade

    Energy Technology Data Exchange (ETDEWEB)

    Jing, Yichao [Brookhaven National Lab. (BNL), Upton, NY (United States); Fedurin, Mikhail [Brookhaven National Lab. (BNL), Upton, NY (United States); Stratakis, Diktys [Brookhaven National Lab. (BNL), Upton, NY (United States)

    2015-05-03

    One of the operation modes for Accelerator Test Facility (ATF) upgrade is to provide high peak current, high quality electron beam for users. Such operation requires a bunch compressing system with a very large compression ratio. The CSR originating from the strong compressors generally could greatly degrade the quality of the electron beam. In this paper, we present our design for the entire bunch compressing system that will limit the effect of CSR on the e-beam’s quality. We discuss and detail the performance from the start to end simulation of such a compressor for ATF.

  15. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory.

    Science.gov (United States)

    Yoshida, Keisuke; Maekawa, Toshio; Zhu, Yujuan; Renard-Guillet, Claire; Chatton, Bruno; Inoue, Kentaro; Uchiyama, Takeru; Ishibashi, Ken-ichi; Yamada, Takuji; Ohno, Naohito; Shirahige, Katsuhiko; Okada-Hatakeyama, Mariko; Ishii, Shunsuke

    2015-10-01

    Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcription factor ATF7 in innate immunological memory. ATF7 suppressed a group of genes encoding factors involved in innate immunity in macrophages by recruiting the histone H3K9 dimethyltransferase G9a. Treatment with lipopolysaccharide, which mimics bacterial infection, induced phosphorylation of ATF7 via the kinase p38, which led to the release of ATF7 from chromatin and a decrease in repressive histone H3K9me2 marks. A partially disrupted chromatin structure and increased basal expression of target genes were maintained for long periods, which enhanced resistance to pathogens. ATF7 might therefore be important in controlling memory in cells of the innate immune system.

  16. ATF3 Expression in the corpus luteum: possible role in luteal regression

    Science.gov (United States)

    The present study investigated the induction and possible role of activating transcription factor 3 (ATF3) in the corpus luteum. Postpubertal cattle were treated at midcycle with prostaglandin F2alpha(PGF) for 0–4 hours. Luteal tissue was processed for immunohistochemistry, in situ hybridization, an...

  17. Mechanical Property and Oxidation Behavior of ATF cladding developed in KAERI

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun-Gil; Kim, Il-Hyun; Jung, Yang-Il; Park, Dong-Jun; Park, Jung-Hwan; Park, Jeong-Yong; Koo, Yang-Hyun [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-10-15

    To realize the coating cladding, coating material (Cr-based alloy) as well as coating technology (3D laser coating and arc ion plating combined with vacuum annealing) can be developed to meet the fuel cladding criteria. The coated Zr cladding can be produced after the optimization of coating technologies. The coated cladding sample showed the good oxidation/corrosion and adhesion properties without the spalling and/or severe interaction with the Zr alloy cladding from the various tests. Thus, it is known that the mechanical property and oxidation behavior of coated cladding concept developed in KAERI is reasonable for applying the ATF cladding in LWRs. At the present time various ATF concepts have been proposed and developing in many countries. The ATF concepts with potentially improved accident performance can be summarized to the coating cladding, Mo-Zr cladding, FeCrAl cladding, and SiCf/SiC cladding. Regarding the cladding performance, ATF cladding concepts will be evaluated with respect to the accident scenarios and normal operations of LWRs as well as to the fuel cladding fabrication.

  18. Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

    Science.gov (United States)

    Bu, Li-Jia; Yu, Han-Qing; Fan, Lu-Lu; Li, Xiao-Qiu; Wang, Fang; Liu, Jia-Tao; Zhong, Fei; Zhang, Cong-Jun; Wei, Wei; Wang, Hua; Sun, Guo-Ping

    2017-01-01

    AIM To clarify the mechanisms involved in the critical endoplasmic reticulum (ER) stress initiating unfolded protein response pathway modified by melatonin. METHODS Hepatoma cells, HepG2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure HepG2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes’ expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis. RESULTS In the present study, we first identified that melatonin selectively blocked activating transcription factor 6 (ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 siRNA contributed the enhanced HepG2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed. CONCLUSION These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis. PMID:28246472

  19. Experimental and Theoretical Progress of Linear Collider Final Focus Design and ATF2 Facility

    CERN Document Server

    Seryi, Andrei; Zimmermann, Frank; Kubo, Kiyoshi; Kuroda, Shigeru; Okugi, Toshiyuki; Tauchi, Toshiaki; Terunuma, Nobuhiro; Urakawa, Junji; White, Glen; Woodley, Mark; Angal-Kalinin, Deepa

    2014-01-01

    In this brief overview we will reflect on the process of the design of the linear collider (LC) final focus (FF) optics, and will also describe the theoretical and experimental efforts on design and practical realisation of a prototype of the LC FF optics implemented in the ATF2 facility at KEK, Japan, presently being commissioned and operated.

  20. Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene.

    Science.gov (United States)

    Maekawa, Toshio; Kim, Seungjoon; Nakai, Daisuke; Makino, Chieko; Takagi, Tsuyoshi; Ogura, Hiroo; Yamada, Kazuyuki; Chatton, Bruno; Ishii, Shunsuke

    2010-01-06

    Many symptoms induced by isolation rearing of rodents may be relevant to neuropsychiatric disorders, including depression. However, identities of transcription factors that regulate gene expression in response to chronic social isolation stress remain elusive. The transcription factor ATF-7 is structurally related to ATF-2, which is activated by various stresses, including inflammatory cytokines. Here, we report that Atf-7-deficient mice exhibit abnormal behaviours and increased 5-HT receptor 5B (Htr5b) mRNA levels in the dorsal raphe nuclei. ATF-7 silences the transcription of Htr5B by directly binding to its 5'-regulatory region, and mediates histone H3-K9 trimethylation via interaction with the ESET histone methyltransferase. Isolation-reared wild-type (WT) mice exhibit abnormal behaviours that resemble those of Atf-7-deficient mice. Upon social isolation stress, ATF-7 in the dorsal raphe nucleus is phosphorylated via p38 and is released from the Htr5b promoter, leading to the upregulation of Htr5b. Thus, ATF-7 may have a critical role in gene expression induced by social isolation stress.

  1. ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver.

    Science.gov (United States)

    Zhao, Yunze; Zhou, Jie; Liu, Dan; Dong, Fang; Cheng, Hui; Wang, Weili; Pang, Yakun; Wang, Yajie; Mu, Xiaohuan; Ni, Yanli; Li, Zhuan; Xu, Huiyu; Hao, Sha; Wang, Xiaochen; Ma, Shihui; Wang, Qian-fei; Xiao, Guozhi; Yuan, Weiping; Liu, Bing; Cheng, Tao

    2015-11-19

    The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.

  2. C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.

    Science.gov (United States)

    Huggins, Christopher J; Mayekar, Manasi K; Martin, Nancy; Saylor, Karen L; Gonit, Mesfin; Jailwala, Parthav; Kasoji, Manjula; Haines, Diana C; Quiñones, Octavio A; Johnson, Peter F

    2015-12-14

    The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBPβ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg(-/-) mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant, N-acetyl-cysteine. Cebpg(-/-) mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBPγ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.

  3. Murine cytomegalovirus targets transcription factor ATF4 to exploit the unfolded-protein response.

    Science.gov (United States)

    Qian, Zhikang; Xuan, Baoqin; Chapa, Travis J; Gualberto, Nathaniel; Yu, Dong

    2012-06-01

    The unfolded-protein response (UPR), activated by sensor molecules PERK, ATF6, and IRE1 to resolve endoplasmic reticulum (ER) stress, has emerged as a key target for host cells and viruses to control the infection outcomes. The UPR regulates ER protein folding, controls cell fate upon ER stress, and plays an important role in innate immunity. We and others have shown that human cytomegalovirus (HCMV) modulates the UPR. We show here that murine CMV (MCMV), the widely used CMV model for small animal infection, regulated the UPR in a manner similar to that of HCMV. This modulatory ability was triggered by virion entry and enhanced by viral immediate-early and early gene expression. Thus, while vulnerable at early times, MCMV became resistant to exogenous ER stress at late times of infection. MCMV activated the PERK-ATF4 pathway but only induced a subset of representative ATF4 targets at levels somewhat lower than those by the ER stress inducer tunicamycin. Moreover, MCMV induced ER chaperone Bip but actively blocked IRE1-mediated Xbp1(s) protein accumulation. ATF4 depletion severely attenuated viral growth at a low multiplicity of infection by modestly reducing viral DNA synthesis and more pronouncedly inhibiting late gene transcription. Collectively, we show that the UPR is a conserved target of CMVs and identify ATF4, a key UPR component, as a factor critical for MCMV infection. This work sets the stage for using the MCMV model to explore the role of this stress response in CMV biology, particularly during infection of the host, which is difficult to study in HCMV.

  4. ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex

    Directory of Open Access Journals (Sweden)

    Richard T. Timms

    2016-10-01

    Full Text Available The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.

  5. ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex.

    Science.gov (United States)

    Timms, Richard T; Tchasovnikarova, Iva A; Antrobus, Robin; Dougan, Gordon; Lehner, Paul J

    2016-10-11

    The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.

  6. ATF3 upregulation in glia during Wallerian degeneration: differential expression in peripheral nerves and CNS white matter

    Directory of Open Access Journals (Sweden)

    Coffin Robert S

    2004-03-01

    Full Text Available Abstract Background Many changes in gene expression occur in distal stumps of injured nerves but the transcriptional control of these events is poorly understood. We have examined the expression of the transcription factors ATF3 and c-Jun by non-neuronal cells during Wallerian degeneration following injury to sciatic nerves, dorsal roots and optic nerves of rats and mice, using immunohistochemistry and in situ hybridization. Results Following sciatic nerve injury – transection or transection and reanastomosis – ATF3 was strongly upregulated by endoneurial, but not perineurial cells, of the distal stumps of the nerves by 1 day post operation (dpo and remained strongly expressed in the endoneurium at 30 dpo when axonal regeneration was prevented. Most ATF3+ cells were immunoreactive for the Schwann cell marker, S100. When the nerve was transected and reanastomosed, allowing regeneration of axons, most ATF3 expression had been downregulated by 30 dpo. ATF3 expression was weaker in the proximal stumps of the injured nerves than in the distal stumps and present in fewer cells at all times after injury. ATF3 was upregulated by endoneurial cells in the distal stumps of injured neonatal rat sciatic nerves, but more weakly than in adult animals. ATF3 expression in transected sciatic nerves of mice was similar to that in rats. Following dorsal root injury in adult rats, ATF3 was upregulated in the part of the root between the lesion and the spinal cord (containing Schwann cells, beginning at 1 dpo, but not in the dorsal root entry zone or in the degenerating dorsal column of the spinal cord. Following optic nerve crush in adult rats, ATF3 was found in some cells at the injury site and small numbers of cells within the optic nerve displayed weak immunoreactivity. The pattern of expression of c-Jun in all types of nerve injury was similar to that of ATF3. Conclusion These findings raise the possibility that ATF3/c-Jun heterodimers may play a role in

  7. Operational Experiences Tuning the ATF2 Final Focus Optics Towards Obtaining a 37nm Electron Beam IP Spot Size

    CERN Document Server

    White, Glen; Woodley, Mark; Bai, Sha; Bambade, Philip; Renier, Yves; Bolzon, Benoit; Kamiya, Yoshio; Komamiya, Sachio; Oroku, Masahiro; Yamaguchi, Yohei; Yamanaka, Takashi; Kubo, Kiyoshi; Kuroda, Shigeru; Okugi, Toshiyuki; Tauchi, Toshiaki; Marin, Eduardo

    2010-01-01

    The primary aim of the ATF2 research accelerator is to test a scaled version of the final focus optics planned for use in next-generation linear lepton colliders. ATF2 consists of a 1.3 GeV linac, damping ring providing lowemittance electron beams (<12pm in the vertical plane), extraction line and final focus optics. The design details of the final focus optics and implementation at ATF2 are presented elsewhere. The ATF2 accelerator is currently being commissioned, with a staged approach to achieving the design IP spot size. It is expected that as we implement more demanding optics and reduce the vertical beta function at the IP, the tuning becomes more difficult and takes longer. We present here a description of the implementation of the tuning procedures and describe operational experiences and performances

  8. Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI through inhibiting ATF4-CHOP pathway in mice.

    Directory of Open Access Journals (Sweden)

    Jianhua Rao

    Full Text Available BACKGROUND: Low-dose lipopolysaccharide (LPS preconditioning-induced liver protection has been demonstrated during ischemia-reperfusion injury (IRI in several organs but has not been sufficiently elucidated underlying causal mechanism. This study investigated the role of low-dose LPS preconditioning on ATF4-CHOP pathway as well as the effects of the pathway on tissue injury and inflammation in a mouse model of liver partial-warm IRI. METHODS: LPS (100 µg/kg/d was injected intraperitoneally two days before ischemia. Hepatic injury was evaluated based on serum alanine aminotransferase levels, histopathology, and caspase-3 activity. The ATF4-CHOP pathway and its related apoptotic molecules were investigated after reperfusion. The role of LPS preconditioning on apoptosis and ATF4-CHOP pathway was examined in vitro. Moreover, the effects of the ATF4-CHOP pathway on apoptosis, Caspase-12, and Caspase-3 were determined with ATF4 small interfering RNA (siRNA. Inflammatory cytokine expression was also checked after reperfusion. Inflammatory cytokines and related signaling pathways were analyzed in vitro in macrophages treated by LPS preconditioning or ATF4 siRNA. RESULTS: LPS preconditioning significantly attenuated liver injury after IRI. As demonstrated by in vitro experiments, LPS preconditioning significantly reduced the upregulation of the ATF4-CHOP pathway and inhibited Caspase-12 and Caspase-3 activation after IRI. Later experiments showed that ATF4 knockdown significantly suppressed CHOP, cleaved caspase-12 and caspase-3 expression, as well as inhibited hepatocellular apoptosis. In addition, in mice pretreated with LPS, TNF-α and IL-6 were inhibited after reperfusion, whereas IL-10 was upregulated. Similarly, low-dose LPS significantly inhibited TNF-α, IL-6, ATF4-CHOP pathway, NF-κB pathway, and ERK1/2 in high-dose LPS-stimulated macrophages, whereas IL-10 and cytokine signaling (SOCS-3 suppressor were induced. Importantly, ATF4 siRNA is

  9. Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway.

    Science.gov (United States)

    Chaveroux, Cédric; Sarcinelli, Carmen; Barbet, Virginie; Belfeki, Sofiane; Barthelaix, Audrey; Ferraro-Peyret, Carole; Lebecque, Serge; Renno, Toufic; Bruhat, Alain; Fafournoux, Pierre; Manié, Serge N

    2016-06-03

    The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked β-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.

  10. Parameters Optimization for a Novel Vacuum Laser Acceleration Test at BNL-ATF

    CERN Document Server

    Shao, Lei; Zhou, Feng

    2005-01-01

    This paper presents a new VLA theory model which has revealed that the injection electrons with low energy and small incident angle relative to the laser beam are captured and significantly accelerated in a strong laser field. For the further step for verifying the novel-VLA mechanics, we propose to use the BNL-ATF Terawatt CO2 laser and a high-brightness electron beam to carry out a proof-of-principle beam experiment. Experiment setup including the laser injection optics and electron extraction system and beam diagnostics is presented. Extensive optimized simulation results with ATF practical parameters are also presented, which shows that even when the laser intensity is not very high, the net energy gain still can be seen obviously. This could be prospect for a new revolution of vacuum laser acceleration.

  11. Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression during Endoplasmic Reticulum Stress.

    Directory of Open Access Journals (Sweden)

    Andrea D'Osualdo

    Full Text Available Perturbation of endoplasmic reticulum (ER homeostasis triggers the ER stress response (also known as Unfolded Protein Response, a hallmark of many pathological disorders. However the connection between ER stress and inflammation remains largely unexplored. Recent data suggest that ER stress controls the activity of inflammasomes, key signaling platforms that mediate innate immune responses. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. Although involved in different types of inflammatory responses, XBP-1 splicing was not required for NLRP1 induction. This study provides further evidence that links ER stress with innate.

  12. Beam-based alignment at the KEK-ATF damping ring

    Energy Technology Data Exchange (ETDEWEB)

    Woodley, Mark D.; Nelson, Janice; Ross, Marc; Turner, James; Wolski, A.; Kubo, Kiyoshi

    2004-06-30

    The damping rings of a future linear collider will have demanding alignment and stability requirements in order to achieve the low vertical emittance necessary for high luminosity. The Accelerator Test Facility (ATF) at KEK has successfully demonstrated the vertical emittance below 5 pm that is specified for the GLC/NLC Main Damping Rings. One contribution to this accomplishment has been the use of Beam Based Alignment (BBA) techniques. The mode of operation of the ATF presents particular challenges for BBA, and we describe here how we have deduced the offsets of the BPMs with respect to the quadrupoles. We also discuss a technique that allows for direct measurements of the beam-to-quad offsets.

  13. Performance Comparison of Different System Identification Algorithms for FACET and ATF2

    CERN Document Server

    Pfingstner, J; Schulte, D

    2013-01-01

    Good system knowledge is an essential ingredient for the operation of modern accelerator facilities. For example, beam-based alignment algorithms and orbit feedbacks rely strongly on a precise measurement of the orbit response matrix. The quality of the measurement of this matrix can be improved over time by statistically combining the effects of small system excitations with the help of system identification algorithms. These small excitations can be applied in a parasitic mode without stopping the accelerator operation (on-line). In this work, different system identification algorithms are used in simulation studies for the response matrix measurement at ATF2. The results for ATF2 are finally compared with the results for FACET, latter originating from an earlier work.

  14. 4D Emittance Measurements Using Multiple Wire and Waist Scan Methods in the ATF Extraction Line

    Energy Technology Data Exchange (ETDEWEB)

    Rimbault, C.; Bambade, P.; Brossard, J.; /Orsay, LAL; Alabau, M.; /Valencia U., IFIC; Kuroda, S.; /KEK, Tsukuba; Scarfe, A.; /Manchester U.; Woodley, M.; /SLAC

    2011-11-02

    Emittance measurements performed in the diagnostic section of the Accelerator Test Facility (ATF) extraction line since 1998 led to vertical emittances three times larger than the expected ones, with a strong dependence on intensity. An experimental program is pursued to investigate potential sources of emittance growth and find possible remedies. This requires efficient and reliable emittance measurement techniques. In the past, several phase-space reconstruction methods developed at SLAC and KEK have been used to estimate the vertical emittance, based on multiple location beam size measurements and dedicated quadrupole scans. These methods have been shown to be very sensitive to measurement errors and other fluctuations in the beam conditions. In this context new emittance measurements have been performed revisiting these methods and newly developed ones with a systematic approach to compare and characterise their performance in the ATF extraction line.

  15. Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells

    Directory of Open Access Journals (Sweden)

    Cho Hyunju

    2013-01-01

    Full Text Available Abstract Background Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4. To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2 cells and the results were used to update the model and our current understanding of the signaling induced by palmitate. Results The three key things from the in silico simulation and experimental results are: 1 palmitate induces different signaling pathways (PKR (double-stranded RNA-activated protein kinase, PERK (PKR-like ER kinase, PKA (cyclic AMP (cAMP-dependent protein kinase A in a time dependent-manner, 2 both ATF4 and CREB1 (cAMP-responsive element-binding protein 1 interact with the Atf4 promoter to contribute to a prolonged accumulation of ATF4, and 3 CREB1 is involved in ER-stress induced apoptosis upon palmitate treatment, by regulating ATF4 expression and possibly Ca2+ dependent-CaM (calmodulin signaling pathway. Conclusion The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.

  16. ATF3 is a novel nuclear marker for migrating ependymal stem cells in the rat spinal cord.

    Science.gov (United States)

    Mladinic, Miranda; Bianchetti, Elena; Dekanic, Ana; Mazzone, Graciela L; Nistri, Andrea

    2014-05-01

    The present study identified ATF3 as a novel dynamic marker for ependymal stem/progenitor cells (nestin, vimentin and SOX2 positive) around the central canal of the neonatal or adult rat spinal cord. While quiescent ependymal cells showed cytoplasmic ATF3 expression, during 6-24h in vitro these cells mobilized and acquired intense nuclear ATF3 staining. Their migratory pattern followed a centrifugal pathway toward the dorsal and ventral funiculi, reminiscent of the rostral migratory stream of the brain subventricular stem cells. Thus, the chain cell formation was, by analogy, termed funicular migratory stream (FMS). The FMS process preceded the strong proliferation of ependymal cells occurring only after 24h in vitro. Pharmacological inhibition of MAPK-p38 and JNK/c-Jun (upstream effectors of ATF3 activation) prevented the FMS mobilization of ATF3 nuclear-positive cells. Excitotoxicity or ischemia-like conditions, reported to evoke neuronal and glial injury, did not further enhance migration of ependymal cells at 24h, suggesting that, at this early stage of damage, the FMS phenomenon had peaked and that more extensive repair processes are delayed beyond this time point. ATF3 is, therefore, useful to identify activation and migration of endogenous stem cells of the rat spinal cord in vitro.

  17. ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Xiao-shan Wan

    2014-01-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD. In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4 and CCAAT enhancer binding protein homologous protein (CHOP. Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH, and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

  18. Effects and mechanisms of ATF4 on skin cancer cell proliferation%ATF4对皮肤癌细胞增殖的影响及相关机制

    Institute of Scientific and Technical Information of China (English)

    陈娟; 王翼

    2016-01-01

    Objective: To investigate the effects and mechanisms of knockdown/over-expression of ATF4 on the skin cancer cell proliferation.Methods: hTe expression of ATF4 in different types of skin cancer cells was measured by Western blot. Atfer knockdown or over-expression of ATF4 in A431 cells, the proliferation and cell cycle distribution were measured by CCK-8 assay, colony formation assay or lfow cytometry. hTe protein levels of some cell cycle regulators, such as cyclin D1, cyclin E, P21 and p-Rb/Rb were determined by Western blot. Results: ATF4 was highly expressed in all 3 types of skin cancer cells (P<0.05). ATF4 knockdown repressedthe cell cycle entrance into S-phase from G0/G1 phase followed by a lower cell proliferation rate. Over-expression of ATF4 increased A431 cell proliferation and facilitated cell cycle progression (P<0.05). Furthermore, the protein levels of cyclin D1, cyclin E and p-Rb were significantly decreased after ATF4 knockdown, but the expression of P21 was increased. Over-expression of ATF4 increased the protein levels of cyclin D1, cyclin E and p-Rb, but decreased the P21 expression (P<0.05).Conclusion: ATF4 promotes human squamous cell carcinoma, and its potential mechanisms may be related to promotion of cell cycle transition and expression of cell cycle regulators, suggesting that ATF4 may be a potential new target of treating skin cancer.%目的:探讨沉默/过表达ATF4对人皮肤癌细胞增殖的影响及其相关作用机制。方法:Western blot技术检测不同类型皮肤癌细胞中ATF4的蛋白表达水平。构建ATF4沉默/过表达的A431皮肤癌细胞株,采用CCK-8法、克隆形成实验和流式细胞术检测A431细胞增殖能力的变化及细胞周期分布;Western blot技术检测细胞周期调控因子cyclin D1、cyclin E、P21和p-Rb/Rb的蛋白表达水平。结果:ATF4在3种不同类型的皮肤癌细胞中均呈高表达。CCK-8法和克隆形成实验结果显示沉默ATF4的A431细胞存活率和

  19. Functional analysis of atfA gene to stress response in pathogenic thermal dimorphic fungus Penicillium marneffei.

    Science.gov (United States)

    Nimmanee, Panjaphorn; Woo, Patrick C Y; Vanittanakom, Pramote; Youngchim, Sirida; Vanittanakom, Nongnuch

    2014-01-01

    Penicillium marneffei, the pathogenic thermal dimorphic fungus is a causative agent of a fatal systemic disease, penicilliosis marneffei, in immunocompromised patients especially HIV patients. For growth and survival, this fungus has to adapt to environmental stresses outside and inside host cells and this adaptation requires stress signaling pathways and regulation of gene expression under various kinds of stresses. In this report, P. marneffei activating transcription factor (atfA) gene encoding bZip-type transcription factor was characterized. To determine functions of this gene, atfA isogenic mutant strain was constructed using the modified split marker recombination method. The phenotypes and susceptibility to varieties of stresses including osmotic, oxidative, heat, UV, cell wall and cell membrane stresses of the mutant strain were compared with the wild type and the atfA complemented strains. Results demonstrated that the mRNA expression level of P. marneffei atfA gene increased under heat stress at 42°C. The atfA mutant was more sensitive to sodium dodecyl sulphate, amphotericin B and tert-butyl hydroperoxide than the wild type and complemented strains but not hydrogen peroxide, menadione, NaCl, sorbitol, calcofluor white, itraconazole, UV stresses and heat stress at 39°C. In addition, recovery of atfA mutant conidia after mouse and human macrophage infections was significantly decreased compared to those of wild type and complemented strains. These results indicated that the atfA gene was required by P. marneffei under specific stress conditions and might be necessary for fighting against host immune cells during the initiation of infection.

  20. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2.

    Science.gov (United States)

    Chen, Xuhua; Johnson, Gary S; Schnabel, Robert D; Taylor, Jeremy F; Johnson, Gayle C; Parker, Heidi G; Patterson, Edward E; Katz, Martin L; Awano, Tomoyuki; Khan, Shahwanaz; O'Brien, Dennis P

    2008-02-01

    Neonatal encephalopathy with seizures (NEWS) is a previously undescribed autosomal recessive disease of standard poodle puppies. Affected puppies are small and weak at birth. Many die in their first week of life. Those surviving past 1 week develop ataxia, a whole-body tremor, and, by 4 to 6 weeks of age, severe generalized clonic-tonic seizures. None have survived to 7 weeks of age. Cerebella from affected puppies were reduced in size and often contained dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons. We used deoxyribonucleic acid samples from related standard poodles to map the NEWS locus to a 2.87-Mb segment of CFA36, which contains the canine ortholog of ATF2. This gene encodes activating transcription factor 2 (ATF-2), which participates in the cellular responses to a wide variety of stimuli. We amplified and sequenced all coding regions of canine ATF2 from a NEWS-affected puppy and identified a T > G transversion that predicts a methionine-to-arginine missense mutation at amino acid position 51. Methionine-51 lies within a hydrophobic docking site for mitogen-activated protein kinases that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2 activation. All 20 NEWS-affected puppies in the standard poodle family were homozygous for the mutant G allele. The 58 clinically normal family members were either G/T heterozygotes or homozygous for the ancestral T allele. There are no previous reports of spontaneous ATF2 mutations in people or animals; however, atf2-knockout mice have cerebellar lesions that are similar to those in puppies with NEWS.

  1. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver.

    Science.gov (United States)

    Fusakio, Michael E; Willy, Jeffrey A; Wang, Yongping; Mirek, Emily T; Al Baghdadi, Rana J T; Adams, Christopher M; Anthony, Tracy G; Wek, Ronald C

    2016-05-01

    Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, and ATF6-is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.

  2. Production of tetraacetyl phytosphingosine (TAPS) in Wickerhamomyces ciferrii is catalyzed by acetyltransferases Sli1p and Atf2p.

    Science.gov (United States)

    Ter Veld, Frank; Wolff, Daniel; Schorsch, Christoph; Köhler, Tim; Boles, Eckhard; Poetsch, Ansgar

    2013-10-01

    Wickerhamomyces ciferrii secretes tetraacetyl phytosphingosine (TAPS), and in this study, the catalyzing acetyltransferases were identified using mass spectrometry-based proteomics. The proteome of wild-type strain NRRL Y-1031 served as control and was compared to the tetraacetyl phytosphingosine defective mating type NRRL Y-1031-27. Acetylation of phytosphingosine in W. ciferrii is catalyzed by acetyltransferases Sli1p and Atf2p, encoded by genes similar to Saccharomyces cerevisiae YGR212W and YGR177C, respectively. Ablation of SLI1 resulted in an almost complete loss of tri- and tetraacetyl phytosphingosines, whereas the loss ATF2 resulted in an 15-fold increase in triacetyl phytosphingosine. Most likely, it is the concerted action of these two acetyltransferases that yields tetraacetyl phytosphingosine, in which Sli1p catalyzes initial O- and N-acetylation, producing triacetyl phytosphingosine. Finally, Atf2p catalyzes final O-acetylation to yield tetraacetyl phytosphingosine. The current study demonstrates that mass spectrometry-based proteomics can be employed to identify key steps in ill-explored metabolite biosynthesis pathways of nonconventional microorganisms. Furthermore, the identification of phytosphingosine as substrate for alcohol acetyltransferase Atf2p broadens the known substrate range of this enzyme. This interesting property of Atf2p may be exploited to enhance the secretion of heterologous compounds.

  3. Geometric wakefield regimes study of a rectangular tapered collimator for ATF2

    CERN Document Server

    Fuster-Martinez, Nuria; Latina, Andrea; Snuverink, Jochem

    2016-01-01

    In this paper we study the discrepancy found between the wakefield impact effect induced by a rectangular tapered collimator prototype for ATF2 calculated using analytical models, calculated from CST PS numerical simulations and implemented in the tracking code PLACET v1.0.0. In order to get consistent results between the analytical calculations, CST PS simulations and the tracking code PLACET v1.0.0 the collimator wakefield module in PLACET v1.0.0 has to be modified. The changes have been implemented in the tracking code PLACET v1.0.1.

  4. Development and quality assessments of commercial heat production of ATF FeCrAl tubes

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, Yukinori [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-09-01

    Development and quality assessment of the 2nd generation ATF FeCrAl tube production with commercial manufacturers were conducted. The manufacturing partners include Sophisticated Alloys, Inc. (SAI), Butler, PA for FeCrAl alloy casting via vacuum induction melting, Oak Ridge National Laboratory (ORNL) for extrusion process to prepare the master bars/tubes to be tube-drawn, and Rhenium Alloys, Inc. (RAI), North Ridgeville, OH, for tube-drawing process. The masters bars have also been provided to Los Alamos National Laboratory (LANL) who works with Century Tubes, Inc., (CTI), San Diego, CA, as parallel tube production effort under the current program.

  5. Fabrication Control Plan for ORNL RH-LOCA ATF Test Specimens to be Irradiated in the ATR

    Energy Technology Data Exchange (ETDEWEB)

    Field, Kevin G. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Howard, Richard [Idaho National Lab. (INL), Idaho Falls, ID (United States); Teague, Michael [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2014-06-01

    The purpose of this fabrication plan is (1) to summarize the design of a set of rodlets that will be fabricated and then irradiated in the Advanced Test Reactor (ATR) and (2) provide requirements for fabrication and acceptance criteria for inspections of the Light Water Reactor (LWR) – Accident Tolerant Fuels (ATF) rodlet components. The functional and operational (F&OR) requirements for the ATF program are identified in the ATF Test Plan. The scope of this document only covers fabrication and inspections of rodlet components detailed in drawings 604496 and 604497. It does not cover the assembly of these items to form a completed test irradiation assembly or the inspection of the final assembly, which will be included in a separate INL final test assembly specification/inspection document. The controls support the requirements that the test irradiations must be performed safely and that subsequent examinations must provide valid results.

  6. Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation.

    Science.gov (United States)

    Lin, Kuan-Liang; Chou, Ching-Heng; Hsieh, Shu-Chen; Hwa, Su-Yang; Lee, Ming-Ta; Wang, Fung-Fang

    2010-11-01

    Deficiency of the collagen receptor discoidin domain receptor tyrosine kinase (DDR2) in mice and humans results in dwarfism and short limbs, of which the mechanism remains unknown. Here we report that DDR2 is a key regulator of osteoblast differentiation. DDR2 mRNA expression was increased at an early stage of induced osteoblast differentiation. In the subchondral bone of human osteoarthritic knee, DDR2 was detected in osteoblastic cells. In mouse embryos, DDR2 expression was found from E11 to E15, preceding osteocalcin (OCN) and coinciding with Runx2 expression. Activating transcription factor 4 (ATF4) enhanced DDR2 mRNA expression, and knockdown of ATF4 expression delayed DDR2 induction during osteoblast differentiation. A CCAAT/enhancer binding protein (C/EBP) binding site at -1150 bp in the DDR2 promoter was required for ATF4-mediated DDR2 activation. C/EBPβ bound to and cooperated with ATF4 in stimulating DDR2 transcription; accordingly, the ATF4 mutants deficient of C/EBPβ binding were incapable of transactivating DDR2. Overexpression of DDR2 increased osteoblast-specific gene expression. Conversely, knockdown of DDR2 suppressed osteogenic marker gene expression and matrix mineralization during the induced osteogenesis. The stimulation of p38 MAPK by DDR2 was required for DDR2-induced activation of Runx2 and OCN promoters. Together our findings uncover a pathway in which ATF4, by binding to C/EBPβ transcriptionally upregulates DDR2 expression, and DDR2, in turn, activates Runx2 through p38 MAPK to promote osteoblast differentiation.

  7. Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease.

    Science.gov (United States)

    Teramachi, Jumpei; Hiruma, Yuko; Ishizuka, Seiichi; Ishizuka, Hisako; Brown, Jacques P; Michou, Laëtitia; Cao, Huiling; Galson, Deborah L; Subler, Mark A; Zhou, Hua; Dempster, David W; Windle, Jolene J; Roodman, G David; Kurihara, Noriyoshi

    2013-06-01

    Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D₂ (1,25-(OH)₂D₃; also know as calcitriol). The increased 1,25-(OH)₂D₃ sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)₂D₃'s effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors' sensitivity to 1,25-(OH)₂D₃ in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase [TRAP]-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)₂D₃, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)₂D₃. Because TAF12 directly interacts with the cyclic adenosine monophosphate-dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an

  8. Concentrated bovine milk whey active proteins facilitate osteogenesis through activation of the JNK-ATF4 pathway.

    Science.gov (United States)

    Tsuji-Naito, Kentaro; Jack, Ralph W

    2012-01-01

    Concentrated fractions of low molecular weight whey proteins (1-30 kDa), that is concentrated bovine milk whey active proteins (CBP), have been found to enhance bone formation in both in vivo and clinical studies, but the underlying mechanisms are poorly understood. In this study, we found that CBP promoted osteoblastic differentiation in normal human osteoblasts, and determined the involvement of the c-jun NH2-terminal kinase (JNK)-activating transcription factor 4 (ATF4) pathway. We observed that alkaline phosphatase activity and mineralization were significantly induced by CBP treatment. In addition, mRNA expression of ATF4 was intensely elevated in CBP-treated osteoblasts, indicating that the late-phase events of differentiation were promoted. We found that CBP activated the phosphorylation of JNK and extracellular signal-regulated kinase (ERK). Furthermore, pathway analyses using the various signaling pathway-specific inhibitors revealed that JNK activation, but not ERK activation, is essential for CBP-induced mineralization and ATF4 expression. Our results indicate that the JNK-mediated ATF4 pathway is required for CBP-promotive osteogenesis.

  9. Coffee Polyphenols Change the Expression of STAT5B and ATF-2 Modifying Cyclin D1 Levels in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Carlota Oleaga

    2012-01-01

    Full Text Available Background. Epidemiological studies suggest that coffee consumption reduces the risk of cancer, but the molecular mechanisms of its chemopreventive effects remain unknown. Objective. To identify differentially expressed genes upon incubation of HT29 colon cancer cells with instant caffeinated coffee (ICC or caffeic acid (CA using whole-genome microarrays. Results. ICC incubation of HT29 cells caused the overexpression of 57 genes and the underexpression of 161, while CA incubation induced the overexpression of 12 genes and the underexpression of 32. Using Venn-Diagrams, we built a list of five overexpressed genes and twelve underexpressed genes in common between the two experimental conditions. This list was used to generate a biological association network in which STAT5B and ATF-2 appeared as highly interconnected nodes. STAT5B overexpression was confirmed at the mRNA and protein levels. For ATF-2, the changes in mRNA levels were confirmed for both ICC and CA, whereas the decrease in protein levels was only observed in CA-treated cells. The levels of cyclin D1, a target gene for both STAT5B and ATF-2, were downregulated by CA in colon cancer cells and by ICC and CA in breast cancer cells. Conclusions. Coffee polyphenols are able to affect cyclin D1 expression in cancer cells through the modulation of STAT5B and ATF-2.

  10. Finding ATF4/p75NTR/IL-8 Signal Pathway in Endothelial–Mesenchymal Transition by Safrole Oxide

    Science.gov (United States)

    Zhao, Wenbo; Yue, Hongwei; Su, Le; Zhang, ShangLi; Zhao, Jing

    2014-01-01

    Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease. PMID:24905361

  11. Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide.

    Directory of Open Access Journals (Sweden)

    Di Ge

    Full Text Available Targeting the endothelial-to-mesenchymal transition (EndoMT may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO, 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4, p75 neurotrophin receptor (p75NTR, and interleukin 8 (IL-8 was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

  12. Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide.

    Science.gov (United States)

    Ge, Di; Jing, Qingchuan; Zhao, Wenbo; Yue, Hongwei; Su, Le; Zhang, ShangLi; Zhao, Jing

    2014-01-01

    Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

  13. MiR-214 regulates the function of osteoblast under simulated microgravity by targeting ATF4

    Science.gov (United States)

    Li, Yingxian; Wang, Xiaogang; Li, Qi; Lv, Ke; Wan, Yumin; Li, Yinghui; Bai, Yanqiang

    Background: MicroRNAs (miRNAs) are small fragments of single-stranded RNA containing 18-24 nucleotides, and are generated from endogenous transcripts. MicroRNAs function in post-transcriptional gene silencing by targeting the 3'-untranslated region (UTR) of mRNAs, resulting in translational repression. Growing evidence shows that microRNAs (miRNAs) regu-late various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; How-ever, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast dif-ferentiation remains elusive. Methods: To study the potential involvement of miRNAs in osteoblast differentiation under stimulated microgravity, we analyzed the expression of 20 bone relative miRNAs using real time PCR platform to find particularly miRNAs whose expression is altered during osteoblast differentiation. TargetScan, miRBase and Miranda were used to predict the target gene of candidate miRNA. To investigate whether ATF4 can be directly targeted by miR-214, we engineered luciferase reporters that have either the wild-type 3'UTRs of these genes, or the mutant UTRs with a 6 base pair (bp) deletion in the target sites. Lastly, to address the in vivo role of miR-214 in bone formation, tail suspension mice model was used to simulate the change of osteoblast function and bone loss. Results: Recent studies have sug-gested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify miR-214 in MC3T3-E1 cells, which is a primary mouse osteoblasts cell line, to promote osteoblast differentiation by repressing Activating Transcription Factor4 (ATF4) ex-pression at the posttranscriptional level. What is more, miR-214 was found to be transcribed in C2C12 cells during bone morphogenetic protein 2-induced (BMP2-induced) osteogenesis, and overexpression of miR-214 attenuated BMP2-induced osteoblastogenesis

  14. Proceedings of US-Japan heliotron-stellarator workshop: Volume 3

    Energy Technology Data Exchange (ETDEWEB)

    1987-01-01

    This paper is the third of four volumes on the US-Japan Heliotron-Stellarator Workshop. It contains talks on the following: Heliotron EICRF Heating Experiment; CHS Heating Systems (NBI, ECH, ICH); ICH Program for ATF; ICRF Wave Propagation; the HBQM Heliac Work; configuration studies; compact torsatron studies; low aspect ratio torsatron design; optimized small stellarator designs; configuration studies for ATF; currents in ATF; currents in ATF; computations of 3-D equilibria with islands; magnetic surface mapping studies; magnetic field alignment and mapping on ATF; divertor experiments in IMS; PMI program and wall conditioning for ATF; hard X-ray suppression on ATF; plasma rotation and potential measurement; and status of heavy ion beam probe for ATF.

  15. MICRON-SCALE LASER-WIRE AT THE ATF-II AT KEK COMMISSIONING AND RESULTS

    CERN Document Server

    Nevay, L J; Walczak, R; Blair, G A; Boogert, S; Deacon, L C; Karataev, P; Aryshev, A; Terunuma, N; Urakawa, J

    2011-01-01

    We present the first results from the commissioning of the upgraded laser-wire experiment at the Accelerator Test Facility 2 (ATF-II) at KEK. A new laser transport line and beam diagnostics were used to collide 150 mJ, 167 ps long laser pulses with 1.28 GeV, 30 ps long electron bunches to measure the vertical transverse size. Additionally, a new detector was installed with a reduced area for lower background. Initial scans showing a convoluted beam size of 18.4 ± 0.4 μm were used to tune the electron beam optics and reduce this down to 8.0 ± 0.3 μm. Laser pulse energy and charge dependency were investigated showing a linear relationship in both with a minimum laser energy of 20 mJ required for adequate signal to make a laser-wire scan.

  16. Experiment studies on the polarized gamma-rays generation at KEK-ATF

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Ping; PEI Guo-Xi

    2009-01-01

    Polarized positrons can be created through electron-positron pair creation from circularly polarized gamma-rays. Laser-Compton scattering is an efficient method to generate circularly polarized gamma-rays. A high finesse 2-mirror optical stacking cavity had been installed on the straight section of the electron storage ring at KEK-ATF. A 1064 nm circularly polarized pulsed laser beam was stacked in the cavity. Polarized gamma-rays with a maximum energy of 28.3 MeV were produced via inverse Compton scattering of the enhanced laser pulse off an electron beam of 1.28 GeV. The number of generated gamma photons per collision was estimated by a photon detector. It was found that the experimental result was in agreement with the simulated value.

  17. DESIGN AND PERFORMANCE OF INTRA-TRAIN FEEDBACK SYSTEMS AT ATF2

    CERN Document Server

    Resta-Lopez, J

    2009-01-01

    The major goals of the final focus test beam line facility ATF2 are to provide electron beams with a few tens of nanometer beam sizes and beam stability control at the nanometer level. In order to achieve such a level of stability beam-based feedback systems are necessary at different timescales to correct static and dynamic effects. In particular, we present the design of intra-train feedback systems to correct the impact of fast jitter sources. We study a bunchto- bunch feedback system installed in the extraction line to combat the ring extraction transverse jitters. In addition, we design a bunch-to-bunch feedback system at the interaction point for correction of position jitter due to the fast vibration of the magnets in the final focus. Optimum feedback software algorithms are discussed and simulation results are presented.

  18. Measured Thermal and Fast Neutron Fluence Rates for ATF-1 Holders During ATR Cycle 157D

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Larry Don [Idaho National Lab. (INL), Idaho Falls, ID (United States); Miller, David Torbet [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-03-01

    This report contains the thermal (2200 m/s) and fast (E>1MeV) neutron fluence rate data for the ATF-1 holders located in core for ATR Cycle 157D which were measured by the Radiation Measurements Laboratory (RML) as requested by the Power Reactor Programs (ATR Experiments) Radiation Measurements Work Order. This report contains measurements of the fluence rates corresponding to the particular elevations relative to the 80-ft. core elevation. The data in this report consist of (1) a table of the ATR power history and distribution, (2) a hard copy listing of all thermal and fast neutron fluence rates, and (3) plots of both the thermal and fast neutron fluence rates. The fluence rates reported are for the average power levels given in the table of power history and distribution.

  19. Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

    Directory of Open Access Journals (Sweden)

    Petrović Isidora

    2011-01-01

    Full Text Available The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene.

  20. The Yeast ATF1 Acetyltransferase Efficiently Acetylates Insect Pheromone Alcohols: Implications for the Biological Production of Moth Pheromones.

    Science.gov (United States)

    Ding, Bao-Jian; Lager, Ida; Bansal, Sunil; Durrett, Timothy P; Stymne, Sten; Löfstedt, Christer

    2016-04-01

    Many moth pheromones are composed of mixtures of acetates of long-chain (≥10 carbon) fatty alcohols. Moth pheromone precursors such as fatty acids and fatty alcohols can be produced in yeast by the heterologous expression of genes involved in insect pheromone production. Acetyltransferases that subsequently catalyze the formation of acetates by transfer of the acetate unit from acetyl-CoA to a fatty alcohol have been postulated in pheromone biosynthesis. However, so far no fatty alcohol acetyltransferases responsible for the production of straight chain alkyl acetate pheromone components in insects have been identified. In search for a non-insect acetyltransferase alternative, we expressed a plant-derived diacylglycerol acetyltransferase (EaDAcT) (EC 2.3.1.20) cloned from the seed of the burning bush (Euonymus alatus) in a yeast system. EaDAcT transformed various fatty alcohol insect pheromone precursors into acetates but we also found high background acetylation activities. Only one enzyme in yeast was shown to be responsible for the majority of that background activity, the acetyltransferase ATF1 (EC 2.3.1.84). We further investigated the usefulness of ATF1 for the conversion of moth pheromone alcohols into acetates in comparison with Ea DAcT. Overexpression of ATF1 revealed that it was capable of acetylating these fatty alcohols with chain lengths from 10 to 18 carbons with up to 27- and 10-fold higher in vivo and in vitro efficiency, respectively, compared to Ea DAcT. The ATF1 enzyme thus has the potential to serve as the missing enzyme in the reconstruction of the biosynthetic pathway of insect acetate pheromones from precursor fatty acids in yeast.

  1. Interplay of CREB and ATF2 in Ionizing Radiation-Induced Neuroendocrine Differentiation of Prostate Cancer Cells

    Science.gov (United States)

    2012-06-01

    cross-talk between Hh and androgen signaling in prostate cancer. Source of Funding: NCI RO1-CA111618; DOD W81XWH-06 377 WHAT CAN THE HAIR FOLLICLES ...demonstrated that targeting CREB signaling can increase IR-induced cell death. We also demonstrated that IR induces NED in xenograft nude mouse models and in...heterodimer to regulate gene transcription [21]. While some target genes can be activated by CREB and ATF2 equally or cooperatively [22-24

  2. Letter Report Documenting Progress of Second Generation ATF FeCrAl Alloy Fabrication

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, Y. [ORNL; Yang, Y. [ORNL; Field, K. G. [ORNL; Terrani, K. [ORNL; Pint, B. A. [ORNL; Snead, L. L. [ORNL

    2014-06-10

    Development of the 2nd generation ATF FeCrAl alloy has been initiated, and a candidate alloy was selected for trial tube fabrication through hot-extrusion and gun-drilling processes. Four alloys based on Fe-13Cr-4.5Al-0.15Y in weight percent were newly cast with minor alloying additions of Mo, Si, Nb, and C to promote solid-solution and second-phase precipitate strengthening. The alloy compositions were selected with guidance from computational thermodynamic tools. The lab-scale heats of ~ 600g were arc-melted and drop-cast, homogenized, hot-forged and -rolled, and then annealed producing plate shape samples. An alloy with Mo and Nb additions (C35MN) processed at 800°C exhibits very fine sub-grain structure with the sub-grain size of 1-3μm which exhibited more than 25% better yield and tensile strengths together with decent ductility compared to the other FeCrAl alloys at room temperature. It was found that the Nb addition was key to improving thermal stability of the fine sub-grain structure. Optimally, grains of less than 30 microns are desired, with grains up to and order of magnitude in desired produced through Nb addition. Scale-up effort of the C35MN alloy was made in collaboration with a commercial cast company who has a capability of vacuum induction melting. A 39lb columnar ingot with ~81mm diameter and ~305mm height (with hot-top) was commercially cast, homogenized, hot-extruded, and annealed providing 10mm-diameter bar-shape samples with the fine sub-grain structure. This commercial heat proved consistent with materials produced at ORNL at the lab-scale. Tubes and end caps were machined from the bar sample and provided to another work package for the ATF-1 irradiation campaign in the milestone M3FT-14OR0202251.

  3. A Project to Design and Build the Magnets for a New Test Beamline, the ATF2, at KEK

    Energy Technology Data Exchange (ETDEWEB)

    Spencer, Cherrill M.; /slac; Sugahara, Ryuhei; Masuzawa, Mika; /KEK, Tsukuba; Bolzon, Benoit; Jeremie, Andrea; /Annecy, LAPP

    2011-02-07

    In order to achieve the high luminosity required at the proposed International Linear Collider (ILC), it is critical to focus the beams to nanometer size with the ILC Beam Delivery System, and to maintain the beams collisions with a nanometer-scale stability. To establish the technologies associated with this ultra-high precision beam handling, a special beamline has been designed and built as an extension of the existing extraction beamline of the Accelerator Test Facility at KEK, Japan. The ATF provides an adequate ultra-low emittance electron beam that is comparable to the ILC requirements; the ATF2 mimics the ILC final focus system to create a tightly focused, stable beam. There are 37 magnets in the ATF2, 29 quadrupoles, 5 sextupoles and 3 bends. These magnets had to be acquired in a short time and at minimum cost, which led to various acquisition strategies; but nevertheless they had to meet strict requirements on integrated strength, physical dimensions, compatibility with existing magnet movers and beam position monitors, mechanical stability and field stability and quality. This paper will describe how 2 styles of quadrupoles, 2 styles of sextupoles, one dipole style and their supports were designed, fabricated, refurbished or modified, measured and aligned by a small team of engineers from 3 continents.

  4. Analysis of Performance of Selected AFC, ATF Fuels, and Lanthanide Transport

    Energy Technology Data Exchange (ETDEWEB)

    Unal, Cetin [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Galloway, Jack D. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-09-29

    We started to look at the performance of ATF concept in LWRs late in FY14 and finish our studies in FY15. The work has been presented in AFC review meetings, ICAPP and TOPFUEL conferences. The final version of the work is accepted for publication in Nuclear Engineering and Science Journal (NES). The copy of ICAPP and NES papers are attached separately to this document as our milestone deliverables. We made an important progress in the modeling of lanthanide transport in FY15. This work produced an ANS Winter Meeting paper and GLOBAL 2015 paper. GLOBAL 2015 paper is also attached as deliverable of FY15. The work on the lanthanide transport is preliminary. We are exploring other potential mechanisms, in addition to “liquid-like” diffusion mechanisms, proposed by Robert Mariani [1] before we analyze data that will be taken by Ohio State University. This year, we concentrate on developing diffusion kernels and principles of modeling. Next year, this work will continue and analyze the Ohio State data and develop approaches to solve multicomponent diffusion. In addition to three papers we attached to this report, we have done some research on coupling and the development of gas release model for metallic fuels in FY15. They are also preliminary in nature; therefore, we give the summary of what we found rather than an extended report that will be done in FY16.

  5. Viability of thin wall tube forming of ATF FeCrAl

    Energy Technology Data Exchange (ETDEWEB)

    Maloy, Stuart Andrew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Aydogan, Eda [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Anderoglu, Osman [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Lavender, Curt [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Yamamoto, Yukinori [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-09-16

    Fabrication of thin walled tubing of FeCrAl alloys is critical to its success as a candidate enhanced accident tolerant fuel cladding material. Alloys that are being investigated are Generation I and Generation II FeCrAl alloys produced at ORNL and an ODS FeCrAl alloy, MA-956 produced by Special Metals. Gen I and Gen II FeCrAl alloys were provided by ORNL and MA-956 was provided by LANL (initially produced by Special Metals). Three tube development efforts were undertaken. ORNL led the FeCrAl Gen I and Gen II alloy development and tube processing studies through drawing tubes at Rhenium Corporation. LANL received alloys from ORNL and led tube processing studies through drawing tubes at Century Tubing. PNNL led the development of tube processing studies on MA-956 through pilger processing working with Sandvik Corporation. A summary of the recent progress on tube development is provided in the following report and a separate ORNL report: ORNL/TM-2015/478, “Development and Quality Assessments of Commercial Heat Production of ATF FeCrAl Tubes”.

  6. Viability of thin wall tube forming of ATF FeCrAl

    Energy Technology Data Exchange (ETDEWEB)

    Maloy, Stuart Andrew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Aydogan, Eda [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Anderoglu, Osman [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Lavender, Curt [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Yamamoto, Yukinori [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-09-16

    Fabrication of thin walled tubing of FeCrAl alloys is critical to its success as a candidate enhanced accident-tolerant fuel cladding material. Alloys that are being investigated are Generation I and Generation II FeCrAl alloys produced at ORNL and an ODS FeCrAl alloy, MA-956 produced by Special Metals. Gen I and Gen II FeCrAl alloys were provided by ORNL and MA-956 was provided by LANL (initially produced by Special Metals). Three tube development efforts were undertaken. ORNL led the FeCrAl Gen I and Gen II alloy development and tube processing studies through drawing tubes at Rhenium Corporation. LANL received alloys from ORNL and led tube processing studies through drawing tubes at Century Tubing. PNNL led the development of tube processing studies on MA-956 through pilger processing working with Sandvik Corporation. A summary of the recent progress on tube development is provided in the following report and a separate ORNL report: ORNL/TM-2015/478, “Development and Quality Assessments of Commercial Heat Production of ATF FeCrAl Tubes”.

  7. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kook Hwan [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jeong, Yeon Taek [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Kim, Seong Hun [Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jung, Hye Seung; Park, Kyong Soo [Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744 (Korea, Republic of); Lee, Hae-Youn [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Lee, Myung-Shik, E-mail: mslee0923@skku.edu [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of)

    2013-10-11

    Highlights: •Metformin induces FGF21 expression in an AMPK independent manner. •Metformin enhances FGF21 expression by inhibiting mitochondrial complex I activity. •The PERK-eIF2α-ATF4 axis is required for metformin-induced FGF21 expression. •Metformin activates the ATF4-FGF21 axis in the liver of mouse. •Metformin increases serum FGF21 level in diabetic human subjects. -- Abstract: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6 months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin.

  8. Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation

    Science.gov (United States)

    Kozel, Caitlin; Thompson, Brytteny; Hustak, Samantha; Moore, Chelsea; Nakashima, Akio; Singh, Chingakham Ranjit; Reid, Megan; Cox, Christian; Papadopoulos, Evangelos; Luna, Rafael E.; Anderson, Abbey; Tagami, Hideaki; Hiraishi, Hiroyuki; Slone, Emily Archer; Yoshino, Ken-ichi; Asano, Masayo; Gillaspie, Sarah; Nietfeld, Jerome; Perchellet, Jean-Pierre; Rothenburg, Stefan; Masai, Hisao; Wagner, Gerhard; Beeser, Alexander; Kikkawa, Ushio; Fleming, Sherry D.; Asano, Katsura

    2016-01-01

    ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila. The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions. PMID:27325740

  9. Role of ATF7-TAF12 interactions in the VDR hyper-sensitivity of osteoclast precursors in Paget’s disease

    Science.gov (United States)

    Teramachi, Jumpei; Hiruma, Yuko; Ishizuka, Seiichi; Ishizuka, Hisako; Brown, Jacques P.; Michou, Laëtitia; Cao, Huiling; Galson, Deborah L; Subler, Mark A; Zhou, Hua; Dempster, David W; Windle, Jolene J; Roodman, G. David; Kurihara, Noriyoshi

    2013-01-01

    Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-(OH)2D3. The increased 1,25-(OH)2D3 sensitivity is mediated by TAF12, a co-activator of VDR, which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3’s effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors sensitivity to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL-precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (TRAP-TAF12 mice), formed OCL at very low levels of 1,25-(OH)2D3, although the OCL failed to exhibit other hallmarks of PD OCL, including RANKL hyper-sensitivity and hyper-multinucleation. ChIP analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDRE), in the presence of 1,25-(OH)2D3. Since TAF12 directly interacts with the ATF7 transcription factor and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined if TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either WT or MVNP-expressing OCL with an anti-TAF12 antibody followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCL. Knockdown of ATF7 in MVNP-expressing cells decreased CYP24A1 induction by 1,25-(OH)2D3 as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hyper-sensitivity of OCL precursors to 1

  10. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.

