SHMUTZ & PROTON-DIAMANT H + Irradiated/Written-Hyper/Super-conductivity(HC/SC) Precognizance/Early Experiments Connections: Wet-Graphite Room-Tc & Actualized MgB2 High-Tc: Connection to Mechanical Bulk-Moduli/Hardness: Diamond Hydrocarbon-Filaments, Disorder, Nano-Powders:C,Bi,TiB2,TiC

NASA Astrophysics Data System (ADS)

Wunderman, Irwin; Siegel, Edward Carl-Ludwig; Lewis, Thomas; Young, Frederic; Smith, Adolph; Dresschhoff-Zeller, Gieselle

2013-03-01

SHMUTZ: ``wet-graphite''Scheike-....[Adv.Mtls.(7/16/12)]hyper/super-SCHMUTZ-conductor(S!!!) = ``wet''(?)-``graphite''(?) = ``graphene''(?) = water(?) = hydrogen(?) =ultra-heavy proton-bands(???) = ...(???) claimed room/high-Tc/high-Jc superconductOR ``p''-``wave''/ BAND(!!!) superconductIVITY and actualized/ instantiated MgB2 high-Tc superconductors and their BCS- superconductivity: Tc Siegel[ICMAO(77);JMMM 7,190(78)] connection to SiegelJ.Nonxline-Sol.40,453(80)] disorder/amorphous-superconductivity in nano-powders mechanical bulk/shear(?)-moduli/hardness: proton-irradiated diamond, powders TiB2, TiC,{Siegel[Semis. & Insuls.5:39,47, 62 (79)])-...``VS''/concommitance with Siegel[Phys.Stat.Sol.(a)11,45(72)]-Dempsey [Phil.Mag. 8,86,285(63)]-Overhauser-(Little!!!)-Seitz-Smith-Zeller-Dreschoff-Antonoff-Young-...proton-``irradiated''/ implanted/ thermalized-in-(optimal: BOTH heat-capacity/heat-sink & insulator/maximal dielectric-constant) diamond: ``VS'' ``hambergite-borate-mineral transformable to Overhauser optimal-high-Tc-LiBD2 in Overhauser-(NW-periodic-table)-Land: CO2/CH4-ETERNAL-sequestration by-product: WATER!!!: physics lessons from

Entropy of Stationary Nonequilibrium Measures of Boundary Driven Symmetric Simple Exclusion Processes

NASA Astrophysics Data System (ADS)

Bernardin, Cédric; Landim, Claudio

2010-12-01

We examine the entropy of stationary nonequilibrium measures of boundary driven symmetric simple exclusion processes. In contrast with the Gibbs-Shannon entropy (Bahadoran in J. Stat. Phys. 126(4-5):1069-1082, 2007; Derrida et al. in J. Stat. Phys. 126(4-5):1083-1108, 2007), the entropy of nonequilibrium stationary states differs from the entropy of local equilibrium states.

FRAUD/SABOTAGE Killing Nuclear-Reactors Need Modeling!!!: "Super"alloys GENERIC ENDEMIC Wigner's-Disease/.../IN-stability: Ethics? SHMETHICS!!!

NASA Astrophysics Data System (ADS)

Asphahani, Aziz; Siegel, Sidney; Siegel, Edward

2010-03-01

Carbides solid-state chemistry domination of old/new nuclear- reactors/spent-fuel-casks/refineries/jet/missile/rocket-engines in austenitic/FCC Ni/Fe-based(so miscalled)``super"alloys(182/82; Hastelloy-X,600,304/304L-SSs,...,690!!!) GENERIC ENDEMIC EXTANT detrimental(synonyms): Wigner's-diseas(WD)[J.Appl.Phys.17,857 (1946)]/Ostwald-ripening/spinodal-decomposition/overageing- embrittlement/thermal-leading-to-mechanical(TLTM)-INstability: Mayo[Google:``If Leaks Could Kill"; at flickr.com search on ``Giant-Magnotoresistance"; find: Siegel[J.Mag.Mag.Mtls.7,312 (1978)]<<<``Fert"-"Gruenberg"(1988/89)2007-physics Nobel/Wolf/ Japan-prizes]necessitating NRC-inspections of 40+25 = 65 Westin- ``KLouse PWRs(12/2006)]-Lai[Met.Trans.AIME,9A,827(1978)]-Sabol- Stickler[Phys.Stat.Sol.(1970)]-Ashpahani[Intl.Conf. H in Metals, Paris(1977]-Russell[Prog.Mtls.Sci.(1983)]-Pollard[last UCS rept. (9/1995)]-Lofaro[BNL/DOE/NRC Repts.]-Pringle[Nuclear-Power:From Physics to Politics(1979)]-Hoffman[animatedsoftware.com], what DOE/NRC MISlabels as ``butt-welds" ``stress-corrosion cracking" endpoint's ROOT-CAUSE ULTIMATE-ORIGIN is WD overageing-embritt- lement caused brittle-fracture cracking from early/ongoing AEC/ DOE-n"u"tional-la"v"atories sabotage!!!

FRAUD/SABOTAGE Killing Nuclear-Reactors Need Modeling!!!: ``Super'' alloys GENERIC ENDEMIC Wigner's-Disease/.../IN-stability: Ethics? SHMETHICS!!!

NASA Astrophysics Data System (ADS)

O'Grady, Joseph; Bument, Arlden; Siegel, Edward

2011-03-01

Carbides solid-state chemistry domination of old/new nuclear-reactors/spent-fuel-casks/refineries/jet/missile/rocket-engines is austenitic/FCC Ni/Fe-based (so miscalled)"super"alloys(182/82;Hastelloy-X,600,304/304L-SSs,...690!!!) GENERIC ENDEMIC EXTANT detrimental(synonyms): Wigner's-disease(WD) [J.Appl.Phys.17,857 (46)]/Ostwald-ripening/spinodal-decomposition/overageing-embrittlement/thermal-leading-to-mechanical(TLTM)-INstability: Mayo[Google: fLeaksCouldKill > ; - Siegel [ J . Mag . Mag . Mtls . 7 , 312 (78) = atflickr . comsearchonGiant - Magnotoresistance [Fert" [PRL(1988)]-"Gruenberg"[PRL(1989)] 2007-Nobel]necessitating NRC inspections on 40+25=65 Westin"KL"ouse PWRs(12/2006)]-Lai [Met.Trans.AIME, 9A,827(78)]-Sabol-Stickler[Phys.Stat.Sol.(70)]-Ashpahani[ Intl.Conf. Hydrogen in Metals, Paris(1977]-Russell [Prog.Mtls.Sci.(1983)]-Pollard [last UCS rept.(9/1995)]-Lofaro [BNL/DOE/NRC Repts.]-Pringle [ Nuclear-Power:From Physics to Politics(1979)]-Hoffman [animatedsoftware.com], what DOE/NRC MISlabels as "butt-welds" "stress-corrosion cracking" endpoint's ROOT-CAUSE ULTIMATE-ORIGIN is WD overageing-embrittlement caused brittle-fracture cracking from early/ongoing AEC/DOE-n"u"tional-la"v"atories sabotage!!!

Blowpipe Mineralogy for Physics/Environment: Highest-Possible-Tc SC Quest; BOTH PERMANENT FOREVER Carb-IDES SOLID-State Sequestration AND Drought(s)-Elimination

NASA Astrophysics Data System (ADS)

Segler, Kurt; Williams, W.; Siegel, E.