    Science.gov (United States)

    Bouman, L; Schlierf, A; Lutz, A K; Shan, J; Deinlein, A; Kast, J; Galehdar, Z; Palmisano, V; Patenge, N; Berg, D; Gasser, T; Augustin, R; Trümbach, D; Irrcher, I; Park, D S; Wurst, W; Kilberg, M S; Tatzelt, J; Winklhofer, K F

    2011-05-01

    Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.

  11. Opportunities for the LWR ATF materials development program to contribute to the LBE-cooled ADS materials qualification program

    Science.gov (United States)

    Gong, Xing; Li, Rui; Sun, Maozhou; Ren, Qisen; Liu, Tong; Short, Michael P.

    2016-12-01

    Accelerator-driven systems (ADS) are a promising approach for nuclear waste disposal. Nevertheless, the principal candidate materials proposed for ADS construction, such as the ferritic/martensitic steel, T91, and austenitic stainless steels, 316L and 15-15Ti, are not fully compatible with the liquid lead-bismuth eutectic (LBE) coolant. Under some operating conditions, liquid metal embrittlement (LME) or liquid metal corrosion (LMC) may occur in these steels when exposed to LBE. These environmentally-induced material degradation effects pose a threat to ADS reactor safety, as failure of the materials could initiate a severe accident, in which fission products are released into the coolant. Meanwhile, parallel efforts to develop accident-tolerant fuels (ATF) in light water reactors (LWRs) could provide both general materials design philosophies and specific material solutions to the ADS program. In this paper, the potential contributions of the ATF materials development program to the ADS materials qualification program are evaluated and discussed in terms of service conditions and materials performance requirements. Several specific areas where coordinated development may benefit both programs, including composite materials and selected coatings, are discussed.

  12. Hepatic maturation of human iPS cell-derived hepatocyte-like cells by ATF5, c/EBPα, and PROX1 transduction.

    Science.gov (United States)

    Nakamori, Daiki; Takayama, Kazuo; Nagamoto, Yasuhito; Mitani, Seiji; Sakurai, Fuminori; Tachibana, Masashi; Mizuguchi, Hiroyuki

    2016-01-15

    Hepatocyte-like cells differentiated from human iPS cells (human iPS-HLCs) are expected to be utilized in drug development and research. However, recent hepatic characterization of human iPS-HLCs showed that these cells resemble fetal hepatocytes rather than adult hepatocytes. Therefore, in this study, we aimed to develop a method to enhance the hepatic function of human iPS-HLCs. Because the gene expression levels of the hepatic transcription factors (activating transcription factor 5 (ATF5), CCAAT/enhancer-binding protein alpha (c/EBPα), and prospero homeobox protein 1 (PROX1)) in adult liver were significantly higher than those in human iPS-HLCs and fetal liver, we expected that the hepatic functions of human iPS-HLCs could be enhanced by adenovirus (Ad) vector-mediated ATF5, c/EBPα, and PROX1 transduction. The gene expression levels of cytochrome P450 (CYP) 2C9, 2E1, alpha-1 antitrypsin, transthyretin, Na+/taurocholate cotransporting polypeptide, and uridine diphosphate glucuronosyl transferase 1A1 and protein expression levels of CYP2C9 and CYP2E1 were upregulated by ATF5, c/EBPα, and PROX1 transduction. These results suggest that the hepatic functions of the human iPS-HLCs could be enhanced by ATF5, c/EBPα, and PROX1 transduction. Our findings would be useful for the hepatic maturation of human iPS-HLCs.

  13. The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3 as a prominent node in a cholesterol-sensing network.

    Directory of Open Access Journals (Sweden)

    Jayoung Kim

    Full Text Available Elevated circulating cholesterol is a systemic risk factor for cardiovascular disease and metabolic syndrome, however the manner in which the normal prostate responds to variations in cholesterol levels is poorly understood. In this study we addressed the molecular and cellular effects of elevated and suppressed levels of circulating cholesterol on the normal prostate. Integrated bioinformatic analysis was performed using DNA microarray data from two experimental formats: (1 ventral prostate from male mice with chronically elevated circulating cholesterol and (2 human prostate cells exposed acutely to cholesterol depletion. A cholesterol-sensitive gene expression network was constructed from these data and the transcription factor ATF3 was identified as a prominent node in the network. Validation experiments confirmed that elevated cholesterol reduced ATF3 expression and enhanced proliferation of prostate cells, while cholesterol depletion increased ATF3 levels and inhibited proliferation. Cholesterol reduction in vivo alleviated dense lymphomononuclear infiltrates in the periprostatic adipose tissue, which were closely associated with nerve tracts and blood vessels. These findings open new perspectives on the role of cholesterol in prostate health, and provide a novel role for ATF3, and associated proteins within a large signaling network, as a cholesterol-sensing mechanism.

  14. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway.

    Directory of Open Access Journals (Sweden)

    Valérie Carraro

    Full Text Available In mammals, plasma amino acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that amino acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by amino acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following amino acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBPβ to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the amino acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2α/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver.

  15. Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy*

    Science.gov (United States)

    Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Murry, Daryl J.; Fox, Daniel K.; Bongers, Kale S.; Lira, Vitor A.; Meyerholz, David K.; Talley, John J.; Adams, Christopher M.

    2015-01-01

    Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. PMID:26338703

  16. Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis.

    Science.gov (United States)

    Notte, Annick; Rebucci, Magali; Fransolet, Maude; Roegiers, Edith; Genin, Marie; Tellier, Celine; Watillon, Kassandra; Fattaccioli, Antoine; Arnould, Thierry; Michiels, Carine

    2015-05-01

    Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol-induced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRE1α). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors.

  17. Development of a Turn-by-Turn Beam Position Monitoring System for Multiple Bunch Operation of the ATF Damping Ring

    CERN Document Server

    Burrows, P N; Kraljevic, N Blaskovic; Christian, G B; Davis, M R; Perry, C; Apsimon, R J; Constance, B; Gerbershagen, A; Resta-Lopez, J

    2012-01-01

    An FPGA-based monitoring system has been developed to study multi-bunch beam instabilities in the damping ring (DR) of the KEK Accelerator Test Facility (ATF). The system utilises a stripline beam position monitor (BPM) and single-stage down-mixing BPM processor. The system is designed to record the horizontal and/or vertical positions of up to three bunches in the DR with c. 150ns bunch spacing, or the head bunch of up to three trains in a multi-bunch mode with a bunch spacing of 5.6 ns. The FPGA firmware and data acquisition software allow the recording of turnby-turn data. An overview of the system and performance results will be presented.

  18. Over-expression of ATF3 Inhibits the Proliferation of Esophageal Squamous Carcinoma Cells%激活转录因子3的过表达对食管癌细胞生长的抑制作用

    Institute of Scientific and Technical Information of China (English)

    谢仰民; 谢剑君; 周飞; 侯健; 曹君君; 许丽艳; 李恩民

    2009-01-01

    背景与目的:激活转录因子3(activating transcription factor 3,ATF3)在食管癌中表达异常下调,但其功能仍不清楚.本研究拟探讨ATF3在食管癌细胞过表达对癌细胞生长及裸鼠成瘤的影响. 材料与方法:利用分子克隆技术将ATF3基因完整编码区克隆至真核细胞表达载体pcDNA3中,获得重组表达质粒;将该表达质粒转染食管癌EC109细胞并用G418筛选稳定表达的细胞克隆;用Western blot检测ATF3的过表达效果;对ATF3过表达的细胞与相应对照细胞进行细胞克隆形成实验和裸鼠体内成瘤实验,以分析ATF3过表达对食管癌细胞生长的影响. 结果:ATF3的过表达在体外可以降低食管癌细胞的克隆形成能力;在体内可以抑制食管癌细胞在雌鼠中的成瘤能力,但对雄鼠中的成瘤能力没有明显影响.结论:ATF3的过表达可以抑制食管癌细胞的生长,ATF3可能在食管癌的发生发展中发挥重要作用.%BACKGROUND AND AIM: ATF3 was down-regulated in esophageal squamous cell carcinoma (ESCC), but the roles of ATF3 in ESCC cells still remained unclear. The purpose of this study was to explore the effect of ATF3 on the proliferation of ESCC cells. MATERIALS AND METHODS: The recombinant expressing plasmid was constructed by inserting the full coding sequence of ATF3 gene into the eukaryotic expressing vector pcDNA3. Then, the expressing plasmid was stably transfected into EC 109 cells, an ESCC cell line, and the over-expressing ATF3 cell clones were obtained. Colony formation assay and tumor formation assay in nude mice were used to explore the effect of ATF3 over-expression on the proliferation of ESCC cells. RESULTS: With the over-expression of ATF3, the colony formation ability of EC109 cells was decreased and the tumor formation of EC109 cells in female mice was inhibited. CONCLUSION: Over-expression of ATF3 could inhibit the proliferation of ESCC cells and ATF3 may play important roles in the progression of ESCC.

  19. Urotensin II inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating ATF expression and via the ERK and Akt pathway.

    Directory of Open Access Journals (Sweden)

    Yen-Ling Chen

    Full Text Available BACKGROUND AND PURPOSE: Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Urotensin II (U-II, a potent vasoactive peptide, participates in vascular and myocardial remodeling after injury. We investigated the protective effect of U-II on doxorubicin (DOX-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs and the potential mechanisms involved in this process. EXPERIMENTAL APPROACH: Cultured HUVECs were treated with vehicle, DOX (1 µM, U-II, or U-II plus DOX. Apoptosis was evaluated by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells. KEY RESULTS: U-II reduced the quantity of cleaved caspase-3 and cytosol cytochrome c and increased Bcl-2 expression, which results in protecting HUVECs from DOX-induced apoptosis. U-II induced Activating transcription factor 3 (ATF3 at both mRNA and protein levels in U-II-treated cells. Knockdown of ATF3 with ATF3 siRNA significantly reduced ATF3 protein levels and U-II protective effect under DOX-treated condition. U-II downregulated p53 expression in DOX-induced HUVECs apoptosis, and it rapidly activated extracellular signal-regulated protein kinase (ERK and Akt. The DOX induced change of p53 was not affected by U-II antagonist (urantide under ATF-3 knockdown. The inhibitory effect of U-II on DOX-increased apoptosis was attenuated by inhibitors of ERK (U0126 and PI3K/Akt (LY294002. CONCLUSION AND IMPLICATIONS: Our observations provide evidence that U-II protects HUVECs from DOX-induced apoptosis. ERK-Akt phosphorylation, ATF3 activation, and p53 downregulation may play a signal-transduction role in this process.

  20. 耐力训练对心肌PERK/eIF2α/ATF4信号通路激活的影响%Effects of Endurance Exercise Training on PERK/eIF2α/ATF4 Signaling Pathway in Cardiac Muscle

    Institute of Scientific and Technical Information of China (English)

    王蕴红; 王智强; 刘晓然; 陈怡月; 李丁丁; 余海燕; 姚政立

    2016-01-01

    探讨内质网应激机制在耐力训练对心肌功能影响过程中的作用.方法:通过建立不同运动方式、运动训练状态和不同恢复阶段的动物模型,测定心肌中与内质网应激相关的信号通路PERK/eIF2α/ATF4激活水平的变化.结果:无论是急性运动,还是4或10周的递增负荷耐力训练,都没有显著激活PERK/eIF2α/ATF4信号通路,但是以延长运动时间为特征的耐力训练能够激活PERK/eIF2α/ATF4信号通路.结论:以递增运动时间为特征的耐力训练能够激活PERK/eIF2α/ ATF4信号通路,该通路的激活对运动心肌的结构和功能变化可能产生影响.

  1. Negative Regulation of IRF7 Activation by ATF4 Suggests a Cross Regulation Between the Interferon Responses and the Cellular Integrated Stress Responses

    OpenAIRE

    Liang, Qiming; Deng, Hongying; Sun, Chiao-Wang; Tim M. Townes; Zhu, Fanxiu

    2010-01-01

    Cells react to viral infection by exhibiting interferon (IFN)-based innate immune responses and integrated stress responses, but little is known about the interrelationships between the two. We here report a linkage between these two host protective cellular mechanisms. We found that IRF7, the master regulator of type I IFN gene expression, interacts with ATF4, a key component of the integrated stress responses whose translation is induced by viral infection and various stresses. We have demo...

  2. Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis

    Science.gov (United States)

    Pant, Ila; Rao, S. Girish; Kondaiah, Paturu

    2016-01-01

    Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF. PMID:27708346

  3. Linear Collider Test Facility: Twiss Parameter Analysis at the IP/Post-IP Location of the ATF2 Beam Line

    Energy Technology Data Exchange (ETDEWEB)

    Bolzon, Benoit; /Annecy, LAPP; Jeremie, Andrea; /Annecy, LAPP; Bai, Sha; /Beijing, Inst. High Energy Phys.; Bambade, Philip; /KEK, Tsukuba; White, Glen; /SLAC

    2012-07-02

    At the first stage of the ATF2 beam tuning, vertical beam size is usually bigger than 3 {micro}m at the IP. Beam waist measurements using wire scanners and a laser wire are usually performed to check the initial matching of the beam through to the IP. These measurements are described in this paper for the optics currently used ({beta}{sub x} = 4cm and {beta}{sub y} = 1mm). Software implemented in the control room to automate these measurements with integrated analysis is also described. Measurements showed that {beta} functions and emittances were within errors of measurements when no rematching and coupling corrections were done. However, it was observed that the waist in the horizontal (X) and vertical (Y) plane was abnormally shifted and simulations were performed to try to understand these shifts. They also showed that multiknobs are needed in the current optics to correct simultaneously {alpha}{sub x}, {alpha}{sub y} and the horizontal dispersion (D{sub x}). Such multiknobs were found and their linearity and orthogonality were successfully checked using MAD optics code. The software for these multiknobs was implemented in the control room and waist scan measurements using the {alpha}{sub y} knob were successfully performed.

  4. 结直肠癌组织ATF3及其靶基因Cyclin D1与Maspin表达的临床意义分析%Expression of ATF3 and target genes Cyclin D1 and Maspin in colorectal cancer tissues

    Institute of Scientific and Technical Information of China (English)

    臧盛兵; 郁万媛; 陈虹; 施磊健; 李婷婷; 陈安敏; 陈虹; 黄爱民

    2012-01-01

    OBJECTIVE: To study the expressions of ATF3 and its target genes Cyclin Dland Maspin in colorectal neoplasms by tissue chips, and investigate the meaning of ATF3 expression in colorectal neoplasms. METHODS: Tissue chips were constructed, which contained colorectal cancer and non-neoplastic colorectal mucosa tissue. The expressions of ATF3,Cyclin D1 and Maspin were determined by immunohistochemistry assay. RRSULTS: The expressions of ATF3 (70. 3%),Cyclin D1 (51.4%) and Maspin (59. 5%) in colorectal neoplasms were higher than that in normal colorectal mucosa tissue (21. 6% ,2. 7% and 13. 5% respectively) .which showed significantly difference (all P values were 0. 000). ATF3 expression had not association with age,gender,tumor location,tumor size or histological type,but with invasive extent and lymphatic node metastasis, the expressions of ATF3 in colorectal neoplasms invading the serous membrane (83. 3%) and lymphatic node metastasis (92. 3%) were higher than that in those invading muscularis propria (38. 9%) and without lymphatic node metastasis (45. 7%) ,χ2 values were 13. 290 and 17. 110,and all P values were 0. 000. Cyclin Dl expression was not associated with age,gender,tumor location or tumor size,but with histological type,invasive extent and lymphatic node metastasis. The expression of Cyclin D1 in colorectal cancer with low differentiation (71. 4%), serous membrane invasion (61. 1%) and lymphatic node metastasis (69. 2%) were higher than that in those with high differentiation (39. 1%), muscularis propria invasion (28. 8%) and without lymphatic node metastasis (31. 4%) ,χ2 values were7. 268,6. 019 and 10. 550,and P values were 0. 007,0. 014 and 0. 001 respectively. Maspin expressions were not significantly associated with age, gender, tumor location, tumor size, histological type, invasive extent or lymphatic node metastasis (all P>0. 05). ATF3,Cyclin D1 and Maspin wew all high expressions in colorectal neoplasms, ATF3 expression was positively

  5. Enhanced activation of PERK-ATF4 pathway by Brefeldin A and cisplatin in human lung cancer GLC-82 ;cells%布雷菲德菌素A联合顺铂增强肺癌GLC-82细胞PERK-ATF4通路的激活水平

    Institute of Scientific and Technical Information of China (English)

    吴明松; 郑翔; 耿娜娜; 张志敏; 赵彦禹; 王哲; 李学英

    2016-01-01

    目的:研究PERK-ATF4通路的激活水平,以探讨布雷菲德菌素A(BFA)与顺铂(CDDP)的协同抗肺癌的分子机制。方法:以BFA、CDDP单独或联合处理人肺癌GLC-82细胞24、48 h,然后用定量PCR和Western Blot检测PERK、ATF4、p-PERK的表达水平。结果:药物处理24和48 h 后,GLC-82细胞PERK的mRNA和蛋白表达水平在CDDP组最低,在BFA组升高(P<0.05),在BFA+CDDP组进一步升高(P <0.01),其磷酸化水平均显著降低(P <0.01);ATF4表达在CDDP组中差异无显著性,在BFA组中升高,在BFA+CDDP组进一步升高(P <0.05或P <0.01),也高于BFA组和CDDP组(P <0.05或P <0.01)。结论:BFA联合CDDP上调PERK、ATF4水平,该通路可能是BFA与顺铂协同抗肺癌的分子机制之一。%Objective To investigate the molecular mechanisms of synergistic effects of BFA and CDDP on human lung cancer GLC-82 cells, and to test the levels of PERK-ATF4 pathway. Methods GLC-82 cells were incubated with 50 ng/mL of BFA or/and 2 μg/mL of CDDP for 24 or 48 hours. The levels of PERK, p-PERK and ATF4 in GLC-82 were analyzed by real-time PCRand/or Western Blot. Results The levels of PERK were lowest in CDDP group, but higher in BFA group (P < 0.05), the highest in group of BFA+CDDP (P < 0.05 or P < 0.01). The p-PERK level decreased in group of BFA+CDDP (P < 0.05 or P < 0.01). There was no significant change of ATF4 expression in CDDP group, but ATF4 expression increased slightly in BFA group, and increased further in group of BFA+CDDP (P < 0.05 or P < 0.01)which was also higher than that in BFA group or CDDP group (P < 0.05 or P < 0.01). Conclusions The upregulated levels of PERK and ATF4 by the combination of BFA and CDDP may be one of the mechanisms of synergistic anti-cancer effect of BFA and CDDP on GLC-82 cells.

  6. 内质网应激PERK-ATF4-CHOP通路在苦参碱诱导视网膜母细胞瘤细胞凋亡中的作用%Role of Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway in Matrine Induced Retinoblastoma Apoptosis

    Institute of Scientific and Technical Information of China (English)

    来小丹; 欧阳净; 石英

    2015-01-01

    Objective To analyze the role of endoplasmic reticulum stress PERK-ATF4-CHOP pathway in matrine induced retinoblastoma cells apoptosis. Methods Different concentrations of 0, 1. 0, 2. 0, 4. 0 g/L matrine was used to treat the HOX-Rb44 cells for 24 h,the cell viability was determined by MTT assay, HOX-RB44 apoptosis situation was determined by ow cytometry,western blot analysis was used to dectect the Bax,Bcl-2,GRP78,GRP94,AFT4,peIF2α and CHOP expression. Results As the increase of concentration of ma-trine,HOX-Rb44 apoptosis rate increased significantly ( P < 0. 05 ) , GRP78 and GRP94 increased significantly, and ATF and PERK downstream peIF2α and CHOP were also increased significantly. Conclusion Matrine could promoted HOX-Rb44 cell apoptosis, endo-plasmic reticulum stress, where PERK-ATF4-CHOP pathway may play an important role.%目的:探讨内质网应激 PERK-ATF4-CHOP通路在苦参碱诱导视网膜母细胞瘤细胞凋亡中的作用。方法采用0,1.0,2.0,4.0 g/L苦参碱处理HOX-Rb44细胞24 h,MTT、流式细胞术分析细胞增殖活性及凋亡情况,Western Blot检测凋亡相关蛋白Bax,Bcl-2,内质网应激相关蛋白GRP94,GRP78,ATF4以及PERK下游peIF2α及CHOP蛋白表达水平。结果随着苦参碱质量浓度的增加,HOX-Rb44细胞增殖抑制增加,凋亡率显著升高( P<0.05),GRP78与GRP94的表达水平逐渐升高,ATF及PERK下游peIF2α及CHOP蛋白表达升高。结论苦参碱处理视网膜母细胞瘤细胞能诱导细胞凋亡,内质网应激、PERK-ATF4-CHOP通路可能在其中有重要作用。

  7. PERK-eIF2α-ATF4 pathway mediated by endoplasmic reticulum stress response is involved in osteodifferentiation of human periodontal ligament cells under cyclic mechanical force.

    Science.gov (United States)

    Yang, Shuang-Yan; Wei, Fu-Lan; Hu, Li-Hua; Wang, Chun-Ling

    2016-08-01

    To prevent excess accumulation of unfolded proteins in endoplasmic reticulum (ER), eukaryotic cells have signaling pathways from the ER to the cytosol or nucleus. These processes are known as the endoplasmic reticulum stress (ERS) response. Protein kinase R like endoplasmic reticulum kinase (PERK) is a major transducer of the ERS response and it directly phosphorylate α-subunit of eukaryotic initiation factor 2 (eIF2α), resulting in translational attenuation. Phosphorylated eIF2α specifically promoted the translation of the activating transcription factor 4 (ATF4). ATF4 is a known important transcription factor which plays a pivotal role in osteoblast differentiation and bone formation. Furthermore, ATF4 is a downstream target of PERK. Studies have shown that PERK-eIF2α-ATF4 signal pathway mediated by ERS was involved in osteoblastic differentiation of osteoblasts. We have known that orthodontic tooth movement is a process of periodontal ligament cells (PDLCs) osteodifferentiation and alveolar bone remodeling under mechanical force. However, the involvement of PERK-eIF2α-ATF4 signal pathway mediated by ERS in osteogenic differentiation of PDLCs under mechanical force has not been unclear. In our study, we applied the cyclic mechanical force at 10% elongation with 0.5Hz to mimic occlusal force, and explored whether PERK-eIF2α-ATF4 signaling pathway mediated by ERS involved in osteogenic differentiation of PDLCs under mechanical force. Firstly, cyclic mechanical force will induce ERS and intensify several osteoblast marker genes (ATF4, OCN, and BSP). Next, we found that PERK overexpression increased eIF2α phosphorylation and expression of ATF4, furthermore induced BSP, OCN expression, thus it will promote osteodifferentiation of hPDLCs; mechanical force could promote this effect. However, PERK(-/-) cells showed the opposite changes, which will inhibit osteodifferentiation of hPDLCs. Taken together, our study proved that PERK-eIF2α-ATF4 signaling pathway

  8. A Low-Protein, High-Carbohydrate Diet Stimulates Thermogenesis in the Brown Adipose Tissue of Rats via ATF-2.

    Science.gov (United States)

    de França, Suélem A; dos Santos, Maísa P; Przygodda, Franciele; Garófalo, Maria Antonieta R; Kettelhut, Isis C; Magalhães, Diego A; Bezerra, Kalinne S; Colodel, Edson M; Flouris, Andreas D; Andrade, Cláudia M B; Kawashita, Nair H

    2016-03-01

    The aim of this study was to evaluate thermogenesis in the interscapular brown adipose tissue (IBAT) of rats submitted to low-protein, high-carbohydrate (LPHC) diet and the involvement of adrenergic stimulation in this process. Male rats (~100 g) were submitted to LPHC (6%-protein; 74%-carbohydrate) or control (C; 17%-protein; 63%-carbohydrate) isocaloric diets for 15 days. The IBAT temperature was evaluated in the rats before and after the administration of noradrenaline (NA) (20 µg 100 g b w(-1) min(-1)). The expression levels of uncoupling protein 1 (UCP1) and other proteins involved in the regulation of UCP1 expression were determined by Western blot (Student's t test, P ≤ 0.05). The LPHC diet promoted a 1.1 °C increase in the basal temperature of IBAT when compared with the basal temperature in the IBAT of the C group. NA administration promoted a 0.3 °C increase in basal temperature in the IBAT of the C rats and a 0.5 °C increase in the IBAT of the LPHC group. The level of UCP1 increased 60% in the IBAT of LPHC-fed rats, and among the proteins involved in its expression, such as β3-AR and α1-AR, there was a 40% increase in the levels of p38-MAPK and a 30% decrease in CREB when compared to the C rats. The higher sympathetic flux to IBAT, which is a consequence of the administration of the LPHC diet to rats, activates thermogenesis and increases the expression of UCP1 in the tissue. Our results suggest that the increase in UCP1 content may occur via p38 MAPK and ATF2.

  9. Dehydroepiandrosterone sulfate mediates activation of transcription factors CREB and ATF-1 via a Gα11-coupled receptor in the spermatogenic cell line GC-2.

    Science.gov (United States)

    Shihan, Mazen; Kirch, Ulrike; Scheiner-Bobis, Georgios

    2013-12-01

    Dehydroepiandrosterone sulfate (DHEAS) is a circulating steroid produced in the adrenal cortex, brain, and gonads. Whereas a series of investigations attest to neuroprotective effects of the steroid in the brain, surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. Here we demonstrate that DHEAS acting on the spermatogenic cell line GC-2 induces a time- and concentration-dependent phosphorylation of c-Src and Erk1/2 and activates the transcription factors activating transforming factor-1 (ATF-1) and cyclic AMP-responsive element binding protein (CREB). These actions are consistent with the non-classical signaling pathway of testosterone and suggest that DHEAS is a pro-androgen that is converted into testosterone in order to exert its biological activity. The fact, however, that steroid sulfatase mRNA was not detected in the GC-2 cells and the clear demonstration of DHEAS-induced activation of Erk1/2, ATF-1 and CREB after silencing the androgen receptor by small interfering RNA (siRNA) clearly contradict this assumption and make it appear unlikely that DHEAS has to be converted in the cytosol into a different steroid in order to activate the kinases and transcription factors mentioned. Instead, it is likely that the DHEAS-induced signaling is mediated through the interaction of the steroid with a membrane-bound G-protein-coupled receptor, since silencing of Guanine nucleotide-binding protein subunit alpha-11 (Gnα11) leads to the abolition of the DHEAS-induced stimulation of Erk1/2, ATF-1, and CREB. The investigation presented here shows a hormone-like activity of DHEAS on a spermatogenic cell line. Since DHEAS is produced in male and female reproductive organs, these findings could help to define new roles for DHEAS in the physiology of reproduction.

  10. UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression.

    Science.gov (United States)

    Bromati, Carla R; Lellis-Santos, Camilo; Yamanaka, Tatiana S; Nogueira, Tatiane C A; Leonelli, Mauro; Caperuto, Luciana C; Gorjão, Renata; Leite, Adriana R; Anhê, Gabriel F; Bordin, Silvana

    2011-01-01

    Endocrine pancreas from pregnant rats undergoes several adaptations that comprise increase in β-cell number, mass and insulin secretion, and reduction of apoptosis. Lactogens are the main hormones that account for these changes. Maternal pancreas, however, returns to a nonpregnant state just after the delivery. The precise mechanism by which this reversal occurs is not settled but, in spite of high lactogen levels, a transient increase in apoptosis was already reported as early as the 3rd day of lactation (L3). Our results revealed that maternal islets displayed a transient increase in DNA fragmentation at L3, in parallel with decreased RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation (pAKT), a known prosurvival kinase. Wortmannin completely abolished the prosurvival action of prolactin (PRL) in cultured islets. Decreased pAKT in L3-islets correlated with increased Tribble 3 (TRB3) expression, a pseudokinase inhibitor of AKT. PERK and eIF2α phosphorylation transiently increased in islets from rats at the first day after delivery, followed by an increase in immunoglobulin heavy chain-binding protein (BiP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islets from L3 rats. Chromatin immunoprecipitation (ChIP) and Re-ChIP experiments further confirmed increased binding of the heterodimer ATF4/CHOP to the TRB3 promoter in L3 islets. Treatment with PBA, a chemical chaperone that inhibits UPR, restored pAKT levels and inhibited the increase in apoptosis found in L3. Moreover, PBA reduced CHOP and TRB3 levels in β-cell from L3 rats. Altogether, our study collects compelling evidence that UPR underlies the physiological and transient increase in β-cell apoptosis after delivery. The UPR is likely to counteract prosurvival actions of PRL by reducing pAKT through ATF4/CHOP-induced TRB3 expression.

  11. Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response.

    Science.gov (United States)

    Yamazaki, Hiroaki; Hiramatsu, Nobuhiko; Hayakawa, Kunihiro; Tagawa, Yasuhiro; Okamura, Maro; Ogata, Ryouji; Huang, Tao; Nakajima, Shotaro; Yao, Jian; Paton, Adrienne W; Paton, James C; Kitamura, Masanori

    2009-07-15

    Shiga toxin has the potential to induce expression of inflammation-associated genes, although the underlying mechanisms are not well understood. We examined the effects of subtilase cytotoxin (SubAB), an AB(5) toxin produced by some Shiga toxigenic Escherichia coli, on the activation of NF-kappaB. SubAB is known to be a protease which selectively degrades GRP78/Bip. Treatment of NRK-52E cells with SubAB caused rapid cleavage of GRP78. Following the degradation of GRP78, transient activation of NF-kappaB was observed with a peak at 6-12 h; the activation subsided within 24 h despite the continuous absence of intact GRP78. The activation of NF-kappaB was preceded by transient phosphorylation of Akt. Treatment of the cells with a selective inhibitor of Akt1/2 or an inhibitor of PI3K attenuated SubAB-induced NF-kappaB activation, suggesting that activation of Akt is an event upstream of NF-kappaB. Degradation of GRP78 caused the unfolded protein response (UPR), and inducers of the UPR mimicked the stimulatory effects of SubAB on Akt and NF-kappaB. SubAB triggered the three major branches of the UPR including the IRE1-XBP1, PERK, and ATF6 pathways. Dominant-negative inhibition of IRE1alpha, XBP1, or PERK did not attenuate activation of NF-kappaB by SubAB. In contrast, genetic and pharmacological inhibition of ATF6 significantly suppressed SubAB-triggered Akt phosphorylation and NF-kappaB activation. These results suggested that loss of GRP78 by SubAB leads to transient phosphorylation of Akt and consequent activation of NF-kappaB through the ATF6 branch of the UPR.

  12. Non-destructive Preirradiation Assessment of UN / U-Si “LANL1” ATF formulation

    Energy Technology Data Exchange (ETDEWEB)

    Vogel, Sven C. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Losko, Adrian Simon [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Pokharel, Reeju [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Ickes, Timothy Lee [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Hunter, James F. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Brown, Donald William [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Voit, Stewart Lancaster [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Tremsin, Anton S. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Bourke, Mark Andrew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); McClellan, Kenneth James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-09-15

    The goal of the Advanced Non-destructive Fuel Examination (ANDE) work package is the development and application of non-destructive neutron imaging and scattering techniques to ceramic and metallic nuclear fuels, ultimately also to irradiated fuels. The results of these characterizations provide complete pre- and post-irradiation on length scales ranging from mm to nm, guide destructive examination, and inform modelling efforts. Besides technique development and application to samples to be irradiated, the ANDE work package also examines possible technologies to provide these characterization techniques pool-side, e.g. at the Advanced Test Reactor (ATR) at Idaho National Laboratory (INL) using laser-driven intense pulsed neutron and gamma sources. Neutron tomography and neutron diffraction characterizations were performed on nine pellets; four UN/ U-Si composite formulations (two enrichment levels), three pure U3Si5 reference formulations (two enrichment levels), and two reject pellets with visible flaws (to qualify the technique). The 235U enrichments ranged from 0.2 to 8.8 wt. %. The nitride/silicide composites are candidate compositions for use as Accident Tolerant Fuel (ATF). The monophase U3Si5 material was included as a reference. Pellets from the same fabrication batches will be inserted in the Advanced Test Reactor at Idaho during 2016. We have also proposed a data format to build a database for characterization results of individual pellets. Neutron data reported in this report were collected in the LANSCE run cycle that started in September 2015 and ended in March 2016. This report provides the results for the characterized samples and discussion in the context of ANDE and APIE. We quantified the gamma spectra of several samples in their received state as well as after neutron irradiation to ensure that the neutron irradiation does not add significant activation that would complicate shipment and

  13. Perfluorocarbon inhibits lipopolysaccharide-induced macrophage inflammatory protein-2 expression and activation of ATF-2 and c-Jun in A549 pulmonary epithelial cells.

    Science.gov (United States)

    Hu, Y; Li, C S; Li, Y Q; Liang, Y; Cao, L; Chen, L A

    2016-04-30

    The signaling pathway that mediates the anti-inflammatory effects of perfluorocarbon (PFC) in alveolar epithelial cells treated with lipopolysaccharide (LPS) remains unclear. To evaluate the role of macrophage-inflammatory protein-2 (MIP-2), four A549 treatment groups were utilized: (1) untreated control, (2) 10 μg/mL of LPS, (3) 10 μg/mL of LPS+30% PFC and (4) 30% PFC. MIP-2 mRNA expression was determined by qPCR and ELISA. Mitogen-activated protein kinase (MAPK) activation was determined by Western blot analysis, and MIP-2 expression was determined by qPCR following treatment with MAPK inhibitors. PFC suppressed LPS-induced MIP-2 mRNA levels (P≤0.035) and MIP-2 secretion (P≤0.046). LPS induced ATF-2 and c-Jun phosphorylation, which was suppressed by PFC. Finally, inhibitors of ERK, JNK, and p38 suppressed LPS-induced MIP-2 mRNA expression. Thus, PFC inhibits LPS-induced MIP-2 expression and ATF-2 and c-Jun phosphorylation. To fully explore the therapeutic potential of PFC for acute lung injury (ALI), in vivo analyses are required to confirm these effects.

  14. Influence of the valine zipper region on the structure and aggregation of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5).

    Science.gov (United States)

    Ciaccio, Natalie A; Reynolds, T Steele; Middaugh, C Russell; Laurence, Jennifer S

    2012-11-01

    Protein aggregation is a major problem for biopharmaceuticals. While the control of aggregation is critically important for the future of protein pharmaceuticals, mechanisms of aggregate assembly, particularly the role that structure plays, are still poorly understood. Increasing evidence indicates that partially folded intermediates critically influence the aggregation pathway. We have previously reported the use of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5) as a partially folded model system to investigate protein aggregation. This domain contains three regions with differing structural propensity: a N-terminal polybasic region, a central helical leucine zipper region, and a C-terminal extended valine zipper region. Additionally, a centrally positioned cysteine residue readily forms an intermolecular disulfide bond that reduces aggregation. Computational analysis of ATF5 predicts that the valine zipper region facilitates self-association. Here we test this hypothesis using a truncated mutant lacking the C-terminal valine zipper region. We compare the structure and aggregation of this mutant to the wild-type (WT) form under both reducing and nonreducing conditions. Our data indicate that removal of this region results in a loss of α-helical structure in the leucine zipper and a change in the mechanism of self-association. The mutant form displays increased association at low temperature but improved resistance to thermally induced aggregation.

  15. Microarray hybridization analysis of light-dependent gene expression in Penicillium chrysogenum identifies bZIP transcription factor PcAtfA.

    Science.gov (United States)

    Wolfers, Simon; Kamerewerd, Jens; Nowrousian, Minou; Sigl, Claudia; Zadra, Ivo; Kürnsteiner, Hubert; Kück, Ulrich; Bloemendal, Sandra

    2015-04-01

    The fungal velvet complex is a light-dependent master regulator of secondary metabolism and development in the major penicillin producer, Penicillium chrysogenum. However, the light-dependent mechanism is unclear. To identify velvet-dependent transcriptional regulators that show light-regulated expression, we performed microarray hybridizations with RNA isolated from P. chrysogenum ΔPcku70 cultures grown under 13 different long-term, light-dependent growth conditions. We compared these expression data to data from two velvet complex deletion mutants; one lacked a subunit of the velvet complex (ΔPcvelA), and the other lacked a velvet-associated protein (ΔPclaeA). We sought to identify genes that were up-regulated in light, but down-regulated in ΔPcvelA and ΔPclaeA. We identified 148 co-regulated genes that displayed this regulatory pattern. In silico analyses of the co-regulated genes identified six proteins with fungal-specific transcription factor domains. Among these, we selected the bZIP transcription factor, PcAtfA, for functional characterization in deletion and complementation strains. Our data clearly indicates that PcAtfA governs spore germination. This comparative analysis of different microarray hybridization data sets provided results that may be useful for identifying genes for future functional analyses.

  16. Armament Technology Facility (ATF)

    Data.gov (United States)

    Federal Laboratory Consortium — The Armament Technology Facility is a 52,000 square foot, secure and environmentally-safe, integrated small arms and cannon caliber design and evaluation facility....

  17. Expressions of p-PERK,ATF4 and CHOP protein in rat model of gesta-tional diabetes mellitus%妊娠期糖尿病大鼠胰腺组织中 p-PERK、ATF4和 CHOP 蛋白的表达∗

    Institute of Scientific and Technical Information of China (English)

    丰树焕; 张东铭; 乐婷; 张苏河; 付艳芹

    2015-01-01

    Aim: To investigate the relationship between the activation of p-PERK,ATF4 and CHOP protein and isletβ cell apoptosis of pregnant rats with high sucrose and fat diet. Methods: Thirty healthy female SD rats were allocated into two groups randomly: control group(n = 15) and gestational diabetes mellitus(GDM) model group(n = 15). Twenty-one days after gestation,intravenous glucose tolerance test(IVGTT) and intravenous insulin releasing test(IVIRT) were per-formed;the pancreas was removed for examination of morphological and ultra structural changes; the islet β cell apoptosis index was calculated by TUNEL;the expression of p-PERK in pancreatic tissue was analyzed by immunohistochemistry;the expressions of ATF4 and CHOP protein were analyzed by Western blot. Results: The first-phase insulin secretion of rats in the GDM model group was inhibited,and the insulin secretion peak was delayed;the islet morphology was not regular,the reducing was not obvious,some cells degenerated,blood capillaries dilated,and there was hyperemia or bleeding occurred in the GDM model group by means of HE staining;the apoptotic rate increased in the GDM model group(t = 21. 164,P <0. 001);compared with control group,the level of p-PERK,ATF4,and CHOP in pancreatic tissue increased significantly in the GDM model group(t = 44. 178,49. 249,and 39. 664,P < 0. 05). Correlation analysis showed that the expression level of ATF4 was positively correlated with CHOP protein in islet tissue from rats in the GDM model group( r = 0. 810,P =0. 004). Conclusion: The activation expressions of ATF4 and PERK protein may participate in apoptosis of pancreatic βcells in GDM rats induced by high sucrose and fat diet.%目的::探讨磷酸化蛋白激酶 R 样内质网激酶(p-PERK)、C/ EBP 同源蛋白(CHOP)、ATF4蛋白的表达与高脂高糖诱导的妊娠期糖尿病大鼠胰岛β细胞凋亡的关系。方法:30只雌性 SD 大鼠分为模型组(高脂高糖喂养)和对照组(普食喂养),每组15

  18. DESIGN AND INITIAL RESULTS OF A TURN-BY-TURN BEAM POSITION MONITORING SYSTEM FOR MULTIPLE BUNCH OPERATION OF THE ATF DAMPING RING

    CERN Document Server

    Christian, G B; Bett, D R; Burrows, P N; Davis, M R; Gerbershagen, A; Perry, C; Constance, B; Resta-Lopez, J

    2011-01-01

    An FPGA-based monitoring system has been developed to study multi-bunch beam instabilities in the damping ring (DR) of the KEK Accelerator Test Facility (ATF), utilising a stripline beam position monitor (BPM) and existing BPM processor hardware. The system is designed to record the horizontal and/or vertical positions of up to three bunches in the DR in single-bunch multi-train mode or the head bunch of up to three trains in multi-bunch mode, with a bunch spacing of 5.6 ns. The FPGA firmware and data acquisition software were modified to record turn-by-turn data for up to six channels and 1–3 bunches in the DR. An overview of the system and initial results will be presented.

  19. The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

    Science.gov (United States)

    Rozpędek, W.; Pytel, D.; Mucha, B.; Leszczyńska, H.; Diehl, J. Alan; Majsterek, I.

    2016-01-01

    Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents. PMID:27211800

  20. The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Rozpedek, W; Pytel, D; Mucha, B; Leszczynska, H; Diehl, J A; Majsterek, I

    2016-01-01

    Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.

  1. Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway

    Directory of Open Access Journals (Sweden)

    Yu-Jen Wu

    2013-08-01

    Full Text Available Sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, has potent anti-microbial and anti-tumorigenesis effects towards melanoma and bladder cancer cells. In this study, we investigated the effects of sinulariolide on hepatocellular carcinoma (HCC cell growth and protein expression. Sinulariolide suppressed the proliferation and colony formation of HCC HA22T cells in a dose-dependent manner and induced both early and late apoptosis according to flow cytometry, Annexin V/PI stain and TUNEL/DAPI stain analyses. A mechanistic analysis demonstrated that sinulariolide-induced apoptosis was activated through a mitochondria-related pathway, showing up-regulation of Bax, Bad and AIF, and down- regulation of Bcl-2, Bcl-xL, MCl-1 and p-Bad. Sinulariolide treatment led to loss of the mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and caspase-3. Sinulariolide-induced apoptosis was significantly blocked by the caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK. The increased expression of cleaved PARP also suggested that caspase-independent apoptotic pathway was involved. In the western blotting; the elevation of ER chaperones GRP78; GRP94; and CALR; as well as up-regulations of PERK/eIF2α/ATF4/CHOP; and diminished cell death with pre-treatment of eIF2α phosphatase inhibitor; salubrinal; implicated the involvement of ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway following sinulariolide treatment in hepatoma cells. The current study suggested sinulariolide-induced hepatoma cell cytotoxicity involved multiple apoptotic signal pathways. This may implicate that sinulariolide is a potential compound for the treatment of hepatocellular carcinoma.

  2. THAP and ATF-2 regulated sterol carrier protein-2 promoter activities in the larval midgut of the yellow fever mosquito, Aedes aegypti.

    Directory of Open Access Journals (Sweden)

    Rong Peng

    Full Text Available Expression of sterol carrier protein-2 (SCP-2 in Aedes aegypti shows a distinct temporal/spatial pattern throughout the life cycle. In order to identify the transcription factors responsible for the larval temporal/spatial regulation of AeSCP-2 transcription, AeSCP-2 promoter activities were studied in vivo via transient transfection of promoter/reporter gene assays. Regulatory sequences upstream -1.3 kb of the transcription start site of AeSCP-2 were found to be critical for the in vivo temporal/spatial promoter activity. Interestingly, the -1.6 kb promoter sequence efficiently drove the larval midgut-specific siRNA expression, indicating that the -1.6 kb upstream sequence is sufficient for temporal/spatial AeSCP-2 transcriptional activity. Four transcription factors were identified in the midgut nuclear extract from feeding larvae via labeled -1.6/-1.3 kb DNA probe pull-down and proteomic analysis. Co-transfection of the promoter/reporter gene with inducible siRNA expression of each transcription factor was performed to confirm the regulatory function of individual transcription factor on AeSCP-2 transcriptional activities in the larval midgut. The results indicate that two of the identified transcription factors, Thanatos-associated protein (THAP and activating transcription factor-2 (ATF-2, antagonistically control AeSCP-2 transcriptional activity in the midgut of feeding larvae via the regulatory sequences between -1.6 to -1.3 kb 5' upstream of the transcription start site. In vivo expression knockdown of THAP and ATF-2 resulted in significant changes in developmental progression, which may be partially due to their effects on AeSCP-2 expression.

  3. SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation.

    Directory of Open Access Journals (Sweden)

    Gopinathan Pillai Sreekanth

    Full Text Available Dengue virus (DENV infection causes organ injuries, and the liver is one of the most important sites of DENV infection, where viral replication generates a high viral load. The molecular mechanism of DENV-induced liver injury is still under investigation. The mitogen activated protein kinases (MAPKs, including p38 MAPK, have roles in the hepatic cell apoptosis induced by DENV. However, the in vivo role of p38 MAPK in DENV-induced liver injury is not fully understood. In this study, we investigated the role of SB203580, a p38 MAPK inhibitor, in a mouse model of DENV infection. Both the hematological parameters, leucopenia and thrombocytopenia, were improved by SB203580 treatment and liver transaminases and histopathology were also improved. We used a real-time PCR microarray to profile the expression of apoptosis-related genes. Tumor necrosis factor α, caspase 9, caspase 8, and caspase 3 proteins were significantly lower in the SB203580-treated DENV-infected mice than that in the infected control mice. Increased expressions of cytokines including TNF-α, IL-6 and IL-10, and chemokines including RANTES and IP-10 in DENV infection were reduced by SB203580 treatment. DENV infection induced the phosphorylation of p38MAPK, and its downstream signals including MAPKAPK2, HSP27 and ATF-2. SB203580 treatment did not decrease the phosphorylation of p38 MAPK, but it significantly reduced the phosphorylation of MAPKAPK2, HSP27, and ATF2. Therefore, SB203580 modulates the downstream signals to p38 MAPK and reduces DENV-induced liver injury.

  4. Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP

    DEFF Research Database (Denmark)

    Kim, Mi-Ju; Hong, Kyung-Soo; Kim, Hak-Bong

    2013-01-01

    In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, a...

  5. Afatinib down-regulates MCL-1 expression through the PERK-eIF2α-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Liu, Xianfang; Lv, Zhenghua; Zou, Jidong; Liu, Xiuxiu; Ma, Juke; Wang, Jinhua; Sa, Na; Jing, Peihang; Xu, Wei

    2016-01-01

    Afatinib is the second generation of irreversible inhibitor of EGFR, HER2 and HER4, which has shown encouraging phase II and III clinical outcomes in the treatment of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism of afatinib-induced apoptosis in HNSCC is poorly understood. In the present investigation, we discovered that down-regulation of MCL-1, an anti-apoptotic member of BCL-2 family, was responsible for afatinib-triggered apoptosis. And the inactivation of AKT-mTOR signaling caused by afatinib lead to translational inhibition of MCL-1 expression. As a crucial branch of ER stress, PERK-eIF2α-ATF4 axis was also stimulated in HNSCC cells after afatinib incubation. Silencing either eIF2α or ATF4 by siRNA transfection relieved afatinib-caused suppression of AKT-mTOR activity, attenuating MCL-1 down-regulation as well as subsequent apoptosis. Collectively, the results show that afatinib hampers AKT-mTOR activation by stimulating PERK-eIF2α-ATF4 signaling pathway, giving rise to MCL-1 down-regulation mediated apoptosis in HNSCC cells. Therefore, our findings reveal the elaborate molecular network of afatinib-induced apoptosis in HNSCC, which would provide substantial theoretical underpinnings for afatinib clinical application and highlight its promising prospect in HNSCC treatment.

  6. NEAMS-ATF M3 Milestone Report: Literature Review of Modeling of Radiation-Induced Swelling in Fe-Cr-Al Steels

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Xianming [Idaho National Lab. (INL), Idaho Falls, ID (United States). Fuel Modeling and Simulation Dept.; Biner, Suleyman Bulent [Idaho National Lab. (INL), Idaho Falls, ID (United States). Fuel Modeling and Simulation Dept.; Jiang, Chao [Idaho National Lab. (INL), Idaho Falls, ID (United States). Fuel Modeling and Simulation Dept.

    2015-12-01

    Fe-Cr-Al steels are proposed as accident-tolerant-fuel (ATF) cladding materials in light water reactors due to their excellent oxidation resistance at high temperatures. Currently, the understanding of their performance in reactor environment is still limited. In this review, firstly we reviewed the experimental studies of Fe-Cr-Al based alloys with particular focus on the radiation effects in these alloys. Although limited data are available in literature, several previous and recent experimental studies have shown that Fe-Cr-Al based alloys have very good void swelling resistance at low and moderate irradiation doses but the growth of dislocation loops is very active. Overall, the behavior of radiation damage evolution is similar to that in Fe-Cr ferritic/martensitic alloys. Secondly, we reviewed the rate theory-based modeling methods for modeling the coevolution of voids and dislocation loops in materials under irradiation such as Frenkel pair three-dimensional diffusion model (FP3DM) and cluster dynamics. Finally, we summarized and discussed our review and proposed our future plans for modeling radiation damage in Fe-Cr-Al based alloys.

  7. In utero TNF-α treatment induces telomere shortening in young adult mice in an ATF7-dependent manner.

    Science.gov (United States)

    Liu, Binbin; Maekawa, Toshio; Chatton, Bruno; Ishii, Shunsuke

    2016-01-01

    Epidemiological studies indicate that exposure to stress during intrauterine life is associated with shorter telomeres in young adulthood, and a correlation between telomere length in early life and lifespan has been suggested. However, empirical studies evaluating these phenomena have not been performed, and the mechanism of stress-induced telomere shortening remains unknown. Since the level of tumour necrosis factor α (TNF-α) in peripheral blood cells is increased by various psychological stresses, the effect of TNF-α administration to pregnant mice on telomere length in adulthood was examined in the present study. In utero TNF-α treatment-induced telomere shortening in adult mice. Telomere shortening was observed in certain tissues such as the bone marrow, spleen, and lung, and was detected at specific age ranges during adulthood. Telomere shortening was not observed in mice lacking the stress-responsive transcription factor ATF7, which contributes to heterochromatin formation in the absence of stress. The present study identified the conditions under which in utero TNF-α treatment induces telomere shortening in adulthood.

  8. Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress-induced cell death during the unfolded protein response.

    Science.gov (United States)

    Hiramatsu, Nobuhiko; Messah, Carissa; Han, Jaeseok; LaVail, Matthew M; Kaufman, Randal J; Lin, Jonathan H

    2014-05-01

    Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress-induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop((-)/(-)) cells are partially resistant to ER stress-induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress-induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a "two-hit" model of ER stress-induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

  9. Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway

    Science.gov (United States)

    Wang, Sheng-Fan; Chen, Meng-Shian; Chou, Yueh-Ching; Ueng, Yune-Fang; Yin, Pen-Hui; Yeh, Tien-Shun; Lee, Hsin-Chen

    2016-01-01

    Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin. Clinically, the high expression of xCT was associated with a poorer prognosis for gastric cancer patients under adjuvant chemotherapy. Moreover, we found that mitochondrial dysfunction enhanced cisplatin resistance and up-regulated xCT expression, as well as intracellular glutathione (GSH). The xCT inhibitors, siRNA against xCT or BSO decreased mitochondrial dysfunction-enhanced cisplatin resistance. We further demonstrated that the upregulation of the eIF2α-ATF4 pathway contributed to mitochondrial dysfunction-induced xCT expression, and activated eIF2α kinase GCN2, but not PERK, stimulated the eIF2α-ATF4-xCT pathway in response to mitochondrial dysfunction-increased reactive oxygen species (ROS) levels. In conclusion, our results suggested that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway might contribute to mitochondrial dysfunction-enhanced cisplatin resistance and could be a potential target for gastric cancer therapy. PMID:27708226

  10. The ATF/CREB site is the key element for transcription of the human RNA methyltransferase like 1 (RNMTL1) gene, a newly discovered 17p13.3 gene

    Institute of Scientific and Technical Information of China (English)

    JIAN; XU; JING; DE; ZHU; MIN; NI; DA; FANG; WAN; JIAN; REN; GU

    2002-01-01

    The human RNA methyltransferase like i gene (RNMTL1) is one of thirteen newly discovered geneswithin a 116 Kb segment of the chromosome 17p13.3 that suffers from a high frequent loss of heterozygosityin human hepatocellular carcinoma in China[1-5]. To understand the molecular mechanisms underlyingtranscription control of the RNMTL1 gene in human cancers, we decline using of the conventional approachwhere the cis-elements bound by the known transcription factors are primary targets, and carried out thesystematic analyses to dissect the promoter structure and identify/characterize the key cis-elements thatare responsible for its strong expression in cell. The molecular approaches applied included 1, the primerextension for mapping of the transcription starts; 2, the transient transfection/reporter assays on a largenumber of deletion and site-specific mutants of the promoter segment for defining the minimal promoterand the crucial elements within; and 3, the electrophoresis mobility shift assay with specific antibodies forreconfirming the nature of the transcription factors and their cognate cis-elements. We have shown that theinteraction of an ATF/CREB element (-38 to -31) and its cognate transcription factors play a predominantrole in the promoter activity of the RNMTL1 gene. The secondary DNA structures of the ATF/CREBelement play a more vital role in the protein-DNA interaction. Finally, we reported a novel mechanismunderlying the YY1 mediated transcription repression, namely, the ATF/CREB dependent transcription-repression by YY1 is executed in absence of its own sequence-specific binding.

  11. The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway.

    Science.gov (United States)

    Zhang, Lei; Yue, Yaping; Ouyang, Meishuo; Liu, Huaxiang; Li, Zhenzhong

    2017-02-16

    Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data

  12. 异相睡眠剥夺对大鼠脑内质网应激相关蛋白ATF4表达的影响%Effects of rapid eye movement sleep deprivation on expression of activating transcription factor 4 in rat brain

    Institute of Scientific and Technical Information of China (English)

    江波; 赵忠新

    2008-01-01

    目的 研究异相睡眠(REM 睡眠)剥夺对大鼠海马及额叶内质网应激相关蛋白转录活化因子4(ATF4)表达的影响.方法 大鼠采用完全随机数字表法分为6组:空白对照组(CC组)、环境对照组(TC)、睡眠剥夺(SD)6h、12 h、1 d、3 d组,每组10只.采用改良多平台睡眠剥夺法建立REM 睡眠剥夺大鼠模型,免疫组织化学及Westemblot方法测定不同时间点大鼠额叶及海马ATF4蛋白的表达.结果 CC组大鼠海鸟及额叶均未检测出ATF4.TC组海马、额叶均有ATF4表达,SD组海马、额叶6 h时开始表达ATF4,12 h后达到高峰,1 d、3 d呈逐渐下降趋势.结论 REM睡眠剥夺可诱发内质网应激,睡眠剥夺后大鼠海马与额叶发生内质网应激的时间及发展趋势基本相同.%Objective To investigate the expression of endoplasmic reticulum stress-related protein activating transcription factor 4 (ATF4, also known as CAMP-response element protein 2) in rat brain after rapid eye movement (REM) sleep deprivation. Methods Using a modified multiple platform method, REM sleep deprivation for different time lengths was induced in 4 groups of rats (n=10, for 6, 12, 24, and 72 h, respectively), with 10 normal rats as the cage control and another 10 as the tank control groups. Immunohistochemistry and Western blotting were performed to detect ATF4 protein expression in the hippocampus and frontal lobe of the rats. Results No ATF4 was detected in the cage control group. ATF4 expression was detected in the brain tissues of the rats in the tank control group, and the expression peaked after REM sleep deprivation for 12 h, followed by gradual declination as the sleep deprivation was prolonged to 24 and 72 h. Conclusion REM sleep deprivation can induce endoplasmic reticulum stress. The timing of endoplasmic reticulum stress onset and the course of its development following sleep deprivation are almost identical in the frontal lobe and hippocampus of rats.