2010-03-01

Detailed are old blowpipe[Kraus,Hunt,Ramsdell, Mineralogy (1936)] new applications:charcoal-block reduction of borates to yield (``N-NW'' of MgB2) Overhauser-[PR 35,1,411(1987); Intl.J.Mod.Phys.1,2 & 4,927(1987)]-``land'' predicted high-EST- POSSIBLE Tc SC ˜ ``LiD2''; very-early: Siegel[Phys.Stat.Sol.(a) 11,45(1972);Semiconductors & Insulators 5: 39,47,62(1979)] carb- IDES SOLID-state phase-TRANSITIONED CHEMICALLY-REDOX"-REACTED STABLE PERMANENT LONG-term STRATEGY, NOT ``CO2" BUT NON-gas Carbon-``ELEMENT"-sequestration: PROFITABLE MARKETABLE SALEABLE VALUABLE USEFUL ``Grab and Sell" TRUMPS ``cap and trade"!!!; Mott alloying/vertical metal-insulator transitions in ``borax-(GLASS)- beads"; and very-early Siegel [3rd Intl.Conf.Alt.Energy,Hemi- sphere/Springer(1980)-vol.5/p.459] ``FLYING-WATER" ``Hindenberg- effect"(H2-UP;H2O-DOWN) via H2-maximal-Archimedes-buoyancy ``chemical-rain-in-piplines", only via Siegel GMR enabled diffusive-magnetoresistance(DMR)enabled Siegel proprietary ``magnetic-H-valve": Renewables-H2-H2O purposely flexible versatile agile scaleable retrofitable integrated operating- system for PERMANENT drought(s)-elimination FOREVER!!!

Basic Studies in Plasma Physics

DTIC Science & Technology

1998-01-31

Process in One Dimension, (with B. Derrida and E. Speer), Jour. Stat. Phys., 1997, to appear. [16] Comment on "Phase Separation in Two-Dimensional Fluids...Short version to appear in January 1997 in Physics Today ; the long version is to appear in Jour. Stat. Phys., 87, 463-468, 1997. [25] Microscopic...SIAM J. Math. Anal. 27, 110-134, 1996. [31] Microscopic-Shock Profiles: Exact Solution of a Non-Equilibrium System, (with B. Derrida , S. Janowsky and

Fast wave power flow along SOL field lines in NSTX

NASA Astrophysics Data System (ADS)

Perkins, R. J.; Bell, R. E.; Diallo, A.; Gerhardt, S.; Hosea, J. C.; Jaworski, M. A.; Leblanc, B. P.; Kramer, G. J.; Phillips, C. K.; Roquemore, L.; Taylor, G.; Wilson, J. R.; Ahn, J.-W.; Gray, T. K.; Green, D. L.; McLean, A.; Maingi, R.; Ryan, P. M.; Jaeger, E. F.; Sabbagh, S.

2012-10-01

On NSTX, a major loss of high-harmonic fast wave (HHFW) power can occur along open field lines passing in front of the antenna over the width of the scrape-off layer (SOL). Up to 60% of the RF power can be lost and at least partially deposited in bright spirals on the divertor floor and ceiling [1,2]. The flow of HHFW power from the antenna region to the divertor is mostly aligned along the SOL magnetic field [3], which explains the pattern of heat deposition as measured with infrared (IR) cameras. By tracing field lines from the divertor back to the midplane, the IR data can be used to estimate the profile of HHFW power coupled to SOL field lines. We hypothesize that surface waves are being excited in the SOL, and these results should benchmark advanced simulations of the RF power deposition in the SOL (e.g., [4]). Minimizing this loss is critical optimal high-power long-pulse ICRF heating on ITER while guarding against excessive divertor erosion.[4pt] [1] J.C. Hosea et al., AIP Conf Proceedings 1187 (2009) 105. [0pt] [2] G. Taylor et al., Phys. Plasmas 17 (2010) 056114. [0pt] [3] R.J. Perkins et al., to appear in Phys. Rev. Lett. [0pt] [4] D.L. Green et al., Phys. Rev. Lett. 107 (2011) 145001.

Perils of Neglecting Lattice Relaxation in the Pressure Dependence of Deep Luminescence Bands in Wide Gap Semiconductors

NASA Astrophysics Data System (ADS)

Iota, V.; Weinstein, B. A.

1998-03-01

Deep defect states are often assumed to be insensitive to pressure because of their localized atomic-like character. In apparent conflict with this, experiments on widegap II-VI materials find that the pressure shifts of many 'midgap' photoluminescence (PL) bands associated with large-lattice-relaxation defects are more rapid than the shift of the bandgap(B. Weinstein, T. Ritter, et. al., Phys. Stat. Sol. (b) 198), 167 (1996). To study this, we measured the effects of pressure on the PL and PL-excitation (PLE) bands arising from the Zn-vacancy (V_Zn) and the P_Se deep acceptor centers in ZnSe. Using the observed pressure variation of the Stokes shifts and the established 1 atm. configuration coordinate (CC) models( D.Y. Jeon, H.P Gislason, G.D. Watkins, Phys. Rev. B 48), 7872 (1993), we were able to infer quantitative CC-diagrams at any pressure. Our results show that the pressure dependence of the lattice relaxation contributes a substantial fraction (several meV/kbar) to the overall shift of the PL-bands, and, hence, must be included. For the case of the V_Zn, simple calculations of the Jahn-Teller splitting using dangling-bond orbitals support this conclusion. figures

Totally Asymmetric Limit for Models of Heat Conduction

NASA Astrophysics Data System (ADS)

De Carlo, Leonardo; Gabrielli, Davide

2017-08-01

We consider one dimensional weakly asymmetric boundary driven models of heat conduction. In the cases of a constant diffusion coefficient and of a quadratic mobility we compute the quasi-potential that is a non local functional obtained by the solution of a variational problem. This is done using the dynamic variational approach of the macroscopic fluctuation theory (Bertini et al. in Rev Mod Phys 87:593, 2015). The case of a concave mobility corresponds essentially to the exclusion model that has been discussed in Bertini et al. (J Stat Mech L11001, 2010; Pure Appl Math 64(5):649-696, 2011; Commun Math Phys 289(1):311-334, 2009) and Enaud and Derrida (J Stat Phys 114:537-562, 2004). We consider here the convex case that includes for example the Kipnis-Marchioro-Presutti (KMP) model and its dual (KMPd) (Kipnis et al. in J Stat Phys 27:6574, 1982). This extends to the weakly asymmetric regime the computations in Bertini et al. (J Stat Phys 121(5/6):843-885, 2005). We consider then, both microscopically and macroscopically, the limit of large externalfields. Microscopically we discuss some possible totally asymmetric limits of the KMP model. In one case the totally asymmetric dynamics has a product invariant measure. Another possible limit dynamics has instead a non trivial invariant measure for which we give a duality representation. Macroscopically we show that the quasi-potentials of KMP and KMPd, which are non local for any value of the external field, become local in the limit. Moreover the dependence on one of the external reservoirs disappears. For models having strictly positive quadratic mobilities we obtain instead in the limit a non local functional having a structure similar to the one of the boundary driven asymmetric exclusion process.

Rapid change of blob structure in the outer scrape-off layer (SOL)

NASA Astrophysics Data System (ADS)

Cohen, R. H.

2005-10-01

Nonlinear structures (``blobs'') driven by the magnetic field curvature and highly elongated along the field lines may exist in the tokamak SOL.footnotetextS.I. Krasheninnikov. Phys. Lett. A 283, 368 (2001) The contact of the blob end with the divertor plate significantly affects the blob structure and velocity. However, the strong shearing of the flux-tube near the X-point makes impossible direct electrical contact of the blob in the upper SOL and the divertor, so that the sheath boundary condition (BC) has to be replaced by a BC imposed near the X point.footnotetextD. Ryutov, R.H. Cohen. Contr. Pl. Phys 44, 168 (2004) We show that, at larger distances from the separatrix, in the far SOL, the connection between the upper SOL and the divertor plate is re-established, and the sheath BC becomes again relevant. During the blob's outward radial motion, this event is reflected in a sudden change of its length, from the blob extending only to the X point to the blob extending down to the plate. Likewise, a blob initially existing only in the divertor leg becomes suddenly longer, and extends to the whole SOL.

Kinetic studies of divertor heat fluxes in Alcator C-Mod

NASA Astrophysics Data System (ADS)

Pankin, A. Y.; Bateman, G.; Kritz, A. H.; Rafiq, T.; Park, G. Y.; Chang, C. S.; Brunner, D.; Hughes, J. W.; Labombard, B.; Terry, J.

2010-11-01

The kinetic XGC0 code [C.S. Chang et al, Phys. Plasmas 11 (2004) 2649] is used to model the H- mode pedestal and SOL regions in Alcator C-Mod discharges. The self-consistent simulations in this study include kinetic neoclassical physics and anomalous transport models along with the ExB flow shear effects. The heat fluxes on the divertor plates are computed and the fluxes to the outer plate are compared with experimental observations. The dynamics of the radial electric field near the separatrix and in the SOL region are computed with the XGC0 code, and the effect of the anomalous transport on the heat fluxes in the SOL region is investigated. In particular, the particle and thermal diffusivities obtained in the analysis mode are compared with predictions from the theory-based anomalous transport models such as MMM95 [G. Bateman et al, Phys. Plasmas 5 (1998) 1793] and DRIBM [T. Rafiq et al, to appear in Phys. Plasmas (2010)]. It is found that there is a notable pinch effect in the inner separatrix region. Possible physical mechanisms for the particle and thermal pinches are discussed.

SOL Thermal Instability due to Radial Blob Convection

NASA Astrophysics Data System (ADS)

D'Ippolito, D. A.

2005-10-01

C-Mod datafootnotetextM. Greenwald, Plasma Phys. Contr. Fusion 44, R27 (2002). suggests a density limit when rapid perpendicular convection dominates SOL heat transport. This is supported by a recent analysisfootnotetextD.A. Russell et al., Phys. Rev. Lett. 93, 265001 (2004). of BOUT code turbulence simulations, which shows that rapid outwards convection of plasma by turbulent blobs is enhanced when the X-point collisionality is large, resulting in a synergistic effect between blob convection and X-point cooling. This work motivates the present analysis of SOL thermal equilibrium and instability including an RX-regime modelfootnotetextJ.R. Myra and D.A. D'Ippolito, Lodestar Report LRC-05-105 (2005). of blob particle and heat transport. Two-point (midplane, X-point) SOL thermal equilibrium and stability models are considered including both two-field (T) and four-field (n,T) treatments. The conditions under which loss of thermal equilibrium or thermal instabilities occur are established, and relations to the C-Mod data are described.

Figures of Merit for Magnetic Recording Media

NASA Astrophysics Data System (ADS)

Skomski, Ralph; Sellmyer, D. J.

2007-03-01

Since the first nucleation-field calculations for hard-soft nanostructures with multilayered [1] and arbitrary [2] geometries, exchange-spring magnets have attracted much attention in various areas of magnetism, including magnetic recording. Ultrahigh storage densities correspond to the strong-coupling limit, realized on small length scales and described by volume-averaged anisotropies. Second-order perturbation theory yields finite-size corrections that describe a partial decoupling of the phases. Since soft phases reduce the nucleation field, nanostructuring can be used to reduce the coercivity Hc while maintaining the energy barrier EB. However, the ratio EB/Hc is an ill-defined figure of merit, because the comparison with the Stoner-Wohlfarth model requires the introduction of a particle volume, as contrasted to an area. By using elongated particles with a continuous anisotropy gradient, it is possible to reduce the coercivity by a factor scaling as the bit size divided by the domain-wall width of the hard phase. However, with decreasing bit size this effect becomes less pronounced. In the strong-coupling limit, thermal stability yields a maximum storage density of order γ/kBT, where γ is the domain-wall energy of the hard phase. - This research is supported by NSF MRSEC, INSIC, and NCMN. [1] S. Nieber and H. Kronm"uller, phys. stat. sol. (b) 153, 367 (1989). [2] R. Skomski and J. M. D. Coey, Phys. Rev. B 48, 15812 (1993).

Operation of SCINDA Receiver at the University of Calcutta and Space Weather Studies

DTIC Science & Technology

2015-02-18

Terr . Phys., 2014]. (ii) The pole ward gradient of the Equatorial Ionization Anomaly (EIA) introduces more intense propagation effects on...in the Indian longitude sector: Case studies, T. Das, K.S. Paul and A. Paul, J. Atmos. Sol. Terr . Phys., http://dx.doi.org/10.1016/j.jastp

Cylindrical Organic Solar Cells with Carbon Nanotube Charge Collectors

NASA Astrophysics Data System (ADS)

Zakhidov, Dante; Lou, Raymond; Ravi, Nav; Mielczarek, Kamil; Cook, Alexander

2009-10-01

Traditional organic photovoltaic devices (OPV) are built on a flat glass substrates coated by ITO. The maximum area covered by the solar cells is limited to a two dimensional plane. Moreover the light absorption is not maximized for a very thin photoactive layer. We suggest here a cylindrical design which has a vertical structure of optical fiber coated by OPV, with light incident from the side and from edge. The sunlight, entering via a smaller area is captured into optical fiber, which allows more sunlight to be absorbed by a cylindrical OPV overcoating with multiple reflections inside the optical fiber. Instead of using brittle ITO as a hole collecting layer in the cylindrical OPV, transparent sheets of multi-walled carbon nanotubes are applied. Their highly conductive nature and 3-D collection of carriers from the P3HT/PCBM photoactive layer allows for increased efficiency over a planar geometry while keeping the device transparent. Aluminum is used as the electron collecting layer and as a cylindrical mirror. [4pt] [1] Ulbricht, et.al, phys. stat. sol. (b) 243, No. 13, 3528 - 3532 (2006) / DOI 10.1002/pssb.200669181

Electronic Promoters and Semiconductor Oxidation: Alkali Metals on Si(111) Surfaces.

DTIC Science & Technology

1986-04-25

SPAS, Caiimissariate a’ l’Energie Atctmique, CEN Saclay, France. 1. T. Narusawa, S. Komiya, and A. Hiraki , Appi. Phys. Lett. 20, 272 (1972). 2. J...Raisanen, and N. Troullier, Phys. Rev. B (in press). 10. K. Okuno, T. Ito, M. Iwami, and A. Hiraki , Sol. State Commun. 34, 493 (1980) and references

Hopf bifurcation in a nonlocal nonlinear transport equation stemming from stochastic neural dynamics

NASA Astrophysics Data System (ADS)

Drogoul, Audric; Veltz, Romain

2017-02-01

In this work, we provide three different numerical evidences for the occurrence of a Hopf bifurcation in a recently derived [De Masi et al., J. Stat. Phys. 158, 866-902 (2015) and Fournier and löcherbach, Ann. Inst. H. Poincaré Probab. Stat. 52, 1844-1876 (2016)] mean field limit of a stochastic network of excitatory spiking neurons. The mean field limit is a challenging nonlocal nonlinear transport equation with boundary conditions. The first evidence relies on the computation of the spectrum of the linearized equation. The second stems from the simulation of the full mean field. Finally, the last evidence comes from the simulation of the network for a large number of neurons. We provide a "recipe" to find such bifurcation which nicely complements the works in De Masi et al. [J. Stat. Phys. 158, 866-902 (2015)] and Fournier and löcherbach [Ann. Inst. H. Poincaré Probab. Stat. 52, 1844-1876 (2016)]. This suggests in return to revisit theoretically these mean field equations from a dynamical point of view. Finally, this work shows how the noise level impacts the transition from asynchronous activity to partial synchronization in excitatory globally pulse-coupled networks.