  13. Intestinal DMBT1 expression is modulated by Crohn's disease-associated IL23R variants and by a DMBT1 variant which influences binding of the transcription factors CREB1 and ATF-2.

    Directory of Open Access Journals (Sweden)

    Julia Diegelmann

    Full Text Available OBJECTIVES: DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs regarding inflammatory bowel disease (IBD susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. METHODS: Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn's disease (CD patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. RESULTS: IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0 × 10(-7, OR 1.42; 95% CI 1.24-1.63. All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1 × 10(-18. The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. CONCLUSION: We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important

  14. Bee Venom Accelerates Wound Healing in Diabetic Mice by Suppressing Activating Transcription Factor-3 (ATF-3) and Inducible Nitric Oxide Synthase (iNOS)-Mediated Oxidative Stress and Recruiting Bone Marrow-Derived Endothelial Progenitor Cells.

    Science.gov (United States)

    Badr, Gamal; Hozzein, Wael N; Badr, Badr M; Al Ghamdi, Ahmad; Saad Eldien, Heba M; Garraud, Olivier

    2016-10-01

    Multiple mechanisms contribute to impaired diabetic wound healing including impaired neovascularization and deficient endothelial progenitor cell (EPC) recruitment. Bee venom (BV) has been used as an anti-inflammatory agent for the treatment of several diseases. Nevertheless, the effect of BV on the healing of diabetic wounds has not been studied. Therefore, in this study, we investigated the impact of BV on diabetic wound closure in a type I diabetic mouse model. Three experimental groups were used: group 1, non-diabetic control mice; group 2, diabetic mice; and group 3, diabetic mice treated with BV. We found that the diabetic mice exhibited delayed wound closure characterized by a significant decrease in collagen production and prolonged elevation of inflammatory cytokines levels in wounded tissue compared to control non-diabetic mice. Additionally, wounded tissue in diabetic mice revealed aberrantly up-regulated expression of ATF-3 and iNOS followed by a marked elevation in free radical levels. Impaired diabetic wound healing was also characterized by a significant elevation in caspase-3, -8, and -9 activity and a marked reduction in the expression of TGF-β and VEGF, which led to decreased neovascularization and angiogenesis of the injured tissue by impairing EPC mobilization. Interestingly, BV treatment significantly enhanced wound closure in diabetic mice by increasing collagen production and restoring the levels of inflammatory cytokines, free radical, TGF-β, and VEGF. Most importantly, BV-treated diabetic mice exhibited mobilized long-lived EPCs by inhibiting caspase activity in the wounded tissue. Our findings reveal the molecular mechanisms underlying improved diabetic wound healing and closure following BV treatment. J. Cell. Physiol. 231: 2159-2171, 2016. © 2016 Wiley Periodicals, Inc.

  15. Energy confinement scaling from the international stellarator database

    Energy Technology Data Exchange (ETDEWEB)

    Stroth, U. [Max-Planck-Institut fuer Plasmaphysik, Garching (Germany); Murakami, M.; Dory, R.A.; Yamada, H.; Okamura, S.; Sano, F.; Obiki, T.

    1995-09-01

    An international stellarator database on global energy confinement is presented comprising data from the ATF, CHS and Heliotron E heliotron/torsatrons and the W7-A and W7-AS shearless stellarators. Regression expressions for the energy confinement time are given for the individual devices and the combined dataset. A comparison with tokamak L mode confinement is discussed on the basis of various scaling expressions. In order to make this database available to interested colleagues, the structure of the database and the parameter list are explained in detail. More recent confinement results incorporating data from enhanced confinement regimes such as H mode are reported elsewhere. (author).

  16. ATF Neutron Irradiation Program Technical Plan

    Energy Technology Data Exchange (ETDEWEB)

    Geringer, J. W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Materials Science and Technology Division; Katoh, Yutai [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Materials Science and Technology Division

    2016-03-01

    The Japan Atomic Energy Agency (JAEA) under the Civil Nuclear Energy Working Group (CNWG) is engaged in a cooperative research effort with the U.S. Department of Energy (DOE) to explore issues related to nuclear energy, including research on accident-tolerant fuels and materials for use in light water reactors. This work develops a draft technical plan for a neutron irradiation program on the candidate accident-tolerant fuel cladding materials and elements using the High Flux Isotope Reactor (HFIR). The research program requires the design of a detailed experiment, development of test vehicles, irradiation of test specimens, possible post-irradiation examination and characterization of irradiated materials and the shipment of irradiated materials to JAEA in Japan. This report discusses the technical plan of the experimental study.

  17. ATF Neutron Irradiation Program Technical Plan

    Energy Technology Data Exchange (ETDEWEB)

    Geringer, J. W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Materials Science and Technology Division; Katoh, Yutai [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Materials Science and Technology Division

    2016-03-01

    The Japan Atomic Energy Agency (JAEA) under the Civil Nuclear Energy Working Group (CNWG) is engaged in a cooperative research effort with the U.S. Department of Energy (DOE) to explore issues related to nuclear energy, including research on accident-tolerant fuels and materials for use in light water reactors. This work develops a draft technical plan for a neutron irradiation program on the candidate accident-tolerant fuel cladding materials and elements using the High Flux Isotope Reactor (HFIR). The research program requires the design of a detailed experiment, development of test vehicles, irradiation of test specimens, possible post irradiation examination and characterization of irradiated materials and the shipment of irradiated materials to JAEA in Japan. This report discusses the technical plan of the experimental study.

  18. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    Science.gov (United States)

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment.

  19. Staged electron laser accelerator (STELLA) experiment at brookhaven ATF

    Energy Technology Data Exchange (ETDEWEB)

    Pogorelsky, I.V.; Steenbergen, A. van; Gallardo, J.C. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1998-03-01

    The STELLA experiment is being prepared at the BNL Accelerator Test Facility (STF). The goal of the experiment is to demonstrate quasi-monochromatic inverse Cherenkov acceleration (ICA) of electrons bunched to the laser wavelength period. Microbunches on the order of 2 {mu}m in length separated by 10.6 {mu}m will be produced using an inverse free electron laser (IFEL) accelerator driven by a CO{sub 2} laser. The design and simulations for two phases of this experiment including demonstration of 10 MeV and 100 MeV acceleration are presented. (author)

  20. Fast ion behavior during neutral beam injection in ATF

    Energy Technology Data Exchange (ETDEWEB)

    Wade, M.R.; Thomas, C.E.; Colchin, R.J.; Rome, J.A.; England, A.C.; Fowler, R.H. [Oak Ridge National Lab., TN (United States); Aceto, S.C. [Rensselaer Polytechnic Inst., Troy, NY (United States)

    1993-09-01

    In stellarators, single-particle confinement properties can be more complex than in their tokamak counterparts. Fast-ion behavior in tokamaks has been well characterized through an abundance of measurements on various devices and in general has been shown to be consistent with classical slowing-down theory, although anomalous ion behavior has been observed during intense beam injection in ISX-B, during fishbone instabilities in PDX, and in experiments on TFR. In contrast, fast ion behavior in stellarators is not as wel established experimentally with the primary experiments to date focusing o near-perpendicular or perpendicular neutral beam injection (NBI) on the Wendelstein 7-A stellarator (91 and Heliotron-E. This paper addresses fast-ion confinement properties in a large-aspect-ratio, moderate-shear stellarator, the Advanced Toroidal Facility, during tangential NBI. The primary data used in this study are the experimentally measured energy spectra of charge-exchange neutrals escaping from the plasma, using a two-dimensional scanning neutral particle analyzer. This diagnostic method is well established, having been used on several devices since the early 1970`s. Various aspects of fast-ion behavior are investigated by comparing these data with computed theoretical spectra based on energeticion distributions derived from the fastion Fokker-Planck equation. Ion orbits are studied by computer orbit following, by the computation of J* surfaces, and by Monte Carlo calculations.

  1. Magnetic design for the ATF beamline. number sign. 1

    Energy Technology Data Exchange (ETDEWEB)

    Fernow, R.C.

    1992-02-05

    This report gives a self-consistent conceptual design for the final focusing'' beam optics and analysis spectrometer optics for the Grating Acceleration Experiment, the Inverse Cerenkov Acceleration Experiment, and the Nonlinear Compton Scattering Experiment. The introductory section describes the basic principles and constraints involved in the overall design. The next two sections give second order TRANSPORT calculations for the final focus system and the spectrometer system for the three experiments. The fourth section presents Monte Carlo simulations of the expected x-y distributions for the spectrometer detector for the three experiments. Appendices A and B contains further details about the assumptions used in the Monte Carlo simulations. Appendix C contains the working drawings used for determining distances on the experimental floor.

  2. Magnetic design for the ATF beamline {number_sign} 1

    Energy Technology Data Exchange (ETDEWEB)

    Fernow, R.C.

    1992-02-05

    This report gives a self-consistent conceptual design for the ``final focusing`` beam optics and analysis spectrometer optics for the Grating Acceleration Experiment, the Inverse Cerenkov Acceleration Experiment, and the Nonlinear Compton Scattering Experiment. The introductory section describes the basic principles and constraints involved in the overall design. The next two sections give second order TRANSPORT calculations for the final focus system and the spectrometer system for the three experiments. The fourth section presents Monte Carlo simulations of the expected x-y distributions for the spectrometer detector for the three experiments. Appendices A and B contains further details about the assumptions used in the Monte Carlo simulations. Appendix C contains the working drawings used for determining distances on the experimental floor.

  3. ATF4, A Novel Mediator of the Anabolic Actions of PTH on Bone

    Science.gov (United States)

    2012-01-01

    50mMKCl, 1mM dithiothreitol, 0.25% Nonidet P - 40 , 5 mM NaF, 1 mM EGTA, 5 mM MgCl2, 0.25 mM phenyl- methylsulfonyl fluoride), and the immunoprecipitated...0.25% Nonidet P - 40 , 5 mM sodium fluoride, 1 mM EGTA, 5 mM MgCl2). The immunoprecipi- tated complexes were suspended in SDS sample buffer and...activating deoxyri- bonucleic acid-binding proteins. Endocr Rev 14:269–290 40 . Sassone-Corsi P 1994 Goals for signal transduction pathways: linking

  4. Elastic Modulus Measurement of ORNL ATF FeCrAl Alloys

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Zachary T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Terrani, Kurt A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Yamamoto, Yukinori [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-10-01

    Elastic modulus and Poisson’s ratio for a number of wrought FeCrAl alloys, intended for accident tolerant fuel cladding application, are determined via resonant ultrasonic spectroscopy. The results are reported as a function of temperature from room temperature to 850°C. The wrought alloys were in the fully annealed and unirradiated state. The elastic modulus for the wrought FeCrAl alloys is at least twice that of Zr-based alloys over the temperature range of this study. The Poisson’s ratio of the alloys was 0.28 on average and increased very slightly with increasing temperature.

  5. EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue : a case report

    NARCIS (Netherlands)

    Flucke, Uta; Mentzel, Thomas; Verdijk, Marian A.; Slootweg, Pieter J.; Creytens, David H.; Suurmeijer, Albert J. H.; Tops, Bastiaan B. J.

    2012-01-01

    Soft tissue myoepithelial tumors, a recently defined entity, include benign and malignant lesions showing a considerable morphological and immunohistochemical heterogeneity. EWSR1 rearrangements are well recognized in this tumor type, and some of the partner genes have been identified. Herein we des

  6. EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report.

    NARCIS (Netherlands)

    Flucke, U.; Mentzel, T.; Verdijk, M.A.J.; Slootweg, P.J.; Creytens, D.H.; Suurmeijer, A.J.H.; Tops, B.B.J.

    2012-01-01

    Soft tissue myoepithelial tumors, a recently defined entity, include benign and malignant lesions showing a considerable morphological and immunohistochemical heterogeneity. EWSR1 rearrangements are well recognized in this tumor type, and some of the partner genes have been identified. Herein we des

  7. EPS-AG Sacherer Prize: Beam Optics Developments for SPS, RHIC, LHC, CLIC and ATF2

    CERN Document Server

    Tomas, R

    2011-01-01

    Highlights of linear and nonlinear optics studies are presented from various accelerators. At the LHC, optics correction is of critical importance to guarantee safe beam operation. Preparation for LHC opticsmeasurements and corrections has been a major activity during the last decade. In particular, SPS and RHIC have served as excellent research and development machines to test new techniques and instrumentation, such as the measurement of resonance driving terms with and without AC dipoles. Together with a meticulous field quality specification, a careful installation strategy and an elaborate magnet model, these efforts have paid off in the LHC, where a record low beta-beating for hadron colliders below 10% has been achieved. Looking further into the future, the performance of the Final Focus System (FFS) is of critical importance for a future linear collider like CLIC, since it determines the IP beam spot sizes. The large chromatic aberrations required the development of novel non-linear optimization metho...

  8. CALIBRATION ERRORS IN THE CAVITY BEAM POSITION MONITOR SYSTEM AT THE ATF2

    CERN Document Server

    Cullinan, F; Joshi, N; Lyapin, A

    2011-01-01

    It has been shown at the Accelerator Test Facility at KEK, that it is possible to run a system of 37 cavity beam position monitors (BPMs) and achieve high working resolution. However, stability of the calibration constants (position scale and radio frequency (RF) phase) over a three/four week running period is yet to be demonstrated. During the calibration procedure, random beam jitter gives rise to a statistical error in the position scale and slow orbit drift in position and tilt causes systematic errors in both the position scale and RF phase. These errors are dominant and have been evaluated for each BPM. The results are compared with the errors expected after a tested method of beam jitter subtraction has been applied.

  9. Transverse Laser Beam Shaping in High Brightness Electron Gun at ATF

    CERN Document Server

    Roychowdhury, S

    2005-01-01

    The brightness of electron beams from a photo injector is influenced by the transverse and longitudinal distribution of the laser beam illuminating the cathode. Previous studies at Brookhaven Accelerator Test Facility have shown that formation of an ideal e-beam with lowest transverse emittance requires uniform circular distribution of the emitted electrons. The use of the uniformly distributed power of the laser beam may not lead to that of the emitted electrons because of the non-uniform quantum efficiency. A proper shaping of the laser beam can compensate for this non-uniformity. In this paper we describe the use of digital light processing (DLP) technique based on digital mirror device (DMD) for spatial modulation of the laser beam, for measurements of the quantum efficiency map, and for creating the desirable e-beam density profiles. A DMD is aμelectronic mechanical system (MEMS) comprising of millions of highly reflectiveμmirrors controlled by underlying electronics. We present exper...

  10. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

    NARCIS (Netherlands)

    Kohl, S.; Zobor, D.; Chiang, W.C.; Weisschuh, N.; Staller, J.; Menendez, I.G.; Chang, S.; Beck, S.C.; Garrido, M. Garcia; Sothilingam, V.; Seeliger, M.W.; Stanzial, F.; Benedicenti, F.; Inzana, F.; Heon, E; Vincent, A.; Beis, J.; Strom, T.M.; Rudolph, G.; Roosing, S.; Hollander, A.I. den; Cremers, F.P.M.; Lopez, I.; Ren, H.; Moore, A.T.; Webster, A.R.; Michaelides, M.; Koenekoop, R.K.; Zrenner, E.; Kaufman, R.J.; Tsang, S.H.; Wissinger, B.; Lin, J.H.

    2015-01-01

    Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozyg

  11. Development of improved ATF engineering alloy - Mechanical testing of Phase 2 alloy

    Energy Technology Data Exchange (ETDEWEB)

    Anderoglu, Osman [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Lovato, Manuel L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Maloy, Stuart Andrew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-06-15

    In this report we present the results on the tensile testing of phase 2 FeCrAl alloys (Mo and Nb added for high temperature strength) developed at Oak Ridge National Laboratory. We also compare FeCrAl with MA956 which is an ODS FeCrAl.

  12. Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

    DEFF Research Database (Denmark)

    Gurzov, E N; Barthson, J; Marhfour, I

    2012-01-01

    Destruction of insulin-producing pancreatic β-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration o...

  13. Genetherapy with adenovirus expressing ATF-BPTI hybrid protein inhibits proteolysis by rheumatoid synovial fibroblasts

    NARCIS (Netherlands)

    Laan, W.H. van der; Grimbergen, J.M.; Verheijen, J.H.; Pha, Q.

    1998-01-01

    In rheumatoid arthritis (RA), irreversible joint damage is the result of degradation of articular structures such as cartilage, bone and tendons. The plasminogen activator (PA) system has been shown to be involved in the proteolytic degradation of cartilage matrix by rheumatoid synovial fibroblasts

  14. Thermal and electrical joint test for the helical field coils in the Advanced Toroidal Facility

    Energy Technology Data Exchange (ETDEWEB)

    Brown, R.L.; Johnson, R.L.

    1985-01-01

    Initial feasibility studies of a number of configurations for the Advanced Toroidal Facility (ATF) resulted in the selection of a resistive copper continuous-coil torsatron as the optimum device considering the physics program, cost, and schedule. Further conceptual design work was directed toward optimization of this configuration and, if possible, a shorter schedule. It soon became obvious that in order to shorten the schedule, a number of design and fabrication activities should proceed in parallel. This was most critical for the vacuum vessel and the helical field (HF) coils. If the HF coils were wound in place on a completed vacuum vessel, the overall schedule would be significantly (greater than or equal to12 months) longer. The approach of parallel scheduel paths requires that the HF coils be segmented into parts of less than or equal to180 of poloidal angle and that joints be made on a turn-by-turn basis when the segments are installed. It was obvious from the outset that the compact and complex geometry of the joint design presented a special challenge in the areas of reliability, assembly, maintenance, disassembly, and cost. Also, electrical, thermal, and force excursions are significant for these joints. A number of soldered, welded, brazed, electroplated, and bolted joints were evaluated. The evaluations examined fabrication feasibility and complexity, thermal-electrical performance at approximately two-thirds of the steady-state design conditions, and installation and assembly processes. Results of the thermal-electrical tests were analyzed and extrapolated to predict performance at peak design parameters. The final selection was a lap-type joint clamped with insulated bolts that pass through the winding packing. 3 refs., 4 figs.

  15. THE HEAT-SENSITIVE ANALYSIS OF THE atfes1a MUTANT SEEDS IN ARABIDOPSIS THALIANA%拟南芥atfes1a突变体种子的热敏感性分析

    Institute of Scientific and Technical Information of China (English)

    杨颖; 杨传燕; 刘箭

    2010-01-01

    根据基因芯片数据等生物信息学资料,我们锁定一些未知的且被高温诱导的基因,并获得了一个推测编码蛋白含armadillo/beta-catenin repeat(简称ARM)结构域的突变体salk-021784,该突变体缺失AtFes1A基因,该基因编码一种受高温诱导的ARM 蛋白.利用抗体检测了在拟南芥种子发育过程中AtFes1A的热诱导表达特征, 通过表型分析发现,热处理后的突变体种子萌发率明显低于热处理后的野生型,表明AtFes1A蛋白与拟南芥耐热有关.

  16. 28 CFR 16.106 - Exemption of the Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF)-Limited Access.

    Science.gov (United States)

    2010-07-01

    ... subsection (e)(5) would restrict the ability of trained investigators and intelligence analysts to exercise their judgment in reporting on investigations and impede the development of criminal intelligence... physical safety of witnesses and informants. (10) From subsection (e)(5) because in the collection...

  17. High Temperature Mechanical Properties, Fractography and Synchrotron Studies of ATF clad materials from the UCSB-NSUF Irradiations.

    Energy Technology Data Exchange (ETDEWEB)

    Saleh, Tarik A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Maloy, Stuart Andrew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Romero, Tobias J. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Sprouster, David [Brookhaven National Lab. (BNL), Upton, NY (United States); Ecker, Lynne [Brookhaven National Lab. (BNL), Upton, NY (United States)

    2015-02-23

    A variety of tensile samples of Ferritic and Oxide Dispersion Strengthened (ODS or nanostructured ferritic) steels were placed the ATR reactor over 2 years achieving doses of roughly 4-6 dpa at temperatures of roughly 290°C. Samples were shipped to Wing 9 in the CMR facility at Los Alamos National Laboratory and imaged then tested in tension. This report summarizes the room temperature tensile tests, the elevated temperature tensile tests (300°C) and fractography and reduction of area calculations on those samples. Additionally small samples were cut from the undeformed grip section of these tensile samples and sent to the NSLS synchrotron for high energy X-ray analysis, initial results will be described here.

  18. Chemical compatibility between UO2 fuel and SiC cladding for LWRs. Application to ATF (Accident-Tolerant Fuels)

    Science.gov (United States)

    Braun, James; Guéneau, Christine; Alpettaz, Thierry; Sauder, Cédric; Brackx, Emmanuelle; Domenger, Renaud; Gossé, Stéphane; Balbaud-Célérier, Fanny

    2017-04-01

    Silicon carbide-silicon carbide (SiC/SiC) composites are considered to replace the current zirconium-based cladding materials thanks to their good behavior under irradiation and their resistance under oxidative environments at high temperature. In the present work, a thermodynamic analysis of the UO2±x/SiC system is performed. Moreover, using two different experimental methods, the chemical compatibility of SiC towards uranium dioxide, with various oxygen contents (UO2±x) is investigated in the 1500-1970 K temperature range. The reaction leads to the formation of mainly uranium silicides and carbides phases along with CO and SiO gas release. Knudsen Cell Mass Spectrometry is used to measure the gas release occurring during the reaction between UO2+x and SiC powders as function of time and temperature. These experimental conditions are representative of an open system. Diffusion couple experiments with pellets are also performed to study the reaction kinetics in closed system conditions. In both cases, a limited chemical reaction is observed below 1700 K, whereas the reaction is enhanced at higher temperature due to the decomposition of SiC leading to Si vaporization. The temperature of formation of the liquid phase is found to lie between 1850 < T < 1950 K.

  19. The Study of Advanced Accelerator Physics Research at UCLA Using the ATF at BNL: Vacuum Acceleration by Laser of Free Electrons

    Energy Technology Data Exchange (ETDEWEB)

    Cline, David B. [Univ. of California, Los Angeles, CA (United States)

    2016-09-07

    An experiment was designed and data were taken to demonstrate that a tightly focused laser on vacuum can accelerate an electron beam in free space. The experiment was proof-of-principle and showed a clear effect for the laser beam off and on. The size of the effect was about 20% and was consistent over 30 laser and beam shots.

  20. The Study of Advanced Accelerator Physics Research at UCLA Using the ATF at BNL: Vacuum Acceleration by Laser of Free Electrons

    Energy Technology Data Exchange (ETDEWEB)

    Cline, David B. [Univ. of California, Los Angeles, CA (United States)

    2016-09-07

    An experiment was designed and data taken to demonstrate that a tightly focused laser on vacuum can accelerate an electron beam in free space. The experiment was proof-of-principle and showed a clear effect for the laser beam off and on. The size of the effect was about 20% and was consistent over 30 laser and beam shots.

  1. Physical mechanism determining the radial electric field and its radial structure in a toroidal plasma

    Energy Technology Data Exchange (ETDEWEB)

    Ida, Katsumi; Miura, Yukitoshi; Itoh, Sanae [and others

    1994-10-01

    Radial structures of plasma rotation and radial electric field are experimentally studied in tokamak, heliotron/torsatron and stellarator devices. The perpendicular and parallel viscosities are measured. The parallel viscosity, which is dominant in determining the toroidal velocity in heliotron/torsatron and stellarator devices, is found to be neoclassical. On the other hand, the perpendicular viscosity, which is dominant in dictating the toroidal rotation in tokamaks, is anomalous. Even without external momentum input, both a plasma rotation and a radial electric field exist in tokamaks and heliotrons/torsatrons. The observed profiles of the radial electric field do not agree with the theoretical prediction based on neoclassical transport. This is mainly due to the existence of anomalous perpendicular viscosity. The shear of the radial electric field improves particle and heat transport both in bulk and edge plasma regimes of tokamaks. (author) 95 refs.

  2. Cloning the activating transcription factor 5 gene and detection of its expressional localization in cultivated cells%激活转录因子5的克隆及其在真核细胞中的表达定位

    Institute of Scientific and Technical Information of China (English)

    叶雄俊; 常智杰; 林桂亭; 张志文; 辛殿祺; 王晓峰; 郭应禄

    2005-01-01

    目的克隆激活转录因子(ATF)5,构建其真核表达载体,观察其在细胞中的表达定位.方法根据人ATF5的cDNA序列设计引物,通过巢式PCR扩增ATF5全长及其N端(ATF5/N)和C端(ATF5/C),构建重组表达质粒pCS2MT-ATF5、pCS2MT-ATF5/N和pCS2MT-ATF5/C及融合绿色荧光蛋白(GFP)基因的质粒pEGFP-ATF5.将表达质粒转染293T和Cos-7细胞,Western blot检测其表达情况,荧光显微镜观察ATF5在293T和Hela细胞的定位.结果巢式PCR产物与预期大小一致,重组质粒pCS2MT-ATF5、pCS2MT-ATF5/N和pCS2MT-ATF5/C能表达携带Myc标签的蛋白Myc-ATF5、Myc-ATF5/N和Myc-ATF5/C,分子量分别为52、35和43×103.荧光显微镜观察发现融合了GFP的ATF5蛋白定位在细胞核.结论成功的克隆和表达ATF5基因为进一步研究其在肾肿瘤发生、发展过程中的作用奠定了基础.

  3. Alternatives to traditional transportation fuels 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-12-01

    Interest in alternative transportation fuels (ATF`s) has increased in recent years due to the drives for cleaner air and less dependence upon foreign oil. This report, Alternatives to Traditional Transportation Fuels 1996, provides information on ATFs, as well as the vehicles that consume them.

  4. Negative regulation of TLR-signaling pathways by activating transcription factor-3.

    Science.gov (United States)

    Whitmore, Mark M; Iparraguirre, Amaya; Kubelka, Lindsey; Weninger, Wolfgang; Hai, Tsonwin; Williams, Bryan R G

    2007-09-15

    Activating transcription factor-3 (ATF3) is rapidly induced by LPS in mouse macrophages and regulates TLR4 responses. We show that ATF3 is rapidly induced by various TLRs in mouse macrophages and plasmacytoid dendritic cells (DCs), as well as plasmacytoid and myeloid subsets of human DCs. In primary macrophages from mice with a targeted deletion of the atf3 gene (ATF3-knockout (KO)), TLR-stimulated levels of IL-12 and IL-6 were elevated relative to responses in wild-type macrophages. Similarly, targeted deletion of atf3 correlated with enhanced responsiveness of myeloid DCs to TLR activation as measured by IL-12 secretion. Ectopic expression of ATF3 antagonized TLR-stimulated IL-12p40 activation in a reporter assay. In vivo, CpG-oligodeoxynucleotide, a TLR9 agonist, given i.p. to ATF3-KO mice resulted in enhanced cytokine production from splenocytes. Furthermore, while ATF3-KO mice challenged with a sublethal dose of PR8 influenza virus were delayed in body weight recovery in comparison to wild type, the ATF3-KO mice showed higher titers of serum neutralizing Ab against PR8 5 mo postinfection. Thus, ATF3 behaves as a negative regulatory transcription factor in TLR pathways and, accordingly, deficiency in atf3 alters responses to immunological challenges in vivo. ATF3 dysregulation merits further exploration in diseases such as type I diabetes and cancer, where altered innate immunity has been implicated in their pathogenesis.

  5. Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling.

    Science.gov (United States)

    Li, Yulin; Li, Zhenya; Zhang, Congcong; Li, Ping; Wu, Yina; Wang, Chunxiao; Lau, Wayne Bond; Ma, Xin-Liang; Du, Jie

    2017-03-01

    Background -Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. Methods -We used a discovery-driven/nonbiased approach to indentify increased ATF3 expression in hypertensive heart. We employed loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examine the mechanisms through transcriptome, CHIP-seq analysis and in vivo and vitro experiments. Results -ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the pro-fibrotic/hypertrophic phenotype in ATF3KO cells. Finally, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the pro-fibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced TGF-β signaling-related pro-fibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. Conclusions -Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects heart by suppressing Map2K3 expression and subsequent p38-TGF-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive

  6. Activating transcription factor 4 regulates osteoclast differentiation in mice.

    Science.gov (United States)

    Cao, Huiling; Yu, Shibing; Yao, Zhi; Galson, Deborah L; Jiang, Yu; Zhang, Xiaoyan; Fan, Jie; Lu, Binfeng; Guan, Youfei; Luo, Min; Lai, Yumei; Zhu, Yibei; Kurihara, Noriyoshi; Patrene, Kenneth; Roodman, G David; Xiao, Guozhi

    2010-08-01

    Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4-/- bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4-/- BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity.

  7. Activating transcription factor 4 regulates osteoclast differentiation in mice

    Science.gov (United States)

    Cao, Huiling; Yu, Shibing; Yao, Zhi; Galson, Deborah L.; Jiang, Yu; Zhang, Xiaoyan; Fan, Jie; Lu, Binfeng; Guan, Youfei; Luo, Min; Lai, Yumei; Zhu, Yibei; Kurihara, Noriyoshi; Patrene, Kenneth; Roodman, G. David; Xiao, Guozhi

    2010-01-01

    Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4–/– bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4–/– BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity. PMID:20628199

  8. Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

    Science.gov (United States)

    Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L.; Shiozaki, Yuji; Okamura, Kayo; Chick, Wallace S.; Williams, Kristina; Zhao, Xiaoyun; Rahman, Shaikh Mizanoor; Tintut, Yin; Adams, Christopher M.

    2016-01-01

    Emerging evidence indicates that upregulation of the ER stress–induced pro-osteogenic transcription factor ATF4 plays an important role in vascular calcification, a common complication in patients with aging, diabetes, and chronic kidney disease (CKD). In this study, we demonstrated the pathophysiological role of ATF4 in vascular calcification using global Atf4 KO, smooth muscle cell–specific (SMC-specific) Atf4 KO, and transgenic (TG) mouse models. Reduced expression of ATF4 in global ATF4-haplodeficient and SMC-specific Atf4 KO mice reduced medial and atherosclerotic calcification under normal kidney and CKD conditions. In contrast, increased expression of ATF4 in SMC-specific Atf4 TG mice caused severe medial and atherosclerotic calcification. We further demonstrated that ATF4 transcriptionally upregulates the expression of type III sodium-dependent phosphate cotransporters (PiT1 and PiT2) by interacting with C/EBPβ. These results demonstrate that the ER stress effector ATF4 plays a critical role in the pathogenesis of vascular calcification through increased phosphate uptake in vascular SMCs. PMID:27812542

  9. Magnetic field of a combined plasma trap

    Science.gov (United States)

    Kotenko, V. G.; Moiseenko, V. E.; Ågren, O.

    2012-06-01

    This paper presents numerical simulations performed on the structure of a magnetic field created by the magnetic system of a combined plasma trap. The magnetic system includes the stellarator-type magnetic system and one of the mirror-type. For the stellarator type magnetic system the numeric model contains a magnetic system of an l=2 torsatron with the coils of an additional toroidal magnetic field. The mirror-type magnetic system element is considered as being single current-carrying turn enveloping the region of existence of closed magnetic surfaces of the torsatron. The calculations indicate the existence of a vast area of the values of the additional magnetic field magnitude and magnetic field of the single turn where, in principle, the implementation of the closed magnetic surface configuration is quite feasible.

  10. Modular stellarator reactor: a fusion power plant

    Energy Technology Data Exchange (ETDEWEB)

    Miller, R.L.; Bathke, C.G.; Krakowski, R.A.; Heck, F.M.; Green, L.; Karbowski, J.S.; Murphy, J.H.; Tupper, R.B.; DeLuca, R.A.; Moazed, A.

    1983-07-01

    A comparative analysis of the modular stellarator and the torsatron concepts is made based upon a steady-state ignited, DT-fueled, reactor embodiment of each concept for use as a central electric-power station. Parametric tradeoff calculations lead to the selection of four design points for an approx. 4-GWt plant based upon Alcator transport scaling in l = 2 systems of moderate aspect ratio. The four design points represent high-aspect ratio. The four design points represent high-(0.08) and low-(0.04) beta versions of the modular stellarator and torsatron concepts. The physics basis of each design point is described together with supporting engineering and economic analyses. The primary intent of this study is the elucidation of key physics and engineering tradeoffs, constraints, and uncertainties with respect to the ultimate power reactor embodiment.

  11. In Vitro Anticancer Activity of Phlorofucofuroeckol A via Upregulation of Activating Transcription Factor 3 against Human Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Hyun Ji Eo

    2016-03-01

    Full Text Available Phlorofucofuroeckol A (PFF-A, one of the phlorotannins found in brown algae, has been reported to exert anti-cancer property. However, the molecular mechanism for the anti-cancer effect of PFF-A has not been known. Activating transcription factor 3 (ATF3 has been reported to be associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which PFF-A stimulates ATF3 expression and apoptosis in human colorectal cancer cells. PFF-A decreased cell viability through apoptosis of human colorectal cancer cells. PFF-A increased ATF3 expression through regulating transcriptional activity. The responsible cis-element for ATF3 transcriptional activation by PFF-A was cAMP response element binding protein (CREB, located between positions −147 and −85 of the ATF3 promoter. Inhibition of p38, c-Jun N-terminal kinases (JNK, glycogen synthase kinase (GSK 3β, and IκB kinase (IKK-α blocked PFF-A-mediated ATF3 expression. ATF3 knockdown by ATF3 siRNA attenuated the cleavage of poly (ADP-ribose polymerase (PARP by PFF-A, while ATF3 overexpression increased PFF-A-mediated cleaved PARP. These results suggest that PFF-A may exert anti-cancer property through inducing apoptosis via the ATF3-mediated pathway in human colorectal cancer cells.

  12. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3.

    Science.gov (United States)

    St Germain, Carly; Niknejad, Nima; Ma, Laurie; Garbuio, Kyla; Hai, Tsonwin; Dimitroulakos, Jim

    2010-07-01

    The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

  13. BOOK REVIEW: Stellarator and Heliotron Devices

    Science.gov (United States)

    Johnson, John L.

    1999-02-01

    Pfirsch-Schlüter current driven magnetic islands and the interpretation of sawtooth instabilities in Heliotron E. The treatment of particle orbits in Chapter 6 includes a derivation of drift equations, a discussion of the characteristics of trapped particle confinement in a heliotron and one of the Monte Carlo method for studying transport phenomena. A good treatment of neoclassical transport in a stellarator, with emphasis on the relation between parallel viscosity driven fluxes and bootstrap current, is given in Chapter 7. This is the best treatment I have found, outside of the original references, but it is still demanding. In addition, a radial electric field is introduced into the energy transport equations. The treatment of heating and confinement of heliotron plasmas in Chapter 8 is a good combination of providing results from experiments on the Heliotron E and DR heliotrons and the ATF and CHS stellarators and showing how theoretical interpretation is formulated. The discussions of ray tracing and energy absorption for both ECRH and ICRF heating techniques, as well as a treatment of neutral beam injection, are very clear. Measurements of bootstrap current and plasma rotation, as well as the density limits associated with pellet injection, are discussed. The chapter ends with a discussion of what may be the author's favourite topic, pressure gradient driven turbulence, in which he describes mixing length and scale invariance techniques. Finally, a discussion of the characteristics of a steady state fusion reactor, including a treatment of the containment, slowing down and energy transfer of the alpha particles, one of the toroidal Alfvén modes driven by these particles and some physics of divertors are given in Chapter 9. A reviewer is usually expected to find some faults. I had no problem in finding one as soon as I received the book: indeed, I did not like its title. I have always maintained that Lyman Spitzer defined a stellarator as any toroidal device in

  14. Simultaneous saccharification and fermentation of Agave tequilana fructans by Kluyveromyces marxianus yeasts for bioethanol and tequila production.

    Science.gov (United States)

    Flores, Jose-Axel; Gschaedler, Anne; Amaya-Delgado, Lorena; Herrera-López, Enrique J; Arellano, Melchor; Arrizon, Javier

    2013-10-01

    Agave tequilana fructans (ATF) constitute a substrate for bioethanol and tequila industries. As Kluyveromyces marxianus produces specific fructanases for ATF hydrolysis, as well as ethanol, it can perform simultaneous saccharification and fermentation. In this work, fifteen K. marxianus yeasts were evaluated to develop inoculums with fructanase activity on ATF. These inoculums were added to an ATF medium for simultaneous saccharification and fermentation. All the yeasts, showed exo-fructanhydrolase activity with different substrate specificities. The yeast with highest fructanase activity in the inoculums showed the lowest ethanol production level (20 g/l). Five K. marxianus strains were the most suitable for the simultaneous saccharification and fermentation of ATF. The volatile compounds composition was evaluated at the end of fermentation, and a high diversity was observed between yeasts, nevertheless all of them produced high levels of isobutyl alcohol. The simultaneous saccharification and fermentation of ATF with K. marxianus strains has potential for industrial application.

  15. Proceedings of US-Japan heliotron-stellarator workshop: Volume 1

    Energy Technology Data Exchange (ETDEWEB)

    1987-01-01

    This paper is the first of four volumes on the US-Japan Heliotron-Stellarator workshop. It contains talks on the Heliotron E experiment, the compact helical system (CHS) program, the status of the ATF project, the status of the W VII-AS, the status of the TJ-II program, the ATF experimental plans, the ATF diagnostics, the compact Helical system, and the CHS experimental program and diagnostics. (LSP)

  16. Differential expression of two activating transcription factor 5 isoforms in papillary thyroid carcinoma

    Science.gov (United States)

    Vicari, Luisa; La Rosa, Cristina; Forte, Stefano; Calabrese, Giovanna; Colarossi, Cristina; Aiello, Eleonora; Salluzzo, Salvatore; Memeo, Lorenzo

    2016-01-01

    Background Activating transcription factor 5 (ATF5) is a member of the activating transcription/cAMP response element-binding protein family of basic leucine zipper proteins that plays an important role in cell survival, differentiation, proliferation, and apoptosis. The ATF5 gene generates two transcripts: ATF5 isoform 1 and ATF5 isoform 2. A number of studies indicate that ATF5 could be an attractive target for therapeutic intervention in several tumor types; however, so far, the role of ATF5 has not been investigated in papillary thyroid carcinoma (PTC). Methods Quantitative real-time reverse transcription polymerase chain reaction and immuno-histochemical staining were used to study ATF5 mRNA and protein expression in PTC. Results We report here that ATF5 is expressed more in PTC tissue than in normal thyroid tissue. Furthermore, this is the first study that describes the presence of both ATF5 isoforms in PTC. Conclusion These findings could provide potential applications in PTC cancer treatment.

  17. 76 FR 68373 - Proposed Revision to Vintage Date Requirements

    Science.gov (United States)

    2011-11-04

    ... (71 FR 25748) on May 2, 2006. In that earlier rulemaking, TTB liberalized the vintage date... Register (43 FR 37672) by TTB's predecessor agency, the Bureau of Alcohol, Tobacco and Firearms (ATF), on... Federal Register (42 FR 30517) on June 15, 1977, ATF noted that the wine industry advocated that the...

  18. 75 FR 80845 - Agency Information Collection Activities: Proposed Collection; Comments Requested

    Science.gov (United States)

    2010-12-23

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau..., NFA Special Tax Renewal Registration and Return, ATF F 5630.5RC, NFA Special Tax Location Registration Listing, ATF F 5630.7, NFA Special Tax Registration and Return National Firearms Act. The Department...

  19. Activating transcription factor 6 poly morphisms and haplotypes ars associated with impaired glucose homeostasis ans type 2 diabetis in dutch Caucasians

    NARCIS (Netherlands)

    Meex, S.J.; Greevenbroek, van M.M.J.; Ayoubi, T.A.; Vlietinck, R.; Vliet-Ostaptchouk, J.V.; Hofker, M.H.; Vermeulen, V.; Schalkwijk, C.G.; Feskens, E.J.M.; Boer, J.M.A.; Stehouwer, C.D.A.; Kallen, van der C.J.H.; Bruin, de T.W.A.

    2007-01-01

    Context: Activating transcription factor 6 (ATF6) is critical for initiation and full activation of the unfolded protein response. An association between genetic variation in ATF6 and type 2 diabetes (DM2) was recently reported in Pima Indians. Objectives: To investigate the broader significance of

  20. 77 FR 33630 - Residency Requirements for Aliens Acquiring Firearms (2011R-23P)

    Science.gov (United States)

    2012-06-07

    ... for Aliens Acquiring Firearms (2011R-23P) AGENCY: Bureau of Alcohol, Tobacco, Firearms, and Explosives... (ATF) by removing the 90-day State residency requirement for aliens lawfully present in the United... permit ATF to impose a regulatory requirement that aliens lawfully present in the United States...

  1. Activating transcription factor 4 mediates a multidrug resistance phenotype of esophageal squamous cell carcinoma cells through transactivation of STAT3 expression.

    Science.gov (United States)

    Zhu, Hongwu; Chen, Xiong; Chen, Bin; Chen, Bei; Fan, Jianyong; Song, Weibing; Xie, Ziying; Jiang, Dan; Li, Qiuqiong; Zhou, Meihua; Sun, Dayong; Zhao, Yagang

    2014-11-01

    Multidrug resistance (MDR) is a major challenge to the clinical treatment of esophageal cancer. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, relatively little is known about the expression and function of ATF4 in esophageal squamous cell carcinoma (ESCC) MDR. In this study, we investigate the potential role and mechanisms of ATF4 in ESCC MDR. We demonstrated that overexpression of ATF4 promotes the MDR phenotype in ESCC cells, while depletion of ATF4 in the MDR ESCC cell line induces drug re-sensitization. We also demonstrated that ATF4 transactivates STAT3 expression by directly binding to the signal transducers and activators of transcription 3 (STAT3) promoter, resulting in MDR in ESCC cells. Significantly, inhibition of STAT3 by small interfering RNA (siRNA) or a selective inhibitor (JSI-124) reintroduces therapeutic sensitivity. In addition, increased Bcl-2, survivin, and MRP1 expression levels were observed in ATF4-overexpressing cells. In conclusion, ATF4 may promote MDR in ESCC cells through the up-regulation of STAT3 expression, and thus is an attractive therapeutic target to combat therapeutic resistance in ESCC.

  2. 78 FR 76322 - Agency Information Collection Activities: Proposed Collection; Comments Requested: FFL Out-of...

    Science.gov (United States)

    2013-12-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau... Justice (DOJ), Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF), will submit the following... information, please contact Tracey Robertson, Tracey.Robertson@atf.gov or (304) 616-4647, Chief,...

  3. Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

    Directory of Open Access Journals (Sweden)

    Carly St. Germain

    2010-07-01

    Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

  4. Cloning and characterization of a gene involved in triacylglycerol biosynthesis and identification of additional homologous genes in the oleaginous bacterium Rhodococcus opacus PD630.

    Science.gov (United States)

    Alvarez, Adrian F; Alvarez, Héctor M; Kalscheuer, Rainer; Wältermann, Marc; Steinbüchel, Alexander

    2008-08-01

    The oleaginous bacterium Rhodococus opacus strain PD630 serves as a model organism to investigate the metabolism of storage triacylglycerols (TAGs) in bacteria. The key enzyme catalysing the last step of TAG biosynthesis in bacteria is a promiscuous acyltransferase (Atf), exhibiting acyl-CoA acyltransferase activity to both diacylglycerols (DGAT activity) and fatty alcohols (wax ester synthase, WS activity). An 800 bp PCR product was obtained from chromosomal DNA of strain PD630 by using degenerate primers designed from conserved stretches of Atf proteins of Acinetobacter baylyi strain ADP1 and Mycobacterium smegmatis mc(2)155. The atf fragment was used as a probe on a strain PD630 gene library, resulting in the identification of a 3948 bp chromosomal DNA fragment containing the complete atf1 gene. An atf1 disruption mutant of strain PD630 exhibited a TAG-leaky phenotype and accumulated up to 50 % less fatty acids than the wild-type, with significantly reduced oleic acid content when cultivated in the presence of gluconate or oleic acid. Whereas DGAT activity was drastically reduced in comparison to the wild-type, WS activity remained almost unchanged in the mutant. RT-PCR analysis of gluconate-grown cells of strain PD630 showed that there is expression of atf1 under conditions of TAG synthesis. To identify additional Atfs in strain PD630, PCR employing non-degenerate primers deduced from Rhodococcus jostii RHA1 sequence data was used. This yielded nine additional atf-homologous genes exhibiting 88-99 % sequence identity to the corresponding strain RHA1 enzymes. Besides Atf1 only Atf2 exhibited high DGAT and/or WS activity when heterologously expressed in Escherichia coli.

  5. Advanced fusion concepts: project summaries

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-12-01

    This report contains descriptions of the activities of all the projects supported by the Advanced Fusion Concepts Branch of the Office of Fusion Energy, US Department of Energy. These descriptions are project summaries of each of the individual projects, and contain the following: title, principle investigators, funding levels, purpose, approach, progress, plans, milestones, graduate students, graduates, other professional staff, and recent publications. Information is given for each of the following programs: (1) reverse-field pinch, (2) compact toroid, (3) alternate fuel/multipoles, (4) stellarator/torsatron, (5) linear magnetic fusion, (6) liners, and (7) Tormac. (MOW)

  6. Pulsed supersonic helium beams for plasma edge diagnosis

    Science.gov (United States)

    Diez-Rojo, T.; Herrero, V. J.; Tanarro, I.; Tabarés, F. L.; Tafalla, D.

    1997-03-01

    An experimental setup for the production of pulsed supersonic He beams to be used for plasma edge diagnosis in fusion devices is described. A compromise between compact design, low cost, and good quality of the probe beams has been met. The main characteristics of the generated beams, such as pulse shape, absolute flux intensity, and velocity distribution, differ in general from those expected for ideal beam performance and have been determined and optimized experimentally. A first test of this He beam source at the TJ-I UP Torsatron in Madrid is also reported.

  7. Pulsed supersonic helium beams for plasma edge diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Diez-Rojo, T.; Herrero, V.J.; Tanarro, I. [Instituto de Estructura de la Materia (CSIC), Serrano 123, 28006 Madrid (Spain); Tabares, F.L.; Tafalla, D. [Asociacion EURATOM-CIEMAT para Fusion, Avenue Complutense 22, 28040 Madrid (Spain)

    1997-03-01

    An experimental setup for the production of pulsed supersonic He beams to be used for plasma edge diagnosis in fusion devices is described. A compromise between compact design, low cost, and good quality of the probe beams has been met. The main characteristics of the generated beams, such as pulse shape, absolute flux intensity, and velocity distribution, differ in general from those expected for ideal beam performance and have been determined and optimized experimentally. A first test of this He beam source at the TJ-I UP Torsatron in Madrid is also reported. {copyright} {ital 1997 American Institute of Physics.}

  8. Integrated microfluidic approach for quantitative high-throughput measurements of transcription factor binding affinities.

    Science.gov (United States)

    Glick, Yair; Orenstein, Yaron; Chen, Dana; Avrahami, Dorit; Zor, Tsaffrir; Shamir, Ron; Gerber, Doron

    2016-04-07

    Protein binding to DNA is a fundamental process in gene regulation. Methodologies such as ChIP-Seq and mapping of DNase I hypersensitive sites provide global information on this regulation in vivo In vitro methodologies provide valuable complementary information on protein-DNA specificities. However, current methods still do not measure absolute binding affinities. There is a real need for large-scale quantitative protein-DNA affinity measurements. We developed QPID, a microfluidic application for measuring protein-DNA affinities. A single run is equivalent to 4096 gel-shift experiments. Using QPID, we characterized the different affinities of ATF1, c-Jun, c-Fos and AP-1 to the CRE consensus motif and CRE half-site in two different genomic sequences on a single device. We discovered that binding of ATF1, but not of AP-1, to the CRE half-site is highly affected by its genomic context. This effect was highly correlated with ATF1 ChIP-seq and PBM experiments. Next, we characterized the affinities of ATF1 and ATF3 to 128 genomic CRE and CRE half-site sequences. Our affinity measurements explained that in vivo binding differences between ATF1 and ATF3 to CRE and CRE half-sites are partially mediated by differences in the minor groove width. We believe that QPID would become a central tool for quantitative characterization of biophysical aspects affecting protein-DNA binding.

  9. Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway.

    Science.gov (United States)

    Hsu, Shih-Che; Huang, Shih-Ming; Chen, Ann; Sun, Chiao-Yin; Lin, Shih-Hua; Chen, Jin-Shuen; Liu, Shu-Ting; Hsu, Yu-Juei

    2014-08-01

    The Klotho gene functions as an aging suppressor gene. Evidence from animal models suggests that induction of Klotho expression may be a potential treatment for age-associated diseases. However, the molecular mechanism involved in regulating renal Klotho gene expression remains unclear. In this study, we determined that resveratrol, a natural polyphenol, induced renal Klotho expression both in vivo and in vitro. In the mouse kidney, resveratrol administration markedly increased both Klotho mRNA and protein expression. In resveratrol-treated NRK-52E cells, increased Klotho expression was accompanied by the upregulation and nuclear translocation of activating transcription factor 3 (ATF3) and c-Jun. ATF3 or c-Jun overexpression enhanced the transcriptional activation of Klotho. Conversely, resveratrol-induced Klotho expression was attenuated in the presence of dominant-negative ATF3 or c-Jun. Coimmunoprecipitation and a chromatin immunoprecipitation assay revealed that ATF3 physically interacted with c-Jun and that the ATF3/c-Jun complex directly bound to the Klotho promoter through ATF3- and AP-1-binding elements. c-Jun cotransfection augmented the effects of ATF3 on Klotho transcription in vitro. Although Sirtuin 1 mRNA expression was induced by resveratrol and involved in regulating Klotho mRNA expression, it was not the primary cause for the aforementioned ATF3/c-Jun pathway. In summary, resveratrol enhances the renal expression of the anti-aging Klotho gene, and the transcriptional factors ATF3 and c-Jun functionally interact and coordinately regulate the resveratrol-mediated transcriptional activation of Klotho.

  10. 77 FR 59548 - Privacy Act; Implementation

    Science.gov (United States)

    2012-09-28

    ... certain functions of the Bureau of Alcohol, Tobacco and Firearms (ATF) to the Department of Justice, and the remaining functions reorganized as the Alcohol and Tobacco Tax and Trade Bureau (TTB) within...

  11. 77 FR 32136 - Agency Information Collection Activities:

    Science.gov (United States)

    2012-05-31

    ... of Alcohol, Tobacco, Firearms and Explosives Agency Information Collection Activities: Proposed... ACTION: 30-Day Notice of Information Collection Under Review: The Department of Justice (DOJ), Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) will be submitting the following information...

  12. 75 FR 81650 - Agency Information Collection Activities:

    Science.gov (United States)

    2010-12-28

    ... Bureau of Alcohol, Tobacco, Firearms, and Explosives Agency Information Collection Activities: Proposed Collection; Comments Requested ACTION: 30-Day Notice of Information Collection Under Review: Open Letter to...), Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF) will be submitting the following...

  13. 激活转录因子5启动子区甲基化水平的研究%DNA methylation level of promoter region of activating transcription factor 5 in glioma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    目的:研究临床胶质瘤标本中激活转录因子5(ATF5)启动子区CpG岛甲基化状态及临床意义。创新点:首次发现在胶质瘤标本中ATF5的甲基化水平下调,其表达水平下调。方法:收集35临床胶质瘤组织及5例急性脑外伤组织作为对照,应用亚硫酸盐测序技术检测ATF5的甲基化水平,并结合临床病理资料进行分析;实时荧光定量聚合酶链式反应(qRT-PCR)检测所有标本中ATF5 mRNA的表达水平变化。结论:5例正常脑组织、10例低级别胶质瘤及25例高级别胶质瘤的甲基化比例分别为87.78%、73.89%和47.70%(图2),两组相比差异有统计学意义(P<0.05;图3a和3b);qRT-PCR结果表明,与对照相比,胶质瘤标本中ATF5表达水平上升(P<0.05;图3d)。综上所述,胶质瘤组织中ATF5基因启动子区CpG岛的甲基化状态对该基因的表达有重要意义。%Transcription factors, which represent an important class of proteins that play key roles in controling celular proliferation and cel cycle modulation, are attractive targets for cancer therapy. Previous researches have shown that the expression level of activating transcription factor 5 (ATF5) was frequently increased in glioma and its acetylation level was related to glioma. The purposes of this study were to explore the methylation level of ATF5 in clinical glioma tissues and to explore the effect of ATF5 methylation on the expression of ATF5 in glioma. Methylation of the promoter region of ATF5 was assayed by bisulfite-specific polymerase chain reaction (PCR) sequencing analysis in 35 cases of glioma and 5 normal tissues. Quantitative real-time PCR (qRT-PCR) was also performed to detect ATF5 mRNA expression in 35 cases of glioma and 5 normal tissues. Clinical data were collected from the patients and analyzed. The percentages of methylation of the ATF5 gene in the promoter region in healthy control, patients with wel-differentiated glioma

  14. 78 FR 64246 - Commerce in Explosives; List of Explosives Materials

    Science.gov (United States)

    2013-10-28

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF JUSTICE Bureau of Alcohol, Tobacco, Firearms, and Explosives Commerce in Explosives; List of Explosives Materials AGENCY: Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF); Department of Justice. ACTION:...

  15. Simulation Prediction and Experiment Setup of Vacuum Laser Acceleration at Brookhaven National Lab-Accelerator Test Facility

    CERN Document Server

    Shao, L; Ding, X; Ho, Y K; Kong, Q; Xu, J J; Pogorelsky, I; Yakimenko, V; Kusche, K

    2011-01-01

    This paper presents the pre-experiment plan and prediction of the first stage of Vacuum Laser Acceleration (VLA) collaborating by UCLA, Fudan University and ATF-BNL. This first stage experiment is a Proof-of-Principle to support our previously posted novel VLA theory. Simulations show that based on ATF's current experimental conditions, the electron beam with initial energy of 15MeV can get net energy gain from intense CO2 laser beam. The difference of electron beam energy spread is observable by ATF beam line diagnostics system. Further this energy spread expansion effect increases along with the laser intensity increasing. The proposal has been approved by ATF committee and experiment will be the next project.

  16. 76 FR 10066 - Agency Information Collection Activities: Proposed Collection; Comments Requested

    Science.gov (United States)

    2011-02-23

    ... technological collection techniques or other forms of information technology, e.g., permitting electronic... existence and validity of a legal entity before ATF approves the transfer of an NFA firearm to that...

  17. Experiment list: SRX122485 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available antibody=Atf3 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Santa Cruz || chip antibody ...catalog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100

  18. The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice.

    Science.gov (United States)

    Di Certo, Maria Grazia; Corbi, Nicoletta; Strimpakos, Georgios; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Guglielmotti, Angelo; Batassa, Enrico Maria; Pisani, Cinzia; Floridi, Aristide; Benassi, Barbara; Fanciulli, Maurizio; Magrelli, Armando; Mattei, Elisabetta; Passananti, Claudio

    2010-03-01

    The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.

  19. Steam Oxidation of FeCrAl and SiC in the Severe Accident Test Station (SATS)

    Energy Technology Data Exchange (ETDEWEB)

    Pint, Bruce A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Unocic, Kinga A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Terrani, Kurt A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-08-01

    Numerous research projects are directed towards developing accident tolerant fuel (ATF) concepts that will enhance safety margins in light water reactors (LWR) during severe accident scenarios. In the U.S. program, the high temperature steam oxidation performance of ATF solutions has been evaluated in the Severe Accident Test Station (SATS) at Oak Ridge National Laboratory (ORNL) since 2012 [1-3] and this facility continues to support those efforts in the ATF community. Compared to the current UO2/Zr-based alloy fuel system, alternative cladding materials can offer slower oxidation kinetics and a smaller enthalpy of oxidation that can significantly reduce the rate of heat and hydrogen generation in the core during a coolant-limited severe accident [4-5]. Thus, steam oxidation behavior is a key aspect of the evaluation of ATF concepts. This report summarizes recent work to measure steam oxidation kinetics of FeCrAl and SiC specimens in the SATS.

  20. Sequence Classification: 891376 [

    Lifescience Database Archive (English)

    Full Text Available l acetyltransferase, may play a role in steroid detoxification; forms volatile esters during fermentation, which is important in brew...ing; Atf2p || http://www.ncbi.nlm.nih.gov/protein/6321616 ...

  1. Signaling pathways in PACAP regulation of VIP gene expression in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Falktoft, Birgitte; Georg, Birgitte; Fahrenkrug, Jan

    2009-01-01

    0126 attenuated the VIP mRNA expression by 93%, 58%, 58% and 40%, respectively. PACAP modulated the phosphorylation of ERK1/2 (pERK1/2) and CREB/ATF-1 (pCREB/ATF-1) concomitant with a translocation of PKA to the nucleus. Inhibition of conventional PKC isoforms and MEK1/2 completely abolished pERK1...

  2. Signaling pathways in PACAP regulation of VIP gene expression in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Falktoft, B.; Georg, B.; Fahrenkrug, J.

    2009-01-01

    0126 attenuated the VIP mRNA expression by 93%. 58%, 58% and 40%, respectively. PACAP modulated the phosphorylation of ERK1/2 (pERK1/2) and CREB/ATF-1 (pCREB/ATF-1) concomitant with a translocation of PKA to the nucleus. Inhibition of conventional PKC isoforms and MEK1/2 completely abolished pERK1...

  3. Present Status And First Results of the Final Focus Beam Line at the KEK Accelerator Test Facility

    Energy Technology Data Exchange (ETDEWEB)

    Bambade, P.; /Orsay /KEK, Tsukuba; Alabau Pons, M.; /Valencia U., IFIC; Amann, J.; /SLAC; Angal-Kalinin, D.; /Daresbury; Apsimon, R.; /Oxford U., JAI; Araki, S.; Aryshev, A.; /KEK, Tsukuba; Bai, S.; /Beijing, Inst. High Energy Phys.; Bellomo, P.; /SLAC; Bett, D.; /Oxford U., JAI; Blair, G.; /Royal Holloway, U. of London; Bolzon, B.; /Savoie U.; Boogert, S.; Boorman, G.; /Royal Holloway, U. of London; Burrows, P.N.; Christian, G.; Coe, P.; Constance, B.; /Oxford U., JAI; Delahaye, Jean-Pierre; /CERN; Deacon, L.; /Royal Holloway, U. of London; Elsen, E.; /DESY /Valencia U., IFIC /KEK, Tsukuba /Beijing, Inst. High Energy Phys. /Savoie U. /Fermilab /Ecole Polytechnique /KEK, Tsukuba /Kyungpook Natl. U. /KEK, Tsukuba /Pohang Accelerator Lab. /Kyoto U., Inst. Chem. Res. /Savoie U. /Daresbury /Tokyo U. /Royal Holloway, U. of London /Kyungpook Natl. U. /Pohang Accelerator Lab. /Tokyo U. /KEK, Tsukuba /SLAC /University Coll. London /KEK, Tsukuba /SLAC /Royal Holloway, U. of London /KEK, Tsukuba /Tokyo U. /SLAC /Tohoku U. /KEK, Tsukuba /Tokyo U. /Pohang Accelerator Lab. /Brookhaven /SLAC /Oxford U., JAI /SLAC /Orsay /KEK, Tsukuba /Oxford U., JAI /Orsay /Fermilab /Tohoku U. /Manchester U. /CERN /SLAC /Tokyo U. /KEK, Tsukuba /Oxford U., JAI /Hiroshima U. /KEK, Tsukuba /CERN /KEK, Tsukuba /Oxford U., JAI /Ecole Polytechnique /SLAC /Oxford U., JAI /Fermilab /SLAC /Liverpool U. /SLAC /Tokyo U. /SLAC /Tokyo U. /KEK, Tsukuba /SLAC /CERN

    2011-11-11

    ATF2 is a final-focus test beam line which aims to focus the low emittance beam from the ATF damping ring to a vertical size of about 37 nm and to demonstrate nanometer level beam stability. Several advanced beam diagnostics and feedback tools are used. In December 2008, construction and installation were completed and beam commissioning started, supported by an international team of Asian, European, and U.S. scientists. The present status and first results are described.

  4. STELLA Experiment - Microbunch Diagnostic

    Energy Technology Data Exchange (ETDEWEB)

    He, P.; Liu, Y.; Cline, D. B.; Babzien, M.; Gallardo, J. C.; Kusche, K. P.; Pogorelsky, I. V.; Skaritka, J.; van Steenbergen, A.; Yakimenko, V.; Kimura, W. D.

    1998-07-01

    A microbunch diagnostic system is built at the Accelerator Test Facility (ATF) of Brookhaven National Laboratory for monitoring microbunches (10-fs bunch length) produced by the Inverse Free Electron Laser accelerator in Staged Electron Laser Acceleration experiment. It is similar to one already demonstrated at the ATF. With greatly improved beam optics conditions higher order harmonic coherent transition radiation will be measurable to determine the microbunch length and shape.

  5. Present status and first results of the final focus beam line at the KEK Accelerator Test Facility

    CERN Document Server

    Bambade, P; Amann, J; Angal-Kalinin, D; Apsimon, R; Araki, S; Aryshev, A; Bai, S; Bellomo, P; Bett, D; Blair, G; Bolzon, B; Boogert, S; Boorman, G; Burrows, P N; Christian, G; Coe, P; Constance, B; Delahaye, Jean-Pierre; Deacon, L; Elsen, E; Faus-Golfe, A; Fukuda, M; Gao, J; Geffroy, N; Gianfelice-Wendt, E; Guler, H; Hayano, H; Heo, A -Y; Honda, Y; Huang, J Y; Hwang, W H; Iwashita, Y; Jeremie, A; Jones, J; Kamiya, Y; Karataev, P; Kim, E -S; Kim, H -S; Kim, S H; Komamiya, S; Kubo, K; Kume, T; Kuroda, S; Lam, B; Lyapin, A; Masuzawa, M; McCormick, D; Molloy, S; Naito, T; Nakamura, T; Nelson, J; Okamoto, D; Okugi, T; Oroku, M; Park, Y J; Parker, B; Paterson, E; Perry, C; Pivi, M; Raubenheimer, T; Renier, Y; Resta-Lopez, J; Rimbault, C; Ross, M; Sanuki, T; Scarfe, A; Schulte, D; Seryi, A; Spencer, C; Suehara, T; Sugahara, R; Swinson, C; Takahashi, T; Tauchi, T; Terunuma, N; Tomas, R; Urakawa, J; Urner, D; Verderi, M; Wang, M -H; Warden, M; Wendt, M; White, G; Wittmer, W; Wolski, A; Woodley, M; Yamaguchi, Y; Yamanaka, T; Yan, Y; Yoda, H; Yokoya, K; Zhou, F; Zimmermann, F

    2010-01-01

    ATF2 is a final-focus test beam line which aims to focus the low emittance beam from the ATF damping ring to a vertical size of about 37 nm and to demonstrate nanometer level beam stability. Several advanced beam diagnostics and feedback tools are used. In December 2008, construction and installation were completed and beam commissioning started, supported by an international team of Asian, European, and U.S. scientists. The present status and first results are described.

  6. Experiment list: SRX187193 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX187193 mm9 TFs and others Batf Blood Th17 NA 16949726,88.8,19.8,1387 GSM1004788:... SL3313; Mus musculus; ChIP-Seq source_name=Th17 in vitro || genotype=B-ATF ko || control=SL3314 || factor=B...-ATF || application=ChIP-Seq || cell type=Th17 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/eachData/bw/SR

  7. A Novel Gene Delivery System Targeting Urokinase Receptor

    Institute of Scientific and Technical Information of China (English)

    Xing-Hui SUN; Li TAN; Chun-Yang LI; Chang TONG; Jin FAN; Ping LI; Yun-Song ZHU

    2004-01-01

    Recombinant proteins that combine different functions required for cell targeting and intracellular delivery of DNA present an attractive approach for the development of nonviral gene delivery vectors. Here, we described a novel protein termed ATF-lys10 which facilitated cell-specific gene transfer via receptor-mediated endocytosis. ATF-lys 10 was composed of the amino-terminal fragment of urokinase and ten lysines at the carboxyl terminus. Bacterially expressed ATF-lys 10 protein existed in soluble form, and had antigenicity of human urokinase. Purified ATF-lys 10 specifically bound to uPAR-expressing cells and formed protein-DNA complexes with plasmid pGL3-control. After neutralization of excess negative charge with poly-L-lysine, these complexes served as a specific gene delivery vector for uPAR-expressing cells. Lysosomotropic compounds, such as chloroquine, drastically increased the ATF-lysl0 mediated gene delivery efficiency. Our results suggest that the recombinant protein ATF-lys 10 with the properties of DNA binding and tumor cell targeting represents a promising method for gene transfer and expression in tumor cells.

  8. Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification.

    Science.gov (United States)

    Duan, Xiao-Hui; Chang, Jin-Rui; Zhang, Jing; Zhang, Bao-Hong; Li, Yu-Lin; Teng, Xu; Zhu, Yi; Du, Jie; Tang, Chao-Shu; Qi, Yong-Fen

    2013-09-01

    Our previous work reported that endoplasmic reticulum stress (ERS)-mediated apoptosis was activated during vascular calcification (VC). Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis. However, whether ATF4 is involved in ERS-mediated apoptosis contributing to VC remains unclear. In the present study, in vivo VC was induced in rats by administering vitamin D3 plus nicotine. Vascular smooth muscle cell (VSMC) calcification in vitro was induced by incubation in calcifying media containing β-glycerophosphate and CaCl2. ERS inhibitors taurine or 4-phenylbutyric acid attenuated ERS and VSMC apoptosis in calcified rat arteries, reduced calcification and retarded the VSMC contractile phenotype transforming into an osteoblast-like phenotype in vivo. Inhibition of ERS retarded the VSMC phenotypic transition into an osteoblast-like cell phenotype and reduced VSMC calcification and apoptosis in vitro. Interestingly, ATF4 was activated in calcified aortas and calcified VSMCs in vitro. ATF4 knockdown attenuated ERS-induced apoptosis in calcified VSMCs. ATF4 deficiency blocked VSMC calcification and negatively regulated the osteoblast phenotypic transition of VSMCs in vitro. Our results demonstrate that ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to VC.

  9. SRAP polymorphisms associated with superior freezing tolerance in alfalfa (Medicago sativa spp. sativa).

    Science.gov (United States)

    Castonguay, Yves; Cloutier, Jean; Bertrand, Annick; Michaud, Réal; Laberge, Serge

    2010-05-01

    Sequence-related amplified polymorphism (SRAP) analysis was used to uncover genetic polymorphisms among alfalfa populations recurrently selected for superior tolerance to freezing (TF populations). Bulk DNA samples (45 plants/bulk) from each of the cultivar Apica (ATF0), and populations ATF2, ATF4, ATF5, and ATF6 were evaluated with 42 different SRAP primer pairs. Several polymorphisms that progressively intensified or decreased with the number of recurrent cycles were identified. Four positive polymorphisms (F10-R14, Me4-R8, F10-R8 and F11-R9) that, respectively, yielded 540-, 359-, 213-, and 180-bp fragments were selected for further analysis. SRAP amplifications with genotypes within ATF populations confirmed that the polymorphisms identified with bulk DNA samples were reflecting changes in the frequency of their occurrence in response to selection. In addition, the number of genotypes cumulating multiple polymorphisms markedly increased in response to recurrent selection. Independent segregation of the four SRAP polymorphisms suggests location at unlinked loci. Homology search gave matches with BAC clones from syntenic Medicago truncatula for the four SRAP fragments. Analysis of the relationship with low temperature tolerance showed that multiple SRAP polymorphisms are more frequent in genotypes that maintain superior regrowth after freezing. These results show that SRAP analysis of bulk DNA samples from recurrent selections is an effective approach for the identification of genetic polymorphisms associated with quantitative traits in allogamous species. These polymorphisms could be useful tools for indirect selection of freezing tolerance in alfalfa.

  10. Convective Heat Transfer Coefficients of Automatic Transmission Fluid Jets with Implications for Electric Machine Thermal Management: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Bennion, Kevin; Moreno, Gilberto

    2015-09-29

    Thermal management for electric machines (motors/ generators) is important as the automotive industry continues to transition to more electrically dominant vehicle propulsion systems. Cooling of the electric machine(s) in some electric vehicle traction drive applications is accomplished by impinging automatic transmission fluid (ATF) jets onto the machine's copper windings. In this study, we provide the results of experiments characterizing the thermal performance of ATF jets on surfaces representative of windings, using Ford's Mercon LV ATF. Experiments were carried out at various ATF temperatures and jet velocities to quantify the influence of these parameters on heat transfer coefficients. Fluid temperatures were varied from 50 degrees C to 90 degrees C to encompass potential operating temperatures within an automotive transaxle environment. The jet nozzle velocities were varied from 0.5 to 10 m/s. The experimental ATF heat transfer coefficient results provided in this report are a useful resource for understanding factors that influence the performance of ATF-based cooling systems for electric machines.

  11. Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone

    Science.gov (United States)

    Yu, Shibing; Franceschi, Renny T.; Luo, Min; Fan, Jie; Jiang, Di; Cao, Huiling; Kwon, Tae-Geon; Lai, Yumei; Zhang, Jian; Patrene, Kenneth; Hankenson, Kurt; Roodman, G. David; Xiao, Guozhi

    2009-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4). Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton. PMID:19851510

  12. Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.

    Directory of Open Access Journals (Sweden)

    Shibing Yu

    Full Text Available Parathyroid hormone (PTH is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4. Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton.

  13. Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer.

    Science.gov (United States)

    Huang, Jing; Qian, Weiping; Wang, Liya; Wu, Hui; Zhou, Hongyu; Wang, Andrew Yongqiang; Chen, Hongbo; Yang, Lily; Mao, Hui

    2016-01-01

    Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.

  14. Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.

    Science.gov (United States)

    Srivastava, Ritesh K; Li, Changzhao; Wang, Yong; Weng, Zhiping; Elmets, Craig A; Harrod, Kevin S; Deshane, Jessy S; Athar, Mohammad

    2016-10-01

    Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4(+/+) wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4(+/-) heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca(++) homeostasis. ATO induces Ca(++)-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca(++) homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic.

  15. A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis.

    Science.gov (United States)

    Bagheri-Yarmand, Rozita; Sinha, Krishna M; Gururaj, Anupama E; Ahmed, Zamal; Rizvi, Yasmeen Q; Huang, Su-Chen; Ladbury, John E; Bogler, Oliver; Williams, Michelle D; Cote, Gilbert J; Gagel, Robert F

    2015-05-01

    The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.

  16. Alternative approaches to plasma confinement

    Science.gov (United States)

    Roth, J. R.

    1978-01-01

    The paper discusses 20 plasma confinement schemes each representing an alternative to the tokamak fusion reactor. Attention is given to: (1) tokamak-like devices (TORMAC, Topolotron, and the Extrap concept), (2) stellarator-like devices (Torsatron and twisted-coil stellarators), (3) mirror machines (Astron and reversed-field devices, the 2XII B experiment, laser-heated solenoids, the LITE experiment, the Kaktus-Surmac concept), (4) bumpy tori (hot electron bumpy torus, toroidal minimum-B configurations), (5) electrostatically assisted confinement (electrostatically stuffed cusps and mirrors, electrostatically assisted toroidal confinement), (6) the Migma concept, and (7) wall-confined plasmas. The plasma parameters of the devices are presented and the advantages and disadvantages of each are listed.

  17. Design and Implementation of a 200kW, 28GHz gyrotron system for the Compact Toroidal Hybrid Experiment

    Science.gov (United States)

    Hartwell, G. J.; Knowlton, S. F.; Ennis, D. A.; Maurer, D. A.; Bigelow, T.

    2016-10-01

    The Compact Toroidal Hybrid (CTH) is an l = 2 , m = 5 torsatron/tokamak hybrid (R0 = 0.75 m, ap 0.2 m, and | B | supplement the existing 15 kW klystron system operating at the fundamental frequency; the latter will be used to initially generate the plasma. Ray-tracing calculations that guide the selection of launching position, antenna focal length, and beam-steering characteristics of the ECRH have been performed with the TRAVIS code [ 1 ] . The calculated absorption is up to 95.7% for vertically propagating rays, however, the absorption is more sensitive to magnetic field variations than for a side launch where the field gradient is tokamak-like. The design of the waveguide path and components for the top-launch scenario will be presented. This work is supported by U.S. Department of Energy Grant No. DE-FG02-00ER54610.

  18. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

    Directory of Open Access Journals (Sweden)

    Brooke M Baker

    Full Text Available Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt.

  19. In vacuum diamond sensor scanner for beam halo measurements in the beam line at the KEK Accelerator Test Facility

    Science.gov (United States)

    Liu, S.; Bogard, F.; Cornebise, P.; Faus-Golfe, A.; Fuster-Martínez, N.; Griesmayer, E.; Guler, H.; Kubytskyi, V.; Sylvia, C.; Tauchi, T.; Terunuma, N.; Bambade, P.

    2016-10-01

    The investigation of beam halo transverse distributions is important for the understanding of beam losses and the control of backgrounds in Future Linear Colliders (FLC). A novel in vacuum diamond sensor (DSv) scanner with four strips has been designed and developed for the investigation of the beam halo transverse distributions and also for the diagnostics of Compton recoil electrons after the interaction point (IP) of ATF2, a low energy (1.3 GeV) prototype of the final focus system for the ILC and CLIC linear collider projects. Using the DSv, a dynamic range of ∼106 has been successfully demonstrated and confirmed for the first time in simultaneous beam core (∼109 electrons) and beam halo (∼103 electrons) measurements at ATF2. This report presents the characterization, performance studies and tests of diamond sensors using an α source, as well as using the electron beams at PHIL, a low energy < 5 MeV photo-injector at LAL, and at ATF2. First beam halo measurement results using the DSv at ATF2 with different beam intensities and vacuum levels are also presented. Such measurements not only allow one to evaluate the different sources of beam halo generation but also to define the requirements for a suitable collimation system to be installed at ATF2, as well as to optimize its performance during future operation.

  20. A Taiwanese Propolis Derivative Induces Apoptosis through Inducing Endoplasmic Reticular Stress and Activating Transcription Factor-3 in Human Hepatoma Cells

    Directory of Open Access Journals (Sweden)

    Fat-Moon Suk

    2013-01-01

    Full Text Available Activating transcription factor-(ATF- 3, a stress-inducible transcription factor, is rapidly upregulated under various stress conditions and plays an important role in inducing cancer cell apoptosis. NBM-TP-007-GS-002 (GS-002 is a Taiwanese propolin G (PPG derivative. In this study, we examined the antitumor effects of GS-002 in human hepatoma Hep3B and HepG2 cells in vitro. First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners. Several main apoptotic indicators were found in GS-002-treated cells, such as the cleaved forms of caspase-3, caspase-9, and poly(ADP-ribose polymerase (PARP. GS-002 also induced endoplasmic reticular (ER stress as evidenced by increases in ER stress-responsive proteins including glucose-regulated protein 78 (GRP78, growth arrest- and DNA damage-inducible gene 153 (GADD153, phosphorylated eukaryotic initiation factor 2α (eIF2α, phosphorylated protein endoplasmic-reticular-resident kinase (PERK, and ATF-3. The induction of ATF-3 expression was mediated by mitogen-activated protein kinase (MAPK signaling pathways in GS-002-treated cells. Furthermore, we found that GS-002 induced more cell apoptosis in ATF-3-overexpressing cells. These results suggest that the induction of apoptosis by the propolis derivative, GS-002, is partially mediated through ER stress and ATF-3-dependent pathways, and GS-002 has the potential for development as an antitumor drug.

  1. Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Lale Ozcan

    2016-06-01

    Full Text Available Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4. As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR, represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.

  2. Measurement of impulse peak insertion loss from two acoustic test fixtures and four hearing protector conditions with an acoustic shock tube.

    Science.gov (United States)

    Murphy, William J; Fackler, Cameron J; Berger, Elliott H; Shaw, Peter B; Stergar, Mike

    2015-01-01

    Impulse peak insertion loss (IPIL) was studied with two acoustic test fixtures and four hearing protector conditions at the E-A-RCAL Laboratory. IPIL is the difference between the maximum estimated pressure for the open-ear condition and the maximum pressure measured when a hearing protector is placed on an acoustic test fixture (ATF). Two models of an ATF manufactured by the French-German Research Institute of Saint-Louis (ISL) were evaluated with high-level acoustic impulses created by an acoustic shock tube at levels of 134 decibels (dB), 150 dB, and 168 dB. The fixtures were identical except that the E-A-RCAL ISL fixture had ear canals that were 3 mm longer than the National Institute for Occupational Safety and Health (NIOSH) ISL fixture. Four hearing protection conditions were tested: Combat Arms earplug with the valve open, ETYPlugs ® earplug, TacticalPro headset, and a dual-protector ETYPlugs earplug with TacticalPro earmuff. The IPILs measured for the E-A-RCAL fixture were 1.4 dB greater than the National Institute for Occupational Safety and Health (NIOSH) ISL ATF. For the E-A-RCAL ISL ATF, the left ear IPIL was 2.0 dB greater than the right ear IPIL. For the NIOSH ATF, the right ear IPIL was 0.3 dB greater than the left ear IPIL.

  3. Submission of FeCrAl feedstock for support of AFC ATR-2 Irradiations

    Energy Technology Data Exchange (ETDEWEB)

    Field, Kevin G [ORNL; Barrett, Kristine E. [Idaho National Laboratory (INL); Sun, Zhiqian [ORNL; Yamamoto, Yukinori [ORNL

    2016-09-01

    The Advanced Test Reactor (ATR) is currently being used to test accident tolerant fuel (ATF) forms destined for commercial nuclear power plant deployment. One irradiation program using the ATR for ATF concepts, Accident Tolerant Fuel-2 (ATF-2), is a water loop irradiation test using miniaturized fuel pins as test articles. This complicated testing configuration requires a series of pre-test experiments and verification including a flowing loop autoclave test and a sensor qualification test (SQT) prior to full test train deployment within the ATR. In support of the ATF-2 irradiation program, Oak Ridge National Laboratory (ORNL) has supplied two different Generation II FeCrAl alloys in rod stock form to Idaho National Laboratory (INL). These rods will be machined into dummy pins for deployment in the autoclave test and SQT. Post-test analysis of the dummy pins will provide initial insight into the performance of Generation II FeCrAl alloys in the ATF-2 irradiation experiment as well as within a commercial nuclear reactor.

  4. Low viscosity automatic transmission fluids with enhanced friction durability

    Institute of Scientific and Technical Information of China (English)

    Kenji Yatsunami; Samuel H. Tersigni; TANG Hong- zhi; Lee D. Saathoff; Christopher S. Cleveland; Mark Jones

    2009-01-01

    This study focused on the development of a new low viscosity automatic transmission fluid (ATF) with enhanced friction durability to meet the needs of new step type automatic transmissions. Recent high fuel prices encourage increased efficiency in the driveline, including the transmission. Reduction in fluid viscosity and wider use of slip control in torque con-verter clutches are two ways to practically improve fuel efficiency. Increased torque and more shifting is seen with a variety of new transmission hardware platforms, such as wet starting clutches, dual clutches and seven - or eight - speed ATs.This suggests the need for enhanced levels of friction durability from the ATF. The new challenge from this hardware for the ATF formulator lies in the need to simultaneously meet the wear, friction durability and torque capacity requirements at low viscosity in a cost- effective manner. This report introduced a new low viscosity fluid that represents a different commercial ATF formulation style. The new chemistry employs a low viscosity for increased fuel economy, while easily doubling the friction durability of current conven-tional ATFs and offering higher torque and better EP.

  5. Fluoride removal from water using activated and MnO2-coated Tamarind Fruit (Tamarindus indica) shell: batch and column studies.

    Science.gov (United States)

    Sivasankar, V; Ramachandramoorthy, T; Chandramohan, A

    2010-05-15

    The present work is concerned with the defluoridation capacities of activated (ATFS) and MnO(2)-coated Tamarind Fruit Shell (MTFS), using batch and column sorption techniques. In the batch technique, the dynamics of fluoride sorption, with respect to pH, [F](o) and sorbent dose, was studied. The applicability of pseudo-first order for ATFS and Ritchie-second order for MTFS was observed. The kinetics data were found to fit well with Temkin isotherm for ATFS and Langmuir for MTFS. The interaction of co-ions in the defluoridation capacity of the sorbent was studied. Column experiments were carried out under a constant fluoride concentration of 2mg/l, flow rate and different bed depths. The capacities of the breakthrough and exhaustion points increased with increase in the bed depth for ATFS unlike MTFS. The Thomson model was applied to the column experimental results. The characterization of the sorbents, ATFS and MTFS, was done using the FTIR, SEM and XRD techniques.

  6. Economic Evaluation Guide for alternative transportation fuels

    Energy Technology Data Exchange (ETDEWEB)

    de Percin, D.; Werner, J.F. Jr.

    1992-01-01

    The production of this Economic Evaluation Guide is one activity of AVFCAP. The guide is intended for use by project managers and fleet operators in the public sector. Public fleets have been identified as one of the most likely areas where ATFs will first gain widespread use, because of existing and impending state and federal legislative mandates, as well as for practical reasons such as centralized servicing and refueling. The purpose of this guide is to provide balanced decision-support information to project managers who are considering conducting, or currently managing, ATF demonstration programs. Information for this guide was gathered as part of a related AVFCAP activity, the development of an Information Resource Database. Economic issues related to the development and implementation of ATF programs at the local government level are extremely complex, and require an analysis of federal policies and national and international economics that is generally beyond the scope of local government project managers. The intent of this guide is to examine the information available on the economic evaluation of ATFs, and identify key elements that will help local governments realistically assess the potential costs and savings of an ATF program. The guide also discusses how these various economic factors are related, and how local government priorities affect how different factors are weighed.

  7. Economic Evaluation Guide for alternative transportation fuels

    Energy Technology Data Exchange (ETDEWEB)

    de Percin, D.; Werner, J.F. Jr.

    1992-12-31

    The production of this Economic Evaluation Guide is one activity of AVFCAP. The guide is intended for use by project managers and fleet operators in the public sector. Public fleets have been identified as one of the most likely areas where ATFs will first gain widespread use, because of existing and impending state and federal legislative mandates, as well as for practical reasons such as centralized servicing and refueling. The purpose of this guide is to provide balanced decision-support information to project managers who are considering conducting, or currently managing, ATF demonstration programs. Information for this guide was gathered as part of a related AVFCAP activity, the development of an Information Resource Database. Economic issues related to the development and implementation of ATF programs at the local government level are extremely complex, and require an analysis of federal policies and national and international economics that is generally beyond the scope of local government project managers. The intent of this guide is to examine the information available on the economic evaluation of ATFs, and identify key elements that will help local governments realistically assess the potential costs and savings of an ATF program. The guide also discusses how these various economic factors are related, and how local government priorities affect how different factors are weighed.

  8. Measurement of impulse peak insertion loss from two acoustic test fixtures and four hearing protector conditions with an acoustic shock tube

    Directory of Open Access Journals (Sweden)

    William J Murphy

    2015-01-01

    Full Text Available Impulse peak insertion loss (IPIL was studied with two acoustic test fixtures and four hearing protector conditions at the E-A-RCAL Laboratory. IPIL is the difference between the maximum estimated pressure for the open-ear condition and the maximum pressure measured when a hearing protector is placed on an acoustic test fixture (ATF. Two models of an ATF manufactured by the French-German Research Institute of Saint-Louis (ISL were evaluated with high-level acoustic impulses created by an acoustic shock tube at levels of 134 decibels (dB, 150 dB, and 168 dB. The fixtures were identical except that the E-A-RCAL ISL fixture had ear canals that were 3 mm longer than the National Institute for Occupational Safety and Health (NIOSH ISL fixture. Four hearing protection conditions were tested: Combat Arms earplug with the valve open, ETYPlugs ® earplug, TacticalPro headset, and a dual-protector ETYPlugs earplug with TacticalPro earmuff. The IPILs measured for the E-A-RCAL fixture were 1.4 dB greater than the National Institute for Occupational Safety and Health (NIOSH ISL ATF. For the E-A-RCAL ISL ATF, the left ear IPIL was 2.0 dB greater than the right ear IPIL. For the NIOSH ATF, the right ear IPIL was 0.3 dB greater than the left ear IPIL.

  9. Submission of FeCrAl Feedstock for Support of AFC ATR-2 Irradiations

    Energy Technology Data Exchange (ETDEWEB)

    Field, Kevin G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Barrett, Kristine E. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Sun, Zhiqian [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Yamamoto, Yukinori [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-09-16

    The Advanced Test Reactor (ATR) is currently being used to test accident tolerant fuel (ATF) forms destined for commercial nuclear power plant deployment. One irradiation program using the ATR for ATF concepts, Accident Tolerant Fuel-2 (ATF-2), is a water loop irradiation test using miniaturized fuel pins as test articles. This complicated testing configuration requires a series of pre-test experiments and verification including a flowing loop autoclave test and a sensor qualification test (SQT) prior to full test train deployment within the ATR. In support of the ATF-2 irradiation program, Oak Ridge National Laboratory (ORNL) has supplied two different Generation II FeCrAl alloys in rod stock form to Idaho National Laboratory (INL). These rods will be machined into dummy pins for deployment in the autoclave test and SQT. Post-test analysis of the dummy pins will provide initial insight into the performance of Generation II FeCrAl alloys in the ATF-2 irradiation experiment as well as within a commercial nuclear reactor.

  10. The BNL Accelerator Test Facility and experimental program

    Energy Technology Data Exchange (ETDEWEB)

    Ben-Zvi, I. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States). Dept. of Physics

    1992-09-01

    The Accelerator Test Facility (ATF) at BNL is a users` facility for experiments in Accelerator and Beam Physics. The ATF provides high brightness electron beams and high-power laser pulses synchronized to the electron beam, suitable for studies of new methods of high-gradient acceleration and state-of-the-art Free-Electron Lasers. The electrons are produced by a laser photocathode rf gun and accelerated to 50 MeV by two traveling wave accelerator sections. The lasers include a 10 mJ, 10 ps ND:YAG laser and a 500 mJ, 10 to 100 ps C0{sub 2} laser. A number of users from National Laboratories, universities and industry take part in experiments at the ATF. The experimental program includes various laser acceleration schemes, Free-Electron Laser experiments and a program on the development of high-brightness electron beams. The ATF`s experimental program commenced in early 1991 at an energy of about 4 MeV. The full program, with 50 MeV and the high-power laser will begin operation this year.

  11. Thermal aging of melt-spun NdFeB magnetic powder in hydrogen

    Science.gov (United States)

    Pinkerton, Frederick E.; Balogh, Michael P.; Ellison, Nicole; Foto, Aldo; Sechan, Martin; Tessema, Misle M.; Thompson, Margarita P.

    2016-11-01

    High energy product neodymium-iron-boron (NdFeB) magnets are the premier candidate for demanding electrified vehicle traction motor applications. Injection molded (IM) or compression molded (CM) magnets made using NdFeB powders are promising routes to improve motor efficiency, cost, and manufacturability. However, IM and CM NdFeB magnets are susceptible to substantial thermal aging losses at motor operating temperatures when exposed to the automatic transmission fluid (ATF) used as a lubricant and cooling medium. The intrinsic coercivity Hci of NdFeB IM and CM magnets degrades by as much as 18% when aged for 1000 h in ATF at 150 °C, compared to a 3% loss when aged in air. Here we report aging studies of rapidly quenched NdFeB powder in air, ATF, and H2 gas. Expansion of the NdFeB crystal lattice in both ATF and H2 identified hydrogen dissociated from the ATF during aging and diffused into the primary NdFeB phase as the probable cause of the coercivity loss of IM and CM magnets.

  12. Understanding and modeling alternating tangential flow filtration for perfusion cell culture.

    Science.gov (United States)

    Kelly, William; Scully, Jennifer; Zhang, Di; Feng, Gang; Lavengood, Mathew; Condon, Jason; Knighton, John; Bhatia, Ravinder

    2014-01-01

    Alternating tangential flow (ATF) filtration has been used with success in the Biopharmaceutical industry as a lower shear technology for cell retention with perfusion cultures. The ATF system is different than tangential flow filtration; however, in that reverse flow is used once per cycle as a means to minimize fouling. Few studies have been reported in the literature that evaluates ATF and how key system variables affect the rate at which ATF filters foul. In this study, an experimental setup was devised that allowed for determination of the time it took for fouling to occur for given mammalian (PER.C6) cell culture cell densities and viabilities as permeate flow rate and antifoam concentration was varied. The experimental results indicate, in accordance with D'Arcy's law, that the average resistance to permeate flow (across a cycle of operation) increases as biological material deposits on the membrane. Scanning electron microscope images of the post-run filtration surface indicated that both cells and antifoam micelles deposit on the membrane. A unique mathematical model, based on the assumption that fouling was due to pore blockage from the cells and micelles in combination, was devised that allowed for estimation of sticking factors for the cells and the micelles on the membrane. This model was then used to accurately predict the increase in transmembane pressure during constant flux operation for an ATF cartridge used for perfusion cell culture.

  13. Employing libraries of zinc finger artificial transcription factors to screen for homologous recombination mutants in Arabidopsis.

    Science.gov (United States)

    Lindhout, Beatrice I; Pinas, Johan E; Hooykaas, Paul J J; van der Zaal, Bert J

    2006-11-01

    A library of genes for zinc finger artificial transcription factors (ZF-ATF) was generated by fusion of DNA sequences encoding three-finger Cys(2)His(2) ZF domains to the VP16 activation domain under the control of the promoter of the ribosomal protein gene RPS5A from Arabidopsis thaliana. After introduction of this library into an Arabidopsis homologous recombination (HR) indicator line, we selected primary transformants exhibiting multiple somatic recombination events. After PCR-mediated rescue of ZF sequences, reconstituted ZF-ATFs were re-introduced in the target line. In this manner, a ZF-ATF was identified that led to a 200-1000-fold increase in somatic HR (replicated in an independent second target line). A mutant plant line expressing the HR-inducing ZF-ATF exhibited increased resistance to the DNA-damaging agent bleomycin and was more sensitive to methyl methanesulfonate (MMS), a combination of traits not described previously. Our results demonstrate that the use of ZF-ATF pools is highly rewarding when screening for novel dominant phenotypes in Arabidopsis.

  14. Rapid ester biosynthesis screening reveals a high activity alcohol-O-acyltransferase (AATase) from tomato fruit.

    Science.gov (United States)

    Lin, Jyun-Liang; Zhu, Jie; Wheeldon, Ian

    2016-05-01

    Ethyl and acetate esters are naturally produced in various yeasts, plants, and bacteria. The biosynthetic pathways that produce these esters share a common reaction step, the condensation of acetyl/acyl-CoA with an alcohol by alcohol-O-acetyl/acyltransferase (AATase). Recent metabolic engineering efforts exploit AATase activity to produce fatty acid ethyl esters as potential diesel fuel replacements as well as short- and medium-chain volatile esters as fragrance and flavor compounds. These efforts have been limited by the lack of a rapid screen to quantify ester biosynthesis. Enzyme engineering efforts have also been limited by the lack of a high throughput screen for AATase activity. Here, we developed a high throughput assay for AATase activity and used this assay to discover a high activity AATase from tomato fruit, Solanum lycopersicum (Atf-S.l). Atf1-S.l exhibited broad specificity towards acyl-CoAs with chain length from C4 to C10 and was specific towards 1-pentanol. The AATase screen also revealed new acyl-CoA substrate specificities for Atf1, Atf2, Eht1, and Eeb1 from Saccharomyces cerevisiae, and Atf-C.m from melon fruit, Cucumis melo, thus increasing the pool of characterized AATases that can be used in ester biosynthesis of ester-based fragrance and flavor compounds as well as fatty acid ethyl ester biofuels.

  15. Constraints on the uplift mechanism of northern Tibet

    Science.gov (United States)

    Lu, Haijian; Fu, Bihong; Shi, Pilong; Ma, Yuanxu; Li, Haibing

    2016-11-01

    Enhanced latest Oligocene to present uplift of northern Tibet is manifest in a variety of geological records. However, the main controversy is how the crust came to be thickened. Theories seeking to explain the growth of northern Tibet include removal of the mantle lithosphere beneath Tibet and the cessation of fast motion on major strike-slip faults. To address this issue, we conducted a detailed paleomagnetic study in the central Kumkol basin, south of the Altyn Tagh fault (ATF). Combined with our previous study from the Janggalsay area, north of the ATF, magnetic declination data suggest fast strike-slip motion for the left-lateral ATF between 22 and 15 Ma. However, the fast motion along the ATF terminated between 15 and Tibet at ∼15 Ma. Our results argue in support of a Mid-Miocene transition in tectonic regime from extrusion to distributed shortening in northern Tibet and emphasize the role of the ATF in governing widespread and simultaneous uplift of northern Tibet.

  16. Micron-scale laser-wire scanner for the KEK Accelerator Test Facility extraction line

    Science.gov (United States)

    Boogert, Stewart T.; Blair, Grahame A.; Boorman, Gary; Bosco, Alessio; Deacon, Lawrence C.; Karataev, Pavel; Aryshev, Alexander; Fukuda, Masafumi; Terunuma, Nobihiro; Urakawa, Junji; Corner, Laura; Delerue, Nicolas; Foster, Brian; Howell, David; Newman, Myriam; Senanayake, Rohan; Walczak, Roman; Ganaway, Fred

    2010-12-01

    A laser-wire transverse electron beam size measurement system has been constructed and operated at the Accelerator Test Facility (ATF) extraction line at KEK. The construction of the system is described in detail along with the environment of the ATF related to the laser wire. A special set of electron beam optics was developed to generate an approximately 1μm vertical focus at the laser-wire location. The results of our operation at the ATF extraction line are presented, where a minimum rms electron beam size of 4.8±0.3μm was measured, and smaller electron beam sizes can be measured by developing the method further. The beam size at the laser-wire location was changed using quadrupoles and the resulting electron beam size measured, and vertical emittance extracted.

  17. Enhanced Accident Tolerant LWR Fuels: Metrics Development

    Energy Technology Data Exchange (ETDEWEB)

    Shannon Bragg-Sitton; Lori Braase; Rose Montgomery; Chris Stanek; Robert Montgomery; Lance Snead; Larry Ott; Mike Billone

    2013-09-01

    The Department of Energy (DOE) Fuel Cycle Research and Development (FCRD) Advanced Fuels Campaign (AFC) is conducting research and development on enhanced Accident Tolerant Fuels (ATF) for light water reactors (LWRs). This mission emphasizes the development of novel fuel and cladding concepts to replace the current zirconium alloy-uranium dioxide (UO2) fuel system. The overall mission of the ATF research is to develop advanced fuels/cladding with improved performance, reliability and safety characteristics during normal operations and accident conditions, while minimizing waste generation. The initial effort will focus on implementation in operating reactors or reactors with design certifications. To initiate the development of quantitative metrics for ATR, a LWR Enhanced Accident Tolerant Fuels Metrics Development Workshop was held in October 2012 in Germantown, MD. This paper summarizes the outcome of that workshop and the current status of metrics development for LWR ATF.

  18. Severe Accident Scoping Simulations of Accident Tolerant Fuel Concepts for BWRs

    Energy Technology Data Exchange (ETDEWEB)

    Robb, Kevin R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-08-01

    Accident-tolerant fuels (ATFs) are fuels and/or cladding that, in comparison with the standard uranium dioxide Zircaloy system, can tolerate loss of active cooling in the core for a considerably longer time period while maintaining or improving the fuel performance during normal operations [1]. It is important to note that the currently used uranium dioxide Zircaloy fuel system tolerates design basis accidents (and anticipated operational occurrences and normal operation) as prescribed by the US Nuclear Regulatory Commission. Previously, preliminary simulations of the plant response have been performed under a range of accident scenarios using various ATF cladding concepts and fully ceramic microencapsulated fuel. Design basis loss of coolant accidents (LOCAs) and station blackout (SBO) severe accidents were analyzed at Oak Ridge National Laboratory (ORNL) for boiling water reactors (BWRs) [2]. Researchers have investigated the effects of thermal conductivity on design basis accidents [3], investigated silicon carbide (SiC) cladding [4], as well as the effects of ATF concepts on the late stage accident progression [5]. These preliminary analyses were performed to provide initial insight into the possible improvements that ATF concepts could provide and to identify issues with respect to modeling ATF concepts. More recently, preliminary analyses for a range of ATF concepts have been evaluated internationally for LOCA and severe accident scenarios for the Chinese CPR1000 [6] and the South Korean OPR-1000 [7] pressurized water reactors (PWRs). In addition to these scoping studies, a common methodology and set of performance metrics were developed to compare and support prioritizing ATF concepts [8]. A proposed ATF concept is based on iron-chromium-aluminum alloys (FeCrAl) [9]. With respect to enhancing accident tolerance, FeCrAl alloys have substantially slower oxidation kinetics compared to the zirconium alloys typically employed. During a severe accident, Fe

  19. The chalcone 2'-hydroxy-4',5'-dimethoxychalcone activates death receptor 5 pathway and leads to apoptosis in human nonsmall cell lung cancer cells.

    Science.gov (United States)

    Yang, Lina; Su, Ling; Cao, Congmei; Xu, Linyan; Zhong, Diansheng; Xu, Lijia; Liu, Xiangguo

    2013-06-01

    Natural chalcones have been proved to inhibit cancer cells with therapeutic potential, but the underlying molecular mechanism is still largely unexplored. Here, we identified a novel chalcone, 2'-hydroxy-4',5'-dimethoxychalcone (HDMC) and demonstrated that HDMC induced apoptosis in various nonsmall cell lung cancer cells. Further study showed that HDMC elevated cellular reactive oxygen species (ROS) levels, thus inducing expressions of ATF4 and C/EBP homologous protein (CHOP). Then, death receptor 5 (DR5) was upregulated through ATF4-CHOP axis and eventually resulted in apoptosis. We also found that downregulation of c-FLIPL contributed to HDMC-induced apoptosis. In conclusion, HDMC induces apoptosis in human nonsmall cell lung cancer cells via activation of DR5 signaling pathway, and ROS-mediated ATF4-CHOP axis is involved in the process. Our results further supported the potential for HDMC to be developed as a new antitumor agent for cancer therapy or chemoprevention.

  20. Mitigating the effects of higher order multipole fields in the magnets of the Accelerator Test Facility 2 at KEK

    Institute of Scientific and Technical Information of China (English)

    BAI Sha; P. Bambade; WANG Dou; GAO Jie; M. Woodley; M. Masuzawa

    2012-01-01

    The ATF2 project is the final focus system prototype for the ILC and CLIC linear collider projects,with the purpose of reaching a 37nm vertical beam size at the interaction point.In the nanometer beam size regime,higher order multipoles in magnets become a crucial point for consideration.The strength and rotation angle of the ATF2 QEA magnets were reconstructed from the IHEP measurements and compared with the KEK ones to be identical.Based on the study of the skew multipoles sensitivity,we report on the analysis of the possible mitigation of the measured multipoles.A suggestion is given which will benefit the ATF2 present commissioning to reach the goal beam size,and also the reduced β optics in future.

  1. Fructanase and fructosyltransferase activity of non-Saccharomyces yeasts isolated from fermenting musts of Mezcal.

    Science.gov (United States)

    Arrizon, Javier; Morel, Sandrine; Gschaedler, Anne; Monsan, Pierre

    2012-04-01

    Fructanase and fructosyltransferase are interesting for the tequila process and prebiotics production (functional food industry). In this study, one hundred thirty non-Saccharomyces yeasts isolated from "Mezcal de Oaxaca" were screened for fructanase and fructosyltransferase activity. On solid medium, fifty isolates grew on Agave tequilana fructans (ATF), inulin or levan. In liquid media, inulin and ATF induced fructanase activities of between 0.02 and 0.27U/ml depending of yeast isolate. High fructanase activity on sucrose was observed for Kluyveromyces marxianus and Torulaspora delbrueckii, while the highest fructanase activity on inulin and ATF was observed for Issatchenkia orientalis, Cryptococcus albidus, and Candida apicola. Zygosaccharomyces bisporus and Candida boidinii had a high hydrolytic activity on levan. Sixteen yeasts belonging to K. marxianus, T. delbrueckii and C. apicola species were positive for fructosyltransferase activity. Mezcal microbiota proved to showed to be a source for new fructanase and fructosyltransferases with potential application in the tequila and food industry.

  2. A sustained deficiency of mitochondrial respiratory complex III induces an apoptotic cell death through the p53-mediated inhibition of pro-survival activities of the activating transcription factor 4.

    Science.gov (United States)

    Evstafieva, A G; Garaeva, A A; Khutornenko, A A; Klepikova, A V; Logacheva, M D; Penin, A A; Novakovsky, G E; Kovaleva, I E; Chumakov, P M

    2014-11-06

    Generation of energy in mitochondria is subjected to physiological regulation at many levels, and its malfunction may result in mitochondrial diseases. Mitochondrial dysfunction is associated with different environmental influences or certain genetic conditions, and can be artificially induced by inhibitors acting at different steps of the mitochondrial electron transport chain (ETC). We found that a short-term (5 h) inhibition of ETC complex III with myxothiazol results in the phosphorylation of translation initiation factor eIF2α and upregulation of mRNA for the activating transcription factor 4 (ATF4) and several ATF4-regulated genes. The changes are characteristic for the adaptive integrated stress response (ISR), which is known to be triggered by unfolded proteins, nutrient and metabolic deficiency, and mitochondrial dysfunctions. However, after a prolonged incubation with myxothiazol (13-17 h), levels of ATF4 mRNA and ATF4-regulated transcripts were found substantially suppressed. The suppression was dependent on the p53 response, which is triggered by the impairment of the complex III-dependent de novo biosynthesis of pyrimidines by mitochondrial dihydroorotate dehydrogenase. The initial adaptive induction of ATF4/ISR acted to promote viability of cells by attenuating apoptosis. In contrast, the induction of p53 upon a sustained inhibition of ETC complex III produced a pro-apoptotic effect, which was additionally stimulated by the p53-mediated abrogation of the pro-survival activities of the ISR. Interestingly, a sustained inhibition of ETC complex I by piericidine did not induce the p53 response and stably maintained the pro-survival activation of ATF4/ISR. We conclude that a downregulation of mitochondrial ETC generally induces adaptive pro-survival responses, which are specifically abrogated by the suicidal p53 response triggered by the genetic risks of the pyrimidine nucleotide deficiency.

  3. Prevention of Paclitaxel-induced allodynia by Minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats

    Directory of Open Access Journals (Sweden)

    Xin Wen-Jun

    2010-11-01

    Full Text Available Abstract Background Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg in rats, but the mechanism is still unclear. Results Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3 in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats. Conclusions Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel

  4. Multiple modes of chromatin configuration at natural meiotic recombination hot spots in fission yeast.

    Science.gov (United States)

    Hirota, Kouji; Steiner, Walter W; Shibata, Takehiko; Ohta, Kunihiro

    2007-11-01

    The ade6-M26 meiotic recombination hot spot of fission yeast is defined by a cyclic AMP-responsive element (CRE)-like heptanucleotide sequence, 5'-ATGACGT-3', which acts as a binding site for the Atf1/Pcr1 heterodimeric transcription factor required for hot spot activation. We previously demonstrated that the local chromatin around the M26 sequence motif alters to exhibit higher sensitivity to micrococcal nuclease before the initiation of meiotic recombination. In this study, we have examined whether or not such alterations in chromatin occur at natural meiotic DNA double-strand break (DSB) sites in Schizosaccharomyces pombe. At one of the most prominent DSB sites, mbs1 (meiotic break site 1), the chromatin structure has a constitutively accessible configuration at or near the DSB sites. The establishment of the open chromatin state and DSB formation are independent of the CRE-binding transcription factor, Atf1. Analysis of the chromatin configuration at CRE-dependent DSB sites revealed both differences from and similarities to mbs1. For example, the tdh1+ locus, which harbors a CRE consensus sequence near the DSB site, shows a meiotically induced open chromatin configuration, similar to ade6-M26. In contrast, the cds1+ locus is similar to mbs1 in that it exhibits a constitutive open configuration. Importantly, Atf1 is required for the open chromatin formation in both tdh1+ and cds1+. These results suggest that CRE-dependent meiotic chromatin changes are intrinsic processes related to DSB formation in fission yeast meiosis. In addition, the results suggest that the chromatin configuration in natural meiotic recombination hot spots can be classified into at least three distinct categories: (i) an Atf1-CRE-independent constitutively open chromatin configuration, (ii) an Atf1-CRE-dependent meiotically induced open chromatin configuration, and (iii) an Atf1-CRE-dependent constitutively open chromatin configuration.

  5. Zinc finger artificial transcription factor-based nearest inactive analogue/nearest active analogue strategy used for the identification of plant genes controlling homologous recombination.

    Science.gov (United States)

    Jia, Qi; van Verk, Marcel C; Pinas, Johan E; Lindhout, Beatrice I; Hooykaas, Paul J J; van der Zaal, Bert J

    2013-12-01

    In previous work, we selected a particular transcription factor, designated VP16-HRU, from a pool of zinc finger artificial transcription factors (ZF-ATFs) used for genome interrogation. When expressed in Arabidopsis thaliana under control of the ribosomal protein S5A promoter, the RPS5A::VP16-HRU construct led to a 200- to 300-fold increase in the frequency of somatic intrachromosomal homologous recombination (iHR). Because the expression of each ZF-ATF leads to a large number of transcriptional changes, we designed a strategy employing a collection of structurally similar ZF-ATFs to filter out the transcriptional changes relevant to the phenotype by deep sequencing. In that manner, 30 transcripts were found to be consistently induced in plants with enhanced homologous recombination (HR). For 25 of the cognate genes, their effect on the HR process was assessed using cDNA/gDNA expression constructs. For three genes, ectopic expression indeed led to enhanced iHR frequencies, albeit much lower than the frequency observed when a HR-inducing ZF-ATF was present. Altogether, our data demonstrate that despite the large number of transcriptional changes brought about by individual ZF-ATFs, causal changes can be identified. In our case, the picture emerged that a natural regulatory switch for iHR does not exist but that ZF-ATFs-like VP16-HRU act as an ectopic master switch, orchestrating the timely expression of a set of plant genes that each by themselves only have modest effects, but when acting together support an extremely high iHR frequency.

  6. 基于单片机控制的数字温度计的设计%Design of digital thermometer based on microcontroller

    Institute of Scientific and Technical Information of China (English)

    胡明钦

    2011-01-01

    Aiming at the requirement of high-precision temperature measurement on most practical application occasions, this paper presented a design scheme of high-precision thermometer based on ATF1504 and smallest system of single-chip computer and adopted by same accuracy frequency measurement technique. In this design, ATF1504 chip is as a programmable logic device, and NTC (Negative Temperature Coefficient)is as temperature sensor. The small accuracy frequency measurement technique is adopted in the thermometer using ATF1504 chip and single-chip computer, which realized temperature precision measurement The experiment results show that the measurement temperature relative error of the designed thermometer is less than 0.3% . The experiments on most practical application occasions show that the thermometer possesses stable operation and high reliability.%基于实际应用中许多场合对温度高精度测量的需求,利用ATF1504芯片与单片机最小系统,采用等精度频率测量技术,设计了一款高精度数字温度计.该方案采用ATF1504芯片作为可编程逻辑器件,以高灵敏度负温度系数热敏电阻为温度传感器.利用ATF1504芯片与单片机配合完成待测信号频率的精确测量,从而实现温度的精确测量.实验数据表明该温度计的测温相对误差小于0.3%.

  7. A Scoping Analysis Of The Impact Of SiC Cladding On Late-Phase Accident Progression Involving Core–Concrete Interaction

    Energy Technology Data Exchange (ETDEWEB)

    Farmer, M. T. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-11-01

    The overall objective of the current work is to carry out a scoping analysis to determine the impact of ATF on late phase accident progression; in particular, the molten core-concrete interaction portion of the sequence that occurs after the core debris fails the reactor vessel and relocates into containment. This additional study augments previous work by including kinetic effects that govern chemical reaction rates during core-concrete interaction. The specific ATF considered as part of this study is SiC-clad UO2.

  8. Entstehung, Abbau und potentielle Verlustquellen wertgebender Aromen während der Produktion von Weizenbieren

    OpenAIRE

    Schneiderbanger, Hubertus Josef

    2016-01-01

    Schwerpunkt der Arbeit war der Einfluss verschiedener Hefestämme und Technologien auf das Aromaspektrum von Weizenbieren. Die Bildung von Aromakomponenten wurde u.a. durch Genexpressionsmessungen der kommerziell am häufigsten verwendeten Hefestämme untersucht. Hierfür wurden die Gene ATF1, ATF2, IAH1, BAT1 und PAD1 getestet. Ein weiterer Aspekt war die Flüchtigkeit von Aromakomponenten im Hinblick auf Verluste während der Gärung. Diese Arbeit berücksichtigt den Aufbau von wertgebenden Aromen ...