GRILLIX: a 3D turbulence code based on the flux-coordinate independent approach

NASA Astrophysics Data System (ADS)

Stegmeir, Andreas; Coster, David; Ross, Alexander; Maj, Omar; Lackner, Karl; Poli, Emanuele

2018-03-01

The GRILLIX code is presented with which plasma turbulence/transport in various geometries can be simulated in 3D. The distinguishing feature of the code is that it is based on the flux-coordinate independent approach (FCI) (Hariri and Ottaviani 2013 Comput. Phys. Commun. 184 2419; Stegmeir et al 2016 Comput. Phys. Commun. 198 139). Cylindrical or Cartesian grids are used on which perpendicular operators are discretised via standard finite difference methods and parallel operators via a field line tracing and interpolation procedure (field line map). This offers a very high flexibility with respect to geometry, especially a separatrix with X-point(s) or a magnetic axis can be treated easily in contrast to approaches which are based on field aligned coordinates and suffer from coordinate singularities. Aiming finally for simulation of edge and scrape-off layer (SOL) turbulence, an isothermal electrostatic drift-reduced Braginskii model (Zeiler et al 1997 Phys. Plasmas 4 2134) has been implemented in GRILLIX. We present the numerical approach, which is based on a toroidally staggered formulation of the FCI, we show verification of the code with the method of manufactured solutions and show a benchmark based on a TORPEX blob experiment, previously performed by several edge/SOL codes (Riva et al 2016 Plasma Phys. Control. Fusion 58 044005). Examples for slab, circular, limiter and diverted geometry are presented. Finally, the results show that the FCI approach in general and GRILLIX in particular are viable approaches in order to tackle simulation of edge/SOL turbulence in diverted geometry.

Higher-order fluctuation-dissipation relations in plasma physics: Binary Coulomb systems

NASA Astrophysics Data System (ADS)

Golden, Kenneth I.

2018-05-01

A recent approach that led to compact frequency domain formulations of the cubic and quartic fluctuation-dissipation theorems (FDTs) for the classical one-component plasma (OCP) [Golden and Heath, J. Stat. Phys. 162, 199 (2016), 10.1007/s10955-015-1395-6] is generalized to accommodate binary ionic mixtures. Paralleling the procedure followed for the OCP, the basic premise underlying the present approach is that a (k ,ω ) 4-vector rotational symmetry, known to be a pivotal feature in the frequency domain architectures of the linear and quadratic fluctuation-dissipation relations for a variety of Coulomb plasmas [Golden et al., J. Stat. Phys. 6, 87 (1972), 10.1007/BF01023681; J. Stat. Phys. 29, 281 (1982), 10.1007/BF01020787; Golden, Phys. Rev. E 59, 228 (1999), 10.1103/PhysRevE.59.228], is expected to be a pivotal feature of the frequency domain architectures of the higher-order members of the FDT hierarchy. On this premise, each member, in its most tractable form, connects a single (p +1 )-point dynamical structure function to a linear combination of (p +1 )-order p density response functions; by definition, such a combination must also remain invariant under rotation of their (k1,ω1) ,(k2,ω2) ,...,(kp,ωp) , (k1+k2+⋯+kp,ω1+ω2+⋯+ωp) 4-vector arguments. Assigned to each 4-vector is a species index that corotates in lock step. Consistency is assured by matching the static limits of the resulting frequency domain cubic and quartic FDTs to their exact static counterparts independently derived in the present work via a conventional time-independent perturbation expansion of the Liouville distribution function in its macrocanonical form. The proposed procedure entirely circumvents the daunting issues of entangled Liouville space paths and nested Poisson brackets that one would encounter if one attempted to use the conventional time-dependent perturbation-theoretic Kubo approach to establish the frequency domain FDTs beyond quadratic order.

Persistence Probabilities of Two-Sided (Integrated) Sums of Correlated Stationary Gaussian Sequences

NASA Astrophysics Data System (ADS)

Aurzada, Frank; Buck, Micha

2018-02-01

We study the persistence probability for some two-sided, discrete-time Gaussian sequences that are discrete-time analogues of fractional Brownian motion and integrated fractional Brownian motion, respectively. Our results extend the corresponding ones in continuous time in Molchan (Commun Math Phys 205(1):97-111, 1999) and Molchan (J Stat Phys 167(6):1546-1554, 2017) to a wide class of discrete-time processes.

Cooperative Effects and Intrinsic Optical Bistability in Collections of Atoms

DTIC Science & Technology

1989-11-01

Solids B115, k63 (1983). 6. H.E. Schmidt, H. Haug and S.W. Koch; Appl. 2 44, 787 (1984). 7. J.W. Haus, Li Wang, M. Scalora and C.M. Bowden, Phys. Rev...maximum aver- I 1] J.W. Haus, L. Wang, M. Scalora and C.M. Bowden, Phys. age passage time for the parameters chosen. In re- Rev. A38 (1988) 4043. 112...Stat. Solidi B121 685 (1984). 10. M. Dagenais and W.F. Sharfin, Appl. Phys. Lett. 45, 210 (1984). 21 11. J.W. Haus, L. Wang, M. Scalora and C.M

Dual controlled release, in situ gelling periodontal sol of metronidazole benzoate and serratiopeptidase: statistical optimization and mechanistic evaluation.

PubMed

Kumari, Neeraj; Pathak, Kamla

2012-01-01

In situ gelling syringeable periodontal sol capable of dual controlled delivery of metronidazole benzoate and serratiopeptidase was designed based on 2(3) factorial design with drug, poloxamer 407 and aerosil as independent variables and sol gel transition characteristics, %CDR(48h) and palatability as responses. The sols had agreeable taste, were mucoadhesive, syringeable and inverted into gels at periodontal cavity temperature. F8 with optimal drug release was identified as the best formulation. The dispersion characteristics of poloxamer significantly affected the pharmacotechnical properties of the in situ gelling systems. Extra design checkpoint generated using Design Expert software 8.02 (Stat-Ease, USA) validated the experimental design. Thus a thermoreversible, in situ gelling and syringeable periodontal sol with acceptable taste characteristics that offered controlled release of metronidazole benzoate and serratiopeptidase was developed for application into the periodontal pocket. The developed optimized sol was satisfactory in terms of taste, syringeability, palatability and incorporation of serratiopeptidase as anti-inflammatory agent, has the potential of developing a therapeutically efficacious system for treatment of periodontal inflammatory anaerobic infections.

Einstein Critical-Slowing-Down is Siegel CyberWar Denial-of-Access Queuing/Pinning/ Jamming/Aikido Via Siegel DIGIT-Physics BEC ``Intersection''-BECOME-UNION Barabasi Network/GRAPH-Physics BEC: Strutt/Rayleigh-Siegel Percolation GLOBALITY-to-LOCALITY Phase-Transition Critical-Phenomenon

NASA Astrophysics Data System (ADS)

Buick, Otto; Falcon, Pat; Alexander, G.; Siegel, Edward Carl-Ludwig

2013-03-01

Einstein[Dover(03)] critical-slowing-down(CSD)[Pais, Subtle in The Lord; Life & Sci. of Albert Einstein(81)] is Siegel CyberWar denial-of-access(DOA) operations-research queuing theory/pinning/jamming/.../Read [Aikido, Aikibojitsu & Natural-Law(90)]/Aikido(!!!) phase-transition critical-phenomenon via Siegel DIGIT-Physics (Newcomb[Am.J.Math. 4,39(1881)]-{Planck[(1901)]-Einstein[(1905)])-Poincare[Calcul Probabilités(12)-p.313]-Weyl [Goett.Nachr.(14); Math.Ann.77,313 (16)]-{Bose[(24)-Einstein[(25)]-Fermi[(27)]-Dirac[(1927)]}-``Benford''[Proc.Am.Phil.Soc. 78,4,551 (38)]-Kac[Maths.Stat.-Reasoning(55)]-Raimi[Sci.Am. 221,109 (69)...]-Jech[preprint, PSU(95)]-Hill[Proc.AMS 123,3,887(95)]-Browne[NYT(8/98)]-Antonoff-Smith-Siegel[AMS Joint-Mtg.,S.-D.(02)] algebraic-inversion to yield ONLY BOSE-EINSTEIN QUANTUM-statistics (BEQS) with ZERO-digit Bose-Einstein CONDENSATION(BEC) ``INTERSECTION''-BECOME-UNION to Barabasi[PRL 876,5632(01); Rev.Mod.Phys.74,47(02)...] Network /Net/GRAPH(!!!)-physics BEC: Strutt/Rayleigh(1881)-Polya(21)-``Anderson''(58)-Siegel[J.Non-crystalline-Sol.40,453(80)

Improved two-point model for limiter scrape-off layer

NASA Astrophysics Data System (ADS)

Tokar, M. Z.; Kobayashi, M.; Feng, Y.

2004-10-01

An analytical model for a limiter scrape-off layer (SOL) is proposed, which takes self-consistently into account both conductive and convective contributions to the heat transport in SOL. The particle flows in the SOL main part are determined by considering the recycling of neutrals. The model allows us to interpret the results of numerical simulation by the code EMC3-EIRENE [Y. Feng, F. Sardei, P. Grigull, K. McCormick, J. Kisslinger, D. Reiter, and Y. Igitkhanov, Plasma Phys. Controlled Fusion 44, 611 (2002)] for the edge region of Tokamak Experiment for Technology Oriented Research (TEXTOR) [Proceedings of the 16th IEEE Symposium on Fusion Engineering, 1995 (Institute for Electrical and Electronics Engineers, Piscataway, NJ, 1995), p. 470].

SolSmart Launches to Support Local Governments | State, Local, and Tribal

Science.gov Websites

Local Governments May 04, 2016 by Erin Nobler As a member of the Solar Technical Assistance Team (STAT ) network, the National Renewable Energy Laboratory (NREL) provides direct technical assistance to state and no-cost technical assistance. Business processes or administrative costs, the so-called "soft

Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

PubMed Central

Gan, Yujun; Buckels, Ashiya; Liu, Ying; Zhang, Yue; Paterson, Andrew J.; Jiang, Jing; Zinn, Kurt R.

2014-01-01

GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed. PMID:25211187

The Free Energy in the Derrida-Retaux Recursive Model

NASA Astrophysics Data System (ADS)

Hu, Yueyun; Shi, Zhan

2018-05-01

We are interested in a simple max-type recursive model studied by Derrida and Retaux (J Stat Phys 156:268-290, 2014) in the context of a physics problem, and find a wide range for the exponent in the free energy in the nearly supercritical regime.

Precise parameterization of the recombination velocity at passivated phosphorus doped surfaces

NASA Astrophysics Data System (ADS)

Kimmerle, Achim; Momtazur Rahman, Md.; Werner, Sabrina; Mack, Sebastian; Wolf, Andreas; Richter, Armin; Haug, Halvard

2016-01-01

We investigate the surface recombination velocity Sp at the silicon-dielectric interface of phosphorus-doped surfaces for two industrially relevant passivation schemes for crystalline silicon solar cells. A broad range of surface dopant concentrations together with a high accuracy of evaluating the latter is achieved by incremental back-etching of the surface. The analysis of lifetime measurements and the simulation of the surface recombination consistently apply a set of well accepted models, namely, the Auger recombination by Richter et al. [Phys. Rev. B 86, 1-14 (2012)], the carrier mobility by Klaassen [Solid-State Electron. 35, 953-959 (1992); 35, 961-967 (1992)], the intrinsic carrier concentration for undoped silicon by Altermatt et al. [J. Appl. Phys. 93, 1598-1604 (2003)], and the band-gap narrowing by Schenk [J. Appl. Phys. 84, 3684-3695 (1998)]. The results show an increased Sp at textured in respect to planar surfaces. The obtained parameterizations are applicable in modern simulation tools such as EDNA [K. R. McIntosh and P. P. Altermatt, in Proceedings of the 35th IEEE Photovoltaic Specialists Conference, Honolulu, Hawaii, USA (2010), pp. 1-6], PC1Dmod [Haug et al., Sol. Energy Mater. Sol. Cells 131, 30-36 (2014)], and Sentaurus Device [Synopsys, Sentaurus TCAD, Zürich, Switzerland] as well as in the analytical solution under the assumption of local charge neutrality by Cuevas et al. [IEEE Trans. Electron Devices 40, 1181-1183 (1993)].

Consequences of parental care on population dynamics

NASA Astrophysics Data System (ADS)

de Oliveira, S. Moss

1999-12-01

We review the results obtained using the Penna model for biological ageing (T.J.P. Penna, J. Stat. Phys. 78 (1995) 1629) when different strategies of parental care are introduced into evolving populations. These results concern to: longevity of semelparous populations; self-organization of female menopause; the spatial distribution of the populations and finally, sexual fidelity.

Statistics of Macroturbulence from Flow Equations

NASA Astrophysics Data System (ADS)

Marston, Brad; Iadecola, Thomas; Qi, Wanming

2012-02-01

Probability distribution functions of stochastically-driven and frictionally-damped fluids are governed by a linear framework that resembles quantum many-body theory. Besides the Fokker-Planck approach, there is a closely related Hopf functional methodfootnotetextOokie Ma and J. B. Marston, J. Stat. Phys. Th. Exp. P10007 (2005).; in both formalisms, zero modes of linear operators describe the stationary non-equilibrium statistics. To access the statistics, we generalize the flow equation approachfootnotetextF. Wegner, Ann. Phys. 3, 77 (1994). (also known as the method of continuous unitary transformationsfootnotetextS. D. Glazek and K. G. Wilson, Phys. Rev. D 48, 5863 (1993); Phys. Rev. D 49, 4214 (1994).) to find the zero mode. We test the approach using a prototypical model of geophysical and astrophysical flows on a rotating sphere that spontaneously organizes into a coherent jet. Good agreement is found with low-order equal-time statistics accumulated by direct numerical simulation, the traditional method. Different choices for the generators of the continuous transformations, and for closure approximations of the operator algebra, are discussed.

Precise parameterization of the recombination velocity at passivated phosphorus doped surfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kimmerle, Achim, E-mail: achim-kimmerle@gmx.de; Momtazur Rahman, Md.; Werner, Sabrina

We investigate the surface recombination velocity S{sub p} at the silicon-dielectric interface of phosphorus-doped surfaces for two industrially relevant passivation schemes for crystalline silicon solar cells. A broad range of surface dopant concentrations together with a high accuracy of evaluating the latter is achieved by incremental back-etching of the surface. The analysis of lifetime measurements and the simulation of the surface recombination consistently apply a set of well accepted models, namely, the Auger recombination by Richter et al. [Phys. Rev. B 86, 1–14 (2012)], the carrier mobility by Klaassen [Solid-State Electron. 35, 953–959 (1992); 35, 961–967 (1992)], the intrinsic carriermore » concentration for undoped silicon by Altermatt et al. [J. Appl. Phys. 93, 1598–1604 (2003)], and the band-gap narrowing by Schenk [J. Appl. Phys. 84, 3684–3695 (1998)]. The results show an increased S{sub p} at textured in respect to planar surfaces. The obtained parameterizations are applicable in modern simulation tools such as EDNA [K. R. McIntosh and P. P. Altermatt, in Proceedings of the 35th IEEE Photovoltaic Specialists Conference, Honolulu, Hawaii, USA (2010), pp. 1–6], PC1Dmod [Haug et al., Sol. Energy Mater. Sol. Cells 131, 30–36 (2014)], and Sentaurus Device [Synopsys, Sentaurus TCAD, Zürich, Switzerland] as well as in the analytical solution under the assumption of local charge neutrality by Cuevas et al. [IEEE Trans. Electron Devices 40, 1181–1183 (1993)].« less

Critical points of the O(n) loop model on the martini and the 3-12 lattices

NASA Astrophysics Data System (ADS)

Ding, Chengxiang; Fu, Zhe; Guo, Wenan

2012-06-01

We derive the critical line of the O(n) loop model on the martini lattice as a function of the loop weight n basing on the critical points on the honeycomb lattice conjectured by Nienhuis [Phys. Rev. Lett.PRLTAO0031-900710.1103/PhysRevLett.49.1062 49, 1062 (1982)]. In the limit n→0 we prove the connective constant μ=1.7505645579⋯ of self-avoiding walks on the martini lattice. A finite-size scaling analysis based on transfer matrix calculations is also performed. The numerical results coincide with the theoretical predictions with a very high accuracy. Using similar numerical methods, we also study the O(n) loop model on the 3-12 lattice. We obtain similarly precise agreement with the critical points given by Batchelor [J. Stat. Phys.JSTPBS0022-471510.1023/A:1023065215233 92, 1203 (1998)].