  9. Análisis del ciclo de vida del desguace de vehículos

    OpenAIRE

    2011-01-01

    Ponencia presentada en el XV Congreso Internacional de Ingeniería de Proyectos celebrado en Huesca, 6-8 de julio de 2011 In Spain, the End-of-Life of vehicles is mainly determined by three agents: Authorized Treatment Facilities (ATFs), shredding plants and dense media plants. The work method that those agents use defines the final fate –reuse, recycling, recuperation or disposal into landfills– of the waste coming from the vehicle. In the case of ATFs, the most common model in Spain is...

  10. Estimativa da degradabilidade ruminal de quatro genótipos de sorgo (Sorghum bicolor (L. Moench utilizando a técnica in situ - DOI: 10.4025/actascianimsci.v27i4.1150 Estimation of ruminal degradability of four genotypes of sorghum (Sorghum bicolor (L. Moench using in situ technique - DOI: 10.4025/actascianimsci.v27i4.1150

    Directory of Open Access Journals (Sweden)

    Eloísa de Oliveira Simões Saliba

    2005-03-01

    Full Text Available O experimento foi conduzido com o objetivo de avaliar a degradabilidade in situ da matéria seca (MS, da fibra em detergente neutro (FDN e da fibra em detergente ácido (FDA do material original de quatro genótipos de sorgo (ATF53*9929036; ATF54*9929036; CMSXS217*9929012 e VOLUMAX. Foram utilizadas 4 vacas Holandesas providas de fistula ruminal alimentadas com silagem de sorgo “ad libitun” e dois quilos de concentrado. O delineamento experimental foi o de blocos inteiramente ao acaso, com quatro repetições (animais, em arranjo de parcelas subdivididas. Os genótipos constituíram as parcelas e os tempos de digestão as sub-parcelas. O genótipo VOLUMAX foi o que apresentou a maior degradabilidade efetiva (DE da MS (56,22; 53,35 e 50,90% em relação aos demais em todas as taxas de passagem (2, 5 e 8%/h respectivamente e os genótipos ATF53*992903 e ATF54*9929036 obtiveram a maior DE da FDN (32,17 e 33,47%, respectivamente e FDA (34,81 e 35,50%, respectivamente para uma taxa de passagem de 2%/hThis experiment was carried out to evaluate “in situ” degradability of dry matter, neutral detergent fiber (NDF and acid detergent fiber (ADF of four sorghum genotypes (ATF53*9929036; ATF54*9929036; 217*9929012 and VOLUMAX. Four Holstein cows with ruminal fistula were fed on sorghum silage “ad libitum”, and 2.0 kg of concentrate. The animals were alloted in a randomized block design, with four replicates, in a split plot arrangement. The genotypes were considered the parcels and the incubation time the sub-parcels. The higher effective dry matter degradability were found in VOLUMAX genotype, (56.22; 53.35 and 50.90% for all passage rates, (2; 5 and 8%/h, respectively. The genotypes ATF53*992903 and ATF54*9929036 showed higher NDF effective degradability, 32.17 and 33.47% respectively, and ADF effective degradability, 34.81 and 35.50%, at 2%/h passage rate

  11. Westinghouse accident tolerant fuel program. Current results and future plans

    Energy Technology Data Exchange (ETDEWEB)

    Ray, Sumit; Xu, Peng; Lahoda, Edward; Hallstadius, Lars; Boylan, Frank [Westinghouse Electric Company LLC, Hopkins, SC (United States)

    2016-07-15

    This paper discusses the current status, results from initial tests, as well as the future direction of the Westinghouse's Accident Tolerant Fuel (ATF) program. The current preliminary testing is addressed that is being performed on these samples at the Massachusetts Institute of Technology (MIT) test reactor, initial results from these tests, as well as the technical learning from these test results. In the Westinghouse ATF approach, higher density pellets play a significant role in the development of an integrated fuel system.

  12. Propagation of a beam halo in accelerator test facility 2 at KEK

    Institute of Scientific and Technical Information of China (English)

    BAI Sha; P.Bambade; GAO Jie

    2013-01-01

    The beam halo is a major issue for interaction region (IR) backgrounds at many colliders,for example,future linear colliders,B factories,and also it is an important problem at ATF2.In this paper,we report on the halo propagation along the ATF2 beam line with realistic apertures,the nonlinear optics influence on the increasing number of halo particles input is analyzed,and the transmitted halo particles distribution just before the last BPM is then described,the results from which will benefit the Compton recoil electrons measurement.

  13. Performance Assessment of Passive Hearing Protection Devices

    Science.gov (United States)

    2014-10-24

    the 170 dB SPL noise level 30 cm 30 cm Distance variable en fonction de la pression Distance between the explosive and the ATF 10...the MATLAB programming language by Mathworks™. For each condition the subject fit him/herself with the appropriate hearing protector according to the

  14. A laser-wire system for the International Linear Collider

    Indian Academy of Sciences (India)

    Nicolas Delerue; Sudhir Dixit; Fred Gannaway; David Howell; Myriam Qurshi; Grahame Blair; Stewart Boogert; Gary Boorman; Chafik Driouichi; Lawerence Deacon; Alexander Aryshev; Pavel Karataev; Nobuhiro Terunnuma; Junji urakawa; Axel Brachmann; Joe Frisch; Marc Ross

    2007-12-01

    A new laser-wire has been installed in the extraction line of the ATF at KEK. It aims at demonstrating that laser-wires can be used to measure micrometre scale beam size. In parallel, studies have been made to specify a laser suitable for the ILC laser-wires.

  15. 75 FR 80847 - Agency Information Collection Activities: Proposed Collection; Comments Requested

    Science.gov (United States)

    2010-12-23

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF JUSTICE... Tax-Exempt Transfer of Firearm and Registration to Special Occupational Taxpayer. The Department of Justice (DOJ), Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF) will submit the...

  16. 78 FR 75375 - Agency Information Collection Activities; Proposed Collection; Comments Requested: Application...

    Science.gov (United States)

    2013-12-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau... Collection; Comments Requested: Application for Tax Paid Transfer and Registration of Firearm ACTION: 60-Day Notice. The Department of Justice (DOJ), Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF),...

  17. 78 FR 75374 - Agency Information Collection Activities; Proposed Collection; Comments Requested:Application for...

    Science.gov (United States)

    2013-12-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau... Collection; Comments Requested:Application for Tax Exempt Transfer and Registration of Firearm ACTION: 60-Day Notice. The Department of Justice (DOJ), Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF),...

  18. Reinstate the Damaged VEGF Signaling Pathway with VEGF-activating Transcription Factor

    Institute of Scientific and Technical Information of China (English)

    Yao-guo Yang; Heng Guan; Chang-wei Liu; Yong-jun Li

    2009-01-01

    Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor(VEGF-ATF)on the VEGF signaling pathway in diabetes mellitus.Methods Totally,20 C57BL/6 mice fed with high fat diet was induced into diabetes mellitus.Ten diabetes mellitus mice received a lower limb muscle injection with VEGF-ATF plasmid,and another ten were as control.VEGF-ATF is an engineered transcription factor designed to increase VEGF expression.Three days later,mice were sacrificed and the injected gastrocnemius was used for analysis.VEGF mRNA and protein expressions were examined by real-time PCR and ELISA respectively.VEGF receptor 2 mRNA expression was tested with RT-PCR.Phosphorylated Akt,Akt,endothelial nitric oxide synthase(eNOS),and phosphorylated eNOS were assessed by western blot.Results At 3 days post-injection,in mice with diabetes mellitus,VEGF gene transfer increased VEGF mRNA copies and VEGF protein expression in injected muscles compared with control;and reinstated the impaired VEGF signaling pathway with increasing the ratios of phosphorylated Akt/Akt and phosphorylated eNOS/eNOS.However,it did not affect the expression of VEGF receptor 2 mRNA.Conclusion Gene transfer with VEGF-ATF is able to reinstate the impaired VEGF downstream pathway,and potentially promote therapeutic angiogenesis in mice with diabetes mcllitus.

  19. 75 FR 44173 - Implementation of the USA PATRIOT Improvement and Reauthorization Act of 2005 Regarding...

    Science.gov (United States)

    2010-07-28

    ..., and Explosives, U.S. Department of Justice, 99 New York Avenue, NE., Washington, DC 20226; Attn: ATF... Explosives; U.S. Department of Justice; ] 99 New York Avenue, NE., Washington, DC 20226, telephone (202) 648... the years have established that organized crime has been involved in the diversion of legal...

  20. Proceedings of the Fiber Optics in the Nuclear Environment Symposium 25-27 March 1980. Volume II. Radiation Physics,

    Science.gov (United States)

    1980-04-30

    emphasis on systems for transmitting nuclear device diagnostic data during, or shortly after, a nuclear explosion . This interest has required...Corp. A1rN: YCPT D. Bartel ATN: T. Neighbors ATTN: YCD E. Brininstool ATfI: ¥CD R. Spray Bell Telephone Labs ATTN: YCP H. Staubs ATTN: J. Fleming

  1. Characterization of ionizing radiation-induced unfolded protein response in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ju; Lee, Yoon Jin; Kang, Seong Man [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-04-15

    Misfolded or unfolded proteins within the endoplasmic reticulum (ER stress), viral infection, or amino acid deprivation induce eukaryotic translation initiation factor 2α phosphorylation (eIF2α) in eukaryotic cells, repressing global protein synthesis coincident with preferential translation of activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of genes involved in amino acid metabolism, cellular redox homeostasis, and regulation of apoptosis. When the eIF2α/ATF4 pathway is initiated by ER stress, the pathway is referred toas the unfolded protein response (UPR). In addition to DNA, proteins may be initial and important targets of ionizing radiation (IR), and the damaged protein can trigger ER stress pathway. Recent investigations suggested that IR induces ER stress followed by UPR in various cell types including intestinal epithelial cells. We conducted this study to determine whether IR can activate UPR in human vascular endothelial cells. Our data have shown that IR increased PERK-dependent eIF2α phosphorylation accompanied by induction in ATF4 protein levels in human vascular endothelial cells without alterations in expressions of XBP-1s and GRP78. Based on these data, we suggest that IR selectively activates PERK branch of unfolded protein response in human vascular endothelial cells.

  2. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

    DEFF Research Database (Denmark)

    Kirchner, Henriette; Sinha, Indranil; Gao, Hui;

    2016-01-01

    of insulin resistance. Results were validated by pyrosequencing. RESULT: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated...

  3. A Laser-Wire System for the International Linear Collider

    Energy Technology Data Exchange (ETDEWEB)

    Delerue, N.; Dixit, S.; Gannaway, F.; Howell, D.; Qurshi, M.; Blair, G.; Boogert, S.; Boorman, G.; Driouichi, C.; Deacon, L.; Aryshev, A.; Karataev, P.; Terunuma, N.; Urakawa, J.; Brachmann, A.; Frisch, J.; Ross, M.; /Oxford U. /Royal Holloway, U. of London /KEK, Tsukuba /SLAC

    2009-04-30

    A new laser-wire has been installed in the extraction line of the ATF at KEK. It aims at demonstrating that laser-wires can be used to measure micrometre scale beam size. In parallel, studies have been made to specify a laser suitable for the ILC laser-wires.

  4. Bunch transverse emittance increase in electron storage rings

    Institute of Scientific and Technical Information of China (English)

    GAO Jie

    2009-01-01

    In this paper a theoretical framework to estimate the bunch transverse emittance growing in electron storage rings due to short range transverse wakefield of the machine is established. New equilibrium emittance equations are derived and applied to explain the experimentally obtained results in ATF damping ring. This equation will be useful for linear collider damping ring design.

  5. 75 FR 1085 - Commerce in Explosives; List of Explosive Materials (2009R-18T)

    Science.gov (United States)

    2010-01-08

    ... [Federal Register Volume 75, Number 5 (Friday, January 8, 2010)] [Notices] [Pages 1085-1087] [FR Doc No: 2010-45] DEPARTMENT OF JUSTICE Bureau of Alcohol, Tobacco, Firearms and Explosives [Docket No. ATF 34N] Commerce in Explosives; List of Explosive Materials (2009R-18T) AGENCY: Bureau of...

  6. 75 FR 3160 - Commerce in Explosives-Storage of Shock Tube With Detonators (2005R-3P)

    Science.gov (United States)

    2010-01-20

    ... of Alcohol, Tobacco, Firearms, and Explosives 27 CFR Part 555 RIN 1140-AA30 Commerce in Explosives... 555 (``Commerce in Explosives''). II. Notice of Proposed Rulemaking On January 29, 2003, ATF published...--COMMERCE IN EXPLOSIVES 0 1. The authority citation for 27 CFR Part 555 continues to read as...

  7. 75 FR 70291 - Commerce in Explosives; List of Explosive Materials (2010R-27T)

    Science.gov (United States)

    2010-11-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau of Alcohol, Tobacco, Firearms and Explosives Commerce in Explosives; List of Explosive Materials (2010R-27T) AGENCY: Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF), Department of...

  8. 77 FR 58410 - Commerce in Explosives; List of Explosive Materials (2012R-10T)

    Science.gov (United States)

    2012-09-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Bureau of Alcohol, Tobacco, Firearms, and Explosives Commerce in Explosives; List of Explosive Materials (2012R-10T) AGENCY: Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF), Department of...

  9. 76 FR 64974 - Commerce in Explosives; List of Explosive Materials (2011R-18T)

    Science.gov (United States)

    2011-10-19

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF JUSTICE Bureau of Alcohol, Tobacco, Firearms and Explosives Commerce in Explosives; List of Explosive Materials (2011R-18T) AGENCY: Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF), Department of...

  10. 19 CFR 19.38 - Supervision of exportation.

    Science.gov (United States)

    2010-04-01

    ... the sales ticket procedure for exportation shall be exported only under Customs supervision as... exportation transactions, examination of articles being exported, and audits of the proprietor's records. (b) Supervision of ATF bonded exports. Customs officers may conduct general supervision of exportations...

  11. FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress.

    Science.gov (United States)

    Shimizu, Makoto; Li, Juan; Maruyama, Ryuto; Inoue, Jun; Sato, Ryuichiro

    2013-02-15

    FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.

  12. An Integrated Real-Time Beamforming and Postfiltering System for Nonstationary Noise Environments

    Directory of Open Access Journals (Sweden)

    Gannot Sharon

    2003-01-01

    Full Text Available We present a novel approach for real-time multichannel speech enhancement in environments of nonstationary noise and time-varying acoustical transfer functions (ATFs. The proposed system integrates adaptive beamforming, ATF identification, soft signal detection, and multichannel postfiltering. The noise canceller branch of the beamformer and the ATF identification are adaptively updated online, based on hypothesis test results. The noise canceller is updated only during stationary noise frames, and the ATF identification is carried out only when desired source components have been detected. The hypothesis testing is based on the nonstationarity of the signals and the transient power ratio between the beamformer primary output and its reference noise signals. Following the beamforming and the hypothesis testing, estimates for the signal presence probability and for the noise power spectral density are derived. Subsequently, an optimal spectral gain function that minimizes the mean square error of the log-spectral amplitude (LSA is applied. Experimental results demonstrate the usefulness of the proposed system in nonstationary noise environments.

  13. A Simple Adaptive Transfer Function for Deriving the Central Blood Pressure Waveform from a Radial Blood Pressure Waveform.

    Science.gov (United States)

    Gao, Mingwu; Rose, William C; Fetics, Barry; Kass, David A; Chen, Chen-Huan; Mukkamala, Ramakrishna

    2016-09-14

    Generalized transfer functions (GTFs) are available to compute the more relevant central blood pressure (BP) waveform from a more easily measured radial BP waveform. However, GTFs are population averages and therefore may not adapt to variations in pulse pressure (PP) amplification (ratio of radial to central PP). A simple adaptive transfer function (ATF) was developed. First, the transfer function is defined in terms of the wave travel time and reflection coefficient parameters of an arterial model. Then, the parameters are estimated from the radial BP waveform by exploiting the observation that central BP waveforms exhibit exponential diastolic decays. The ATF was assessed using the original data that helped popularize the GTF. These data included radial BP waveforms and invasive reference central BP waveforms from cardiac catheterization patients. The data were divided into low, middle, and high PP amplification groups. The ATF estimated central BP with greater accuracy than GTFs in the low PP amplification group (e.g., central systolic BP and PP root-mean-square-errors of 3.3 and 4.2 mm Hg versus 6.2 and 7.1 mm Hg; p ≤ 0.05) while showing similar accuracy in the higher PP amplification groups. The ATF may permit more accurate, non-invasive central BP monitoring in elderly and hypertensive patients.

  14. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

    Directory of Open Access Journals (Sweden)

    Henriette Kirchner

    2016-03-01

    Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

  15. 78 FR 6765 - Amendment to the International Traffic in Arms Regulations: Revision of U.S. Munitions List...

    Science.gov (United States)

    2013-01-31

    ... Alcohol, Tobacco, Firearms and Explosives (ATF) for the purpose of permanent import under its regulations... paragraphs (a)(1) and (a)(2) of this category); (2) Solid propellant rocket motors, hybrid or gel rocket... x 10\\6\\ N s (MT); (3) Solid propellant rocket motors, hybrid or gel rocket motors, or...

  16. Performance Assessment of Active Hearing Protection Devices

    Science.gov (United States)

    2015-05-08

    ten female subjects, ranging in age from 18 to 34 years. All subjects were required to have a computer administered screening audiogram via Hughson...transducers was recorded. This included 8 signals from the ATFs, each equipped with two microphones and pre-amplifiers (one for each “ear drum ”) and 1

  17. Laser Wire and Beam Position Monitor tests

    CERN Document Server

    Boogert, S T; Lyapin, A; Nevay, L; Snuverink, J

    2013-01-01

    This subtask involved two main activities; Firstly the development and subsequent usage of high resolution beam position monitors (BPM) for the International Linear Collider (ILC) and Compact Linear Collider projects (CLIC); and secondly the development of a laser-wire (LW) transverse beam size measurement systems. This report describes the technical progress achieved at a large-scale test ILC compatible BPM system installed at the Accelerator Test Facility 2 (ATF2). The ATF2 is an energy-scaled demonstration system for the final focus systems required to deliver the particle beams to collision at the ILC and CLIC. The ATF2 cavity beam position monitor system is one of the largest of its kind and rivals systems used at free electron lasers. The ATF2 cavity beam position system has achieved a position resolutionof 250 nm (with signal attuenation) and 27 nm (without attenuation). The BPM system has been used routinely for lattice diagnostics, beam based alignment and wakefield measurements. Extensive experience...

  18. Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs.

    Science.gov (United States)

    Tang, Xiaohu; Lucas, Joseph E; Chen, Julia Ling-Yu; LaMonte, Gregory; Wu, Jianli; Wang, Michael Changsheng; Koumenis, Constantinos; Chi, Jen-Tsan

    2012-01-15

    Within solid tumor microenvironments, lactic acidosis, and hypoxia each have powerful effects on cancer pathophysiology. However, the influence that these processes exert on each other is unknown. Here, we report that a significant portion of the transcriptional response to hypoxia elicited in cancer cells is abolished by simultaneous exposure to lactic acidosis. In particular, lactic acidosis abolished stabilization of HIF-1α protein which occurs normally under hypoxic conditions. In contrast, lactic acidosis strongly synergized with hypoxia to activate the unfolded protein response (UPR) and an inflammatory response, displaying a strong similarity to ATF4-driven amino acid deprivation responses (AAR). In certain breast tumors and breast tumor cells examined, an integrative analysis of gene expression and array CGH data revealed DNA copy number alterations at the ATF4 locus, an important activator of the UPR/AAR pathway. In this setting, varying ATF4 levels influenced the survival of cells after exposure to hypoxia and lactic acidosis. Our findings reveal that the condition of lactic acidosis present in solid tumors inhibits canonical hypoxia responses and activates UPR and inflammation responses. Furthermore, these data suggest that ATF4 status may be a critical determinant of the ability of cancer cells to adapt to oxygen and acidity fluctuations in the tumor microenvironment, perhaps linking short-term transcriptional responses to long-term selection for copy number alterations in cancer cells.

  19. Experiment list: SRX122493 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available antibody=Atf4 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Abcam || chip antibody catal...og number 1=ab28830-100 || chip antibody manufacturer 2=Santa Cruz || chip antibody catalog number 2=sc-200

  20. Experiment list: SRX122484 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=0 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cata...log number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 http

  1. Experiment list: SRX122488 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available antibody=Atf3 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Santa Cruz || chip antibody c...atalog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 h

  2. Experiment list: SRX122491 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=60 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cat...alog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 htt

  3. Experiment list: SRX122483 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=0 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cata...log number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 http

  4. Experiment list: SRX122492 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=60 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cat...alog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 htt

  5. Experiment list: SRX122487 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available antibody=Atf3 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Santa Cruz || chip antibody c...atalog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 h

  6. Experiment list: SRX122494 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available hip antibody=Atf4 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Abcam || chip antibody ca...talog number 1=ab28830-100 || chip antibody manufacturer 2=Santa Cruz || chip antibody catalog number 2=sc-2

  7. Experiment list: SRX122489 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=30 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cat...alog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 htt

  8. Experiment list: SRX122490 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ntibody=Atf3 || treatment=LPS || time=30 min || chip antibody manufacturer 1=Santa Cruz || chip antibody cat...alog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 htt

  9. Experiment list: SRX122486 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available antibody=Atf3 || treatment=LPS || time=120 min || chip antibody manufacturer 1=Santa Cruz || chip antibody c...atalog number 1=sc-188 || chip antibody manufacturer 2=Abcam || chip antibody catalog number 2=ab70005-100 h

  10. Dialogue between E. coli free radical pathways and the mitochondria of C. elegans.

    Science.gov (United States)

    Govindan, J Amaranath; Jayamani, Elamparithi; Zhang, Xinrui; Mylonakis, Eleftherios; Ruvkun, Gary

    2015-10-06

    The microbial world presents a complex palette of opportunities and dangers to animals, which have developed surveillance and response strategies to hints of microbial intent. We show here that the mitochondrial homeostatic response pathway of the nematode Caenorhabditis elegans responds to Escherichia coli mutations that activate free radical detoxification pathways. Activation of C. elegans mitochondrial responses could be suppressed by additional mutations in E. coli, suggesting that C. elegans responds to products of E. coli to anticipate challenges to its mitochondrion. Out of 50 C. elegans gene inactivations known to mediate mitochondrial defense, we found that 7 genes were required for C. elegans response to a free radical producing E. coli mutant, including the bZip transcription factor atfs-1 (activating transcription factor associated with stress). An atfs-1 loss-of-function mutant was partially resistant to the effects of free radical-producing E. coli mutant, but a constitutively active atfs-1 mutant growing on wild-type E. coli inappropriately activated the pattern of mitochondrial responses normally induced by an E. coli free radical pathway mutant. Carbonylated proteins from free radical-producing E. coli mutant may directly activate the ATFS-1/bZIP transcription factor to induce mitochondrial stress response: feeding C. elegans with H2O2-treated E. coli induces the mitochondrial unfolded protein response, and inhibition of a gut peptide transporter partially suppressed C. elegans response to free radical damaged E. coli.

  11. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.

    Science.gov (United States)

    Naranjo, José R; Zhang, Hongyu; Villar, Diego; González, Paz; Dopazo, Xose M; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C; Arrabal, María D; Prieto, Angela; Cercós, Pilar; González, Teresa; De la Cruz, Alicia; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen; Gutierrez-Rodriguez, Marta; Li, Jia-Yi; Mellström, Britt

    2016-02-01

    Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.

  12. The BNL Accelerator Test Facility and experimental program

    Energy Technology Data Exchange (ETDEWEB)

    Ben-Zvi, I. (Brookhaven National Lab., Upton, NY (United States) State Univ. of New York, Stony Brook, NY (United States). Dept. of Physics)

    1992-01-01

    The Accelerator Test Facility (ATF) at BNL is a users' facility for experiments in Accelerator and Beam Physics. The ATF provides high brightness electron beams and high-power laser pulses synchronized to the electron beam, suitable for studies of new methods of high-gradient acceleration and state-of-the-art Free-Electron Lasers. The electrons are produced by a laser photocathode rf gun and accelerated to 50 MeV by two traveling wave accelerator sections. The lasers include a 10 mJ, 10 ps ND:YAG laser and a 500 mJ, 10 to 100 ps C0{sub 2} laser. A number of users from National Laboratories, universities and industry take part in experiments at the ATF. The experimental program includes various laser acceleration schemes, Free-Electron Laser experiments and a program on the development of high-brightness electron beams. The ATF's experimental program commenced in early 1991 at an energy of about 4 MeV. The full program, with 50 MeV and the high-power laser will begin operation this year.

  13. Genetic targets of hydrogen sulfide in ventilator-induced lung injury--a microarray study.

    Directory of Open Access Journals (Sweden)

    Sashko Spassov

    Full Text Available Recently, we have shown that inhalation of hydrogen sulfide (H2S protects against ventilator-induced lung injury (VILI. In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million. Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection.

  14. 49 CFR 40.225 - What form is used for an alcohol test?

    Science.gov (United States)

    2010-10-01

    ... colored paper, or have clearly discernable borders or designation statements on Copy 2 and Copy 3. When... foreign-language version of the ATF approved by ODAPC. You may use such a non-English language form only in a situation where both the employee and BAT/STT understand and can use the form in that language....

  15. A Statistically Based Training Diagnostic Tool for Marine Aviation

    Science.gov (United States)

    2014-06-01

    interdiction API aviation preflight indoctrination APR aviation performance record ASPT assault support ATD aviation training division ATF aviation...checklists. ASPT -1802: Introduction to confined area landings (CALs), and assault support techniques. Core Skill TERF-2100: First flight in squadron...conduct a navigation route. Core Skill REC-2300: Introduction to daytime visual reconniassance. ASPT -2400: Introduction to section tactical landings

  16. 77 FR 51698 - Authorization To Seize Property Involved in Drug Offenses for Administrative Forfeiture (2012R-9P)

    Science.gov (United States)

    2012-08-27

    ... its regulations to allow the Director of the Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF... Programs and Services, Bureau of Alcohol, Tobacco, Firearms, and Explosives, U.S. Department of Justice, 99... can be perfected in 60-90 days for minimal cost, including the statutorily required advertisement...

  17. Interaction of Restin with transcription factors

    Institute of Scientific and Technical Information of China (English)

    WU; Yousheng; LU; Fan; QI; Yinxin; WANG; Ruihua; ZHANG; Jia

    2005-01-01

    Restin, a member of melanoma-associated antigen superfamily gene, was first cloned from differentiated leukemia cell induced by all trans-retinoic acid, and was able to inhibit cell proliferation, but the molecular mechanism was not clear. Since Restin was localized in cell nucleus, and its homolog member, Necdin (neuronal growth suppressor factor), could interact with transcription factors p53 and E2F1, we proposed that Restin might also function as Necdin through interacting with some transcription factors. In this study, transcription factors p53, AP1,ATFs and E2Fs were cloned and used in the mammalian two-hybrid system to identify their interaction with Restin. The results showed that only ATF3 had a strong interaction with Restin. It is interesting to know that ATF3 was an important transcription factor for G1 cell cycle initiation in physiological stress response. It was possible that the inhibition of cell proliferation by Restin might be related with the inhibition of ATF3 activity.

  18. Effect of injury on S1 dorsal root ganglia in an experimental model of neuropathic faecal incontinence.

    LENUS (Irish Health Repository)

    Peirce, C

    2011-08-01

    An experimental model of neuropathic faecal incontinence has recently been established. This study aimed to quantify and compare the effect of crush and compression injury on first-order sensory neurones of the inferior rectal nerve (IRN) using a nuclear marker of axonal injury, activating transcription factor (ATF) 3.

  19. Zinc finger artificial transcription factor-based nearest inactive analogue/nearest active analogue strategy used for the identification of plant genes controlling homologous recombination

    NARCIS (Netherlands)

    Jia, Qi; van Verk, Marcel C.; Pinas, Johan E.; Lindhout, Beatrice I.; Hooykaas, Paul J.J.; Van der Zaal, Bert J.

    2013-01-01

    In previous work, we selected a particular transcription factor, designated VP16-HRU, from a pool of zinc finger artificial transcription factors (ZF-ATFs) used for genome interrogation. When expressed in Arabidopsis thaliana under control of the ribosomal protein S5A promoter, the RPS5A::VP16-HRU c

  20. Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress.

    Science.gov (United States)

    Oh, Chang-Kyu; Lee, Seung Joon; Park, Seong-Hwan; Moon, Yuseok

    2016-05-01

    Colorectal cancer (CRC) as an environmental disease is largely influenced by accumulated epithelial stress from diverse environmental causes. We are exposed to ribosome-related insults, including ribosome-inactivating stress (RIS), from the environment, dietary factors, and medicines, but their physiological impacts on the chemotherapy of CRC are not yet understood. Here we revealed the effects of RIS on chemosensitivity and other malignancy-related properties of CRC cells. First, RIS led to bidirectional inhibition of p53-macrophage inhibitory cytokine 1 (MIC-1)-mediated death responses in response to anticancer drugs by either enhancing ATF3-linked antiapoptotic signaling or intrinsically inhibiting MIC-1 and p53 expression, regardless of ATF3. Second, RIS enhanced the epithelial-mesenchymal transition and biogenesis of cancer stem-like cells in an ATF3-dependent manner. These findings indicate that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implying that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for the treatment of environmentally aggravated cancers.

  1. Mechanism of Ras Activation by TGFBeta

    Science.gov (United States)

    2002-07-01

    transcriptional activity of the vitamin D receptor (Yanagi- sawa et al, 1999). Smad3 and Smad4 can also associate with the acute myeloid leukemia family of... Ishii , S. (1999). ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-ß signaling. J Biol Chem 274, 8949

  2. Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer.

    Science.gov (United States)

    Hsu, Hsien-Yeh; Lin, Tung-Yi; Lu, Mei-Kuang; Leng, Pei-Ju; Tsao, Shu-Ming; Wu, Yu-Chung

    2017-03-23

    Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways.

  3. 78 FR 22659 - Revisions to the Export Administration Regulations: Initial Implementation of Export Control Reform

    Science.gov (United States)

    2013-04-16

    ... Control Reform Initiative A. Background B. List of Proposed Rules C. Relationship to Other Rules... the CCL; however, many revisions also affect items or transactions that were already subject to the... Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF), as proposed, BIS is adding a note to...

  4. Experiment list: SRX150420 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available s=Leukemia Chronic Myelogenous 67204862,91.9,16.4,23635 GSM935340: Harvard ChipSeq K562 ATF1 (06-325) std so...urce_name=K562 || biomaterial_provider=ATCC || lab=Harvard || lab description=Struhl - Harvard University ||

  5. Experiment list: SRX150471 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available s=Leukemia Chronic Myelogenous 34337514,69.2,8.6,1665 GSM935391: Harvard ChipSeq K562 ATF3 std source_name=K...562 || biomaterial_provider=ATCC || lab=Harvard || lab description=Struhl - Harvard University || datatype=C

  6. Effects of chronic renal failure rat serum on histone acetyltransferase p300 and activation of activating transcription factor 4 of arterial smooth muscle cells cultured in vitro

    Institute of Scientific and Technical Information of China (English)

    张耀全

    2014-01-01

    Objective To investigate the effects of the rat serum with chronic renal failure(CRF)on ubiquitin-proteasome pathway,histone acetyltransferase p300 and activation of activating transcription factor 4(ATF4)of rat arterial vascular smooth muscle cells(VSMCs)cultured in vitro,and explore the possible mechanism.Methods Objective To establish the rat model of

  7. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    Science.gov (United States)

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

  8. Long-term faulting behavior of eastern Altyn Tagh fault, north Tibetan Plateau

    Science.gov (United States)

    Xu, X.; Klinger, Y.; Tapponnier, P.; Chen, G.; Li, K.; Tan, X. B.

    2015-12-01

    The Altyn Tagh Fault (ATF) bounds the Tibetan Plateau to the north and is the longest continental active strike-slip fault at lithospheric scale within the India-Eurasia collision zone (Wittlinger et al., 1998). Together with other mega strike-slip faults, e.g., the Kunlun, Haiyuan, Xianshuihe and Jiali faults, it plays an important role in both the two end member models, eastward block-like motion and distributed deformation or channel flow, to accommodate the India-Eurasia convergence. However, how much amount of northward motion, from convergence between Indian and Eurasian plates to the south, has been transferred by localized slip on the ATF into eastward motion of the Plateau relative to the Tarim basin is still unclear. Its main reason may be originated from disagreements over quite scattered Quaternary left-slip rates from 2 mm/yr up to 30 mm/yr and also difference in slip rate over time scales of 10 yr from GPS and InSAR to 10 kyr from Quaternary offset-landforms. However, accurate Quaternary long-term average slip rate is the first step for quantitatively evaluating the role of the ATF in transferring northward convergence of the India-Eurasia collision into eastward escape and then for understanding the kinematic model of the Tibetan Plateau. Here we present a synthetic approach to well constrain long-term left-slip rate by identifying paleo-earthquake sequence as precise chronologic bounds for the associated measured cumulative displacements at two sites on the Aksay segment of the ATF. This result is very important not only to establish surface-rupturing earthquake recurrence model to reduce its potential earthquake hazards along the ATF, but also to solve the long-standing dispute over the high or low Quaternary slip rates by using diferent terrace models and geodetic strain rate. Analysis of the paleo-earthquakes from trenches and recent cumulative offsets reveals a Holocene surface-rupturing faulting process, which well constrains the long-term slip

  9. MK3 controls Polycomb target gene expression via negative feedback on ERK

    Directory of Open Access Journals (Sweden)

    Prickaerts Peggy

    2012-08-01

    Full Text Available Abstract Background Gene-environment interactions are mediated by epigenetic mechanisms. Polycomb Group proteins constitute part of an epigenetic cellular transcriptional memory system that is subject to dynamic modulation during differentiation. Molecular insight in processes that control dynamic chromatin association and dissociation of Polycomb repressive complexes during and beyond development is limited. We recently showed that MK3 interacts with Polycomb repressive complex 1 (PRC1. The functional relevance of this interaction, however, remained poorly understood. MK3 is activated downstream of mitogen- and stress-activated protein kinases (M/SAPKs, all of which fulfill crucial roles during development. We here use activation of the immediate-early response gene ATF3, a bona fide PRC1 target gene, as a model to study how MK3 and its effector kinases MAPK/ERK and SAPK/P38 are involved in regulation of PRC1-dependent ATF3 transcription. Results Our current data show that mitogenic signaling through ERK, P38 and MK3 regulates ATF3 expression by PRC1/chromatin dissociation and epigenetic modulation. Mitogenic stimulation results in transient P38-dependent H3S28 phosphorylation and ERK-driven PRC1/chromatin dissociation at PRC1 targets. H3S28 phosphorylation by itself appears not sufficient to induce PRC1/chromatin dissociation, nor ATF3 transcription, as inhibition of MEK/ERK signaling blocks BMI1/chromatin dissociation and ATF3 expression, despite induced H3S28 phosphorylation. In addition, we establish that concomitant loss of local H3K27me3 promoter marking is not required for ATF3 activation. We identify pERK as a novel signaling-induced binding partner of PRC1, and provide evidence that MK3 controls ATF3 expression in cultured cells via negative regulatory feedback on M/SAPKs. Dramatically increased ectopic wing vein formation in the absence of Drosophila MK in a Drosophila ERK gain-of-function wing vein patterning model, supports the

  10. Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Huang J

    2016-07-01

    Full Text Available Jing Huang,1,2 Weiping Qian,3 Liya Wang,1,2 Hui Wu,1 Hongyu Zhou,3 Andrew Yongqiang Wang,4 Hongbo Chen,5 Lily Yang,3 Hui Mao1,2 1Department of Radiology and Imaging Sciences, 2Center for Systems Imaging, 3Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; 4Ocean Nanotech LLC, Springdale, AR, USA; 5School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People’s Republic of China Abstract: Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein-coated magnetic iron oxide (CNIO nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP were engineered on this nanoplatform. High drug loading (~25 wt% and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that

  11. Modified radial v/s biatrial maze for atrial fibrillation in rheumatic valvular heart surgery

    Science.gov (United States)

    Sayed, Sajid A.; Katewa, Ashish; Srivastava, Vivek; Jana, Sujit; Patwardhan, Anil M.

    2014-01-01

    Background Atrial fibrillation (AF) is commonest sustained atrial arrhythmia producing high morbidity. Although Cox's Maze III procedure cures AF in majority, reduced atrial transport function (ATF) is a concern. Radial approach with ablation lines radial from sinus node towards atrioventricular annulii and parallel to atrial coronary arteries, has shown better ATF. Methods Single blind open randomized prospective study of 80 patients was undertaken in two groups (40 each) of modified Cox's maze III and modified radial approach, to evaluate conversion to normal sinus rhythm (NSR) and ATF. Patients undergoing surgery for rheumatic valvular heart disease with continuous AF were prospectively randomized. Ablation lines were created with radiofrequency (RF) bipolar coagulation with cryoablation for the isthmal lesions and coronary sinus. Results were compared at 6 months and ATF was evaluated by atrial filling fraction (AFF) and A/E ratio on echocardiography. Results The rate of conversion to NSR in both groups was statistically insignificant by Fisher's exact test (p > 0.05). ATF was better in modified radial approach compared to modified Cox's Maze III (A/E compared by unpaired t test:0.52 ± 0.08 v/s 0.36 ± 0.10; p < 0.05. AFF compared using Mann Whitney U test: median AFF for radial group was 23 v/s 20 for biatrial group; p < 0.05). Discussion In patients with AF undergoing rheumatic valvular surgery, radiofrequency radial approach is as effective as modified Cox's maze III for conversion to NSR with better atrial transport function. PMID:25443604

  12. Late Cenozoic transpressional mountain building directly north of the Altyn Tagh Fault in the Sanweishan and Nanjieshan, North Tibetan Foreland, China

    Science.gov (United States)

    Cunningham, Dickson; Zhang, Jin; Li, Yanfeng

    2016-09-01

    For many tectonicists, the structural development of the northern Tibetan Plateau stops at the Altyn Tagh Fault (ATF). This study challenges that assumption. Structural field observations and remote sensing analysis indicate that the Sanweishan and Nanjieshan basement cored ridges of the Archean Dunhuang Block, which interrupt the north Tibetan foreland directly north of the ATF, are bound and cut by an array of strike-slip, thrust and oblique-slip faults that have been active in the Quaternary and remain potentially active. The Sanweishan is a SE-tilted block that is bound on its NW margin by a steep south-dipping thrust fault that has also accommodated sinistral strike-slip displacements. The Nanjieshan consists of parallel, but offset basement ridges that record NNW and SSE thrust displacements and sinistral strike-slip. Regional folds characterize the extreme eastern Nanjieshan and appear to have formed above blind thrust faults which break the surface further west. Previously published magnetotelluric data suggest that the major faults of the Sanweishan and Nanjieshan ultimately root to the south within conductive zones that are inferred to merge into the ATF. Therefore, although the southern margin of the Dunhuang Block focuses significant deformation along the ATF, the adjacent cratonic basement to the north is also affected. Collectively, the ATF and structurally linked Sanweishan and Nanjieshan fault array represent a regional asymmetric half-flower structure that is dominated by non-strain partitioned sinistral transpression. The NW-trending Dengdengshan thrust fault system near Yumen City appears to define the northeastern limit of the Sanweishan-Nanjieshan block, which may be regionally viewed as the most northern, but early-stage expression of Tibetan Plateau growth into a slowly deforming, mechanically stiff Archean craton.

  13. The role of unfolded protein response in differentiation of mammary epithelial cells.

    Science.gov (United States)

    Tsuchiya, Megumi; Koizumi, Yumiko; Hayashi, Satoko; Hanaoka, Miyuki; Tokutake, Yukako; Yonekura, Shinichi

    2017-03-18

    The accumulation of misfolded proteins in the ER provokes ER stress by increasing the demand for energy, chaperones, and other proteins that are needed to fold client proteins or to degrade unfoldable secretory cargo. This stress activates a signaling network called the unfolded protein response (UPR). However, recent accumulated data suggested that the UPR also provides important signals for regulating cell differentiation and maturation. However, the relationship between UPR and mammary gland development has not been fully elucidated. To define the involvement of the UPR in mammary gland development, mammary glands were collected from non-pregnant mice, at days 5, 10 and 15 of pregnancy, at days 1 and 7 of lactation, and the expression patterns of UPR-related genes were determined by real-time PCR. We found that the mRNA expression of ATF4 and XBP1 significant increased during pregnancy. Moreover, we found that both ATF4 and XBP1 proteins are expressed in mammary epithelial cells by immunohistological analysis. In order to know the role of ATF4 and XBP1 in the differentiation of mammary epithelial cell, we performed gene knockdown experiment using HC11 cells. We found that ATF4 or XBP1 knockdown suppressed the mRNA expression of beta-casein and lactogenic hormone receptor in differentiating HC11 cells. Our results demonstrate that XBP1 and ATF4, which are UPR-related transcription factors, directly or indirectly participate in cell differentiation mechanisms through the regulation of the expression of lactogenic hormone receptors in mouse mammary epithelial cells.

  14. Apotransferrin-Induced Recovery after Hypoxic/Ischaemic Injury on Myelination

    Directory of Open Access Journals (Sweden)

    Mariano Guardia Clausi

    2010-10-01

    Full Text Available We have previously demonstrated that aTf (apotransferrin accelerates maturation of OLs (oligodendrocytes in vitro as well as in vivo. The purpose of this study is to determine whether aTf plays a functional role in a model of H/I (hypoxia/ischaemia in the neonatal brain. Twenty-four hours after H/I insult, neonatal rats were intracranially injected with aTf and the effects of this treatment were evaluated in the CC (corpus callosum as well as the SVZ (subventricular zone at different time points. Similar to previous studies, the H/I event produced severe demyelination in the CC. Demyelination was accompanied by microglial activation, astrogliosis and iron deposition. Ferritin levels increased together with lipid peroxidation and apoptotic cell death. Histological examination after the H/I event in brain tissue of aTf-treated animals (H/I aTF revealed a great number of mature OLs repopulating the CC compared with saline-treated animals (H/I S. ApoTf treatment induced a gradual increase in MBP (myelin basic protein and myelin lipid staining in the CC reaching normal levels after 15 days. Furthermore, significant increase in the number of OPCs (oligodendroglial progenitor cells was found in the SVZ of aTf-treated brains compared with H/I S. Specifically, there was a rise in cells positive for OPC markers, i.e. PDGFRα and SHH+ cells, with a decrease in cleaved-caspase-3+ cells compared with H/I S. Additionally, neurospheres from aTf-treated rats were bigger in size and produced more O4/MBP+ cells. Our findings indicate a role for aTf as a potential inducer of OLs in neonatal rat brain in acute demyelination caused by H/I and a contribution to the differentiation/maturation of OLs and survival/migration of SVZ progenitors after demyelination in vivo.

  15. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-01-01

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

  16. Research on Vacuum Laser Accelerator and Proof-of Principle Experiment

    Science.gov (United States)

    Shao, Lei

    This thesis discovers a proof-of-principle theory of Vacuum Laser Acceleration (VLA) and proposes a new acceleration mechanism---Capture and Acceleration Scenario (CAS) in our far-field laser acceleration research, which is a promising new scheme in advanced acceleration field. In this thesis, I studied electrons' dynamic behaviors while interacting with intense laser beam. There are two kinds of dynamics trajectories, namely IS (Inelastic Scattering) and CAS. In CAS, electrons can be captured and moving along the laser beam for a long time and receive considerable energy exchange from the laser field, rather than quickly expelled from the intense field region of the laser as predicted by the conventional Ponderomotive Potential Model (PPM). This thesis shows the research on most parameters of both laser beam and electron beam which will affect this VLA scheme. One of the primary factors is the laser intensity. Relatively high laser intensity is critically required for VLA, and there are thresholds of intensity a0( th) for CAS occurrence; the thresholds are different under different laser beam waist widths which is also a very important parameter of laser beam. Laser intensity is still a big obstacle nowadays. In the last decade there are only a few laboratories have the laser power to ˜1019 W/cm2 and above. Our simulation shows that laser intensity threshold of CAS is around a0 = 5˜8, in correspondence to laser power around 1019˜1022 W/cm 2 depending on different wave length and waist width. The interaction is also sensitive to various electron beam parameters, such as the optimal initial electron energy falls in the range of 4--15 MeV, electron incident angle and position, and so on. At last the thesis presents out experimental work on this new VLA scheme. The collaboration is between our UCLA group and Brookhaven National Lab - Accelerator Test Facility (BNL-ATF). At BNL-ATF, they have both intense laser beam and high quality electron beam. The characters of

  17. Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro

    Directory of Open Access Journals (Sweden)

    Seidl Kelly M

    2010-03-01

    Full Text Available Abstract Background The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2 versus another (ATF2. Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2. Results We found that in a dual (MK2 and ATF2 substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38]. Conclusion Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a

  18. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.

    Directory of Open Access Journals (Sweden)

    Xiaohua Shen

    2005-09-01

    Full Text Available The unfolded protein response (UPR is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER. In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR genes, as well as numerous constitutive UPR (c-UPR genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.

  19. Structures and stabilities of group 17 fluorides EF3 (E = I, At, and element 117) with spin-orbit coupling.

    Science.gov (United States)

    Yang, Dong-Dong; Wang, Fan

    2012-12-05

    In this work, a recently developed CCSD(T) approach with spin-orbit coupling (SOC) as well as density functional theory (DFT) using various exchange-correlation (XC) functionals are employed to investigate structures and stabilities of group 17 fluorides EF(3) (E = I, At, and element 117). These molecules are predicted to have bent T-shaped C(2v) structures according to the second-order Jahn-Teller (SOJT) effects or the valance shell electron pair repulsion (VSEPR) theory. For IF(3) and (117)F(3), our results are consistent with previous SOC-DFT calculations. However, different XC functionals provide different results for AtF(3) and our SOC-CCSD(T) calculations show that both the C(2v) and D(3h) structures are minima on the potential energy surface and the C(2v) structure is the global minimum for AtF(3). The performance of XC functionals on structures and stabilities of IF(3) and AtF(3) is found to depend on the fraction of the Hartree-Fock exchange (HFX) included in the XC functionals and the M06-2X functional with 54% of HFX providing results that agree best with CCSD(T) results. In addition, although both the C(2v) and D(3h) structures are minima for AtF(3), the energy barrier between them is only 8 kJ mol(-1) for the C(2v) structure and 0.05 kJ mol(-1) for the D(3h) structure. This indicates that the D(3h) structure could not possibly be observed experimentally and AtF(3) can convert easily between the three C(2v) structures. The SOJT term is shown to be reduced by electron correlation for IF(3) and AtF(3). On the other hand, although SOC decreases the energy difference between the C(2v) and D(3h) structures and reduces the deviation of the C(2v) structure from the D(3h) structure, it decreases the frequency of the bond bending mode, which may indicate that SOC actually increases the SOJT term. This could be related to mixing of spin-singlet E' states to low-energy spin-triplet states due to SOC.

  20. Thomson scattering diagnostic on the Compact Toroidal Hybrid Experiment

    Science.gov (United States)

    Traverso, Peter; Maurer, D. A.; Ennis, D. A.; Hartwell, G. J.

    2016-10-01

    A Thomson scattering system is being commissioned for the non-axisymmetric plasmas of the Compact Toroidal Hybrid (CTH), a five-field period current-carrying torsatron. The system takes a single point measurement at the magnetic axis to both calibrate the two- color soft x-ray Te system and serve as an additional diagnostic for the V3FIT 3D equilibrium reconstruction code. A single point measurement will reduce the uncertainty in the reconstructed peak pressure by an order of magnitude for both current-carrying plasmas and future gyrotron-heated stellarator plasmas. The beam, generated by a frequency doubled Continuum 2 J, Nd:YaG laser, is passed vertically through an entrance Brewster window and a two-aperture optical baffle system to minimize stray light. The beam line propagates 8 m to the CTH device mid-plane with the beam diameter < 3 mm inside the plasma volume. Thomson scattered light is collected by two adjacent f/2 plano-convex condenser lenses and focused onto a custom fiber bundle. The fiber is then re-bundled and routed to a Holospec f/1.8 spectrograph to collect the red-shifted scattered light from 535-565 nm. The system has been designed to measure plasmas with core Te of 100 to 200 eV and densities of 5 ×1018 to 5 ×1019 m-3. Work supported by USDOE Grant DE-FG02-00ER54610.

  1. Research on stellarator-mirror fission-fusion hybrid

    Science.gov (United States)

    Moiseenko, V. E.; Kotenko, V. G.; Chernitskiy, S. V.; Nemov, V. V.; Ågren, O.; Noack, K.; Kalyuzhnyi, V. N.; Hagnestål, A.; Källne, J.; Voitsenya, V. S.; Garkusha, I. E.

    2014-09-01

    The development of a stellarator-mirror fission-fusion hybrid concept is reviewed. The hybrid comprises of a fusion neutron source and a powerful sub-critical fast fission reactor core. The aim is the transmutation of spent nuclear fuel and safe fission energy production. In its fusion part, neutrons are generated in deuterium-tritium (D-T) plasma, confined magnetically in a stellarator-type system with an embedded magnetic mirror. Based on kinetic calculations, the energy balance for such a system is analyzed. Neutron calculations have been performed with the MCNPX code, and the principal design of the reactor part is developed. Neutron outflux at different outer parts of the reactor is calculated. Numerical simulations have been performed on the structure of a magnetic field in a model of the stellarator-mirror device, and that is achieved by switching off one or two coils of toroidal field in the Uragan-2M torsatron. The calculations predict the existence of closed magnetic surfaces under certain conditions. The confinement of fast particles in such a magnetic trap is analyzed.

  2. Design and implementation of a multichannel millimeter wave interferometer for the Compact Toroidal Hybrid experiment

    Energy Technology Data Exchange (ETDEWEB)

    Miller, M. C.; Hanson, J. D.; Hartwell, G. J.; Knowlton, S. F.; Maurer, D. A.; Stevenson, B. A. [Physics Department, Auburn University, Auburn, Alabama 36849 (United States)

    2012-10-15

    A three-channel 1 mm wave interferometer has been designed, assembled, and installed on the Compact Toroidal Hybrid torsatron (CTH). The interferometer design makes novel use of a subharmonic mixer for detection, which simplifies alignment. It employs a single electronically tunable source that is repetitively chirped using a sawtooth waveform of frequency up to 1 MHz. The 15.25 GHz drive oscillator is multiplied in two stages to 122 GHz before a final doubler stage brings it to 244 GHz. Local oscillator (LO) power at 122 GHz is directed through waveguide to the LO input of the subharmonic mixer of each viewing chord, simplifying alignment. Phase detection is performed by directly digitizing the amplified mixer outputs at 50 MHz and processing them with a software algorithm. Initial measurements made with the central chord of the new interferometer agree with those from the existing 4 mm system at low densities. The 1 mm system performs well in current-driven discharges reaching densities over 10{sup 19} m{sup -3}, whereas the lower frequency interferometer is found to be less reliable due to loss of fringes. This is a critical improvement for experiments studying the onset, avoidance, and vacuum magnetic transform dependence of disruptions in the CTH device.

  3. Curvature dependance of blob dynamics in TJ-K

    Energy Technology Data Exchange (ETDEWEB)

    Garland, Stephen; Ramisch, Mirko [Institut fuer Grenzflaechenverfahrenstechnik und Plasmatechnologie, Universitaet Stuttgart (Germany); Fuchert, Golo [Institut Jean Lamour, Universite de Lorraine (France)

    2014-07-01

    Turbulent transport in the scrape-off layer (SOL) is an important area of investigation in magnetic confinement fusion research. Relatively dense and hot, field-aligned, filament-like structures (blobs) have been observed to propagate radially through the SOL in many fusion devices, and contribute significantly to SOL transport. The torsatron TJ-K operates with a low-temperature plasma, allowing Langmuir probe measurements in the entire plasma volume. Despite the low temperature, investigations are relevant to fusion research due to dimensionless plasma parameters similar to those in the edge region of fusion plasmas. Analytical blob models link blob velocity in the SOL to blob polarisation, which can be driven by magnetic field line curvature. In TJ-K, average blob dynamics can be studied in detail using a 2D movable probe and a conditional averaging technique. In addition, a fast camera can be used to supplement probe data, and provide information on individual blob trajectories. With these tools, the connection between magnetic field line curvature and the poloidal component of blob velocity has been studied. Taking into account background E x B flows, initial investigations suggest a correlation between the poloidal component of blob velocity and averaged geodesic magnetic field line curvature.

  4. Investigation of turbulent transport and shear flows in the Edge of toroidal plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Birkenmeier, G.; Koehn, A.; Manz, P.; Nold, B.; Stroth, U. [Institut fuer Plasmaforschung, Universitaet Stuttgart, Stuttgart (Germany); Happel, T. [Lab. Nacional de Fusion, Asociacion EURATOM-CIEMAT, Madrid (Spain); Mahdizadeh, N. [ABB Switzerland Ltd. Corporate Research, Baden-Daettwil (Switzerland); Wilcox, R.; Anderson, D.T. [HSX Plasma Lab., University of Wisconsin, Madison, Wisconsin (United States); Ramisch, M.

    2010-08-15

    Intense Langmuir-probe measurements were carried out in the toroidal low-temperature plasma of the torsatron TJ-K in order to investigate the origin and dynamics of intermittent transport events, so-called blobs, at the transition from closed to open field lines. The statistical properties of the fluctuations at the plasma boundary agree with observations made in fusion edge plasmas. Blobs were found to be generated locally through a change in turbulence drive across the separatrix. The non-linear spectral energy transfer from small-scale fluctuations into large-scale flows was measured with a 128-probe array. The results point to the transfer being a key loss channel for turbulence energy leading to a reduction in turbulent transport. Earlier observations[M.A. Pedrosa et al., Phys. Rev. Lett. 100, 215003 (2008)] of enhanced long-range correlations in the plasma potential through externally induced shear flows in TJ-II stellarator were verified. The newly measured correlation of zonal vorticity and Reynolds stress at induced flow shear indicates an enhancement of zonal-flow drive (copyright 2010 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  5. TGF-mediated oscillations in the proximal intratubular pressure: differences between spontaneously hypertensive rats and Wistar-Kyoto rats

    DEFF Research Database (Denmark)

    Holstein-Rathlou, N H; Leyssac, P P

    1986-01-01

    A highly sensitive oscillatory tubulo-glomerular feedback (TGF) response has previously been demonstrated in normotensive Sprague-Dawley rats. The purpose of the present study was to examine whether such as oscillating TGF-response could be elicited in Wistar-Kyoto rats (WKY) and genetically...... hypertensive rats (SHR) and furthermore if any differences in the TGF-response characteristics between SHR and WKY rats could be detected. The closed loop function of the TGF-system was studied. In 12-18-week-old WKY rats regular oscillations in the intratubular pressure occurred spontaneously. The median...... fluid (ATF). When furosemide was added to the ATF in a concentration of 0.1 mM, the oscillations were abolished in both strains of rats. It is concluded that, in both strains of rats the oscillatory phenomena depend upon TGF activity. It is suggested that the irregular pattern of the oscillations...

  6. Standards for bullets and casings

    Directory of Open Access Journals (Sweden)

    J.F Song

    2002-11-01

    The Office of Law Enforcement Standards (OLES at the National Institute of Standards and Technology (NIST manages research in many different disciplines of forensic science. One of these projects supports the National Integrated Ballistics Information Network (NIBIN. NIST digitized six bullet signatures from samples provided by the Bureau of Alcohol, Tobacco, and Firearms (ATF and the Federal Bureau of Investigation (FBI. Using these signatures as a virtual standard, NIST’s Instrument Shop manufactured 20 reference materials (RM 8240 standard bullets using a numerically-controlled diamond turning machine. Test results show high reproducibility of the bullet signatures on standard bullets. NIST has also developed a new parameter for bullet signature comparisons, using autocorrelation functions, and proposed a diagram for tracing local ballistics measurements to the National Laboratory Center of the ATF and to the FBI. Using an electro-forming process, NIST has manufactured prototype standard casings and test results show high reproducibility for the casing signatures.

  7. Very high resolution optical transition radiation imaging system: Comparison between simulation and experiment

    CERN Document Server

    Bolzon, B; Aumeyr, Thomas; Boogert, Stewart Takashi; Karataev, Pavel; Kruchinin, Konstantin; Lefevre, Thibaut; Mazzoni, Stefano; Nevay, Laurence James; Shevelev, M; Terunuma, N; Urakawa, J; Welsch, Carsten

    2015-01-01

    Optical transition radiation (OTR) has become a commonly used method for 2D beam imaging measurements. In the Accelerator Test Facility 2 (ATF2) at KEK, beam sizes smaller than the OTR point spread function have been measured. Simulations of the OTR imaging system have been performed using the ZEMAX software to study the effects of optical errors such as aberrations, diffraction, and misalignments of optical components. This paper presents a comparison of simulations of the OTR point spread function with experimental data obtained at ATF2. It shows how the quantification and control of optical errors impacts on optimizing the resolution of the system. We also show that the OTR point spread function needs to be predicted accurately to optimize any optical system and to predict the error made on measurement.

  8. The stabilisation of final focus system

    Indian Academy of Sciences (India)

    P A Coe; D Urner; A Reichold

    2007-12-01

    The StaFF (stabilisation of final focus) system will use interferometers to monitor the relative positions and orientations of several key components in the beam-delivery and interaction region. Monitoring the relative positions of the ILC final focus quadrupole magnets will be the most demanding application, where mutual and beam-relative stability will have a direct impact on machine luminosity. Established, laser-based frequency scanning interferometry (FSI) and fixed-frequency interferometry (FFI) offer positional resolution at length scales of the laser wavelength (1500 nm to 1560 nm) and a thousandth of the wavelength, respectively. As part of the ATF at KEK, StaFF will use interferometers to measure lines of a geodetic network to record relative motion between two beam position monitors. Interferometers are being designed and tested in Oxford prior to deployment at the ATF.

  9. Microarray expression analysis of genes involved in innate immune memory in peritoneal macrophages

    Directory of Open Access Journals (Sweden)

    Keisuke Yoshida

    2016-03-01

    Full Text Available Immunological memory has been believed to be a feature of the adaptive immune system for long period, but recent reports suggest that the innate immune system also exhibits memory-like reaction. Although evidence of innate immune memory is accumulating, no in vivo experimental data has clearly implicated a molecular mechanism, or even a cell-type, for this phenomenon. In this study of data deposited into Gene Expression Omnibus (GEO under GSE71111, we analyzed the expression profile of peritoneal macrophages isolated from mice pre-administrated with toll-like receptor (TLR ligands, mimicking pathogen infection. In these macrophages, increased expression of a group of innate immunity-related genes was sustained over a long period of time, and these genes overlapped with ATF7-regulated genes. We conclude that ATF7 plays an important role in innate immune memory in macrophages.

  10. Electric Motor Thermal Management R&D; NREL (National Renewable Energy Laboratory)

    Energy Technology Data Exchange (ETDEWEB)

    Bennion, Kevin

    2015-06-09

    Thermal constraints place significant limitations on how electric motors ultimately perform. Without the ability to remove heat, the motor cannot operate without sacrificing performance, efficiency, and reliability. Finite element analysis and computational fluid dynamics modeling approaches are being increasingly utilized in the design and analysis of electric motors. As the models become more sophisticated, it is important to have detailed and accurate knowledge of both the passive thermal performance and the active cooling performance. In this work, we provide an overview of research characterizing both passive and active thermal elements related to electric motor thermal management. To better characterize the passive thermal performance, work is being performed to measure motor material thermal properties and thermal contact resistances. The active cooling performance of automatic transmission fluid (ATF) jets is also being measured to better understand the heat transfer coefficients of ATF impinging on motor copper windings.

  11. Kinetics and mechanism of uncatalyzed and ruthenium(III)-catalyzed oxidation of formamidine derivative by hexacyanoferrate(III) in aqueous alkaline medium

    Indian Academy of Sciences (India)

    AHMED FAWZY

    2016-05-01

    The catalytic effect of ruthenium(III) on the oxidation of N,N-dimethyl-N-(4H-1,2,4-triazol-3-yl) formamidine (ATF) by hexacyanoferrate(III) (HCF) was studied spectrophotometrically in aqueous alkalinemedium. Both uncatalyzed and catalyzed reactions showed first order kinetics with respect to [HCF],whereas the reaction orders with respect to [ATF] and $[OH^{-}]$ were apparently less than unity over the concentrationrange studied. A first order dependence with respect to $[Ru^{III}]$ was obtained. Increasing ionic strengthincreased the rate of uncatalyzed reaction and decreased the rate of the catalyzed one Plausible mechanisticschemes of oxidation reactions have been proposed. In both cases, the final oxidation products are identifiedas aminotriazole, dimethyl amine and carbon dioxide. The rate laws associated with the reaction mechanismsare derived. The reaction constants involved in the different steps of the mechanisms were calculated. Theactivation and thermodynamic parameters have been computed and discussed.

  12. A new method for typing bovine major histocompatibility complex class II DRB3 alleles by combining two established PCR sequence-based techniques.

    Science.gov (United States)

    Takeshima, S-N; Matsumoto, Y; Miyasaka, T; Arainga-Ramirez, M; Saito, H; Onuma, M; Aida, Y

    2011-09-01

    Recently, two polymerase chain reaction sequence-based typing (PCR-SBT) methods were reported for the genotyping of the bovine leukocyte antigen (BoLA)-DRB3. One technique is a single PCR-SBT (sPCR-SBT) method that generates heterozygous sequences that are subsequently analyzed by the haplofinder program, while the other technique is a nested PCR-SBT (nPCR-SBT) method that allows the analysis of heterozygous sequences using the assign 400ATF software. In this study, these techniques were compared and then integrated to produce an improved genotyping method. The primer set used for sPCR-SBT was more accurate than those used for nPCR-SBT. Combining sPCR-SBT with the assign 400ATF software previously reported for nPCR-SBT enables rapid and accurate genotyping of a large number of DNA samples.

  13. HTLV-1 Tax Protein Stimulation of DNA Binding of bZIP Proteins by Enhancing Dimerization

    Science.gov (United States)

    Wagner, Susanne; Green, Michael R.

    1993-10-01

    The Tax protein of human T cell leukemia virus type-1 (HTLV-I) transcriptionally activates the HTLV-I promoter. This activation requires binding sites for activating transcription factor (ATF) proteins, a family of cellular proteins that contain basic region-leucine zipper (bZIP) DNA binding domains. Data are presented showing that Tax increases the in vitro DNA binding activity of multiple ATF proteins. Tax also stimulated DNA binding by other bZIP proteins, but did not affect DNA binding proteins that lack a bZIP domain. The increase in DNA binding occurred because Tax promotes dimerization of the bZIP domain in the absence of DNA, and the elevated concentration of the bZIP homodimer then facilitates the DNA binding reaction. These results help explain how Tax activates viral transcription and transforms cells.

  14. Estimates of CSR Instability Thresholds for Various Storage Rings

    CERN Document Server

    Zimmermann, Frank

    2010-01-01

    We review the key predictions and conditions by several authors for the onset of longitudinal instabilities due to coherent synchrotron radiation (CSR), and evaluate them numerically for various storage rings, namely the KEKB High Energy Ring (HER) & Low Energy Ring (LER), SuperKEKB HER & LER, old and new designs of the SuperKEKB Damping Ring (DR), SuperB HER & LER, CLIC DR (2009 and 2010 design parameters), SLC DR, and ATF DR. We show that the theoretical uncertainty in the instability onset is at least at the level of 20-30% in bunch intensity. More importantly, we present some doubts about the general applicability for many of these storage rings of some commonly used formulae. To cast further light on these questions, an experiment at lower beam energy on the ATF Damping Ring is proposed.

  15. Seleção de linhagens de sorgo granífero eficientes e responsivas à aplicação de fósforo

    Directory of Open Access Journals (Sweden)

    Fabricio Rodrigues

    2014-08-01

    Full Text Available O objetivo deste trabalho foi selecionar linhagens de sorgo simultaneamente responsivas ao fósforo e com elevada eficiência produtiva quanto a esse nutriente. Foram avaliadas 36 linhagens endogâmicas, em delineamento de blocos ao acaso, com duas repetições. Os caracteres usados para avaliação da eficiência produtiva foram produtividade média e eficiências de absorção, de utilização e de uso de fósforo, com e sem adubação fosfatada. Para análise da responsividade ao nutriente, foram avaliados caracteres de produtividade relativa e de eficiências de recuperação aparente, fisiológica e agronômica. Há variabilidade genética entre as linhagens quanto às eficiências de absorção, de utilização e de uso do fósforo, e quanto à responsividade ao nutriente, o que sugere a possibilidade de produção de híbridos destinados a nichos de mercado diferentes. As linhagens mais responsivas foram P9401, BR007B, BR008B, SC414-12E e SC566, e as mais eficientes, sob baixa disponibilidade de fósforo, foram ATF40B, SC566, BR005R, CMSXS225 e BR012 (R6. As linhagens ATF40B, ATF54 (f61, ATF54 (f596, QL3 e SC566 apresentaram melhor desempenho simultâneo das diferentes eficiências avaliadas e da responsividade ao fósforo. Apenas a avaliação do caráter produtividade, sob diferentes disponibilidades de fósforo, já permite identificar linhagens eficientes e responsivas ao fósforo.

  16. Nickel chloride (NiCl2) induces endoplasmic reticulum (ER) stress by activating UPR pathways in the kidney of broiler chickens.

    Science.gov (United States)

    Guo, Hongrui; Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan; Chen, Kejie; Deng, Jie

    2016-04-05

    It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days. We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94. Concurrently, all the three UPR pathways were activated by dietary NiCl2. Firstly, the PERK pathway was activated by increasing eIF2a and ATF4 mRNA expression. Secondly, the IRE1 pathway was activated duo to increase in IRE1 and XBP1 mRNA expression. And thirdly, the increase of ATF6 mRNA expression suggested that ATF6 pathway was activated. The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound-induced nephrotoxicity.

  17. Mexico-U.S. Relations: Issues for Congress

    Science.gov (United States)

    2010-02-03

    police, engaged in a joint operation in 38 U.S. cities against La Familia Michoacana. The raid resulted in 300 arrests. On October 11, 2009... Familia Michoacana. The raid resulted in 300 arrests. ATF has begun a new intelligence-driven effort known as Gunrunner Impact Teams (GRITs), deployed...México Presenta Teoría Inconsistente en la Muerte de Periodista Norteamericano,” February 4, 2009. 66 Amnesty International, “Mexico: New Reports of

  18. Mission Connect Mild TBI Translational Research Consortium

    Science.gov (United States)

    2010-08-01

    increased chronic inflammation we saw increased IBA 1 and ATF3 with decreased BDNF . Figure 10. Vimentin, like GFAP, appears upregulated in astrocytes...moderate TBI and/or stroke ) we also assessed the presence of blood borne proteins in brain at 18 days post-trauma. When we stained for albumin and...Yi and Hazell. 2004. J. Stroke Cerebrovasc. Dis. 13:129-137. Appendices None

  19. Balance of Activities of Alcohol Acetyltransferase and Esterase in Saccharomyces cerevisiae Is Important for Production of Isoamyl Acetate

    OpenAIRE

    Fukuda, Kiyoshi; Yamamoto, Nagi; Kiyokawa, Yoshifumi; Yanagiuchi, Toshiyasu; Wakai, Yoshinori; Kitamoto, Katsuhiko; Inoue, Yoshiharu; Kimura, Akira

    1998-01-01

    Isoamyl acetate is synthesized from isoamyl alcohol and acetyl coenzyme A by alcohol acetyltransferase (AATFase) in Saccharomyces cerevisiae and is hydrolyzed by esterases at the same time. We hypothesized that the balance of both enzyme activities was important for optimum production of isoamyl acetate in sake brewing. To test this hypothesis, we constructed yeast strains with different numbers of copies of the AATFase gene (ATF1) and the isoamyl acetate-hydrolyzing esterase gene (IAH1) and ...

  20. Ionization Chambers for Monitoring in High-Intensity Neutrino Beams

    CERN Document Server

    McDonald, J; Velissaris, C; Erwin, A R; Ping, H; Viren, B M; Diwan, M V

    2002-01-01

    Radiation-hard ionization chambers were tested using an intense electron beam from the accelerator test facility (ATF) at the Brookhaven National Laboratory (BNL). The detectors were designed to be used as the basic element for monitoring muons in the Main Injector Neutrino beamline (NuMI) at the Fermi National Accelerator Laboratory (FNAL). Measurements of linearity of response, voltage dependence, and the onset of ionization saturation as a function of gap voltage were performed.

  1. Disruption of the ribosomal P complex leads to stress-induced autophagy.

    Science.gov (United States)

    Artero-Castro, Ana; Perez-Alea, Mileidys; Feliciano, Andrea; Leal, Jose A; Genestar, Mónica; Castellvi, Josep; Peg, Vicente; Ramón Y Cajal, Santiago; Lleonart, Matilde E L

    2015-01-01

    The human ribosomal P complex, which consists of the acidic ribosomal P proteins RPLP0, RPLP1, and RPLP2 (RPLP proteins), recruits translational factors, facilitating protein synthesis. Recently, we showed that overexpression of RPLP1 immortalizes primary cells and contributes to transformation. Moreover, RPLP proteins are overexpressed in human cancer, with the highest incidence in breast carcinomas. It is thought that disruption of the P complex would directly affect protein synthesis, causing cell growth arrest and eventually apoptosis. Here, we report a distinct mechanism by which cancer cells undergo cell cycle arrest and induced autophagy when RPLP proteins are downregulated. We found that absence of RPLP0, RPLP1, or RPLP2 resulted in reactive oxygen species (ROS) accumulation and MAPK1/ERK2 signaling pathway activation. Moreover, ROS generation led to endoplasmic reticulum (ER) stress that involved the EIF2AK3/PERK-EIF2S1/eIF2α-EIF2S2-EIF2S3-ATF4/ATF-4- and ATF6/ATF-6-dependent arms of the unfolded protein response (UPR). RPLP protein-deficient cells treated with autophagy inhibitors experienced apoptotic cell death as an alternative to autophagy. Strikingly, antioxidant treatment prevented UPR activation and autophagy while restoring the proliferative capacity of these cells. Our results indicate that ROS are a critical signal generated by disruption of the P complex that causes a cellular response that follows a sequential order: first ROS, then ER stress/UPR activation, and finally autophagy. Importantly, inhibition of the first step alone is able to restore the proliferative capacity of the cells, preventing UPR activation and autophagy. Overall, our results support a role for autophagy as a survival mechanism in response to stress due to RPLP protein deficiency.

  2. Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Lixue Dong

    2017-01-01

    Full Text Available Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”, and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4 is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs. We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER stress response genes such as CHOP (C/EBP homologous protein and ATF3 (activating transcription factor 3. In the current study, we have examined acidosis/GPR4- induced ER stress pathways in human umbilical vein endothelial cells (HUVEC and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α, phosphorylated IRE1α (inositol-requiring enzyme 1α, and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1, was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic

  3. 油品知识讲座(四)自动变速器油%Auto Transmission Oil

    Institute of Scientific and Technical Information of China (English)

    马旭东

    2008-01-01

    @@ 自动变速器油,简称ATF(Automatic Transmission Fluid).从油品分类的角度看,自动变速器油ATF属于润滑油大类中的液力传动油的一种.自动变速器油既是自动变速器的润滑剂,又是自动变速器的工作介质.

  4. Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer's Disease.

    Science.gov (United States)

    Rozpedek, Wioletta; Markiewicz, Lukasz; Diehl, J Alan; Pytel, Dariusz; Majsterek, Ireneusz

    2015-01-01

    Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase β (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid β (Aβ) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β -amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.

  5. Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer’s Disease

    Science.gov (United States)

    Rozpędek, Wioletta; Markiewicz, Łukasz; Diehl, J. Alan; Pytel, Dariusz; Majsterek, Ireneusz

    2016-01-01

    Recent evidence suggests that the development of Alzheimer’s disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase β (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid β (Aβ) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β-amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway. PMID:26282939

  6. Tocotrienols are needed for normal bone calcification in growing female rats.

    Science.gov (United States)

    Norazlina, Mohamed; Ima-Nirwana, Soelaiman; Abul Gapor, Mohd Top; Abdul Kadir Khalid, B

    2002-01-01

    In this study the effects of vitamin E deficiency and supplementation on bone calcification were determined using 4-month-old female Sprague-Dawley rats. The rats weighed between 180 and 200 g. The study was divided in three parts. In experiment I the rats were given normal rat chow (RC, control group), a vitamin E deficient (VED) diet or a 50% vitamin E deficient (50%VED) diet. In experiment 2 the rats were given VED supplemented with 30 mg/kg palm vitamin E (PVE30), 60 mg/kg palm vitamin E (PVE60) or 30 mg/kg pure alpha-tocopherol (ATF). In experiment 3 the rats were fed RC and given the same supplements as in experiment 2. The treatment lasted 8 months. Vitamin E derived from palm oil contained a mixture of ATF and tocotrienols. Rats on the VED and 50%VED diets had lower bone calcium content in the left femur compared to the RC group (91.6 +/- 13.3 mg and 118.3 +/- 26.0 mg cf 165.7 +/- 15.2 mg; P VED group with PVE60 improved bone calcification in the left femur (133.6 +/- 5.0 mg compared with 91.6 +/- 13.3 mg; P VED group. Supplementing the RC group with PVE30, PVE60 or ATF did not cause any significant changes in bone calcium content. In conclusion, vitamin E deficiency impaired bone calcification. Supplementation with the higher dose of palm vitamin E improved bone calcium content, but supplementation with pure ATF alone did not. This effect may be attributed to the tocotrienol content of palm vitamin E. Therefore, tocotrienols play an important role in bone calcification.

  7. Validation of Genotyping-By-Sequencing Analysis in Populations of Tetraploid Alfalfa by 454 Sequencing.

    Science.gov (United States)

    Rocher, Solen; Jean, Martine; Castonguay, Yves; Belzile, François

    2015-01-01

    Genotyping-by-sequencing (GBS) is a relatively low-cost high throughput genotyping technology based on next generation sequencing and is applicable to orphan species with no reference genome. A combination of genome complexity reduction and multiplexing with DNA barcoding provides a simple and affordable way to resolve allelic variation between plant samples or populations. GBS was performed on ApeKI libraries using DNA from 48 genotypes each of two heterogeneous populations of tetraploid alfalfa (Medicago sativa spp. sativa): the synthetic cultivar Apica (ATF0) and a derived population (ATF5) obtained after five cycles of recurrent selection for superior tolerance to freezing (TF). Nearly 400 million reads were obtained from two lanes of an Illumina HiSeq 2000 sequencer and analyzed with the Universal Network-Enabled Analysis Kit (UNEAK) pipeline designed for species with no reference genome. Following the application of whole dataset-level filters, 11,694 single nucleotide polymorphism (SNP) loci were obtained. About 60% had a significant match on the Medicago truncatula syntenic genome. The accuracy of allelic ratios and genotype calls based on GBS data was directly assessed using 454 sequencing on a subset of SNP loci scored in eight plant samples. Sequencing depth in this study was not sufficient for accurate tetraploid allelic dosage, but reliable genotype calls based on diploid allelic dosage were obtained when using additional quality filtering. Principal Component Analysis of SNP loci in plant samples revealed that a small proportion (<5%) of the genetic variability assessed by GBS is able to differentiate ATF0 and ATF5. Our results confirm that analysis of GBS data using UNEAK is a reliable approach for genome-wide discovery of SNP loci in outcrossed polyploids.

  8. Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors.

    Science.gov (United States)

    Meyers, John A; Su, Derrick W; Lerner, Adam

    2009-05-01

    Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold changes were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1/CREB serine 63/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor 3-isobutyl-1-methylxanthine induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic 3-isobutyl-1-methylxanthine-induced ATF-1/CREB phosphorylation. Whereas PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1/CREB serine 63/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1/CREB serine 63/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.

  9. Report on Reactor Physics Assessment of Candidate Accident Tolerant Fuel Cladding Materials in LWRs

    Energy Technology Data Exchange (ETDEWEB)

    Powers, Jeffrey J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); George, Nathan [Univ. of Tennessee, Knoxville, TN (United States); Maldonado, G. Ivan [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Worrall, Andrew [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-08-28

    This work focuses on ATF concepts being researched at Oak Ridge National Laboratory (ORNL), expanding on previous studies of using alternate cladding materials in pressurized water reactors (PWRs). The neutronic performance of two leading alternate cladding materials were assessed in boiling water reactors (BWRs): iron-chromium-aluminum (FeCrAl) cladding, and silicon carbide (SiC)-based composite cladding. This report fulfills ORNL Milestone M3FT-15OR0202332 within the fiscal year 2015 (FY15)

  10. The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans

    OpenAIRE

    Block, Dena H. S.; Kwame Twumasi-Boateng; Hae Sung Kang; Jolie A Carlisle; Alexandru Hanganu; Ty Yu-Jen Lai; Michael Shapira

    2015-01-01

    Author Summary C. elegans provides a tractable genetic model to study the regulation of the evolutionarily conserved innate immune system. One of the central signaling modules of innate immunity in all organisms is the p38 pathway, which has been studied extensively in C. elegans. Such studies identified the transcription factors ATF-7 and SKN-1 as proteins mediating downstream effects of the p38 pathway on immune and oxidative stress gene expression. Previous studies in C. elegans also ident...

  11. Advanced Fuels Campaign FY 2014 Accomplishments Report

    Energy Technology Data Exchange (ETDEWEB)

    Lori Braase; W. Edgar May

    2014-10-01

    The overall goal of ATF development is to identify alternative fuel system technologies to further enhance the safety, competitiveness, and economics of commercial nuclear power. The complex multiphysics behavior of LWR nuclear fuel in the integrated reactor system makes defining specific material or design improvements difficult; as such, establishing desirable performance attributes is critical in guiding the design and development of fuels and cladding with enhanced accident tolerance.

  12. Mexico’s Narco-Insurgency and U.S. Counterdrug Policy

    Science.gov (United States)

    2009-05-01

    weapons are then taken across the border in ones and twos, forming what Mexican officials call “the iron river .”83 Though, as one ATF official notes...was able to overwhelm and annihilate isolated army garrisons, had Bogota nearly cut off from the rest of the country, and controlled roughly 40...cleared the FARC from the departments surrounding Bogota and substantially weakened the guerrillas even in traditional redoubts like Putumayo, Caqueta

  13. Crystal Structure of the Urokinase Receptor in a Ligand-Free Form

    DEFF Research Database (Denmark)

    Xu, Xiang; Gårdsvoll, Henrik; Yuan, Cai;

    2012-01-01

    . The crystal structure of human uPAR in its ligand-free state would clarify this issue, but such information remains unfortunately elusive. We now report the crystal structures of a stabilized, human uPAR (H47C/N259C) in its ligand-free form to 2.4 Å and in complex with amino-terminal fragment (ATF) to 3.2 Å...

  14. The influence of applied tensile stress on power loss in Co-rich amorphous Co-Fe-Si-B ribbons with induced magnetic anisotropy

    DEFF Research Database (Denmark)

    Nielsen, H; Nielsen, K; Nielsen, Otto V

    1982-01-01

    The influence on power loss PTof applied tensile stress σ in amorphous (Co0.89Fe0.11)72Mo3Si15B10(lambda_{s} > 0) and Co73Mo2Si15B10(lambda_{s} <0) ribbons with different induced magnetic anisotropy Kuis reported. The losses are measured under sinusoidal flux conditions atf = 50Hz,J_{max} = 0.57T...

  15. Experiment list: SRX187199 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX187199 mm9 TFs and others Batf Blood Th17 NA 35779340,89.2,14.3,31675 GSM1004794...: SL8349; Mus musculus; ChIP-Seq source_name=Th17 in vitro || genotype=IRF4 wt || control=SL8357 || factor=B...atf || time_point=48h || application=ChIP-Seq || cell type=Th17 http://dbarchive.biosciencedbc.jp/kyushu-u/m

  16. Late Quaternary sinistral slip rate along the Altyn Tagh fault and its structural transformation model

    Institute of Scientific and Technical Information of China (English)

    XU; Xiwei; P.; Tapponnier; J.; Van; Der; Woerd; F.; J.; Ryer

    2005-01-01

    Based on technical processing of high-resolution SPOT images and aerophotos,detailed mapping of offset landforms in combination with field examination and displacement measurement, and dating of offset geomorphic surfaces by using carbon fourteen (14C), cosmogenic nuclides (10Be+26Al) and thermoluminescence (TL) methods, the Holocene sinistral slip rates on different segments of the Altyn Tagh Fault (ATF) are obtained. The slip rates reach 17.5±2 mm/a on the central and western segments west of Aksay Town, 11±3.5 mm/a on the Subei-Shibaocheng segment, 4.8± 1.0 mm/a on the Sulehe segment and only 2.2± 0.2 mm/a on the Kuantanshan segment, an easternmost segment of the ATF. The sudden change points for loss of sinistral slip rates are located at the Subei, Shibaocheng and Shulehe triple junctions where NW-trending active thrust faults splay from the ATF and propagate southeastward. Slip vector analyses indicate that the loss of the sinistral slip rates from west to east across a triple junction has structurally transformed into local crustal shortening perpendicular to the active thrust faults and strong uplifting of the thrust sheets to form the NW-trending Danghe Nanshan,Daxueshan and Qilianshan Ranges. Therefore, the eastward extrusion of the northern Qinghai-Tibetan Plateau is limited and this is in accord with "the imbricated thrusting transformation-limited extrusion model".

  17. Effects of vitamin E on receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in rats treated with nicotine.

    Science.gov (United States)

    Norazlina, M; Maizatul-Neza, J; Azarina, A; Nazrun, A S; Norliza, M; Ima-Nirwana, S

    2010-03-01

    Vitamin E is found to reverse the effects of nicotine on bone and this study aimed to determine its mechanism. Male Sprague Dawley rats were divided into four groups and treated for 3 months: Group 1 was the control group (RC). Groups 2 (N), 3 (N+TT) and 4 (N+ATF) received nicotine 7 mg/kg throughout the treatment period. In addition, groups 3 and 4 received tocotrienol 60 mg/kg and alpha-tocopherol 60 mg/kg respectively during months 2 and 3. Parameters measured were serum osteoprotegerin (OPG), serum receptor activator of nuclear factor kappa B ligand (RANKL), femoral and lumbar bone calcium content and body weight. Nicotine did not affect OPG or RANKL levels but reduced bone calcium content suggesting the calcium loss is not due to increase osteoclastogenesis. OPG was increased in N+ATF while RANKL was slightly increased in N+TT. Both vitamin E supplements restored bone calcium loss induced by nicotine. Nicotine impaired weight gain in all treatment groups starting week 4 however, N+TT group was comparable to RC from week 6 onwards. Bone protective effects of ATF, but not TT, may be partly due to inhibition of osteoclastogenesis.

  18. Endothelin-1 protects human melanocytes from UV-induced DNA damage by activating JNK and p38 signalling pathways.

    Science.gov (United States)

    von Koschembahr, Anne M; Swope, Viki B; Starner, Renny J; Abdel-Malek, Zalfa A

    2015-04-01

    Endothelin-1 is a paracrine factor with mitogenic, melanogenic and survival effects on cultured human melanocytes. We report that endothelin-1 signalling reduced the generation and enhanced the repair of ultraviolet radiation (UV)-induced DNA photoproducts, and inhibited apoptosis of human melanocytes, without increasing cAMP levels, melanin content or proliferation. Treatment with endothelin-1 activated the MAP kinases JNK and p38, as evidenced by phosphorylation of their target, activating transcription factor-2 (ATF-2). Endothelin-1 also enhanced the phosphorylation of JNK, p38 and ATF-2 by UV. The effects of endothelin-1 were dependent on increasing intracellular calcium mobilization by endothelin B receptor signalling. Activation of both JNK and p38 was required for reducing DNA photoproducts, but only JNK partially contributed to the survival effect of endothelin-1. ATF-2 activation depended mainly on JNK, yet was not sufficient for the effect of endothelin-1 on UV-induced DNA damage, suggesting the requirement for other JNK and p38 targets for this effect. Our results underscore the significance of endothelin-1 and endothelin B receptor signalling in reducing the genotoxic effects of UV via activating JNK and p38, hence restoring genomic stability of melanocytes.

  19. Electric Motor Thermal Management R&D. Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Bennion, Kevin [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2016-04-01

    With the push to reduce component volumes, lower costs, and reduce weight without sacrificing performance or reliability, the challenges associated with thermal management increase for power electronics and electric motors. Thermal management for electric motors will become more important as the automotive industry continues the transition to more electrically dominant vehicle propulsion systems. The transition to more electrically dominant propulsion systems leads to higher-power duty cycles for electric drive systems. Thermal constraints place significant limitations on how electric motors ultimately perform, and as thermal management improves, there will be a direct trade-off between motor performance, efficiency, cost, and the sizing of electric motors to operate within the thermal constraints. The goal of this research project is to support broad industry demand for data, analysis methods, and experimental techniques to improve and better understand motor thermal management. Work in FY15 focused on two areas related to motor thermal management: passive thermal performance and active convective cooling. Passive thermal performance emphasized the thermal impact of materials and thermal interfaces among materials within an assembled motor. The research tasks supported the publication of test methods and data for thermal contact resistances and direction-dependent thermal conductivity within an electric motor. Active convective cooling focused on measuring convective heat-transfer coefficients using automatic transmission fluid (ATF). Data for average convective heat transfer coefficients for direct impingement of ATF jets was published. Also, experimental hardware for mapping local-scale and stator-scale convective heat transfer coefficients for ATF jet impingement were developed.

  20. Late Cenozoic sedimentary process and its response to the slip history of the central Altyn Tagh fault, NW China

    Institute of Scientific and Technical Information of China (English)

    陈正乐; 张岳桥; 陈宣华; 王小凤; A.S.Ramon; W.B.Zack

    2001-01-01

    The ENE-striking Altyn Tagh fault (ATF), extending along the northern edge of the Tibetan Plateau, is one of the major important strike-slip faults, and has been known as one of the key areas to debate the eastward extrusion and crustral shortening models of the Tibetan Plateau during and after India-Asia collision. This paper mainly presents new evidence of Late Cenozoic sedimentary process to reconstruct the slip history of the ATF during the Late Cenozoic. Field measurements and laboratory analyses of the sedimentary characteristics in the Late Cenozoic basins in the central Altyn Tagh fault suggest that Late Cenozoic sedimentary sequence should be divided into three units according to facies changes. The paleo-topography reconstruction shows that the sedimentation in these basins was tightly related with the fault, indicating that the ATF has experienced at least three stages of strike slipping in the Late Cenozoic. New geological data from the Late Cenozoic sedimentary basins and the formation of th

  1. In vacuum diamond sensor scanner for beam halo measurements in the beam line at the KEK Accelerator Test Facility

    CERN Document Server

    Liu, Shan; Cornebise, Patrick; Faus-Golfe, Angeles; Fuster-Martínez, Nuria; Griesmayer, Erich; Guler, Hayg; Kubytskyi, Viacheslav; Sylvia, Christophe; Toshiaki, Tauchi; Terunuma, Nobuhiro; Bambade, Philip

    2015-01-01

    The investigation of beam halo transverse distributions is important for the understanding of beam losses and the control of backgrounds in Future Linear Colliders (FLC). A novel in vacuum diamond sensor (DSv) scanner with four strips has been designed and developed for the investigation of the beam halo transverse distributions and also for the diagnostics of Compton recoil electrons after the interaction point (IP) of ATF2, a low energy (1.3 GeV) prototype of the final focus system for the ILC and CLIC linear collider projects. Using the DSv, a dynamic range of $\\sim10^6$ has been successfully demonstrated and confirmed for the first time by simultaneous beam core ($\\sim10^9$ electrons) and beam halo ($\\sim10^3$ electrons) measurements at ATF2. This report presents the characterization, performance studies and tests of the diamond sensors using an $\\alpha$ source as well as using the electron beams at PHIL, a low energy ($< 10$ MeV) photo-injector at LAL, and at ATF2. First beam halo measurement results ...

  2. Electric Motor Thermal Management R&D (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Bennion, K.

    2014-11-01

    Thermal constraints place significant limitations on how electric motors ultimately perform. Without the ability to remove heat, the motor cannot operate without sacrificing performance, efficiency, and reliability. Finite element analysis and computational fluid dynamics modeling approaches are being increasingly utilized in the design and analysis of electric motors. As the models become more sophisticated, it is important to have detailed and accurate knowledge of both the passive thermal performance and the active cooling performance. In this work, we provide an overview of research characterizing both passive and active thermal elements related to electric motor thermal management. To better characterize the passive thermal performance, the effective thermal properties and inter-lamination thermal contact resistances were measured for different stator lamination materials. The active cooling performance of automatic transmission fluid (ATF) jets was also measured to better understand the heat transfer coefficients of ATF impinging on motor copper windings. Ford's Mercon LV was the ATF evaluated in this study. The presentation provides an overview of prior work with a focus on describing future plans for research to be performed during FY15.

  3. Severe Accident Test Station Activity Report

    Energy Technology Data Exchange (ETDEWEB)

    Pint, Bruce A [ORNL; Terrani, Kurt A [ORNL

    2015-06-01

    Enhancing safety margins in light water reactor (LWR) severe accidents is currently the focus of a number of international R&D programs. The current UO2/Zr-based alloy fuel system is particularly susceptible since the Zr-based cladding experiences rapid oxidation kinetics in steam at elevated temperatures. Therefore, alternative cladding materials that offer slower oxidation kinetics and a smaller enthalpy of oxidation can significantly reduce the rate of heat and hydrogen generation in the core during a coolant-limited severe accident. In the U.S. program, the high temperature steam oxidation performance of accident tolerant fuel (ATF) cladding solutions has been evaluated in the Severe Accident Test Station (SATS) at Oak Ridge National Laboratory (ORNL) since 2012. This report summarizes the capabilities of the SATS and provides an overview of the oxidation kinetics of several candidate cladding materials. A suggested baseline for evaluating ATF candidates is a two order of magnitude reduction in the steam oxidation resistance above 1000ºC compared to Zr-based alloys. The ATF candidates are categorized based on the protective external oxide or scale that forms during exposure to steam at high temperature: chromia, alumina, and silica. Comparisons are made to literature and SATS data for Zr-based alloys and other less-protective materials.

  4. Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells

    DEFF Research Database (Denmark)

    Hisatsune, Junzo; Yamasaki, Eiki; Nakayama, Masaaki;

    2007-01-01

    Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade......A-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription...... promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading...

  5. Subamolide a induces mitotic catastrophe accompanied by apoptosis in human lung cancer cells.

    Science.gov (United States)

    Hung, Jen-Yu; Wen, Ching-Wen; Hsu, Ya-Ling; Lin, En-Shyh; Huang, Ming-Shyan; Chen, Chung-Yi; Kuo, Po-Lin

    2013-01-01

    This study investigated the anticancer effects of subamolide A (Sub-A), isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

  6. Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Jen-Yu Hung

    2013-01-01

    Full Text Available This study investigated the anticancer effects of subamolide A (Sub-A, isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM, which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

  7. Upregulating Noxa by ER stress, celastrol exerts synergistic anti-cancer activity in combination with ABT-737 in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhu, Hong; Yang, Wei; He, Ling-juan; Ding, Wan-jing; Zheng, Lin; Liao, Si-da; Huang, Ping; Lu, Wei; He, Qiao-jun; Yang, Bo

    2012-01-01

    The human hepatocellular carcinoma (HCC) represents biologically aggressive and chemo-resistant cancers. Owing to the low affinity with the apoptotic factor Mcl-1, the BH3 mimetic drug ABT-737 failed to exert potent cancer-killing activities in variety of cancer models including HCC. The current study demonstrated that combining ABT-737 and Celastrol synergistically suppressed HCC cell proliferation, and induced apoptosis which was accompanied with the activation of caspase cascade and release of cytochrome c from mitochondria. Further study revealed that the enhanced Noxa caused by Celastrol was the key factor for the synergy, since small interfering RNA-mediated knockdown of Noxa expression in HCC cells resulted in decreased apoptosis and attenuated anti-proliferative effects of the combination. In addition, our study unraveled that, upon Celastrol exposure, the activation of endoplasmic reticulum (ER) stress, specifically, the eIF2α-ATF4 pathway played indispensable roles in the activation of Noxa, which was validated by the observation that depletion of ATF4 significantly abrogated the Noxa elevation by Celastrol. Our findings highlight a novel signaling pathway through which Celastrol increase Noxa expression, and suggest the potential use of ATF4-mediated regulation of Noxa as a promising strategy to improve the anti-cancer activities of ABT-737.

  8. Upregulating Noxa by ER stress, celastrol exerts synergistic anti-cancer activity in combination with ABT-737 in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Hong Zhu

    Full Text Available The human hepatocellular carcinoma (HCC represents biologically aggressive and chemo-resistant cancers. Owing to the low affinity with the apoptotic factor Mcl-1, the BH3 mimetic drug ABT-737 failed to exert potent cancer-killing activities in variety of cancer models including HCC. The current study demonstrated that combining ABT-737 and Celastrol synergistically suppressed HCC cell proliferation, and induced apoptosis which was accompanied with the activation of caspase cascade and release of cytochrome c from mitochondria. Further study revealed that the enhanced Noxa caused by Celastrol was the key factor for the synergy, since small interfering RNA-mediated knockdown of Noxa expression in HCC cells resulted in decreased apoptosis and attenuated anti-proliferative effects of the combination. In addition, our study unraveled that, upon Celastrol exposure, the activation of endoplasmic reticulum (ER stress, specifically, the eIF2α-ATF4 pathway played indispensable roles in the activation of Noxa, which was validated by the observation that depletion of ATF4 significantly abrogated the Noxa elevation by Celastrol. Our findings highlight a novel signaling pathway through which Celastrol increase Noxa expression, and suggest the potential use of ATF4-mediated regulation of Noxa as a promising strategy to improve the anti-cancer activities of ABT-737.

  9. Probing half βy* optics in the Accelerator Test Facility 2

    Science.gov (United States)

    Patecki, M.; Bett, D.; Marin, E.; Plassard, F.; Tomás, R.; Kubo, K.; Kuroda, S.; Naito, T.; Okugi, T.; Tauchi, T.; Terunuma, N.

    2016-10-01

    A nanometer beam size at the interaction point (IP) is required for future linear colliders to achieve the desired rate of particle collisions. KEK Accelerator Test Facility 2 (ATF2), a scaled down implementation of the linear collider beam delivery system, serves for demonstrating the feasibility of the final focus system (FFS). An unprecedented low vertical beam size at the IP of about 40 nm has been already measured in ATF2 using the optics with a nominal βy* . In our study we decrease the βy* value in order to investigate the performance of more chromatic optics and to study the limits of beam focusing at the IP. Stronger beam focusing amplifies the aberrations from the final focus imperfections which cause an increase of the beam size at the IP. Simulations show that the multipolar errors and final doublet fringe fields spoil the IP beam sizes for ultralow βy* optics but can be mitigated either by increasing the value of the horizontal β* or installing a pair of octupole magnets. We report on our first experimental steps towards the ultralow βy* in ATF2. New methods for the beam diagnostics at the IP were developed in order to precisely set the desired optics. βy* value was half the nominal value. The beam tuning was performed and the measured beam size is compared with the simulation results.

  10. Influence of carbon and nitrogen source on production of volatile fragrance and flavour metabolites by the yeast Kluyveromyces marxianus.

    Science.gov (United States)

    Gethins, Loughlin; Guneser, Onur; Demirkol, Aslı; Rea, Mary C; Stanton, Catherine; Ross, R Paul; Yuceer, Yonca; Morrissey, John P

    2015-01-01

    The yeast Kluyveromyces marxianus produces a range of volatile molecules with applications as fragrances or flavours. The purpose of this study was to establish how nutritional conditions influence the production of these metabolites. Four strains were grown on synthetic media, using a variety of carbon and nitrogen sources and volatile metabolites analysed using gas chromatography-mass spectrometry (GC-MS). The nitrogen source had pronounced effects on metabolite production: levels of the fusel alcohols 2-phenylethanol and isoamyl alcohol were highest when yeast extract was the nitrogen source, and ammonium had a strong repressing effect on production of 2-phenylethyl acetate. In contrast, the nitrogen source did not affect production of isoamyl acetate or ethyl acetate, indicating that more than one alcohol acetyl transferase activity is present in K. marxianus. Production of all acetate esters was low when cells were growing on lactose (as opposed to glucose or fructose), with a lower intracellular pool of acetyl CoA being one explanation for this observation. Bioinformatic and phylogenetic analysis of the known yeast alcohol acetyl transferases ATF1 and ATF2 suggests that the ancestral protein Atf2p may not be involved in synthesis of volatile acetate esters in K. marxianus, and raises interesting questions as to what other genes encode this activity in non-Saccharomyces yeasts. Identification of all the genes involved in ester synthesis will be important for development of the K. marxianus platform for flavour and fragrance production.

  11. 汽车自动变速器油的技术现状与发展趋势%Current Technology and Development Trends of Automatic Transmission Fluids

    Institute of Scientific and Technical Information of China (English)

    李茂生; 杜群贵; 贾继欣

    2014-01-01

    The types,characteristics and developing direction of vehicle automatic transmission,and the technical re-quirement,current technological state and development trend of automatic transmission fluids (ATF/CVTF ) were de-scribed.The tribological characteristics and evaluation method of ATF/CVTF were introduced.The development and appli-cation of new automatic transmission fluids and its corresponding evaluation test methods of physical and chemical proper-ties,friction characteristics and wear state,the development of the specifications and standard of automatic transmission flu-ids are key common technologies for development of automatic transmission.%论述汽车自动变速器(AT、CVT)的类型、特点及发展方向,以及与其配套的变速器油(ATF、CVTF)的技术现状和发展趋势,介绍ATF/CVTF的摩擦学特性及其评价方法。开发和应用新型自动变速器油及其相应的摩擦特性测试方法、磨损状态评定手段和油品理化性能测试方法及台架试验方法,制定自动变速器油的规格标准,是促进自动变速器发展的关键共性技术。

  12. 非典型症状与双相障碍%Atypical features and bipolar disorder

    Institute of Scientific and Technical Information of China (English)

    彭代辉; 黄悦琦; 江开达

    2016-01-01

    Bipolar Disorder (BD) features with various of clinical symptoms, leading to the misdiagnosis of major depressive disorder (MDD). The atypical features (ATFs) are regarded as one of valuable index to idenitfy BD from depressed paitents. The ATFs should be helpful to the differenital diagnose of the two diseases. In this forum, we discussed the issue of the relaiton between the ATFs and BD.%概述:双相障碍(Bipolar Disorder,BD)临床症状多样,容易被误诊为抑郁症(Major depressive disorder, MDD)。非典型症状(Atypical Features,ATFs)是一个有用的指标,可以从抑郁状态中识别出双相障碍,有助于双相障碍与抑郁症的鉴别诊断。本文就非典型症状与双相障碍的相关性问题进行讨论。

  13. A 55,000-60,000 Mr receptor protein for urokinase-type plasminogen activator. Identification in human tumor cell lines and partial purification

    DEFF Research Database (Denmark)

    Nielsen, L S; Kellerman, G M; Behrendt, N;

    1988-01-01

    The iodinated Mr approximately equal to 15,000 amino-terminal fragment (ATF) of the urokinase-type plasminogen activator (u-PA) molecule bound specifically to the cell surface of all of seven cultured human tumor cell lines studied. Cross-linking of iodinated ATF to the cell surface using...... a bifunctional amino-reactive reagent followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed with the four cell lines studied the occurrence of a single band migrating with an Mr of 70,000-75,000, indicating complex formation with an Mr of 55,000-60,000 u-PA receptor......-PA-R consists of one polypeptide chain. Two forms of u-PA-R, which differed with respect to affinity to concanavalin A, were identified. u-PA-R retained its ability to bind to ATF after cell lysis, and it was purified approximately 2,200-fold from biosynthetically labeled U937 cells by affinity chromatography...

  14. Gas6 induces cancer cell migration and epithelial–mesenchymal transition through upregulation of MAPK and Slug

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yunhee [Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of); Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Lee, Mira [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, Semi, E-mail: semikim@kribb.re.kr [Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of); Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of)

    2013-04-26

    Highlights: •We investigated the molecular mechanisms underlying Gas6-mediated cancer cell migration. •Gas6 treatment and subsequent Axl activation induce cell migration and EMT via upregulation of Slug. •Slug expression mediated by Gas6 is mainly through c-Jun and ATF-2 in an ERK1/2 and JNK-dependent manner. •The Gas6/Axl-Slug axis may be exploited as a target for anti-cancer metastasis therapy. -- Abstract: Binding of Gas6 to Axl (Gas6/Axl axis) alters cellular functions, including migration, invasion, proliferation, and survival. However, the molecular mechanisms underlying Gas6-mediated cell migration remain poorly understood. In this study, we found that Gas6 induced the activation of JNK and ERK1/2 signaling in cancer cells expressing Axl, resulting in the phosphorylation of activator protein-1 (AP-1) transcription factors c-Jun and ATF-2, and induction of Slug. Depletion of c-Jun or ATF-2 by siRNA attenuated the Gas6-induced expression of Slug. Slug expression was required for cell migration and E-cadherin reduction/vimentin induction induced by Gas6. These results suggest that Gas6 induced cell migration via Slug upregulation in JNK- and ERK1/2-dependent mechanisms. These data provide an important insight into the molecular mechanisms mediating Gas6-induced cell migration.

  15. LIGHT WATER REACTOR ACCIDENT TOLERANT FUELS IRRADIATION TESTING

    Energy Technology Data Exchange (ETDEWEB)

    Carmack, William Jonathan [Idaho National Laboratory; Barrett, Kristine Eloise [Idaho National Laboratory; Chichester, Heather Jean MacLean [Idaho National Laboratory

    2015-09-01

    The purpose of Accident Tolerant Fuels (ATF) experiments is to test novel fuel and cladding concepts designed to replace the current zirconium alloy uranium dioxide (UO2) fuel system. The objective of this Research and Development (R&D) is to develop novel ATF concepts that will be able to withstand loss of active cooling in the reactor core for a considerably longer time period than the current fuel system while maintaining or improving the fuel performance during normal operations, operational transients, design basis, and beyond design basis events. It was necessary to design, analyze, and fabricate drop-in capsules to meet the requirements for testing under prototypic LWR temperatures in Idaho National Laboratory's Advanced Test Reactor (ATR). Three industry led teams and one DOE team from Oak Ridge National Laboratory provided fuel rodlet samples for their new concepts for ATR insertion in 2015. As-built projected temperature calculations were performed on the ATF capsules using the BISON fuel performance code. BISON is an application of INL’s Multi-physics Object Oriented Simulation Environment (MOOSE), which is a massively parallel finite element based framework used to solve systems of fully coupled nonlinear partial differential equations. Both 2D and 3D models were set up to examine cladding and fuel performance.

  16. Unique properties of multiple tandem copies of the M26 recombination hotspot in mitosis and meiosis in Schizosaccharomyces pombe.

    Science.gov (United States)

    Steiner, Walter W; Recor, Chelsea L; Zakrzewski, Bethany M

    2016-11-15

    The M26 hotspot of the fission yeast Schizosaccharomyces pombe is one of the best-characterized eukaryotic hotspots of recombination. The hotspot requires a seven bp sequence, ATGACGT, that serves as a binding site for the Atf1-Pcr1 transcription factor, which is also required for activity. The M26 hotspot is active in meiosis but not mitosis and is active in some but not all chromosomal contexts and not on a plasmid. A longer palindromic version of M26, ATGACGTCAT, shows significantly greater activity than the seven bp sequence. Here, we tested whether the properties of the seven bp sequence were also true of the longer sequence by placing one, two, or three copies of the sequence into the ade6 gene, where M26 was originally discovered. These constructs were tested for activity when located on a plasmid or on a chromosome in mitosis and meiosis. We found that two copies of the 10bp M26 motif on a chromosome were significantly more active for meiotic recombination than one, but no further increase was observed with three copies. However, three copies of M26 on a chromosome created an Atf1-dependent mitotic recombination hotspot. When located on a plasmid, M26 also appears to behave as a mitotic recombination hotspot; however, this behavior most likely results from Atf1-dependent inter-allelic complementation between the plasmid and chromosomal ade6 alleles.

  17. The BNL Accelerator Test Facility and experimental program

    Energy Technology Data Exchange (ETDEWEB)

    Ben-Zvi, I. (Brookhaven National Lab., Upton, NY (United States) State Univ. of New York, Stony Brook, NY (United States). Dept. of Physics)

    1991-01-01

    The Accelerator Test Facility (ATF) at BNL is a users' facility for experiments in Accelerator and Beam Physics. The ATF provides high brightness electron beams and high power laser pulses synchronized to the electron beam, suitable for studies of new methods of high gradient acceleration and state of the art free electron lasers. The electrons are produced by a laser photocathode rf gun and accelerated to 50 to 100 MeV by two traveling wave accelerator sections. The lasers include a 10 mJ, 10 ps Nd:YAG laser and a 100 mJ, 10 ps CO{sub 2} laser. A number of users from National Laboratories, universities and industry take part in experiments at the ATF. The experimental program includes various acceleration schemes, Free-Electron Laser experiments and a program on the development of high brightness electron beams. The AFT's experimental program commenced in early 1991 at an energy of about 4 MeV. The full program, with 50 MeV and the High power laser will begin operation this year. 28 refs., 4 figs.

  18. A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4.

    Science.gov (United States)

    Rauthan, Manish; Ranji, Parmida; Abukar, Ragda; Pilon, Marc

    2015-06-01

    The mevalonate pathway is responsible for the synthesis of cholesterol, coenzyme Q, and prenyl groups essential for small GTPase modification and function, and for the production of dolichols important for protein glycosylation. Statins, i.e., cholesterol-lowering drugs that inhibit the rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase, are lethal to Caenorhabditis elegans even though this animal lacks the branch of the mevalonate pathway that leads to cholesterol synthesis. To better understand the effects of statins that are not related to cholesterol, we have adopted the strategy of isolating statin-resistant C. elegans mutants. Previously, we showed that such mutants often have gain-of-function mutations in ATFS-1, a protein that activates the mitochondrial unfolded protein response. Here, we describe the isolation of a statin-resistant mutant allele of the NDUF-7 protein, which is a component of complex I in the mitochondrial electron transport chain. The novel nduf-7(et19) mutant also exhibits constitutive and ATFS-1-dependent activation of the mitochondrial unfolded protein response (UPR(mt)) and prolonged life span, both of which are mediated through production of ROS. Additionally, lifespan extension, but not activation, of the mitochondrial unfolded protein response was dependent on the pro-apoptotic gene ced-4. We conclude that the nduf-7(et19) mutant allele causes an increase in reactive oxygen species that activate ATFS-1, hence UPR(mt)-mediated statin resistance, and extends life span via CED-4.

  19. Genes and Gene Networks Involved in Sodium Fluoride-Elicited Cell Death Accompanying Endoplasmic Reticulum Stress in Oral Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Yoshiaki Tabuchi

    2014-05-01

    Full Text Available Here, to understand the molecular mechanisms underlying cell death induced by sodium fluoride (NaF, we analyzed gene expression patterns in rat oral epithelial ROE2 cells exposed to NaF using global-scale microarrays and bioinformatics tools. A relatively high concentration of NaF (2 mM induced cell death concomitant with decreases in mitochondrial membrane potential, chromatin condensation and caspase-3 activation. Using 980 probe sets, we identified 432 up-regulated and 548 down-regulated genes, that were differentially expressed by >2.5-fold in the cells treated with 2 mM of NaF and categorized them into 4 groups by K-means clustering. Ingenuity® pathway analysis revealed several gene networks from gene clusters. The gene networks Up-I and Up-II included many up-regulated genes that were mainly associated with the biological function of induction or prevention of cell death, respectively, such as Atf3, Ddit3 and Fos (for Up-I and Atf4 and Hspa5 (for Up-II. Interestingly, knockdown of Ddit3 and Hspa5 significantly increased and decreased the number of viable cells, respectively. Moreover, several endoplasmic reticulum (ER stress-related genes including, Ddit3, Atf4 and Hapa5, were observed in these gene networks. These findings will provide further insight into the molecular mechanisms of NaF-induced cell death accompanying ER stress in oral epithelial cells.

  20. The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans

    Science.gov (United States)

    Peña, Salvador; Sherman, Teresa; Brookes, Paul S.; Nehrke, Keith

    2016-01-01

    The mitochondrial unfolded protein response (UPRmt) is a surveillance pathway that defends proteostasis in the “powerhouse” of the cell. Activation of the UPRmt protects against stresses imposed by reactive oxygen species, respiratory chain deficits, and pathologic bacteria. Consistent with the UPRmt’s role in adaption, we found that either its pharmacological or genetic activation by ethidium bromide (EtBr) or RNAi of the mitochondrial AAA-protease spg-7 was sufficient to reduce death in an anoxia-based Caenorhabditis elegans model of ischemia-reperfusion injury. The UPRmt-specific transcription factor atfs-1 was necessary for protection and atfs-1 gain-of-function (gf) mutants were endogenously protected from both death and dysfunction. Neurons exhibited less axonal degeneration following non-lethal anoxia-reperfusion (A-R) when the UPRmt was pre-activated, and consistent with the concept of mitochondrial stress leading to cell non-autonomous (ie. “remote”) effects, we found that restricted activation of the UPRmt in neurons decreased A-R death. However, expression of the atfs-1(gf) mutant in neurons, which resulted in a robust activation of a neuronal UPRmt, did not upregulate the UPRmt in distal tissues, nor did it protect the worms from A-R toxicity. These findings suggest that remote signaling requires additional component(s) acting downstream of de facto mitochondrial stress. PMID:27459203

  1. Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting.