Validation of the Jarzynski relation for a system with strong thermal coupling: an isothermal ideal gas model.

PubMed

Baule, A; Evans, R M L; Olmsted, P D

2006-12-01

We revisit the paradigm of an ideal gas under isothermal conditions. A moving piston performs work on an ideal gas in a container that is strongly coupled to a heat reservoir. The thermal coupling is modeled by stochastic scattering at the boundaries. In contrast to recent studies of an adiabatic ideal gas with a piston [R.C. Lua and A.Y. Grosberg, J. Phys. Chem. B 109, 6805 (2005); I. Bena, Europhys. Lett. 71, 879 (2005)], the container and piston stay in contact with the heat bath during the work process. Under this condition the heat reservoir as well as the system depend on the work parameter lambda and microscopic reversibility is broken for a moving piston. Our model is thus not included in the class of systems for which the nonequilibrium work theorem has been derived rigorously either by Hamiltonian [C. Jarzynski, J. Stat. Mech. (2004) P09005] or stochastic methods [G.E. Crooks, J. Stat. Phys. 90, 1481 (1998)]. Nevertheless the validity of the nonequilibrium work theorem is confirmed both numerically for a wide range of parameter values and analytically in the limit of a very fast moving piston, i.e., in the far nonequilibrium regime.

Solution of the mean spherical approximation for polydisperse multi-Yukawa hard-sphere fluid mixture using orthogonal polynomial expansions

NASA Astrophysics Data System (ADS)

Kalyuzhnyi, Yurij V.; Cummings, Peter T.

2006-03-01

The Blum-Høye [J. Stat. Phys. 19 317 (1978)] solution of the mean spherical approximation for a multicomponent multi-Yukawa hard-sphere fluid is extended to a polydisperse multi-Yukawa hard-sphere fluid. Our extension is based on the application of the orthogonal polynomial expansion method of Lado [Phys. Rev. E 54, 4411 (1996)]. Closed form analytical expressions for the structural and thermodynamic properties of the model are presented. They are given in terms of the parameters that follow directly from the solution. By way of illustration the method of solution is applied to describe the thermodynamic properties of the one- and two-Yukawa versions of the model.

The Influence of Noise on Turbulent Transport.

NASA Astrophysics Data System (ADS)

Krommes, J. A.

2006-10-01

Recently there have been considerable discussions and contradictory conclusions about the possible influence of numerical noise on measured turbulent fluxes. In the present work, some of the conceptual and analytical foundations of noise-related calculations are reconsidered, and some paradoxes are resolved. An elementary model involving coupled random processes shows that extra noise (e.g., related to numerical sampling errors in δf particle simulations can reduce total transport. (Intuition to the contrary stems from oversimplified models involving independent, additive, and passive advection velocities.) This result is interpreted in terms of the structure of the steady-state spectral balance equation for turbulence in the presence of discreteness-induced noise. The relationship of the Fluctuation-- Dissipation Theorem to general nonequilibrium statistical balances is also discussed. W. M. Nevins, G. W. Hammett, A. M. Dimits, W. Dorland, and D. E. Shumaker, Phys. Plasmas 12, 122305 (2005) W. W. Lee, Bull. Am. Phys. Soc., http://www.aps.org/meet/APR06, abstr.I16.00004 (2006). G. Hu and J. A. Krommes, Phys. Plasmas 1, 863 (1994).) H. A. Rose, J. Stat.Phys.20, 415 (1979).

Riemann-Hypothesis Millennium-Problem(MP) Physics Proof via CATEGORY-SEMANTICS(C-S)/F =C Aristotle SQUARE-of-OPPOSITION(SoO) DEduction-LOGIC DichotomY

NASA Astrophysics Data System (ADS)

Baez, Joao-Joan; Lapidaryus, Michelle; Siegel, Edward Carl-Ludwig

2013-03-01

Riemann-hypothesis physics-proof combines: Siegel-Antono®-Smith[AMS Joint Mtg.(2002)- Abs.973-03-126] digits on-average statistics HIll[Am. J. Math 123, 3, 887(1996)] logarithm-function's (1,0)- xed-point base =units =scale-invariance proven Newcomb [Am. J. Math. 4, 39(1881)]-Weyl[Goett. Nachr.(1914); Math. Ann.7, 313(1916)]-Benford[Proc. Am. Phil. Soc. 78, 4, 51(1938)]-law [Kac,Math. of Stat.-Reasoning(1955); Raimi, Sci. Am. 221, 109(1969)] algebraic-inversion to ONLY Bose-Einstein quantum-statistics(BEQS) with digit d = 0 gapFUL Bose-Einstein Condensation(BEC) insight that digits are quanta are bosons because bosons are and always were quanta are and always were digits, via Siegel-Baez category-semantics tabular list-format matrix truth-table analytics in Plato-Aristotle classic ''square-of-opposition'' : FUZZYICS =CATEGORYICS/Category-Semantics, with Goodkind Bose-Einstein Condensation (BEC) ABOVE ground-state with/and Rayleigh(cut-limit of ''short-cut method''1870)-Polya(1922)-''Anderson''(1958) localization [Doyle and Snell,Random-Walks and Electrical-Networks, MAA(1981)-p.99-100!!!] in Brillouin[Wave-Propagation in Periodic-Structures(1946) Dover(1922)]-Hubbard-Beeby[J.Phys.C(1967)] Siegel[J.Nonxline-Sol.40,453(1980)] generalized-disorder collective-boson negative-dispersion mode-softening universality-principle(G...P) first use of the ``square-of-opposition'' in physics since Plato and Aristote!!!

Maximum of an Airy process plus Brownian motion and memory in Kardar-Parisi-Zhang growth

NASA Astrophysics Data System (ADS)

Le Doussal, Pierre

2017-12-01

We obtain several exact results for universal distributions involving the maximum of the Airy2 process minus a parabola and plus a Brownian motion, with applications to the one-dimensional Kardar-Parisi-Zhang (KPZ) stochastic growth universality class. This allows one to obtain (i) the universal limit, for large time separation, of the two-time height correlation for droplet initial conditions, e.g., C∞=limt2/t1→+∞h(t1) h (t2)¯c/h(t1)2¯c, with C∞≈0.623 , as well as conditional moments, which quantify ergodicity breaking in the time evolution; (ii) in the same limit, the distribution of the midpoint position x (t1) of a directed polymer of length t2; and (iii) the height distribution in stationary KPZ with a step. These results are derived from the replica Bethe ansatz for the KPZ continuum equation, with a "decoupling assumption" in the large time limit. They agree and confirm, whenever they can be compared, with (i) our recent tail results for two-time KPZ with the work by de Nardis and Le Doussal [J. Stat. Mech. (2017) 053212, 10.1088/1742-5468/aa6bce], checked in experiments with the work by Takeuchi and co-workers [De Nardis et al., Phys. Rev. Lett. 118, 125701 (2017), 10.1103/PhysRevLett.118.125701] and (ii) a recent result of Maes and Thiery [J. Stat. Phys. 168, 937 (2017), 10.1007/s10955-017-1839-2] on midpoint position.