    Science.gov (United States)

    Kuo, Jinn-Rung; Shang, Hung-Sheng; Ho, Chun-Te; Lai, Kun-Goung; Liu, Tsan-Zon; Chen, Yin-Ju; Chiou, Jeng-Fong

    2016-11-01

    Cisplatin is commonly recognized as a DNA-damaging drug; however, its versatile antitumor effects have been demonstrated to extend beyond this narrow functional attribute. The present study determined how cisplatin regulates alternative pathways and transcription factors to exert its additional antitumor actions. Cisplatin was observed to be able to trigger an endoplasmic reticulum stress response through aggravated nitrosative stress coupled to perturbed mitochondrial calcium (Ca(2+)) homeostasis, which substantially downregulated glucose-regulated protein (GRP) 78 expression by suppressing the cleavage of activating transcription factor (ATF) 6α (90 kDa) to its active 50 kDa subunit. Concomitantly, the ATF4-ATF3-C/emopamil binding protein homologous protein axis was activated by cisplatin, which triggered cellular glutathione (GSH) depletion by strongly inhibiting γ-glutamylcysteine synthetase heavy chain (γ-GCSh), a key enzyme in GSH biosynthesis. The present study also demonstrated that cisplatin substantially inhibited β-catenin, causing a marked downregulation of survivin and B-cell lymphoma (Bcl)-2. Taken together, the present results uncovered a novel mechanism of cisplatin that could simultaneously trigger the inhibition of three prominent antiapoptotic effector molecules (Bcl-2, survivin and GRP78) and effectively promote GSH depletion by inhibiting γ-GCSh. These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively.

  2. Molecular photoacoustic tomography of breast cancer using receptor targeted magnetic iron oxide nanoparticles as contrast agents.

    Science.gov (United States)

    Xi, Lei; Grobmyer, Stephen R; Zhou, Guangyin; Qian, Weiping; Yang, Lily; Jiang, Huabei

    2014-06-01

    In this report, we present a breast imaging technique combining high-resolution near-infrared (NIR) light induced photoacoustic tomography (PAT) with NIR dye-labeled amino-terminal fragments of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (NIR830-ATF-IONP) for breast cancer imaging using an orthotopic mouse mammary tumor model. We show that accumulation of the targeted nanoparticles in the tumor led to photoacoustic contrast enhancement due to the high absorption of iron oxide nanoparticles (IONP). NIR fluorescence images were used to validate specific delivery of NIR830-ATF-IONP to mouse mammary tumors. We found that systemic delivery of the targeted IONP produced 4- and 10-fold enhancement in photoacoustic signals in the tumor, compared to the tumor of the mice that received non-targeted IONP or control mice. The use of targeted nanoparticles allowed imaging of tumors located as deep as 3.1 cm beneath the normal tissues. Our study indicates the potential of the combination of photoacoustic tomography and receptor-targeted NIR830-ATF-IONP as a clinical tool that can provide improved specificity and sensitivity for breast cancer detection.

  3. Critical Role of AKT Protein in Myeloma-induced Osteoclast Formation and Osteolysis*

    Science.gov (United States)

    Cao, Huiling; Zhu, Ke; Qiu, Lugui; Li, Shuai; Niu, Hanjie; Hao, Mu; Yang, Shengyong; Zhao, Zhongfang; Lai, Yumei; Anderson, Judith L.; Fan, Jie; Im, Hee-Jeong; Chen, Di; Roodman, G. David; Xiao, Guozhi

    2013-01-01

    Abnormal osteoclast formation and osteolysis are the hallmarks of multiple myeloma (MM) bone disease, yet the underlying molecular mechanisms are incompletely understood. Here, we show that the AKT pathway was up-regulated in primary bone marrow monocytes (BMM) from patients with MM, which resulted in sustained high expression of the receptor activator of NF-κB (RANK) in osteoclast precursors. The up-regulation of RANK expression and osteoclast formation in the MM BMM cultures was blocked by AKT inhibition. Conditioned media from MM cell cultures activated AKT and increased RANK expression and osteoclast formation in BMM cultures. Inhibiting AKT in cultured MM cells decreased their growth and ability to promote osteoclast formation. Of clinical significance, systemic administration of the AKT inhibitor LY294002 blocked the formation of tumor tissues in the bone marrow cavity and essentially abolished the MM-induced osteoclast formation and osteolysis in SCID mice. The level of activating transcription factor 4 (ATF4) protein was up-regulated in the BMM cultures from multiple myeloma patients. Adenoviral overexpression of ATF4 activated RANK expression in osteoclast precursors. These results demonstrate a new role of AKT in the MM promotion of osteoclast formation and bone osteolysis through, at least in part, the ATF4-dependent up-regulation of RANK expression in osteoclast precursors. PMID:24005670

  4. 茵陈蒿汤对胆汁淤积性肝纤维化大鼠内质网应激PERK通路的影响%Experimental Study on Effects of Yinchenhao Tang (茵陈蒿汤) on Endoplasmic Reticulum Stress PERK Pathway in Cholestasis Liver Fibrosis Rats

    Institute of Scientific and Technical Information of China (English)

    李木松; 张贵贤; 魏媛媛; 刘震霞

    2016-01-01

    目的:观察茵陈蒿汤对胆汁淤积性肝纤维化大鼠PKR样内质网激酶(PERK)-真核生物翻译起始因子(eIF2α)-转录活性因子4(ATF4)的影响,探讨茵陈蒿汤抗胆汁淤积性肝纤维的作用机制.方法:将35只SD大鼠分为假手术组和造模组,采用胆总管结扎法复制胆汁淤积性肝纤维化大鼠模型,1W后将造模组动物分为模型组和中药组,中药组予以3.5 g/kg茵陈蒿汤灌胃,4W后处死动物.HE、Masson染色观察肝脏组织病理学变化;Western blot法检测各组大鼠肝脏PERK、eIF2α和ATF4蛋白表达的变化.结果:肝脏组织病理学变化显示模型组大鼠肝纤维化程度较假手术组明显增加(P<0.05),中药组大鼠肝纤维化程度较模型组减轻(P<0.05),但仍重于假手术组.Western blot结果显示,模型组肝脏PERK、eIF2α和ATF4蛋白的表达与假手术组相比显著升高(P<0.01),中药组较模型组PERK、eIF2α和ATF4蛋白表达明显降低(P<0.01).结论:抑制PERK、eIF2α和ATF4的活化,从而减少肝细胞凋亡,进而抑制内质网应激在胆汁淤积性肝纤维化中的促进作用,是茵陈蒿汤抗胆汁淤积性肝纤维化的作用机制之一.

  5. cAMP-Induced Histones H3 Dephosphorylation Is Independent of PKA and MAP Kinase Activations and Correlates With mTOR Inactivation.

    Science.gov (United States)

    Rodriguez, Pedro; Rojas, Juan

    2016-03-01

    cAMP is a second messenger well documented to be involved in the phosphorylation of PKA, MAP kinase, and histone H3 (H3). Early, we reported that cAMP also induced H3 dephosphorylation in a variety of proliferating cell lines. Herein, it is shown that cAMP elicits a biphasic H3 dephosphorylation independent of PKA activation in cycling cells. H89, a potent inhibitor of PKA catalytic sub-unite, could not abolish this effect. Additionally, H89 induces a rapid and biphasic H3 serine 10 dephosphorylation, while a decline in the basal phosphorylation of CREB/ATF-1 is observed. Rp-cAMPS, an analog of cAMP and specific inhibitor of PKA, is unable to suppress cAMP-mediated H3 dephosphorylation, whereas Rp-cAMPS effectively blocks CREB/ATF-1 hyper-phosphorylation by cAMP and its inducers. Interestingly, cAMP exerts a rapid and profound H3 dephosphorylation at much lower concentration (50-fold lower, 0.125 mM) than the concentration required for maximal CREB/ATF-1 phosphorylation (5 mM). Much higher cAMP concentration is required to fully induce CREB/ATF-1 gain in phosphate (5 mM), which correlates with the inhibition of H3 dephosphorylation. Also, the dephosphorylation of H3 does not overlap at onset of MAP kinase phosphorylation pathways, p38 and ERK. Surprisingly, rapamycin (an mTOR inhibitor), cAMP, and its natural inducer isoproterenol, elicit identical dephosphorylation kinetics on both S6K1 ribosomal kinase (a downstream mTOR target) and H3. Finally, cAMP-induced H3 dephosphorylation is PP1/2-dependent. The results suggest that a pathway, requiring much lower cAMP concentration to that required for CREB/ATF-1 hyper-phosphorylation, is responsible for histone H3 dephosphorylation and may be linked to mTOR down regulation.

  6. p38丝裂原活化蛋白激酶特异性抑制剂SB203580对溃疡性结肠炎大鼠血清IL-6和IL-1β的影响%Effects of p38 mitogen-activated protein kinase inhibitor SB203580 on the levels of IL-1βand IL-6 in the serum of rats with TNBS-induced colitis

    Institute of Scientific and Technical Information of China (English)

    李军华; 周薇

    2014-01-01

    Objective To investigate the effect of p38 mitogen-activated protein kinase inhibitor SB203580 on the serum levels of IL-1βand IL-6 in rats with TNBS-induced colitis,and to explore the role of p38 in the pathogenesis of colitis.Methods Forty-five healthy SD rats were randomly divided into three groups:normal group,model group,SB203580 group.The rat models of colitis were induced by 2,4,6-trinitrobenzene sulfonic acid(TNBS),the expression of p-ATF2 in colon tissue was examined by immunohistochemistry,the serum levels of IL-1βand IL-6 in rats were detected by ELISA.And the colonic mucosal damage index and histological score were evaluated.At the same time,the relationship between p-ATF2 and IL-1β,IL-6 was analysed.Results Compared with normal group,the expression of p-ATF2 and the serum levels of IL-1βand IL-6 were significantly increased in model group (P<0.05),and the above indicators in rats of SB203580 group was lower than that of model group(P<0.05).There was positive correlation between the expression of p-ATF2 and the levels of IL-1β,IL-6 respectively(r=0.980,0.988,P<0.05).Conclusion p38 MAPK inhibitor SB203580 has protective effects on TNBS-induced ul-cerative colitis through down-regulating the expression of p-ATF2 and levels of IL-1β,IL-6.%目的:观察p38丝裂原活化蛋白激酶(MAPK)特异性抑制剂SB203580对溃疡性结肠炎大鼠血清IL-6和IL-1β的影响,探讨p38MAPK在溃疡性结肠炎中的可能作用。方法45只健康SD大鼠随机均分为正常对照组、模型组、SB203580组。采用三硝基苯磺酸(TNBS)制备大鼠溃疡性结肠炎模型,免疫组织化学方法检测大鼠肠组织活化转录因子2(p-ATF2)表达,ELISA法检测大鼠血清白介素-6(IL-6)和白介素-1β(IL-1β)表达水平,并观察肠道大体形态和组织学改变;同时分析p-ATF2水平与IL-6及IL-1β含量的关系。结果与正常对照组相比,模型组大鼠肠组织p-ATF2水平、血清IL-6及IL-1

  7. Calculation of continuum damping of Alfvén eigenmodes in tokamak and stellarator equilibria

    Energy Technology Data Exchange (ETDEWEB)

    Bowden, G. W.; Hole, M. J. [Plasma Theory and Modelling, Research School of Physics and Engineering, Australian National University, Acton 2601, Australian Capital Territory (Australia); Könies, A. [Max-Planck-Institut für Plasmaphysik, EURATOM-Association, D-17491 Greifswald (Germany)

    2015-09-15

    In an ideal magnetohydrodynamic (MHD) plasma, shear Alfvén eigenmodes may experience dissipationless damping due to resonant interaction with the shear Alfvén continuum. This continuum damping can make a significant contribution to the overall growth/decay rate of shear Alfvén eigenmodes, with consequent implications for fast ion transport. One method for calculating continuum damping is to solve the MHD eigenvalue problem over a suitable contour in the complex plane, thereby satisfying the causality condition. Such an approach can be implemented in three-dimensional ideal MHD codes which use the Galerkin method. Analytic functions can be fitted to numerical data for equilibrium quantities in order to determine the value of these quantities along the complex contour. This approach requires less resolution than the established technique of calculating damping as resistivity vanishes and is thus more computationally efficient. The complex contour method has been applied to the three-dimensional finite element ideal MHD Code for Kinetic Alfvén waves. In this paper, we discuss the application of the complex contour technique to calculate the continuum damping of global modes in tokamak as well as torsatron, W7-X and H-1NF stellarator cases. To the authors' knowledge, these stellarator calculations represent the first calculation of continuum damping for eigenmodes in fully three-dimensional equilibria. The continuum damping of global modes in W7-X and H-1NF stellarator configurations investigated is found to depend sensitively on coupling to numerous poloidal and toroidal harmonics.

  8. Installation of a Thomson scattering diagnostic on the Compact Toroidal Hybrid Experiment

    Science.gov (United States)

    Traverso, P. J.; Maurer, D. A.; Ennis, D. A.; Hartwell, G. J.; Cianciosa, M. R.

    2015-11-01

    A Thomson scattering system is being commissioned for the non-axisymmetric plasmas of the Compact Toroidal Hybrid (CTH), a five-field period current-carrying torsatron. The initial system takes a single point measurement on the magnetic axis and will be used to assess options for an expansion to a multi-point system to enable better 3D equilibrium reconstructions using the V3FIT code. A single point measurement will reduce the uncertainty in the reconstructed peak pressure by an order of magnitude for both current-carrying plasmas and future gyrotron-heated stellarator plasmas. The beam, generated by a frequency doubled Continuum 2 J, Nd:YaG laser, is passed vertically through an entrance Brewster window and a two-aperture optical baffle system to minimize stray light. The beam line is designed to propagate ~ 8 m to the mid-plane of the CTH device with the beam diameter < 3 mm inside the plasma volume. An Andor iStar DH740-18U-C3 image intensified CCD camera is used in conjunction with a Holospec f/1.8 spectrograph to collect the red-shifted scattered light from 532-580 nm. A single point system will initially measure plasmas with core electron temperatures of 100 to 200 eV and densities of 5 ×1018 to 5 ×1019 m-3. This work is supported by U.S. Department of Energy Grant No. DE-FG02-00ER54610.

  9. The endoplasmic reticulum stress pathway involving protein kinase R-like ER kinase-activating transcription factor 4-CCAAT/enhancer binding protein homologous protein implicated in apoptosis in lungs of rats with bronchopulmonary dysplasis%内质网应激相关的蛋白激酶R样内质网激酶-转录活化因子4-CCAAT/增强子结合蛋白同源蛋白通路参与支气管肺发育不良大鼠肺细胞凋亡

    Institute of Scientific and Technical Information of China (English)

    卢红艳; 张婷; 王秋霞; 唐炜

    2015-01-01

    目的 探讨内质网应激(ERS)相关的蛋白激酶R样内质网激酶(PERK)-转录活化因子4(ATF4)-CCAAT/增强子结合蛋白同源蛋白(CHOP)通路在支气管肺发育不良(BPD)大鼠肺细胞凋亡中的作用.方法 将48只新生早产SD大鼠按随机数字表法分为BPD组和对照组.BPD组持续暴露于体积分数为850 mL/L的高体积分数氧(高氧)中,对照组置于空气中.在7 d、14 d和21 d取肺组织,采用DNA断裂的原位末端标记法(TUNEL)检测肺细胞凋亡,实时荧光定量反转录聚合酶链反应(RT-PCR)检测葡萄糖调节蛋白78(GRP78) 、PERK 、ATF4和CHOP mRNA表达,Western blot技术检测GRP78、磷酸化PERK (pho-PERK) 、ATF4和CHOP蛋白表达.结果 随高氧暴露时间延长,BPD组大鼠肺细胞凋亡指数(AI)逐渐增加,与同时间点对照组比较差异均有统计学意义(7 d:15.50±0.58比1.25 ±0.50,14 d:27.75±1.71比3.25 ±0.96,21 d:50.50±3.70比4.00±1.15;t =57.00、20.58、25.16,P均<0.01);GRP78 、PERK 、ATF4和CHOP mRNA表达较同时间点对照组明显上升[GRP78:7 d(33.88 ±3.73)比(11.65±1.00),14 d(54.50 ±2.18)比(12.84±1.41),21d(95.34 ±7.61)比(12.43 ±0.59);PERK:7 d(5.23 ±0.92)比(1.45 ±0.46),14 d(7.60±1.56)比(2.18±0.97),21 d(16.55 ±0.50)比(2.90±1.18);ATF4:7 d(23.04 ±2.45)比(12.56±2.81),14d (28.66 ±2.66)比(15.18 ±2.92),21 d(36.63 ±2.99)比(15.14 ±2.09);CHOP:7 d(2.21 ±0.19)比(0.81 ±0.02),14 d(4.19±0.17)比(0.90±0.08),21 d(6.08 ±0.38)比(0.88±0.10);P均<0.05;GRP78 、pho-PERK 、ATF4和CHOP蛋白表达较对照组亦明显增高[GRP78:7 d(1.33±0.03)比(0.85±0.04),14 d(1.31 ±0.02)比(0.92 ±0.01),21 d(1.82 ±0.28)比(0.87 ±0.01);pho-PERK:7 d(0.68 ±0.02)比(0.54 ±0.01),14 d(1.04±0.01)比(0.65±0.01),21 d(1.29 ±0.02)比(0.73±0.01);ATF4:7 d(1.26±0.01)比(0.83±0.01),14 d(1.39±0.02)比(0.87 ±0.02),21 d(1.67 ±0.02)比(0.94 ±0.02);CHOP:7 d(1.37 ±0.01)比(0.47 ±0.06),14 d(1.50 ±0.04)比(0.74±0.05),21 d(1.61 ±0.03)比(0.55±0.02);P

  10. Hepatoprotective Effect of Quercetin on Endoplasmic Reticulum Stress and Inflammation after Intense Exercise in Mice through Phosphoinositide 3-Kinase and Nuclear Factor-Kappa B

    Directory of Open Access Journals (Sweden)

    Yuhan Tang

    2016-01-01

    Full Text Available The mechanisms underlying intense exercise-induced liver damage and its potential treatments remain unclear. We explored the hepatoprotection and mechanisms of quercetin, a naturally occurring flavonoid, in strenuous exercise-derived endoplasmic reticulum stress (ERS and inflammation. Intense exercise (28 m/min at a 5° slope for 90 min resulted in the leakage of aminotransferases in the BALB/C mice. The hepatic ultrastructural malformations and oxidative stress levels were attenuated by quercetin (100 mg/kg·bw. Intense exercise and thapsigargin- (Tg- induced ERS (glucose-regulated protein 78, GRP78 and inflammatory cytokines levels (IL-6 and TNF-α were decreased with quercetin. Furthermore, quercetin resulted in phosphoinositide 3-kinase (PI3K induction, Ca2+ restoration, and blockade of the activities of Jun N-terminal kinase (JNK, activating transcription factor 6 (ATF6 and especially NF-κB (p65 and p50 nuclear translocation. A PI3K inhibitor abrogated the protection of quercetin on ERS and inflammation of mouse hepatocytes. SP600125 (JNK inhibitor, AEBSF (ATF6 inhibitor, and especially PDTC (NF-κB inhibitor enhanced the quercetin-induced protection against Tg stimulation. Collectively, intense exercise-induced ERS and inflammation were attenuated by quercetin. PI3K/Akt activation and JNK, ATF6, and especially NF-κB suppression were involved in the protection. Our results highlight a novel preventive strategy for treating ERS and inflammation-mediated liver damage induced by intense exercise using natural phytochemicals.

  11. Steam Oxidation Testing in the Severe Accident Test Station

    Energy Technology Data Exchange (ETDEWEB)

    Pint, Bruce A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); McMurray, Jake W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-08-01

    Since 2011, Oak Ridge National Laboratory (ORNL) has been conducting high temperature steam oxidation testing of candidate alloys for accident tolerant fuel (ATF) cladding. These concepts are designed to enhance safety margins in light water reactors (LWR) during severe accident scenarios. In the US ATF community, the Severe Accident Test Station (SATS) has been evaluating candidate materials (including coatings) since 2012. Compared to the current UO2/Zr-based alloy fuel system, alternative cladding materials need to offer slower oxidation kinetics and a smaller enthalpy of oxidation in order to significantly reduce the rate of heat and hydrogen generation in the core during a coolant-limited severe accident. The steam oxidation behavior of candidate materials is a key metric in the evaluation of ATF concepts and also an important input into models. However, prior modeling work of FeCrAl cladding has used incomplete information on the physical properties of FeCrAl. Also, the steam oxidation data being collected at 1200°-1700°C is unique as no prior work has considered steam oxidation of alloys at such high temperatures. In some cases, the results have been difficult to interpret and more fundamental information is needed such as the stability of alumina in flowing steam at 1400°-1500°C. This report summarizes recent work to measure the steam oxidation kinetics of candidate alloys, the evaporation rate of alumina in steam and the development of integral data on FeCrAl compared to conventional Zr-based cladding.

  12. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor.

    Directory of Open Access Journals (Sweden)

    Rinki Minakshi

    Full Text Available The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV is reported to cause apoptosis of infected cells and several of its proteins including the 3a accessory protein, are pro-apoptotic. Since the 3a protein localizes to the endoplasmic reticulum (ER-Golgi compartment, its role in causing ER stress was investigated in transiently transfected cells. Cells expressing the 3a proteins showed ER stress based on activation of genes for the ER chaperones GRP78 and GRP94. Since ER stress can cause differential modulation of the unfolded protein response (UPR, which includes the inositol-requiring enzyme 1 (IRE-1, activating transcription factor 6 (ATF6 and PKR-like ER kinase (PERK pathways, these were individually tested in 3a-expressing cells. Only the PERK pathway was found to be activated in 3a-expressing cells based on (1 increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha and inhibitory effects of a dominant-negative form of eIF2alpha on GRP78 promoter activity, (2 increased translation of activating transcription factor 4 (ATF4 mRNA, and (3 ATF4-dependent activation of the C/EBP homologous protein (CHOP gene promoter. Activation of PERK affects innate immunity by suppression of type 1 interferon (IFN signaling. The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1 degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity.

  13. Extending laser plasma accelerators into the mid-IR spectral domain with a next-generation ultra-fast CO2 laser

    Science.gov (United States)

    Pogorelsky, I. V.; Babzien, M.; Ben-Zvi, I.; Polyanskiy, M. N.; Skaritka, J.; Tresca, O.; Dover, N. P.; Najmudin, Z.; Lu, W.; Cook, N.; Ting, A.; Chen, Y.-H.

    2016-03-01

    Expanding the scope of relativistic plasma research to wavelengths longer than the λ/≈   0.8-1.1 μm range covered by conventional mode-locked solid-state lasers would offer attractive opportunities due to the quadratic scaling of the ponderomotive electron energy and critical plasma density with λ. Answering this quest, a next-generation mid-IR laser project is being advanced at the BNL ATF as a part of the user facility upgrade. We discuss the technical approach to this conceptually new 100 TW, 100 fs, λ  =   9-11 μm CO2 laser BESTIA (Brookhaven Experimental Supra-Terawatt Infrared at ATF) that encompasses several innovations applied for the first time to molecular gas lasers. BESTIA will enable new regimes of laser plasma accelerators. One example is shock-wave ion acceleration (SWA) from gas jets. We review ongoing efforts to achieve stable, monoenergetic proton acceleration by dynamically shaping the plasma density profile from a hydrogen gas target with laser-produced blast waves. At its full power, 100 TW BESTIA promises to achieve proton beams at an energy exceeding 200 MeV. In addition to ion acceleration in over-critical plasma, the ultra-intense mid-IR BESTIA will open up new opportunities in driving wakefields in tenuous plasmas, expanding the landscape of laser wakefield accelerator (LWFA) studies into the unexplored long-wavelength spectral domain. Simple wavelength scaling suggests that a 100 TW CO2 laser beam will be capable of efficiently generating plasma ‘bubbles’ a thousand times greater in volume compared with a near-IR solid state laser of an equivalent power. Combined with a femtosecond electron linac available at the ATF, this wavelength scaling will facilitate the study of external seeding and staging of LWFAs.

  14. Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

    Science.gov (United States)

    Mellon, S H; Wolkowitz, O M; Schonemann, M D; Epel, E S; Rosser, R; Burke, H B; Mahan, L; Reus, V I; Stamatiou, D; Liew, C-C; Cole, S W

    2016-05-24

    Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

  15. An activating transcription factor of Litopenaeus vannamei involved in WSSV genes Wsv059 and Wsv166 regulation.

    Science.gov (United States)

    Li, Xiao-Yun; Yue, Hai-Tao; Zhang, Ze-Zhi; Bi, Hai-Tao; Chen, Yong-Gui; Weng, Shao-Ping; Chan, Siuming; He, Jian-Guo; Chen, Yi-Hong

    2014-12-01

    Members of activating transcription factor/cyclic adenosine 3', 5'-monophosphate response element binding protein (ATF/CREB) family are induced by various stress signals and function as effector molecules. Consequently, cellular changes occur in response to discrete sets of instructions. In this work, we found an ATF transcription factor in Litopenaeus vannamei designated as LvATFβ. The full-length cDNA of LvATFβ was 1388 bp long with an open reading frame of 939 bp that encoded a putative 313 amino acid protein. The protein contained a basic region-leucine zipper (bZip) domain that was a common feature among ATF/CREB transcription factors. LvATFβ was highly expressed in intestines, gills, and heart. LvATFβ expression was dramatically upregulated by white spot syndrome virus (WSSV) infection. Pull-down assay revealed that LvATFβ had strong affinity to promoters of WSSV genes, namely, wsv059 and wsv166. Dual-luciferase reporter assay showed that LvATFβ could upregulate the expression of wsv059 and wsv166. Knocked down LvATFβ resulted in decreased expression of wsv059 and wsv166 in WSSV-challenged L. vannamei. Knocked down expression of wsv059 and wsv166 by RNA interference inhibited the replication and reduce the mortality of L. vannamei during WSSV challenge inoculation. The copy numbers of WSSV in wsv059 and wsv166 knocked down group were significant lower than in the control. These results suggested that LvATFβ may be involved in WSSV replication by regulating the expression of wsv059 and wsv166.

  16. Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons.

    Science.gov (United States)

    Kristiansen, Mark; Hughes, Rosie; Patel, Pritika; Jacques, Thomas S; Clark, Andrew R; Ham, Jonathan

    2010-08-11

    Developing sympathetic neurons depend on NGF for survival. When sympathetic neurons are deprived of NGF in vitro, a well documented series of events, including c-Jun N-terminal kinase (JNK) pathway activation, release of cytochrome c from the mitochondria, and caspase activation, culminates in the death of the neuron by apoptosis within 24-48 h. This process requires de novo gene expression, suggesting that increased expression of specific genes activates the cell death program. Using rat gene microarrays, we found that NGF withdrawal induces the expression of many genes, including mkp1, which encodes a MAPK phosphatase that can dephosphorylate JNKs. The increase in mkp1 mRNA level requires the MLK-JNK-c-Jun pathway, and we show that Mkp1 is an important regulator of JNK-dependent apoptosis in sympathetic neurons. In microinjection experiments, Mkp1 overexpression can inhibit JNK-mediated phosphorylation of c-Jun and protect sympathetic neurons from apoptosis, while Mkp1 knockdown accelerates NGF withdrawal-induced death. Accordingly, the number of superior cervical ganglion (SCG) neurons is reduced in mkp1-/- mice at P1 during the period of developmental sympathetic neuron death. We also show that c-Jun and ATF2 bind to two conserved ATF binding sites in the mkp1 promoter in vitro and in chromatin. Both of these ATF sites contribute to basal promoter activity and are required for mkp1 promoter induction after NGF withdrawal. These results demonstrate that Mkp1 is part of a negative feedback loop induced by the MLK-JNK-c-Jun signaling pathway that modulates JNK activity and the rate of neuronal death in rat sympathetic neurons following NGF withdrawal.

  17. The Tocotrienol-Rich Fraction Is Superior to Tocopherol in Promoting Myogenic Differentiation in the Prevention of Replicative Senescence of Myoblasts.

    Directory of Open Access Journals (Sweden)

    Shy Cian Khor

    Full Text Available Aging results in a loss of muscle mass and strength. Myoblasts play an important role in maintaining muscle mass through regenerative processes, which are impaired during aging. Vitamin E potentially ameliorates age-related phenotypes. Hence, this study aimed to determine the effects of the tocotrienol-rich fraction (TRF and α-tocopherol (ATF in protecting myoblasts from replicative senescence and promoting myogenic differentiation. Primary human myoblasts were cultured into young and senescent stages and were then treated with TRF or ATF for 24 h, followed by an analysis of cell proliferation, senescence biomarkers, cellular morphology and differentiation. Our data showed that replicative senescence impaired the normal regenerative processes of myoblasts, resulting in changes in cellular morphology, cell proliferation, senescence-associated β-galactosidase (SA-β-gal expression, myogenic differentiation and myogenic regulatory factors (MRFs expression. Treatment with both TRF and ATF was beneficial to senescent myoblasts in reclaiming the morphology of young cells, improved cell viability and decreased SA-β-gal expression. However, only TRF treatment increased BrdU incorporation in senescent myoblasts, as well as promoted myogenic differentiation through the modulation of MRFs at the mRNA and protein levels. MYOD1 and MYOG gene expression and myogenin protein expression were modulated in the early phases of myogenic differentiation. In conclusion, the tocotrienol-rich fraction is superior to α-tocopherol in ameliorating replicative senescence-related aberration and promoting differentiation via modulation of MRFs expression, indicating vitamin E potential in modulating replicative senescence of myoblasts.

  18. Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress.

    Science.gov (United States)

    Shimizu, Makoto; Morimoto, Hitomi; Maruyama, Ryuto; Inoue, Jun; Sato, Ryuichiro

    2015-01-01

    Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor α (PPARα) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.

  19. TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate.

    Science.gov (United States)

    Royuela, M; Rodríguez-Berriguete, G; Fraile, B; Paniagua, R

    2008-10-01

    TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.

  20. THE MECHANICAL AND SHIELDING DESIGN OF A PORTABLE SPECTROMETER AND BEAM DUMP ASSEMBLY AT BNLS ACCELERATOR TEST FACILITY.

    Energy Technology Data Exchange (ETDEWEB)

    HU,J.P.; CASEY,W.R.; HARDER,D.A.; PJEROV,S.; RAKOWSKY,G.; SKARITKA,J.R.

    2002-09-05

    A portable assembly containing a vertical-bend dipole magnet has been designed and installed immediately down-beam of the Compton electron-laser interaction chamber on beamline 1 of the Accelerator Test Facility (ATF) at Brookhaven National Laboratory (BNL). The water-cooled magnet designed with field strength of up to 0.7 Tesla will be used as a spectrometer in the Thompson scattering and vacuum acceleration experiments, where field-dependent electron scattering, beam focusing and energy spread will be analyzed. This magnet will deflect the ATF's 60 MeV electron-beam 90{sup o} downward, as a vertical beam dump for the Compton scattering experiment. The dipole magnet assembly is portable, and can be relocated to other beamlines at the ATF or other accelerator facilities to be used as a spectrometer or a beam dump. The mechanical and shielding calculations are presented in this paper. The structural rigidity and stability of the assembly were studied. A square lead shield surrounding the assembly's Faraday Cup was designed to attenuate the radiation emerging from the 1 inch-copper beam stop. All photons produced were assumed to be sufficiently energetic to generate photoneutrons. A safety evaluation of groundwater tritium contamination due to the thermal neutron capturing by the deuterium in water was performed, using updated Monte Carlo neutron-photon coupled transport code (MCNP). High-energy neutron spallation, which is a potential source to directly generate radioactive tritium and sodium-22 in soil, was conservatively assessed in verifying personal and environmental safety.

  1. Neural and Oligodendrocyte Progenitor Cells: Transferrin Effects on Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Lucas Silvestroff

    2013-02-01

    Full Text Available NSC (neural stem cells/NPC (neural progenitor cells are multipotent and self-renew throughout adulthood in the SVZ (subventricular zone of the mammalian CNS (central nervous system. These cells are considered interesting targets for CNS neurodegenerative disorder cell therapies, and understanding their behaviour in vitro is crucial if they are to be cultured prior to transplantation. We cultured the SVZ tissue belonging to newborn rats under the form of NS (neurospheres to evaluate the effects of Tf (transferrin on cell proliferation. The NS were heterogeneous in terms of the NSC/NPC markers GFAP (glial fibrillary acidic protein, Nestin and Sox2 and the OL (oligodendrocyte progenitor markers NG2 (nerve/glia antigen 2 and PDGFRα (platelet-derived growth factor receptor α. The results of this study indicate that aTf (apoTransferrin is able to increase cell proliferation of SVZ-derived cells in vitro, and that these effects were mediated at least in part by the TfRc1 (Tf receptor 1. Since OPCs (oligodendrocyte progenitor cells represent a significant proportion of the proliferating cells in the SVZ-derived primary cultures, we used the immature OL cell line N20.1 to show that Tf was able to augment the proliferation rate of OPC, either by adding aTf to the culture medium or by overexpressing rat Tf in situ. The culture medium supplemented with ferric iron, together with aTf, increased the DNA content, while ferrous iron did not. The present work provides data that could have a potential application in human cell replacement therapies for neurodegenerative disease and/or CNS injury that require the use of in vitro amplified NPCs.

  2. Analysis of neutral lipid biosynthesis in Streptomyces avermitilis MA-4680 and characterization of an acyltransferase involved herein.

    Science.gov (United States)

    Kaddor, Chlud; Biermann, Karolin; Kalscheuer, Rainer; Steinbüchel, Alexander

    2009-08-01

    The physiology of lipid production in Streptomyces avermitilis MA-4680 with regard to the fatty acid composition of the accumulated lipids and their cellular distribution was analyzed. Cells were able to accumulate about ten to 30 lipid granules with diameters between 100 and 500 nm filling about 70-80% of the cell cytoplasm. Gas chromatography/mass spectrometry analyses of total cellular lipids and from isolated triacylglycerols (TAG) confirmed a similar fatty acid composition with a large portion of iso- and anteiso-methyl-branched fatty acids. De novo biosynthesis of wax esters (WE) appeared only during cocultivation on glucose and hexadecanol as carbon source. Homology alignments with the wax ester synthase/acyl-CoA:diacylglycerol acyltransferase (WS/DGAT; AtfA) from Acinetobacter baylyi strain ADP1 yielded one open reading frame in the genome databases of S. avermitilis MA-4680 referred to as SAV7256 with 25.3% homology. The highly conserved HHAxxDG active site motif found in AtfA, which is present in SAV7256, as well as the similar hydrophobicity profiles of AtfA and SAV7256 indicate a similar structure and function of both proteins. High acyl-CoA:diacylglycerol acyltransferase activity (DGAT; 143 pmol (mg min)(-1)) but low wax ester synthase activity (WS; 1.3 pmol (mg min)(-1)) were detected in crude extracts of S. avermitilis, which were consistent with the high TAG and negligible WE content of the cells. This indicates that TAG accumulation in S. avermitilis MA-4680 is mediated by the classical acyl-CoA-dependent DGAT pathway. Heterologous expression experiments in recombinant Escherichia coli BL21(DE3) demonstrated both WS and DGAT enzyme activity of SAV7256. Furthermore, substrate specificities of the acyltransferase SAV7256 will be discussed.

  3. The Cataract-linked Mutant Connexin50D47A Causes Endoplasmic Reticulum Stress in Mouse Lenses.

    Science.gov (United States)

    Berthoud, Viviana M; Minogue, Peter J; Lambert, Paul A; Snabb, Joseph I; Beyer, Eric C

    2016-08-19

    Mice expressing connexin50D47A (Cx50D47A) exhibit nuclear cataracts and impaired differentiation. Cx50D47A does not traffic properly, and homozygous mutant lenses show increased levels of the stress-responsive αB-crystallins. Therefore, we assessed whether expression of Cx50D47A led to endoplasmic reticulum (ER) stress in the lens in vivo Although pharmacologic induction of ER stress can be transduced by three different pathways, we found no evidence for activation of the IRE1α or ATF6 pathways in Cx50D47A-expressing lenses. In contrast, heterozygous and homozygous Cx50D47A lenses showed an increase in phosphorylated PERK immunoreactivity and in the ratio of phosphorylated to total EIF2α (2.4- and 3.3-fold, respectively) compared with wild type. Levels of ATF4 were similar in wild type and heterozygous lenses but elevated in homozygotes (391%). In both heterozygotes and homozygotes, levels of calreticulin protein were increased (184 and 262%, respectively), as was Chop mRNA (1.9- and 12.4-fold, respectively). CHOP protein was increased in homozygotes (384%). TUNEL staining was increased in Cx50D47A lenses, especially in homozygous mice. Levels of two factors that may be pro-survival, Irs2 and Trib3, were greatly increased in homozygous lenses. These results suggest that expression of Cx50D47A induces ER stress, triggering activation of the PERK-ATF4 pathway, which potentially contributes to the lens pathology and leads to increased expression of anti-apoptotic factors, allowing cell survival.

  4. Intratumoral injection of taxol in vivo suppresses A549 tumor showing cytoplasmic vacuolization.

    Science.gov (United States)

    Wang, Chaoyang; Chen, Tongsheng

    2012-04-01

    Based on our recent in vitro studies, this report was designed to explore the mechanism by which high concentration of taxol (70 µM) induced paraptosis-like cell death in human lung carcinoma (A549) cells, and to evaluate the therapeutic efficacy of taxol using A549 tumor-bearing mice in vivo. Exposure of cells to taxol induced time-dependent cytotoxicity and cytoplasmic vacuolization without the involvement of Bax, Bak, Mcl-1, Bcl-XL, and caspase-3. Although taxol treatment induced activating transcription factor 6 (ATF6) cleavage indicative of endoplasmic reticulum (ER) stress, silencing ATF6 by shATF6 did not prevent taxol-induced both cytotoxcity and cytoplasmic vacuolization, suggesting that taxol-induced cytoplasmic vacuolization and cell death were not due to ER stress. Moreover, taxol-treated cells did not show DNA fragmentation and loss of mitochondrial membrane potential, the typical characteristics of apoptosis. In addition, taxol-induced cytoplasmic vacuolization did not show the cellular lysis, the characteristics of oncosis, and positive of β-galactosidase, the characteristic of senescence, indicating that taxol induced paraptosis-like cell death is neither oncosis nor senescence. Moreover, our in vivo data showed that intratumoral injection of taxol (50 mg/kg) in A549 tumor xenograft mice on day 1 and day 19 potently suppressed tumor growth showing significant ER vacuolization without toxicity. In conclusion, high concentration of taxol exhibits a significant anticancer activity by inducing paraptosis-like cell death in vitro and in vivo, without significant toxicity, suggesting a promising therapeutic strategy for apoptosis-resistance cancer by inducing ER vacuolization.

  5. Gearbox fault diagnosis using adaptive zero phase time-varying filter based on multi-scale chirplet sparse signal decomposition

    Science.gov (United States)

    Wu, Chunyan; Liu, Jian; Peng, Fuqiang; Yu, Dejie; Li, Rong

    2013-07-01

    When used for separating multi-component non-stationary signals, the adaptive time-varying filter(ATF) based on multi-scale chirplet sparse signal decomposition(MCSSD) generates phase shift and signal distortion. To overcome this drawback, the zero phase filter is introduced to the mentioned filter, and a fault diagnosis method for speed-changing gearbox is proposed. Firstly, the gear meshing frequency of each gearbox is estimated by chirplet path pursuit. Then, according to the estimated gear meshing frequencies, an adaptive zero phase time-varying filter(AZPTF) is designed to filter the original signal. Finally, the basis for fault diagnosis is acquired by the envelope order analysis to the filtered signal. The signal consisting of two time-varying amplitude modulation and frequency modulation(AM-FM) signals is respectively analyzed by ATF and AZPTF based on MCSSD. The simulation results show the variances between the original signals and the filtered signals yielded by AZPTF based on MCSSD are 13.67 and 41.14, which are far less than variances (323.45 and 482.86) between the original signals and the filtered signals obtained by ATF based on MCSSD. The experiment results on the vibration signals of gearboxes indicate that the vibration signals of the two speed-changing gearboxes installed on one foundation bed can be separated by AZPTF effectively. Based on the demodulation information of the vibration signal of each gearbox, the fault diagnosis can be implemented. Both simulation and experiment examples prove that the proposed filter can extract a mono-component time-varying AM-FM signal from the multi-component time-varying AM-FM signal without distortion.

  6. Survey of Thermal-Fluids Evaluation and Confirmatory Experimental Validation Requirements of Accident Tolerant Cladding Concepts with Focus on Boiling Heat Transfer Characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Nicholas R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wysocki, Aaron J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Terrani, Kurt A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ali, Amir [Univ. of New Mexico, Albuquerque, NM (United States); Liu, Maolong [Univ. of New Mexico, Albuquerque, NM (United States); Blandford, Edward [Univ. of New Mexico, Albuquerque, NM (United States)

    2016-06-01

    The U.S. Department of Energy Office of Nuclear Energy (DOE-NE) Advanced Fuels Campaign (AFC) is working closely with the nuclear industry to develop fuel and cladding candidates with potentially enhanced accident tolerance, also known as accident tolerant fuel (ATF). Thermal-fluids characteristics are a vital element of a holistic engineering evaluation of ATF concepts. One vital characteristic related to boiling heat transfer is the critical heat flux (CHF). CHF plays a vital role in determining safety margins during normal operation and also in the progression of potential transient or accident scenarios. This deliverable is a scoping survey of thermal-fluids evaluation and confirmatory experimental validation requirements of accident tolerant cladding concepts with a focus on boiling heat transfer characteristics. The key takeaway messages of this report are: 1. CHF prediction accuracy is important and the correlations may have significant uncertainty. 2. Surface conditions are important factors for CHF, primarily the wettability that is characterized by contact angle. Smaller contact angle indicates greater wettability, which increases the CHF. Surface roughness also impacts wettability. Results in the literature for pool boiling experiments indicate changes in CHF by up to 60% for several ATF cladding candidates. 3. The measured wettability of FeCrAl (i.e., contact angle and roughness) indicates that CHF should be investigated further through pool boiling and flow boiling experiments. 4. Initial measurements of static advancing contact angle and surface roughness indicate that FeCrAl is expected to have a higher CHF than Zircaloy. The measured contact angle of different FeCrAl alloy samples depends on oxide layer thickness and composition. The static advancing contact angle tends to decrease as the oxide layer thickness increases.

  7. Retinoic acid-activated Ndrg1a represses Wnt/β-catenin signaling to allow Xenopus pancreas, oesophagus, stomach, and duodenum specification.

    Directory of Open Access Journals (Sweden)

    Tiejun Zhang

    Full Text Available How cells integrate multiple patterning signals to achieve early endoderm regionalization remains largely unknown. Between gastrulation and neurulation, retinoic acid (RA signaling is required, while Wnt/β-catenin signaling has to be repressed for the specification of the pancreas, oesophagus, stomach, and duodenum primordia in Xenopus embryos. In attempt to screen for RA regulated genes in Xenopus endoderm, we identified a direct RA target gene, N-myc downstream regulated gene 1a (ndrg1a that showed expression early in the archenteron roof endoderm and late in the developing pancreas, oesophagus, stomach, and duodenum. Both antisense morpholino oligonucleotide mediated knockdown of ndrg1a in Xenopus laevis and the transcription activator-like effector nucleases (TALEN mediated disruption of ndrg1 in Xenopus tropicalis demonstrate that like RA signaling, Ndrg1a is specifically required for the specification of Xenopus pancreas, oesophagus, stomach, and duodenum primordia. Immunofluorescence data suggest that RA-activated Ndrg1a suppresses Wnt/β-catenin signaling in Xenopus archenteron roof endoderm cells. Blocking Wnt/β-catenin signaling rescued Ndrg1a knockdown phenotype. Furthermore, overexpression of the putative Wnt/β-catenin target gene Atf3 phenocopied knockdown of Ndrg1a or inhibition of RA signaling, while Atf3 knockdown can rescue Ndrg1a knockdown phenotype. Lastly, the pancreas/stomach/duodenum transcription factor Pdx1 was able to rescue Atf3 overexpression or Ndrg1a knockdown phenotype. Together, we conclude that RA activated Ndrg1a represses Wnt/β-catenin signaling to allow the specification of pancreas, oesophagus, stomach, and duodenum progenitor cells in Xenopus embryos.

  8. Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment

    Science.gov (United States)

    Mellon, S H; Wolkowitz, O M; Schonemann, M D; Epel, E S; Rosser, R; Burke, H B; Mahan, L; Reus, V I; Stamatiou, D; Liew, C -C; Cole, S W

    2016-01-01

    Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1–4 (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators. PMID:27187237

  9. Thermotolerance induced at a mild temperature of 40°C alleviates heat shock-induced ER stress and apoptosis in HeLa cells.

    Science.gov (United States)

    Bettaieb, Ahmed; Averill-Bates, Diana A

    2015-01-01

    Hyperthermia (39-45°C) has emerged as an alternate prospect for cancer therapy in combination with radiation and chemotherapy. Despite promising progress in the clinic, molecular mechanisms involved in hyperthermia-induced cell death are not clear. Hyperthermia causes protein denaturation/aggregation, which results in cell death by apoptosis and/or necrosis. Hyperthermia also induces thermotolerance, which renders cells resistant to subsequent exposure to lethal heat shock. This study investigates the role of both lethal (42-43°C) and mild (40°C) hyperthermia in regulating ER stress and ER stress-induced apoptosis in HeLa cells. The ability of mild thermotolerance induced at 40°C to alleviate either or both of these processes is also determined. Hyperthermia (42-43°C) induced ER stress, revealed by phosphorylation of PERK, eIF2α and IRE1α, cleavage of ATF6 and increased expression of BiP and sXBP1. Real-time PCR revealed that mRNA levels of ATF6, ATF4, BiP, sXBP1 and CHOP increased in cells exposed to hyperthermia. Moreover, hyperthermia caused disruption of calcium homeostasis and activated the calpain-calpastatin proteolytic system and ER resident caspase 4. Pre-exposure to mild hyperthermia (40°C) alleviated the induction of cytotoxicity and ER stress by hyperthermia (42-43°C) and protected cells against ER stress-induced apoptosis. ShRNA-mediated depletion of Hsp72 abrogated protective effects of mild thermotolerance (40°C) against heat-shock induced ER stress and sensitized cells to ER stress-mediated apoptosis. Our findings show that Hsp72 contributes to the protective effects of mild hyperthermia (40°C) against hyperthermia-induced ER stress and apoptosis.

  10. The Alto Tiberina Near Fault Observatory (northern Apennines, Italy

    Directory of Open Access Journals (Sweden)

    Lauro Chiaraluce

    2014-06-01

    Full Text Available The availability of multidisciplinary and high-resolution data is a fundamental requirement to understand the physics of earthquakes and faulting. We present the Alto Tiberina Near Fault Observatory (TABOO, a research infrastructure devoted to studying preparatory processes, slow and fast deformation along a fault system located in the upper Tiber Valley (northern Apennines, dominated by a 60 km long low-angle normal fault (Alto Tiberina, ATF active since the Quaternary. TABOO consists of 50 permanent seismic stations covering an area of 120 × 120 km2. The surface seismic stations are equipped with 3-components seismometers, one third of them hosting accelerometers. We instrumented three shallow (250 m boreholes with seismometers, creating a 3-dimensional antenna for studying micro-earthquakes sources (detection threshold is ML 0.5 and detecting transient signals. 24 of these sites are equipped with continuous geodetic GPS, forming two transects across the fault system. Geochemical and electromagnetic stations have been also deployed in the study area. In 36 months TABOO recorded 19,422 events with ML ≤ 3.8 corresponding to 23.36e-04 events per day per squared kilometres; one of the highest seismicity rate value observed in Italy. Seismicity distribution images the geometry of the ATF and its antithetic/synthetic structures located in the hanging-wall. TABOO can allow us to understand the seismogenic potential of the ATF and therefore contribute to the seismic hazard assessment of the area. The collected information on the geometry and deformation style of the fault will be used to elaborate ground shaking scenarios adopting diverse slip distributions and rupture directivity models.

  11. Status Report on Activities of the Systems Assessment Task Force, OECD-NEA Expert Group on Accident Tolerant Fuels for LWRs

    Energy Technology Data Exchange (ETDEWEB)

    Bragg-Sitton, Shannon Michelle [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2015-09-01

    The Organization for Economic Cooperation and Development /Nuclear Energy Agency (OECD/NEA) Nuclear Science Committee approved the formation of an Expert Group on Accident Tolerant Fuel (ATF) for LWRs (EGATFL) in 2014. Chaired by Kemal Pasamehmetoglu, INL Associate Laboratory Director for Nuclear Science and Technology, the mandate for the EGATFL defines work under three task forces: (1) Systems Assessment, (2) Cladding and Core Materials, and (3) Fuel Concepts. Scope for the Systems Assessment task force includes definition of evaluation metrics for ATF, technology readiness level definition, definition of illustrative scenarios for ATF evaluation, parametric studies, and selection of system codes. The Cladding and Core Materials and Fuel Concepts task forces will identify gaps and needs for modeling and experimental demonstration; define key properties of interest; identify the data necessary to perform concept evaluation under normal conditions and illustrative scenarios; identify available infrastructure (internationally) to support experimental needs; and make recommendations on priorities. Where possible, considering proprietary and other export restrictions (e.g., International Traffic in Arms Regulations), the Expert Group will facilitate the sharing of data and lessons learned across the international group membership. The Systems Assessment Task Force is chaired by Shannon Bragg-Sitton (INL), while the Cladding Task Force will be chaired by a representative from France (Marie Moatti, Electricite de France [EdF]) and the Fuels Task Force will be chaired by a representative from Japan (Masaki Kurata, Japan Atomic Energy Agency [JAEA]). This report provides an overview of the Systems Assessment Task Force charter and status of work accomplishment.

  12. Final report on accident tolerant fuel performance analysis of APMT-Steel Clad/UO₂ fuel and APMT-Steel Clad/UN-U₃Si₅ fuel concepts

    Energy Technology Data Exchange (ETDEWEB)

    Unal, Cetin [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Galloway, Jack D. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2014-09-12

    In FY2014 our group completed and documented analysis of new Accident Tolerant Fuel (ATF) concepts using BISON. We have modeled the viability of moving from Zircaloy to stainless steel cladding in traditional light water reactors (LWRs). We have explored the reactivity penalty of this change using the MCNP-based burnup code Monteburns, while attempting to minimize this penalty by increasing the fuel pellet radius and decreasing the cladding thickness. Fuel performance simulations using BISON have also been performed to quantify changes to structural integrity resulting from thinner stainless steel claddings. We account for thermal and irradiation creep, fission gas swelling, thermal swelling and fuel relocation in the models for both Zircaloy and stainless steel claddings. Additional models that account for the lower oxidation stainless steel APMT are also invoked where available. Irradiation data for HT9 is used as a fallback in the absence of appropriate models. In this study the isotopic vectors within each natural element are varied to assess potential reactivity gains if advanced enrichment capabilities were levied towards cladding technologies. Recommendations on cladding thicknesses for a robust cladding as well as the constitutive components of a less penalizing composition are provided. In the first section (section 1-3), we present results accepted for publication in the 2014 TOPFUEL conference regarding the APMT/UO₂ ATF concept (J. Galloway & C. Unal, Accident Tolerant and Neutronically Favorable LWR Cladding, Proceedings of WRFPM 2014, Sendai, Japan, Paper No.1000050). Next we discuss our preliminary findings from the thermo-mechanical analysis of UN-U₃Si₅ fuel with APMT clad. In this analysis we used models developed from limited data that need to be updated when the irradiation data from ATF-1 test is available. Initial results indicate a swelling rate less than 1.5% is needed to prevent excessive clad stress.

  13. P38丝裂原活化蛋白激酶对溃疡性结肠炎大鼠淋巴细胞凋亡的影响%Effects of p38 Mitogen-activated Protein Kinase Pathway onLymphocyte Apoptosis in Rats with Colitis

    Institute of Scientific and Technical Information of China (English)

    周薇; 李军华

    2013-01-01

    目的 观察大鼠实验性结肠炎肠组织p38丝裂原活化蛋白激酶(MAPK)的活化及对淋巴细胞凋亡的影响.方法 30只健康SD大鼠随机均分为正常对照组、结肠炎模型组、SB203580组.以三硝基苯磺酸(TNBS)制备大鼠溃疡性结肠炎模型,采用DNA缺口末端标记技术(TUNEL)检测凋亡细胞,免疫组织化学方法检测活化转录因子2(p-ATF2)、Bcl-2和Bax表达.同时分析p-p38,p-ATF2水平与肠道病理损伤指数、MPO含量、Bcl-2和Bax表达的关系.结果 与正常组相比,模型组大鼠肠组织磷酸化p38、p-ATF2,Bcl-2表达和凋亡阳性细胞数百分比及MPO含量显著增高(P<0.01),SB203580组显著降低.Bax表达在模型组明显降低,与SB203580组相比无明显差异.结论 p38蛋白激酶激活参与了溃疡性结肠炎发病,其机制可能与延迟肠组织淋巴细胞凋亡有关.