Derivation of diffusion coefficient of a Brownian particle in tilted periodic potential from the coordinate moments

NASA Astrophysics Data System (ADS)

Zhang, Yunxin

2009-07-01

In this research, diffusion of an overdamped Brownian particle in the tilted periodic potential is investigated. Using the one-dimensional hopping model, the formulations of the mean velocity V and effective diffusion coefficient D of the Brownian particle have been obtained [B. Derrida, J. Stat. Phys. 31 (1983) 433]. Based on the relation between the effective diffusion coefficient and the moments of the mean first passage time, the formulation of effective diffusion coefficient D of the Brownian particle also has been obtained [P. Reimann, et al., Phys. Rev. E 65 (2002) 031104]. In this research, we'll give another analytical expression of the effective diffusion coefficient D from the moments of the particle's coordinate.

Virial Expansion Bounds

NASA Astrophysics Data System (ADS)

Tate, Stephen James

2013-10-01

In the 1960s, the technique of using cluster expansion bounds in order to achieve bounds on the virial expansion was developed by Lebowitz and Penrose (J. Math. Phys. 5:841, 1964) and Ruelle (Statistical Mechanics: Rigorous Results. Benjamin, Elmsford, 1969). This technique is generalised to more recent cluster expansion bounds by Poghosyan and Ueltschi (J. Math. Phys. 50:053509, 2009), which are related to the work of Procacci (J. Stat. Phys. 129:171, 2007) and the tree-graph identity, detailed by Brydges (Phénomènes Critiques, Systèmes Aléatoires, Théories de Jauge. Les Houches 1984, pp. 129-183, 1986). The bounds achieved by Lebowitz and Penrose can also be sharpened by doing the actual optimisation and achieving expressions in terms of the Lambert W-function. The different bound from the cluster expansion shows some improvements for bounds on the convergence of the virial expansion in the case of positive potentials, which are allowed to have a hard core.

Impact of an integrated core/SOL description on the R and B T optimization of tokamak fusion reactors

NASA Astrophysics Data System (ADS)

Siccinio, M.; Fable, E.; Angioni, C.; Saarelma, S.; Scarabosio, A.; Zohm, H.

2018-01-01

An updated and improved version of the 0D divertor and scrape-off layer (SOL) model published in Siccinio et al (2016 Plasma Phys. Control. Fusion 58 125011) was coupled with the 1.5D transport code ASTRA (Pereverzev 1991 IPP Report 5/42, Pereverzev and Yushmanov 2002 IPP Report 5/98 and Fable et al 2013 Plasma Phys. Control. Fusion 55 124028). The resulting numerical tool was employed for various scans in the major radius R and in the toroidal magnetic field B T—for different safety factors q, allowable loop voltages V loop and H factors—in order to identify the most convenient choices for an electricity producing tokamak. Such a scenario analysis was carried out evaluating self-consistently, and simultaneously, the core profile and transport effects, which significantly impact on the fusion power outcome, and the divertor heat loads, which represent one of the most critical issues in view of the realization of fusion power plants (Zohm et al 2013 Nucl. Fusion 53 073019 and Wenninger et al 2017 Nucl. Fusion 57 046002). The main result is that, when divertor limits are enforced, the curves at constant electrical power output are closed on themselves in the R-BT plane, and a maximum achievable power exists—i.e. no benefits would be obtained from a further increase in R and B T once the optimum is reached. This result appears as an intrinsic physical limit for all those devices where a radiative SOL is needed to deal with the power exhaust, and where a lower limit on the power crossing the separatrix (e.g. because of the L-H transition) is present.

Radio-Frequency Emissions from Streamer Collisions: Implications for High-Energy Processes.

NASA Astrophysics Data System (ADS)

Luque, A.

2017-12-01

The production of energetic particles in a discharge corona is possibly linked to the collision of streamers of opposite polarities [Cooray et al. (2009), Kochkin et al. (2012), Østgaard et al. (2016)]. There is also experimental evidence linking it to radio-frequency emissions in the UHF frequency range (300 MHz-3 GHz) [Montanyà et al. (2015), Petersen and Beasley (2014)]. Here we investigate these two links by modeling the radio-frequency emissions emanating from an encounter between two counter-propagating streamers. Our numerical model combines self-consistently a conservative, high-order Finite-Volume scheme for electron transport with a Finite-Difference Time-Domain (FDTD) method for electromagnetic propagation. We also include the most relevant reactions for streamer propagation: impact ionization, dissociative attachment and photo-ionization. Our implementation benefits from massive parallelization by running on a General-Purpose Graphical Processing Unit (GPGPU). With this code we found that streamer encounters emit electromagnetic waves predominantly in the UHF range, supporting the hypothesis that streamer collisions are essential precursors of high-energy processes in electric discharges. References Cooray, V., et al., J. Atm. Sol.-Terr. Phys., 71, 1890, doi:10.1016/j.jastp.2009.07.010 (2009). Kochkin, P. O., et al., J. Phys. D, 45, 425202, doi: 10.1088/0022-3727/45/42/425202 (2012). Montanyà, J., et al., J. Atm. Sol.-Terr. Phys., 136, 94, doi:10.1016/j.jastp.2015.06.009, (2015). Østgaard, N., et al., J. Geophys. Res. (Atmos.), 121, 2939, doi:10.1002/2015JD024394 (2016). Petersen, D., and W. Beasley, Atmospheric Research, 135, 314, doi:10.1016/j.atmosres.2013.02.006 (2014).

Rigorous proof for the nonlocal correlation function in the transverse Ising model with ring frustration.

PubMed

Dong, Jian-Jun; Zheng, Zhen-Yu; Li, Peng

2018-01-01

An unusual correlation function was conjectured by Campostrini et al. [Phys. Rev. E 91, 042123 (2015)PLEEE81539-375510.1103/PhysRevE.91.042123] for the ground state of a transverse Ising chain with geometrical frustration. Later, we provided a rigorous proof for it and demonstrated its nonlocal nature based on an evaluation of a Toeplitz determinant in the thermodynamic limit [J. Stat. Mech. (2016) 11310210.1088/1742-5468/2016/11/113102]. In this paper, we further prove that all the low excited energy states forming the gapless kink phase share the same asymptotic correlation function with the ground state. As a consequence, the thermal correlation function almost remains constant at low temperatures if one assumes a canonical ensemble.

Reconstructing the Morphology of an Evolving Coronal Mass Ejection

DTIC Science & Technology

2009-01-01

694, 707 Wood, B. E., Howard, R. A ., Thernisien, A ., Plunkett, S. P., & Socker, D. G. 2009b, Sol. Phys., 259, 163 Wood, B. E., Karovska , M., Chen, J...Reconstructing the Morphology of an Evolving Coronal Mass Ejection B. E. Wood, R. A . Howard, D. G. Socker Naval Research Laboratory, Space Science...mission, we empirically reconstruct the time-dependent three-dimensional morphology of a coronal mass ejection (CME) from 2008 June 1, which exhibits

Low Temperature Grown and Highly Non-Stoichiometric GaAs and Related Materials

DTIC Science & Technology

1994-08-03

Ser. No. 67 (1983), p. 285.attributed to the nonuniformity of crystal growth 2T. Figielski, T. Wonsinski and A. Mokosa, Phys. Stat. Solidi (a) condition...1.75 pyramidal defect distribution was nonuniform in this pm; sample C, 1.6 pm; and sample D, 0.95 prm. Each sample, the defects being separated...the layers grown on [0011 oriented substrates whereas growth on the near [1101 substrates resulted in compositional nonuniformities , macrosteps for

Nonlinear Waves in Rods

DTIC Science & Technology

1981-05-01

0 and P > 0 everywhere. This also implies from (17) that Www 1Wuu - Wu w1 > 0 so that necking instabilities have been ruled out (see Antman [12], pp... Antman , "Qualitative Theory of the Ordinary Differential Equa- tions of Nonlinear Elasticity," in Mechanics Today, V. 1, ed. S. Nemat- Nasser...the Propagation of Plastic Strain in a Cylindrical Rod," J. Mech. Phys. Sol., 13, 1965, pp. 55-68. 7. S. S. Antman , The Theory of Rods, Handbuch der

Error analysis regarding the calculation of nonlinear force-free field

NASA Astrophysics Data System (ADS)

Liu, S.; Zhang, H. Q.; Su, J. T.