  14. Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of protein kinase A signaling pathway and toxicological relevance

    Energy Technology Data Exchange (ETDEWEB)

    Arana, Maite Rocío, E-mail: arana@ifise-conicet.gov.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Tocchetti, Guillermo Nicolás, E-mail: gtocchetti@live.com.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Domizi, Pablo, E-mail: domizi@ibr-conicet.gov.ar [Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Arias, Agostina, E-mail: agoarias@yahoo.com.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Rigalli, Juan Pablo, E-mail: jprigalli@gmail.com [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Ruiz, María Laura, E-mail: ruiz@ifise-conicet.gov.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); and others

    2015-09-01

    The cAMP pathway is a universal signaling pathway regulating many cellular processes including metabolic routes, growth and differentiation. However, its effects on xenobiotic biotransformation and transport systems are poorly characterized. The effect of cAMP on expression and activity of GST and MRP2 was evaluated in Caco-2 cells, a model of intestinal epithelium. Cells incubated with the cAMP permeable analog dibutyryl cyclic AMP (db-cAMP: 1,10,100 μM) for 48 h exhibited a dose–response increase in GST class α and MRP2 protein expression. Incubation with forskolin, an activator of adenylyl cyclase, confirmed the association between intracellular cAMP and upregulation of MRP2. Consistent with increased expression of GSTα and MRP2, db-cAMP enhanced their activities, as well as cytoprotection against the common substrate 1-chloro-2,4-dinitrobenzene. Pretreatment with protein kinase A (PKA) inhibitors totally abolished upregulation of MRP2 and GSTα induced by db-cAMP. In silico analysis together with experiments consisting of treatment with db-cAMP of Caco-2 cells transfected with a reporter construct containing CRE and AP-1 sites evidenced participation of these sites in MRP2 upregulation. Further studies involving the transcription factors CREB and AP-1 (c-JUN, c-FOS and ATF2) demonstrated increased levels of total c-JUN and phosphorylation of c-JUN and ATF2 by db-cAMP, which were suppressed by a PKA inhibitor. Co-immunoprecipitation and ChIP assay studies demonstrated that db-cAMP increased c-JUN/ATF2 interaction, with further recruitment to the region of the MRP2 promoter containing CRE and AP-1 sites. We conclude that cAMP induces GSTα and MRP2 expression and activity in Caco-2 cells via the PKA pathway, thus regulating detoxification of specific xenobiotics. - Highlights: • cAMP positively modulates the expression and activity of GST and MRP2 in Caco-2 cells. • Such induction resulted in increased cytoprotection against chemical injury. • PKA

  15. Joint DoD/Industry Study on Opportunities in Integrated Diagnostics

    Science.gov (United States)

    1990-01-01

    Meth Director OASD (A/L) WSIG (202) 697-0051 The Pentagon, Room 2B322 Fax 697-3362 Washington, DC 20301-8000 • Mr. Larry Miller Systems Control...12249 Science Drive Orlando, FL 32826 Lt Col Thomas (Tom) May ATF DPML ASD/YFL * Wright Patterson AFB, OH 45433 Mr. Larry Miller Systems Control...CSED Review Panel Dr. Dan Alpert , Director 1 Program in Science, Technology & Society University of Illinois Room 201 912-1/2 West Illinois Street

  16. Determination of Soil Base—Soluble Se by Anodic Stripping Voltammetry with Aurum Thin—Film Electrode

    Institute of Scientific and Technical Information of China (English)

    YANGZENG; HEYING; 等

    1994-01-01

    Determination of soil Se by anodic stripping voltammetry(ASV) with aurum thin-film electrode(ATFE)overcomes the interference of gold peak with selenium peak,and thus has a higher sensitivity with the miniumum detectable concentration being 0.017μg/mL,the standard deviation of the measured results leww than 0.012μg/g,the coefficient of variation lwoer than 10% ,and the recovery rate between 86% to 103%.Besides the measurement conditions,the digestion of soil sample was also studied in detail.

  17. Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response.

    Science.gov (United States)

    Michel, Sebastien; Canonne, Morgane; Arnould, Thierry; Renard, Patricia

    2015-03-01

    Mitochondria-to-nucleus communication, known as retrograde signaling, is important to adjust the nuclear gene expression in response to organelle dysfunction. Among the transcription factors described to respond to mitochondrial stress, CHOP-10 is activated by respiratory chain inhibition, mitochondrial accumulation of unfolded proteins and mtDNA mutations. In this study, we show that altered/impaired expression of mtDNA induces CHOP-10 expression in a signaling pathway that depends on the eIF2α/ATF4 axis of the integrated stress response rather than on the mitochondrial unfolded protein response.

  18. New Engineering & Development Initiatives -- Policy and Technology Choices: Consensus Views of User/Aviation Industry Representatives. Volume I.

    Science.gov (United States)

    1979-03-01

    Paul Drouilhet MIT/LL R. L. Erwin Boeing Lawrence Goldmuntz* ESP Larry Hanes* TI William Harman MIT/LL Wayne Heston* FAA ATF-4 Barry Horowitz* MITRE D...Metro Wayne Co DTW 306 360 1984 Seattle WA Boeing Fld/King Co Intl BFI 504 649 1984 West Palm Beach FL Palm Beach Intl PBI 288 328 1984 Houston TX...Communications East Joppa Road Towson , Maryland 21204 154 Mr. Milton Meisner Federal Aviation Administration 800 Independence Avenue, S.W. AEM-3

  19. The Effect of Chronic Ozone Exposure on the Activation of Endoplasmic Reticulum Stress and Apoptosis in Rat Hippocampus

    Science.gov (United States)

    Rodríguez-Martínez, Erika; Nava-Ruiz, Concepcion; Escamilla-Chimal, Elsa; Borgonio-Perez, Gabino; Rivas-Arancibia, Selva

    2016-01-01

    The chronic exposure to low doses of ozone, like in environmental pollution, leads to a state of oxidative stress, which has been proposed to contribute to neurodegenerative disorders, including Alzheimer’s disease (AD). It induces an increase of calcium in the endoplasmic reticulum (ER), which produces ER stress. On the other hand, different studies show that, in diseases such as Alzheimer’s, there exist disturbances in protein folding where ER plays an important role. The objective of this study was to evaluate the state of chronic oxidative stress on ER stress and its relationship with apoptotic death in the hippocampus of rats exposed to low doses of ozone. We used 108 male Wistar rats randomly divided into five groups. The groups received one of the following treatments: (1) Control (air); (2) Ozone (O3) 7 days; (3) O3 15 days; (4) O3 30 days; (5) O3 60 days; and (6) O3 90 days. Two hours after each treatment, the animals were sacrificed and the hippocampus was extracted. Afterwards, the tissue was processed for western blot and immunohistochemistry using the following antibodies: ATF6, 78 kDa glucose-regulated protein (GRP78) and caspase 12. It was also subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and electronic microscopy. Our results show an increase in ATF6, GRP78 and caspase 12 as well as ER ultrastructural alterations and an increase of TUNEL positive cells after 60 and 90 days of exposure to ozone. With the obtained results, we can conclude that oxidative stress induced by chronic exposure to low doses of ozone leads to ER stress. ER stress activates ATF6 inducing the increase of GRP78 in the cytoplasm, which leads to the increase in the nuclear translocation of ATF6. Finally, the translocation creates a vicious cycle that, together with the activation of the cascade for apoptotic cell death, contributes to the maintenance of ER stress. These events potentially contribute in the neurodegeneration processes

  20. Regulation of eIF2α phosphorylation in hindlimb-unloaded and STS-135 space-flown mice

    Science.gov (United States)

    Zhao, Liming; Tanjung, Nancy; Swarnkar, Gaurav; Ledet, Eric; Yokota, Hiroki

    2012-09-01

    Various environmental stresses elevate the phosphorylation level of eukaryotic translation initiation factor 2 alpha (eIF2α) and induce transcriptional activation of a set of stress responsive genes such as activating transcription factors 3 and 6 (ATF3 and ATF6), CCAAT/enhancer-binding protein homologous protein (CHOP), and Xbp1 (X-box binding protein 1). These stress sources include radiation, oxidation, and stress to the endoplasmic reticulum, and it is recently reported that unloading by hindlimb unloading is such a stress source. No studies, however, have examined the phosphorylation level of eIF2α (eIF2α-p) using skeletal samples that have experienced microgravity in space. In this study we addressed a question: Does a mouse tibia flown in space show altered levels of eIF2α-p? To address this question, we obtained STS-135 flown samples that were harvested 4-7 h after landing. The tibia and femur isolated from hindlimb unloaded mice were employed as non-flight controls. The effects of loading were also investigated in non- flight controls. Results indicate that the level of eIF2α-p of the non-flight controls was elevated during hindlimb unloading and reduced after being released from unloading. Second, the eIF2α-p level of space-flown samples was decreased, and mechanical loading to the tibia caused the reduction of the eIF2α-p level. Third, the mRNA levels of ATF3, ATF6, and CHOP were lowered in space-flown samples as well as in the non-flight samples 4-7 h after being released from unloading. Collectively, the results herein indicated that a release from hindlimb unloading and a return to normal weight environment from space provided a suppressive effect to eIF2α-linked stress responses and that a period of 2-4 h is sufficient to induce this suppressive outcome.

  1. Polynomial algebra reveals diverging roles of the unfolded protein response in endothelial cells during ischemia-reperfusion injury.

    Science.gov (United States)

    Le Pape, Sylvain; Dimitrova, Elena; Hannaert, Patrick; Konovalov, Alexander; Volmer, Romain; Ron, David; Thuillier, Raphaël; Hauet, Thierry

    2014-08-25

    The unfolded protein response (UPR)--the endoplasmic reticulum stress response--is found in various pathologies including ischemia-reperfusion injury (IRI). However, its role during IRI is still unclear. Here, by combining two different bioinformatical methods--a method based on ordinary differential equations (Time Series Network Inference) and an algebraic method (probabilistic polynomial dynamical systems)--we identified the IRE1α-XBP1 and the ATF6 pathways as the main UPR effectors involved in cell's adaptation to IRI. We validated these findings experimentally by assessing the impact of their knock-out and knock-down on cell survival during IRI.

  2. microRNA-26a modulates inflammatory response induced by toll-like receptor 4 stimulation in microglia.

    Science.gov (United States)

    Kumar, Asit; Bhatia, Harsharan Singh; de Oliveira, Antonio Carlos Pinheiro; Fiebich, Bernd L

    2015-12-01

    MiRNAs, a family of small non-coding RNAs, have emerged as novel post-transcriptional regulators of numerous cellular responses. Although the involvement of miRNAs in the regulation of neuroinflammation in various neurological diseases has been previously studied, their role in the production of inflammatory mediators during microglia activation is poorly understood. In this study, the role of miR-26a has been investigated in the modulation of inflammatory response in cultured microglia. Using real-time PCR, the expression of miR-26a was studied in toll-like receptors 4 stimulated primary mouse microglia. miR-26a expression was found to be rapidly reduced after the stimulation of toll-like receptors 4 in microglia. Over-expression of miR-26a significantly decreased the production of inflammatory cytokines such as tumor necrosis factor α and IL-6, whereas knockdown of miR-26a increased the expression of these mediators. Furthermore, using in silico analysis, we identified that the activating transcription factor (ATF) 2 is directly targeted by miR-26a. This finding was confirmed by loss and gain of function studies. Similar to the effect of miR-26a over-expression, knockdown of activating transcription factor 2 inhibited the production of proinflammatory cytokines, particularly IL-6. Taken together, our results suggest the involvement of miR-26a in the regulation of the production of proinflammatory cytokines in microglia. We proposed that in microglia, activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) down-regulates miR-26a. The down-regulation of this miR increases expression of activating transcription factor 2 (ATF2). This event, in addition to the activation of ATF2 by c-Jun N-terminal kinase (JNK), increases interleukin-6 (IL-6) production. On the other hand, miR-26a also increases the production of tumor necrosis factor α (TNFα) by a mechanism independent of ATF2.

  3. Assessment of Four Passive Hearing Protection Devices for Continuous Noise Attenuation, Impulsive Noise Insertion Loss, and Auditory Localization Performance

    Science.gov (United States)

    2014-11-17

    estimated unprotected signal was calculated for each ear of both ATFs for the protected shots. The IPIL was calculated as the difference (in decibels ...devices. Table 21. Attenuation – Combat Arms Earplug™ – vented. All attenuation values in decibels . Test # 125 Hz 250 Hz 500 Hz 1k Hz 2k Hz 4k...Attenuation – Combat Arms Earplug™ – unvented. All attenuation values in decibels . Test # 125 Hz 250 Hz 500 Hz 1k Hz 2k Hz 4k Hz 8k Hz 1 11.7 9.9 7.4 12.0

  4. Study on the Explicit Formula of the Triangular Flat Shell Element Based on the Analytical Trial Functions for Anisotropy Material

    Directory of Open Access Journals (Sweden)

    Xiang-Rong Fu

    2013-01-01

    Full Text Available This paper presents a novel way to formulate the triangular flat shell element. The basic analytical solutions of membrane and bending plate problem for anisotropy material are studied separately. Combining with the conforming displacement along the sides and hybrid element strategy, the triangular flat shell elements based on the analytical trial functions (ATF for anisotropy material are formulated. By using the explicit integral formulae of the triangular element, the matrices used in proposed shell element are calculated efficiently. The benchmark examples showed the high accuracy and high efficiency.

  5. Boiler Control Systems Theory of Operation Manual.

    Science.gov (United States)

    1983-02-01

    9 lfeduce!s routine mtainltenance N through use of bitilt-in air 4up- *,1 ilternd, ltain eisa e Simplifie.. stockintg of -.pare - parto -illre uuanyv...operation pushbuttons and two-position transfer switch. The vertical meter is a I.5v voltmeter scaled 0-ICO representing percent of the nput M vanal-le. The...by the ratio dial seting. Ie 002 Pr aie Set Satieson, curren output. Vertices ale ndiceerds*o ea tof the Storin pae atF iei signel. 1 T1wred i 22A

  6. Smokeless Propellants as Vehicle Borne IED Main Charges: An Initial Threat Assessment

    Science.gov (United States)

    2008-01-01

    inventory records adversely effects accurate theft reporting. Theft reports submitted to ATF from 1997 to 2005 provide some evidence for this assumption... aqu ;;!$ 1.C<O relaji’’e~:recl!l’en=66I,RE). AppendixM United States Department of the Army Washington, DC Field Manual 5-250 Chapter 1, Page 1-2 30...and Propellants, Second Edition. Boca Raton: CRC, 1997 . National Research Council. Black and Smokeless Powders: Technologiesfor Finding Bombs and the

  7. Analysis of Flow Cytometry DNA Damage Response Protein Activation Kinetics Following X-rays and High Energy Iron Nuclei Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Universities Space Research Association; Chappell, Lori J.; Whalen, Mary K.; Gurai, Sheena; Ponomarev, Artem; Cucinotta, Francis A.; Pluth, Janice M.

    2010-12-15

    We developed a mathematical method to analyze flow cytometry data to describe the kinetics of {gamma}H2AX and pATF2 phosphorylations ensuing various qualities of low dose radiation in normal human fibroblast cells. Previously reported flow cytometry kinetic results for these DSB repair phospho-proteins revealed that distributions of intensity were highly skewed, severely limiting the detection of differences in the very low dose range. Distributional analysis reveals significant differences between control and low dose samples when distributions are compared using the Kolmogorov-Smirnov test. Radiation quality differences are found in the distribution shapes and when a nonlinear model is used to relate dose and time to the decay of the mean ratio of phosphoprotein intensities of irradiated samples to controls. We analyzed cell cycle phase and radiation quality dependent characteristic repair times and residual phospho-protein levels with these methods. Characteristic repair times for {gamma}H2AX were higher following Fe nuclei as compared to X-rays in G1 cells (4.5 {+-} 0.46 h vs 3.26 {+-} 0.76 h, respectively), and in S/G2 cells (5.51 {+-} 2.94 h vs 2.87 {+-} 0.45 h, respectively). The RBE in G1 cells for Fe nuclei relative to X-rays for {gamma}H2AX was 2.05 {+-} 0.61 and 5.02 {+-} 3.47, at 2 h and 24-h postirradiation, respectively. For pATF2, a saturation effect is observed with reduced expression at high doses, especially for Fe nuclei, with much slower characteristic repair times (>7 h) compared to X-rays. RBEs for pATF2 were 0.66 {+-} 0.13 and 1.66 {+-} 0.46 at 2 h and 24 h, respectively. Significant differences in {gamma}H2AX and pATF2 levels comparing irradiated samples to control were noted even at the lowest dose analyzed (0.05 Gy) using these methods of analysis. These results reveal that mathematical models can be applied to flow cytometry data to uncover important and subtle differences following exposure to various qualities of low dose radiation.

  8. Spin-orbit and electron correlation effects on the structure of EF3 (E = I, At, and element 117).

    Science.gov (United States)

    Kim, Hyoseok; Choi, Yoon Jeong; Lee, Yoon Sup

    2008-12-18

    Structures and vibrational frequencies of group 17 fluorides EF3 (E = I, At, and element 117) are calculated at the density functional theory (DFT) level of theory using relativistic effective core potentials (RECPs) with and without spin-orbit terms in order to investigate the effects of spin-orbit interactions and electron correlations on the structures and vibrational frequencies of EF3. Various tests imply that spin-orbit and electron correlation effects estimated presently from Hartree-Fock (HF) and DFT calculations with RECPs with and without spin-orbit terms are quite reasonable. Spin-orbit and electron correlation effects generally increase bond lengths and/or angles in both C2v and D3h structures. For IF3, the C2v structure is a global minimum, and the D3h structure is a second-order saddle point in both HF and DFT calculations with and without spin-orbit interactions. Spin-orbit effects for IF3 are negligible in comparison to electron correlation effects. The D3h global minimum is the only minimum structure for (117)F3 in all RECP calculations, and the C2v structure is neither a local minimum nor a saddle point. In the case of AtF3, the C2v structure is found to be a local minimum in all RECP calculations without spin-orbit terms, and the D3h structure becomes a local minimum at the DFT level of theory with and without spin-orbit interactions. In the HF calculation with spin-orbit terms, the D3h structure of AtF3 is a second-order saddle point. AtF3 is a borderline case between the valence-shell-electron-pair-repulsion (VSEPR) structure of IF3 and the non-VSEPR structure of (117)F3. Relativistic effects, including scalar relativistic and spin-orbit effects, and electron correlation effects together or separately stabilize the D3h structures more than the C2v structures. As a result, one may suggest that the VSEPR predictions agree very well with the structures optimized by the nonrelativistic HF level of theory even for heavy-atom molecules but not so

  9. Validation of an Acoustic Head Simulator for the Evaluation of Personal Hearing Protection Devices

    Science.gov (United States)

    2004-11-01

    et recouvert de peau artificielle. Les cavités de chaque côté permettent l’insertion de modules d’oreilles qui reproduisent les mécanismes des...un simulateur de tête époxy chargé d’aluminium et recouvert de peau artificielle. La tête est soutenue par un module de cou souple rattaché à un...des dispositifs de protection personnelle de l’ouie. L’ATF à l’étude consiste en un simulateur de tête époxy chargé d’aluminium et recouvert de peau

  10. Effect of astrocyte-targeted production of IL-6 on traumatic brain injury and its impact on the cortical transcriptome

    DEFF Research Database (Denmark)

    Quintana, Albert; Molinero, Amalia; Borup, Rehannah

    2008-01-01

    (freeze) injury in the cortex, increasing healing and decreasing oxidative stress and apoptosis. To determine the transcriptional basis for these responses here we analyzed the global gene expression profile of the cortex, at 0 (unlesioned), 1 or 4 days post lesion (dpl), in both GFAP-IL6 mice...... stress (Atf4). Furthermore, the presence of IL-6 altered the expression of genes involved in hemostasis (Vwf), cell migration and proliferation (Cap2), and synaptic activity (Vamp2). All these changes in gene expression could underlie the phenotype of the GFAP-IL6 mice after injury, but many other...

  11. Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

    Directory of Open Access Journals (Sweden)

    Brent W. Ferguson

    2011-01-01

    Full Text Available Heparan-sulfate proteoglycans (HSPGs are required for maximal growth factor signaling in prostate cancer progression. The degree of sulfate modification on the covalently attached heparan sulfate (HS chains is one of the determining factors of growth factor-HSPG interactions. Sulfate groups are transferred to HS chains via a series of O-sulfotransferases. In the present study, we demonstrate that Heparan sulfate 2-O-sulfotransferase (2OST is essential for maximal proliferation and invasion of prostate cancer cells in the LNCaP-C4-2B model. We also show that a decrease in invasion due to 2OST siRNA is associated with an increase in actin and E-cadherin accumulation at the cell surface. 2OST expression correlates with increasing metastatic potential in this model. We demonstrate that 2OST expression is upregulated by the stress-inducible transcription factors HIF1α, ATF2, and NFκB. Chromatin immunoprecipitation analysis suggests that HIF1α and ATF2 act directly on the 2OST promoter, while NFκB acts indirectly.

  12. Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator

    Directory of Open Access Journals (Sweden)

    Flávia C. Costa

    2012-01-01

    Full Text Available Sickle cell disease (SCD and β-thalassemia patients are phenotypically normal if they carry compensatory hereditary persistence of fetal hemoglobin (HPFH mutations that result in increased levels of fetal hemoglobin (HbF, γ-globin chains in adulthood. Thus, research has focused on manipulating the reactivation of γ-globin gene expression during adult definitive erythropoiesis as the most promising therapy to treat these hemoglobinopathies. Artificial transcription factors (ATFs are synthetic proteins designed to bind at a specific DNA sequence and modulate gene expression. The artificial zinc finger gg1-VP64 was designed to target the −117 region of the Aγ-globin gene proximal promoter and activate expression of this gene. Previous studies demonstrated that HbF levels were increased in murine chemical inducer of dimerization (CID-dependent bone marrow cells carrying a human β-globin locus yeast artificial chromosome (β-YAC transgene and in CD34+ erythroid progenitor cells from normal donors and β-thalassemia patients. Herein, we report that gg1-VP64 increased γ-globin gene expression in vivo, in peripheral blood samples from gg1-VP64 β-YAC double-transgenic (bigenic mice. Our results demonstrate that ATFs function in an animal model to increase gene expression. Thus, this class of reagent may be an effective gene therapy for treatment of some inherited diseases.

  13. Molecular cloning and characterization of unfolded protein response genes from large yellow croaker (Larimichthys crocea) and their expression in response to dietary fatty acids.

    Science.gov (United States)

    Liao, Kai; Yan, Jing; Li, Songlin; Wang, Tianjiao; Xu, Wei; Mai, Kangsen; Ai, Qinghui

    2017-01-01

    The unfolded protein response (UPR) is a mechanism to cope with perturbed endoplasmic reticulum (ER) functions or accumulation of unfolded protein in the ER in eukaryotic cells. Furthermore, the UPR also participates in a number of physiological and pathological processes, such as nutrient sensing, lipid synthesis, and inflammatory response. In this study, four UPR-related genes (GRP78/BiP, ATF6α, XBP1 and CHO) were isolated characterized from large yellow croaker (Larimichthys crocea), and their expression in response to dietary lipid sources (various fatty acids) such as fish oil (FO), palmic acid (PA), olive oil (OO), sunflower oil (SO), and perilla oil (PO), were examined following feeding. The results showed that the four UPR-related proteins contained highly conserved functional domains and had the closest phylogenetic relationships with other fishes. Additionally, these genes were ubiquitously expressed in large yellow croaker, as in zebrafish and medaka. Moreover, GRP78, ATF6α and spliced XBP1 (XBP1s) mRNA levels in the liver, not in adipose tissue, were significantly increased in the SO group compared to the other groups (P<0.05). These results indicated that dietary SO activated UPR, and the activation of UPR might provide a mechanism to improve ER function, but probably stimulated lipid synthesis and caused inflammatory response in the liver of large yellow croaker.

  14. Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.

    Directory of Open Access Journals (Sweden)

    Erica L Cain

    Full Text Available BACKGROUND: Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6 and the dual specificity phosphatase 12 (dusp12. While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1 which is implicated in metastasis. SIGNIFICANCE: Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.

  15. Phenylbutyric acid induces the cellular senescence through an Akt/p21{sup WAF1} signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hag Dong [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Jang, Chang-Young [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of); Choe, Jeong Min [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Sohn, Jeongwon, E-mail: biojs@korea.ac.kr [Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Kim, Joon, E-mail: joonkim@korea.ac.kr [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of)

    2012-06-01

    Highlights: Black-Right-Pointing-Pointer Phenylbutyric acid induces cellular senescence. Black-Right-Pointing-Pointer Phenylbutyric acid activates Akt kinase. Black-Right-Pointing-Pointer The knockdown of PERK also can induce cellular senescence. Black-Right-Pointing-Pointer Akt/p21{sup WAF1} pathway activates in PERK knockdown induced cellular senescence. -- Abstract: It has been well known that three sentinel proteins - PERK, ATF6 and IRE1 - initiate the unfolded protein response (UPR) in the presence of misfolded or unfolded proteins in the ER. Recent studies have demonstrated that upregulation of UPR in cancer cells is required to survive and proliferate. Here, we showed that long exposure to 4-phenylbutyric acid (PBA), a chemical chaperone that can reduce retention of unfolded and misfolded proteins in ER, induced cellular senescence in cancer cells such as MCF7 and HT1080. In addition, we found that treatment with PBA activates Akt, which results in p21{sup WAF1} induction. Interestingly, the depletion of PERK but not ATF6 and IRE1 also induces cellular senescence, which was rescued by additional depletion of Akt. This suggests that Akt pathway is downstream of PERK in PBA induced cellular senescence. Taken together, these results show that PBA induces cellular senescence via activation of the Akt/p21{sup WAF1} pathway by PERK inhibition.

  16. 西洋参茎叶总皂苷通过抑制内质网应激减轻毒胡萝卜素诱导的心肌细胞凋亡%PQS attenuates cardiomyocyte apoptosis induced by thapsigargin through inhibiting endoplasmic reticulum stress

    Institute of Scientific and Technical Information of China (English)

    刘蜜; 王晓礽; 陶天琪; 徐菲菲; 刘秀华; 史大卓

    2014-01-01

    AIM:To study the effect of Panax quinquefolium saponin (PQS) on cardiomyocyte apoptosis in-duced by thapsigargin ( TG) .METHODS:Primary cultured cardiomyocytes from neonatal SD rats were divided into con-trol group, TG group, PQS (40 mg/L, 80 mg/L and 160 mg/L) +TG group, si-PERK+TG group, and mock+TG group.The cells were treated with 1 μmol/L TG for 24 h to induce apoptosis.The PERK gene in the cardiomyocytes was knocked down by RNAi.The cell viability was detected by CCK-8 assay.Apoptosis was analyzed by flow cytometry.Wes-tern blotting was used to determine the expression of ERS molecules GRP78, CRT, ATF4 and CHOP, anti-apoptosis pro-tein Bcl-2 and pro-apoptosis protein Bax.RESULTS: Compared with control group, TG significantly and the apoptosis, reduced the cell viability (P<0.05), increased the phosphorylation of PERK and eIF2α, increased the expression of GRP78, CRT, ATF4, CHOP and pro-apoptosis protein Bax, and decreased the expression of anti-apoptosis protein Bcl-2 (P<0.05).Compared with TG group, PQS treatment (160 mg/L) significantly reduced the apoptosis and increased the cell viability (P<0.05).All the 3 different concentrations of PQS significantly increased the expression of anti-apoptosis protein Bcl-2 and reduced the expression of pro-apoptosis protein Bax (P<0.05) in a dose-dependent manner.PQS pre-treatment and knockdown of PERK both reduced the protein levels of GRP78, CRT, PERK, p-PERK, eIF2α, p-eIF2α, ATF4, CHOP and pro-apoptosis protein Bax, and increased the expression of anti-apoptosis protein Bcl-2 (P<0.05). CONCLUSION:PQS at concentration of 160 mg/L attenuated cardiomyocyte apoptosis induced by TG.PQS had the simi-lar effect as PERK knockdown on cardiomyocyte apoptosis.The mechanism may be associated with inhibiting PERK-eIF2α-ATF4-CHOP pathway of ERS-related apoptosis.%目的:研究西洋参茎叶总皂苷( PQS)减轻毒胡萝卜素( TG)诱导的心肌细胞凋亡的分子机制。方法:原代培养的心肌

  17. Calcium Homeostasis and ER Stress in Control of Autophagy in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Elżbieta Kania

    2015-01-01

    Full Text Available Autophagy is a basic catabolic process, serving as an internal engine during responses to various cellular stresses. As regards cancer, autophagy may play a tumor suppressive role by preserving cellular integrity during tumor development and by possible contribution to cell death. However, autophagy may also exert oncogenic effects by promoting tumor cell survival and preventing cell death, for example, upon anticancer treatment. The major factors influencing autophagy are Ca2+ homeostasis perturbation and starvation. Several Ca2+ channels like voltage-gated T- and L-type channels, IP3 receptors, or CRAC are involved in autophagy regulation. Glucose transporters, mainly from GLUT family, which are often upregulated in cancer, are also prominent targets for autophagy induction. Signals from both Ca2+ perturbations and glucose transport blockage might be integrated at UPR and ER stress activation. Molecular pathways such as IRE 1-JNK-Bcl-2, PERK-eIF2α-ATF4, or ATF6-XBP 1-ATG are related to autophagy induced through ER stress. Moreover ER molecular chaperones such as GRP78/BiP and transcription factors like CHOP participate in regulation of ER stress-mediated autophagy. Autophagy modulation might be promising in anticancer therapies; however, it is a context-dependent matter whether inhibition or activation of autophagy leads to tumor cell death.

  18. ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB

    Energy Technology Data Exchange (ETDEWEB)

    Mera, Kentaro [Department of Dermatology, Field of Sensory Organology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Kawahara, Ko-ichi [Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tada, Ko-ichi; Kawai, Kazuhiro [Department of Dermatology, Field of Sensory Organology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Hashiguchi, Teruto; Maruyama, Ikuro [Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Kanekura, Takuro, E-mail: takurok@m2.kufm.kagoshima-u.ac.jp [Department of Dermatology, Field of Sensory Organology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2010-06-25

    Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-L{alpha}, an upstream signaling molecule of ER stress, decreased at 1-4 h after 10 mJ/cm{sup 2} irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm{sup 2} UVB at 4 h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.

  19. The unfolded protein response in melanocytes: activation in response to chemical stressors of the endoplasmic reticulum and tyrosinase misfolding.

    Science.gov (United States)

    Manga, Prashiela; Bis, Sabina; Knoll, Kristen; Perez, Beremis; Orlow, Seth J

    2010-10-01

    Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways.

  20. Modeling and HIL Simulation of Flight Conditions Simulating Control System for the Altitude Test Facility

    Science.gov (United States)

    Zhou, Jun; Shen, Li; Zhang, Tianhong

    2016-12-01

    Simulated altitude test is an essential exploring, debugging, verification and validation means during the development of aero-engine. Free-jet engine test can simulate actual working conditions of aero-engine more realistically than direct-connect engine test but with relatively lower cost compared to propulsion wind tunnel test, thus becoming an important developing area of simulated altitude test technology. The Flight Conditions Simulating Control System (FCSCS) is of great importance to the Altitude Test Facility (ATF) but the development of that is a huge challenge. Aiming at improving the design efficiency and reducing risks during the development of FCSCS for ATFs, a Hardware- in-the-Loop (HIL) simulation system was designed and the mathematical models of key components such as the pressure stabilizing chamber, free-jet nozzle, control valve and aero-engine were built in this paper. Moreover, some HIL simulation experiments were carried out. The results show that the HIL simulation system designed and established in this paper is reasonable and effective, which can be used to adjust control parameters conveniently and assess the software and hardware in the control system immediately.

  1. Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity*

    Science.gov (United States)

    Krokowski, Dawid; Jobava, Raul; Guan, Bo-Jhih; Farabaugh, Kenneth; Wu, Jing; Majumder, Mithu; Bianchi, Massimiliano G.; Snider, Martin D.; Bussolati, Ovidio; Hatzoglou, Maria

    2015-01-01

    Cells respond to shrinkage induced by increased extracellular osmolarity via programmed changes in gene transcription and mRNA translation. The immediate response to this stress includes the induction of expression of the neutral amino acid transporter SNAT2. Increased SNAT2-mediated uptake of neutral amino acids is an essential adaptive mechanism for restoring cell volume. In contrast, stress-induced phosphorylation of the α subunit of the translation initiation factor eIF2 (eIF2α) can promote apoptosis. Here we show that the response to mild hyperosmotic stress involves regulation of the phosphorylation of eIF2α by increased levels of GADD34, a regulatory subunit of protein phosphatase 1 (PP1). The induction of GADD34 was dependent on transcriptional control by the c-Jun-binding cAMP response element in the GADD34 gene promoter and posttranscriptional stabilization of its mRNA. This mechanism differs from the regulation of GADD34 expression by other stresses that involve activating transcription factor 4 (ATF4). ATF4 was not translated during hyperosmotic stress despite an increase in eIF2α phosphorylation. The SNAT2-mediated increase in amino acid uptake was enhanced by increased GADD34 levels in a manner involving decreased eIF2α phosphorylation. It is proposed that the induction of the SNAT2/GADD34 axis enhances cell survival by promoting the immediate adaptive response to stress. PMID:26041779

  2. Pulsed strain release on the Altyn Tagh fault, northwest China

    Science.gov (United States)

    Gold, Ryan D.; Cowgill, Eric; Arrowsmith, J. Ramón; Friedrich, Anke M.

    2017-02-01

    Earthquake recurrence models assume that major surface-rupturing earthquakes are followed by periods of reduced rupture probability as stress rebuilds. Although purely periodic, time- or slip-predictable rupture models are known to be oversimplifications, a paucity of long records of fault slip clouds understanding of fault behavior and earthquake recurrence over multiple ruptures. Here, we report a 16 kyr history of fault slip-including a pulse of accelerated slip from 6.4 to 6.0 ka-determined using a Monte Carlo analysis of well-dated offset landforms along the central Altyn Tagh strike-slip fault (ATF) in northwest China. This pulse punctuates a median rate of 8.1+1.2/-0.9 mm /a and likely resulted from either a flurry of temporally clustered ∼Mw 7.5 ground-rupturing earthquakes or a single large >Mw 8.2 earthquake. The clustered earthquake scenario implies rapid re-rupture of a fault reach >195 km long and indicates decoupled rates of elastic strain energy accumulation versus dissipation, conceptualized as a crustal stress battery. If the pulse reflects a single event, slip-magnitude scaling implies that it ruptured much of the ATF with slip similar to, or exceeding, the largest documented historical ruptures. Both scenarios indicate fault rupture behavior that deviates from classic time- or slip-predictable models.

  3. Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice.

    Directory of Open Access Journals (Sweden)

    Nobuhiro Ogawa

    Full Text Available Neuropathic pain can be a debilitating condition. Many types of drugs that have been used to treat neuropathic pain have only limited efficacy. Recent studies indicate that pro-inflammatory mediators including tumor necrosis factor α (TNF-α are involved in the pathogenesis of neuropathic pain. In the present study, we engineered a gene therapy strategy to relieve neuropathic pain by silencing TNF-α expression in the dorsal root ganglion (DRG using lentiviral vectors expressing TNF short hairpin RNA1-4 (LV-TNF-shRNA1-4 in mice. First, based on its efficacy in silencing TNF-α in vitro, we selected shRNA3 to construct LV-TNF-shRNA3 for in vivo study. We used L5 spinal nerve transection (SNT mice as a neuropathic pain model. These animals were found to display up-regulated mRNA expression of activating transcription factor 3 (ATF3 and neuropeptide Y (NPY, injury markers, and interleukin (IL-6, an inflammatory cytokine in the ipsilateral L5 DRG. Injection of LV-TNF-shRNA3 onto the proximal transected site suppressed significantly the mRNA levels of ATF3, NPY and IL-6, reduced mechanical allodynia and neuronal cell death of DRG neurons. These results suggest that lentiviral-mediated silencing of TNF-α in DRG relieves neuropathic pain and reduces neuronal cell death, and may constitute a novel therapeutic option for neuropathic pain.

  4. The proapoptotic dp5 gene is a direct target of the MLK-JNK-c-Jun pathway in sympathetic neurons.

    Science.gov (United States)

    Towers, Emily; Gilley, Jonathan; Randall, Rebecca; Hughes, Rosie; Kristiansen, Mark; Ham, Jonathan

    2009-05-01

    The death of sympathetic neurons after nerve growth factor (NGF) withdrawal requires de novo gene expression. Dp5 was one of the first NGF withdrawal-induced genes to be identified and it encodes a proapoptotic BH3-only member of the Bcl-2 family. To study how dp5 transcription is regulated by NGF withdrawal we cloned the regulatory regions of the rat dp5 gene and constructed a series of dp5-luciferase reporter plasmids. In microinjection experiments with sympathetic neurons we found that three regions of dp5 contribute to its induction after NGF withdrawal: the promoter, a conserved region in the single intron, and sequences in the 3' untranslated region of the dp5 mRNA. A construct containing all three regions is efficiently activated by NGF withdrawal and, like the endogenous dp5, its induction requires mixed-lineage kinase (MLK) and c-Jun N-terminal kinase (JNK) activity. JNKs phosphorylate the AP-1 transcription factor c-Jun, and thereby increase its activity. We identified a conserved ATF site in the dp5 promoter that binds c-Jun and ATF2, which is critical for dp5 promoter induction after NGF withdrawal. These results suggest that part of the mechanism by which the MLK-JNK-c-Jun pathway promotes neuronal apoptosis is by activating the transcription of the dp5 gene.

  5. Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

    LENUS (Irish Health Repository)

    Kelly, Emer

    2009-06-19

    Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

  6. Early implementation of SiC cladding fuel performance models in BISON

    Energy Technology Data Exchange (ETDEWEB)

    Powers, Jeffrey J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-09-18

    SiC-based ceramic matrix composites (CMCs) [5–8] are being developed and evaluated internationally as potential LWR cladding options. These development activities include interests within both the DOE-NE LWR Sustainability (LWRS) Program and the DOE-NE Advanced Fuels Campaign. The LWRS Program considers SiC ceramic matrix composites (CMCs) as offering potentially revolutionary gains as a cladding material, with possible benefits including more efficient normal operating conditions and higher safety margins under accident conditions [9]. Within the Advanced Fuels Campaign, SiC-based composites are a candidate ATF cladding material that could achieve several goals, such as reducing the rates of heat and hydrogen generation due to lower cladding oxidation rates in HT steam [10]. This work focuses on the application of SiC cladding as an ATF cladding material in PWRs, but these work efforts also support the general development and assessment of SiC as an LWR cladding material in a much broader sense.

  7. Evaluation of oleic acid as additive in automatic transmission fluid

    Science.gov (United States)

    Khairuldean, A. K.; Ing, T. Chiong; Bambang, S.; Baharin, T. Kamarul; Wira, J. Y.; Syahrullail, S.

    2012-06-01

    Transmission fluid has already being monopolized by petroleum oil over these years, either mineral oil or synthetic oil, the base oil originated from the crude oil. Currently, with environmental issue becomes globally concerned, it is time to move toward green technology and more to the sustainability, resource renewability and biodegradability. To respond to this challenge, a research focusing on development of environmental friendly lubricant for Automatic Transmission (AT) is conducted. In this paper, the Refined, Bleached, and Deodorized Palm-Olein (RBDPO) mixed with the Automatic Transmission Fluid (ATF), is developed and tested. The research focuses on some parameters such as anti wear and friction coefficient characteristics. The test is conducted using four ball wear tester machine to analyze anti wear of the lubricant as well as to simulate the sliding surface of gear operation inside the transmission which is the most critical operation condition for the lubricant. The method of testing is based on ASTM D4172 Test B condition for wear measurement. By comparing the experimental results between mixed lubricants and the commercial ATF, it can be seen that the palm olein is very potential to become a base oil for transmission lubricant in the future due to its promising performance of the tested physical properties.

  8. Density functional theory calculations of defect and fission gas properties in U-Si fuels

    Energy Technology Data Exchange (ETDEWEB)

    Andersson, Anders David [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-02-03

    Accident tolerant fuels (ATF) are being developed in response to the Fukushima Daiichi accident in Japan. One of the options being pursued is U-Si fuels, such as the U3Si2 and U3Si5 compounds, which benefit from high thermal conductivity (metallic) compared to the UO2 fuel (insulator or semi-conductor) used in current Light Water Reactors (LWRs). The U-Si fuels also have higher fissile density. In order to perform meaningful engineering scale nuclear fuel performance simulations, the material properties of the fuel, including the response to irradiation environments, must be known. Unfortunately, the data available for U-Si fuels are rather limited, in particular for the temperature range where LWRs would operate. The ATF HIP is using multi-scale modeling and simulations to address this knowledge gap. The present study investigates point defect and fission gas properties in U3Si2, which is one of the main fuel candidates, using density functional theory (DFT) calculations. Based on a few assumption regarding entropy contributions, defect and fission diffusivities are predicted. Even though uranium silicides have been shown to amorphize easily at low temperature, we assume that U3Si2 remains crystalline under the conditions expected in Light Water Reactors (LWRs). The temperature and dose where amorphization occurs has not yet been well established.

  9. Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells.

    Science.gov (United States)

    Yan, J; Zhong, N; Liu, G; Chen, K; Liu, X; Su, L; Singhal, S

    2014-07-03

    Pemetrexed, a folate antimetabolite, combined with cisplatin is used as a first-line therapy for malignant pleural mesothelioma (MPM) and locally advanced or metastatic non-small-cell lung cancer (NSCLC). Pemetrexed arrests cell cycle by inhibiting three enzymes in purine and pyrimidine synthesis that are necessary for DNA synthesis. Pemetrexed also promotes apoptosis in target cells, but little is known about its mechanism in cancer cells. We have previously shown that pemetrexed can result in endoplasmic reticulum (ER) stress, and it can lead to downstream apoptosis. In this study, we further elucidate this mechanism. Our data show that pemetrexed increases Noxa expression through activating transcription factor 4 (ATF4) and activating transcription factor 3 (ATF3) upregulation. Furthermore, pemetrexed induces apoptosis by activating the Noxa-Usp9x-Mcl-1 pathway. Inhibition of Noxa by small interfering RNA (siRNA) promotes Usp9x (ubiquitin-specific peptidase 9, X-linked) expression. Moreover, downregulation of the deubiquitinase Usp9x by pemetrexed results in downstream reduction of myeloid cell leukemia 1 (Mcl-1) expression. Mechanistically, Noxa upregulation likely reduces the availability of Usp9x to Mcl-1, thereby promoting its ubiquitination and degradation, leading to the apoptosis of neoplastic cells. Thus, our findings demonstrate that Noxa-Usp9x-Mcl-1 axis may contribute to pemetrexed-induced apoptosis in human lung cancer cells.

  10. ER stress, p66shc, and p-Akt/Akt mediate adjuvant-induced inflammation, which is blunted by argirein, a supermolecule and rhein in rats.

    Science.gov (United States)

    Cong, Xiao-Dong; Ding, Ming-Jian; Dai, De-Zai; Wu, You; Zhang, Yun; Dai, Yin

    2012-06-01

    We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.

  11. IMPACT is a developmentally regulated protein in neurons that opposes the eukaryotic initiation factor 2α kinase GCN2 in the modulation of neurite outgrowth.

    Science.gov (United States)

    Roffé, Martín; Hajj, Glaucia N M; Azevedo, Hátylas F; Alves, Viviane S; Castilho, Beatriz A

    2013-04-12

    The product of the mouse Imprinted and Ancient gene, IMPACT, is preferentially expressed in neurons. We have previously shown that IMPACT overexpression inhibits the activation of the protein kinase GCN2, which signals amino acid starvation. GCN2 phosphorylates the α-subunit of eukaryotic translation initiation factor 2 (eIF2α), resulting in inhibition of general protein synthesis but increased translation of specific messages, such as ATF4. GCN2 is also involved in the regulation of neuronal functions, controlling synaptic plasticity, memory, and feeding behavior. We show here that IMPACT abundance increases during differentiation of neurons and neuron-like N2a cells, whereas GCN2 displays lowered activation levels. Upon differentiation, IMPACT associates with translating ribosomes, enhances translation initiation, and down-regulates the expression of ATF4. We further show that endogenous IMPACT promotes neurite outgrowth whereas GCN2 is a strong inhibitor of spontaneous neuritogenesis. Together, these results uncover the participation of the GCN2-IMPACT module of translational regulation in a highly controlled step in the development of the nervous system.

  12. A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer

    Directory of Open Access Journals (Sweden)

    Christina Marie Gutierrez

    2015-11-01

    Full Text Available Background/Aims: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. Methods: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk versus late/nulliparity (high risk. Results: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. Conclusions: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk.

  13. In vivo association of ATFa with JNK/SAP kinase activities.

    Science.gov (United States)

    Bocco, J L; Bahr, A; Goetz, J; Hauss, C; Kallunki, T; Kedinger, C; Chatton, B

    1996-05-02

    The human ATFa proteins belong to the CREB/ATF family of transcription factors. We have previously shown that the ATFa proteins may contribute to the modulation of the transcriptional activity of the Jun/Fos complexes (Chatton et al. (1994). Oncogene, 9, 375-385). We now show that a protein kinase activity is strongly associated with ATFa in vivo, as revealed by coimmunoprecipitation of ATFa/kinase complexes from whole cell extracts, with antibodies against ATFa. Two independent regions were found to be implicated in kinase binding: a major interaction site is located within the N-terminal 82 residues comprising an important metal-chelating element; a weaker binding site corresponds to the basic sequence element preceding the C-terminal leucine-zipper of ATFa. Induction experiments suggest that each of these ATFa domains may interact with different kinases. The major activity is associated with the ATFa N-terminal domain. Based on its response to various inducers, on both in vitro and in vivo binding assays, and on its immunological properties, this activity most likely corresponds to the 54/55 kDa JNK2 protein. Taken together, these observations suggest that the ATFa proteins, among other CREB/ATF proteins, may be important effectors of cell signalling pathways.

  14. TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress.

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    Yoshinori Tsukumo

    Full Text Available Under ER stress, PKR-like ER-resident kinase (PERK phosphorylates translation initiation factor eIF2α, resulting in repression of global protein synthesis and concomitant upregulation of the translation of specific mRNAs such as activating transcription factor 4 (ATF4. This PERK function is important for cell survival under ER stress and poor nutrient conditions. However, mechanisms of the PERK signaling pathway are not thoroughly understood. Here we identify transducin (beta-like 2 (TBL2 as a novel PERK-binding protein. We found that TBL2 is an ER-localized type-I transmembrane protein and preferentially binds to the phosphorylated form of PERK, but not another eIF2α kinase GCN2 or ER-resident kinase IRE1, under ER stress. Immunoprecipitation analysis using various deletion mutants revealed that TBL2 interacts with PERK via the N-terminus proximal region and also associates with eIF2α via the WD40 domain. In addition, TBL2 knockdown can lead to impaired ATF4 induction under ER stress or poor nutrient conditions such as glucose and oxygen deprivation. Consistently, TBL2 knockdown rendered cells vulnerable to stresses similarly to PERK knockdown. Thus, TBL2 serves as a potential regulator of the PERK pathway.

  15. UVC-induced apoptosis in Dubca cells is independent of JNK activation and p53{sup Ser-15} phosphorylation

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    Chathoth, Shahanas; Thayyullathil, Faisal; Hago, Abdulkader [Cell Signaling Laboratory, Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain (United Arab Emirates); Shahin, Allen [Department of Medical Microbiology, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain (United Arab Emirates); Patel, Mahendra [Cell Signaling Laboratory, Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain (United Arab Emirates); Galadari, Sehamuddin, E-mail: sehamuddin@uaeu.ac.ae [Cell Signaling Laboratory, Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain (United Arab Emirates)

    2009-06-12

    Ultraviolet C (UVC) irradiation in mammalian cell lines activates a complex signaling network that leads to apoptosis. By using Dubca cells as a model system, we report the presence of a UVC-induced apoptotic pathway that is independent of c-Jun N-terminal kinases (JNKs) activation and p53 phosphorylation at Ser{sup 15}. Irradiation of Dubca cells with UVC results in a rapid JNK activation and phosphorylation of its downstream target c-Jun, as well as, phosphorylation of activating transcription factor 2 (ATF2). Pre-treatment with JNK inhibitor, SP600125, inhibited UVC-induced c-Jun phosphorylation without preventing UVC-induced apoptosis. Similarly, inhibition of UVC-induced p53 phosphorylation did not prevent Dubca cell apoptosis, suggesting that p53{sup Ser-15} phosphorylation is not associated with UVC-induced apoptosis signaling. The pan-caspase inhibitor z-VAD-fmk inhibited UVC-induced PARP cleavage, DNA fragmentation, and ultimately apoptosis of Dubca cells. Altogether, our study clearly indicates that UVC-induced apoptosis is independent of JNK and p53 activation in Dubca cells, rather, it is mediated through a caspase dependent pathway. Our findings are not in line with the ascribed critical role for JNKs activation, and downstream phosphorylation of targets such as c-Jun and ATF2 in UVC-induced apoptosis.

  16. Voltage-Dependent Anion Channel 1(VDAC1) Participates the Apoptosis of the Mitochondrial Dysfunction in Desminopathy

    Science.gov (United States)

    Mo, Yanqing; Gong, Qi; Jiang, Aihua; Zhao, Jing

    2016-01-01

    Desminopathies caused by the mutation in the gene coding for desmin are genetically protein aggregation myopathies. Mitochondrial dysfunction is one of pathological changes in the desminopathies at the earliest stage. The molecular mechanisms of mitochondria dysfunction in desminopathies remain exclusive. VDAC1 regulates mitochondrial uptake across the outer membrane and mitochondrial outer membrane permeabilization (MOMP). Relationships between desminopathies and Voltage-dependent anion channel 1 (VDAC1) remain unclear. Here we successfully constructed the desminopathy rat model, evaluated with conventional stains, containing hematoxylin and eosin (HE), Gomori Trichrome (MGT), (PAS), red oil (ORO), NADH-TR, SDH staining and immunohistochemistry. Immunofluorescence results showed that VDAC1 was accumulated in the desmin highly stained area of muscle fibers of desminopathy patients or desminopathy rat model compared to the normal ones. Meanwhile apoptosis related proteins bax and ATF2 were involved in desminopathy patients and desminopathy rat model, but not bcl-2, bcl-xl or HK2.VDAC1 and desmin are closely relevant in the tissue splices of deminopathies patients and rats with desminopathy at protein lever. Moreover, apoptotic proteins are also involved in the desminopathies, like bax, ATF2, but not bcl-2, bcl-xl or HK2. This pathological analysis presents the correlation between VDAC1 and desmin, and apoptosis related proteins are correlated in the desminopathy. Furthermore, we provide a rat model of desminopathy for the investigation of desmin related myopathy. PMID:27941998

  17. Infusion of glucose and lipids at physiological rates causes acute endoplasmic reticulum stress in rat liver.

    Science.gov (United States)

    Boden, Guenther; Song, Weiwei; Duan, Xunbao; Cheung, Peter; Kresge, Karen; Barrero, Carlos; Merali, Salim

    2011-07-01

    Endoplasmic reticulum (ER) stress has recently been implicated as a cause for obesity-related insulin resistance; however, what causes ER stress in obesity has remained uncertain. Here, we have tested the hypothesis that macronutrients can cause acute (ER) stress in rat liver. Examined were the effects of intravenously infused glucose and/or lipids on proximal ER stress sensor activation (PERK, eIF2-α, ATF4, Xbox protein 1 (XBP1s)), unfolded protein response (UPR) proteins (GRP78, calnexin, calreticulin, protein disulphide isomerase (PDI), stress kinases (JNK, p38 MAPK) and insulin signaling (insulin/receptor substrate (IRS) 1/2 associated phosphoinositol-3-kinase (PI3K)) in rat liver. Glucose and/or lipid infusions, ranging from 23.8 to 69.5 kJ/4 h (equivalent to between ~17% and ~50% of normal daily energy intake), activated the proximal ER stress sensor PERK and ATF6 increased the protein abundance of calnexin, calreticulin and PDI and increased two GRP78 isoforms. Glucose and glucose plus lipid infusions induced comparable degrees of ER stress, but only infusions containing lipid activated stress kinases (JNK and p38 MAPK) and inhibited insulin signaling (PI3K). In summary, physiologic amounts of both glucose and lipids acutely increased ER stress in livers 12-h fasted rats and dependent on the presence of fat, caused insulin resistance. We conclude that this type of acute ER stress is likely to occur during normal daily nutrient intake.

  18. Neutronic Analysis on Potential Accident Tolerant Fuel-Cladding Combination U3Si2-FeCrAl

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    Shengli Chen

    2017-01-01

    Full Text Available Neutronic performance is investigated for a potential accident tolerant fuel (ATF, which consists of U3Si2 fuel and FeCrAl cladding. In comparison with current UO2-Zr system, FeCrAl has a better oxidation resistance but a larger thermal neutron absorption cross section. U3Si2 has a higher thermal conductivity and a higher uranium density, which can compensate the reactivity suppressed by FeCrAl. Based on neutronic investigations, a possible U3Si2-FeCrAl fuel-cladding system is taken into consideration. Fundamental properties of the suggested fuel-cladding combination are investigated in a fuel assembly. These properties include moderator and fuel temperature coefficients, control rods worth, radial power distribution (in a fuel rod, and different void reactivity coefficients. The present work proves that the new combination has less reactivity variation during its service lifetime. Although, compared with the current system, it has a little larger deviation on power distribution and a little less negative temperature coefficient and void reactivity coefficient and its control rods worth is less important, variations of these parameters are less important during the service lifetime of fuel. Hence, U3Si2-FeCrAl system is a potential ATF candidate from a neutronic view.

  19. Genome-wide screening for genes associated with valproic acid sensitivity in fission yeast.

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    Lili Zhang

    Full Text Available We have been studying the action mechanisms of valproic acid (VPA in fission yeast Schizosaccharomyces pombe by developing a genetic screen for mutants that show hypersensitivity to VPA. In the present study, we performed a genome-wide screen of 3004 haploid deletion strains and confirmed 148 deletion strains to be VPA sensitive. Of the 148 strains, 93 strains also showed sensitivity to another aliphatic acids HDAC inhibitor, sodium butyrate (SB, and 55 strains showed sensitivity to VPA but not to SB. Interestingly, we found that both VPA and SB treatment induced a marked increase in the transcription activity of Atf1 in wild-type cells. However, in clr6-1, a mutant allele the clr6(+ gene encoding class I HDAC, neither VPA- nor SB induced the activation of Atf1 transcription activity. We also found that VPA, but not SB, caused an increase in cytoplasmic Ca(2+ level. We further found that the cytoplasmic Ca(2+ increase was caused by Ca(2+ influx from extracellular medium via Cch1-Yam8 channel complex. Altogether, our present study indicates that VPA and SB play similar but distinct roles in multiple physiological processes in fission yeast.

  20. Uniform {sup 15}N- and {sup 15}N/{sup 13}C-labeling of proteins in mammalian cells and solution structure of the amino terminal fragment of u-PA

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, A.P.; Petros, A.M.; Meadows, R.P.; Mazar, A.P.; Nettesheim, D.G.; Pederson, T.M.; Fesik, S.W. [Abbott Laboratories, Abbott Park, IL (United States)

    1994-12-01

    Urokinase-type plasminogen activator (u-PA) is a 54-kDa glycoprotein that catalyzes the conversion of plasminogen to plasmin, a broad-specificity protease responsible for the degradation of fibrin clots and extracellular matrix components. The u-PA protein consists of three individual modules: a growth factor domain (GFD), a kringle, and a serine protease domain. The amino terminal fragment (ATF) includes the GFD-responsible for u-PA binding to its receptor-and the kringle domains. This protein was expressed and uniformly {sup 15}N-and {sup 15}N/{sup 13}C-labeled in mammalian cells by methods that will be described. In addition, we present the three-dimensional structure of ATF that was derived from 1299 NOE-derived distance restraints along with the {phi} angle and hydrogen bonding restraints. Although the individual domains in the structures were highly converged, the two domains are structurally independent. The overall structures of the individual domains are very similar to the structures of homologous proteins. However, important structural differences between the growth factor domain of u-PA and other homologous proteins were observed in the region that has been implicated in binding the urokinase receptor. These results may explain, in part, why other growth factors show no appreciable affinity for the urokinase receptor.