2012-02-01

Magnetic field extrapolation is an alternative method to study chromospheric and coronal magnetic fields. In this paper, two semi-analytical solutions of force-free fields (Low and Lou in Astrophys. J. 352:343, 1990) have been used to study the errors of nonlinear force-free (NLFF) fields based on force-free factor α. Three NLFF fields are extrapolated by approximate vertical integration (AVI) Song et al. (Astrophys. J. 649:1084, 2006), boundary integral equation (BIE) Yan and Sakurai (Sol. Phys. 195:89, 2000) and optimization (Opt.) Wiegelmann (Sol. Phys. 219:87, 2004) methods. Compared with the first semi-analytical field, it is found that the mean values of absolute relative standard deviations (RSD) of α along field lines are about 0.96-1.19, 0.63-1.07 and 0.43-0.72 for AVI, BIE and Opt. fields, respectively. While for the second semi-analytical field, they are about 0.80-1.02, 0.67-1.34 and 0.33-0.55 for AVI, BIE and Opt. fields, respectively. As for the analytical field, the calculation error of <| RSD|> is about 0.1˜0.2. It is also found that RSD does not apparently depend on the length of field line. These provide the basic estimation on the deviation of extrapolated field obtained by proposed methods from the real force-free field.

Comment on "Curvature capillary migration of microspheres" by N. Sharifi-Mood, I. B. Liu, K. J. Stebe, Soft Matter, 2015, 11, 6768.

PubMed

Würger, Alois

2016-01-14

In a recent paper, Sharifi-Mood et al. studied colloidal particles trapped at a liquid interface with opposite principal curvatures c1 = -c2. In the theory part, they claim that the trapping energy vanishes at second order in Δc = c1 - c2, which would invalidate our previous result [Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2006, 74, 041402]. Here we show that this claim arises from an improper treatment of the outer boundary condition on the deformation field. For both pinned and moving contact lines, we find that the outer boundary is irrelevant, which confirms our previous work. More generally, we show that the trapping energy is determined by the deformation close to the particle and does not depend on the far-field.

Maximum Path Information and Fokker Planck Equation

NASA Astrophysics Data System (ADS)

Li, Wei; Wang A., Q.; LeMehaute, A.

2008-04-01

We present a rigorous method to derive the nonlinear Fokker-Planck (FP) equation of anomalous diffusion directly from a generalization of the principle of least action of Maupertuis proposed by Wang [Chaos, Solitons & Fractals 23 (2005) 1253] for smooth or quasi-smooth irregular dynamics evolving in Markovian process. The FP equation obtained may take two different but equivalent forms. It was also found that the diffusion constant may depend on both q (the index of Tsallis entropy [J. Stat. Phys. 52 (1988) 479] and the time t.

Knot Invariants and Cellular Automata

DTIC Science & Technology

1993-05-04

behavior might be found in a naturally associated two dimensional statistical mechanics model. The Boltzmann weight TV’b := exp[-/3E(a,b, c ,d)] can be...the Yang-Baxter (star-triangle) equation [10,11]: +, b ) C I k( ) = ± )tI k I The relevance of this result to our problem is the following. The two com...J. Baxter and P. J. Forrester, "Eight-vertex SOS model and generalized Rogers- Ramanujan -type identities," J. Stat. Phys. 35 (1934) 193-266. [13] L. H

Identifying the location of the OMP separatrix in DIII-D using power accounting

DOE PAGES

Stangeby, Peter C.; Canik, John M.; Elder, J. D.; ...

2015-08-07

In order to identify reliable scalings for the scrape-off layer (SOL) power width it is necessary to know the location of the separatrix in divertor tokamaks as accurately as possible, specifically its location at the outside midplane (OMP) the standard reference location. Two methods are described which use power accounting to improve the accuracy of identifying the location of the OMP separatrix. The first uses the infrared-measured deposited power profile at the outer target as the primary input, the 'more » $$P_{{\\rm SOL}}^{{\\rm exhaust}}$$ method'. The second uses the measured power input to the SOL, obtained by subtracting the power radiated from inside the separatrix from the total heating power, the ' $$P_{{\\rm SOL}}^{{\\rm input}}$$ method'. Furthermore, these two power accounting methods are illustrated with the examples of 21 H-mode DIII-D discharges. High spatial resolution Thomson scattering measured profiles of ne and Te for the main SOL near the OMP are also used as primary input to the analysis; only between-edge localized mode data are used here. The Thomson profiles are used to calculate the electron parallel conducted heat flux profiles which are then matched to the measured $$P_{{\\rm SOL}}^{{\\rm exhaust}}$$ and $$P_{{\\rm SOL}}^{{\\rm input}}$$ by adjusting the location of the OMP separatrix relative to that of the Thomson data. For these attached discharges, it is found that the values of $$R_{{\\rm sep}}^{{\\rm omp}}$$ given by the two power accounting methods agree to within ~1 mm of each other and also to within ~1 mm of the values given by the 'standard DIII-D method' described by Porter et al (1998 Phys. Plasmas 5 1410). Lastly, the shifted $$R_{{\\rm sep}}^{{\\rm omp}}$$ results in only modest changes to the values of ne and Te at the OMP separatrix relative to the 'standard' values, increasing $$n_{{\\rm e}}^{{\\rm sep}}$$ by 8% and $$T_{{\\rm e}}^{{\\rm sep}}$$ by 20%.« less

Peak-Flux-Density Spectra of Large Solar Radio Bursts and Proton Emission from Flares.

DTIC Science & Technology

1985-08-19

of the microwave peak (Z 1000 sfu in U-bursts) served as an indicator that the energy release during the impulsive phase was sufficient to produce a... energy or wave- length tends to be prominent in all, and cautions about over-interpreting associa- tions/correlations observed in samples of big flares...Sung, L. S., and McDonald, F. B. (1975) The variation of solar proton energy spectra and size distribution with helio- longitude, Sol. Phys. 41: 189. 28

GBS: Global 3D simulation of tokamak edge region

NASA Astrophysics Data System (ADS)

Zhu, Ben; Fisher, Dustin; Rogers, Barrett; Ricci, Paolo

2012-10-01

A 3D two-fluid global code, namely Global Braginskii Solver (GBS), is being developed to explore the physics of turbulent transport, confinement, self-consistent profile formation, pedestal scaling and related phenomena in the edge region of tokamaks. Aimed at solving drift-reduced Braginskii equations [1] in complex magnetic geometry, the GBS is used for turbulence simulation in SOL region. In the recent upgrade, the simulation domain is expanded into close flux region with twist-shift boundary conditions. Hence, the new GBS code is able to explore global transport physics in an annular full-torus domain from the top of the pedestal into the far SOL. We are in the process of identifying and analyzing the linear and nonlinear instabilities in the system using the new GBS code. Preliminary results will be presented and compared with other codes if possible.[4pt] [1] A. Zeiler, J. F. Drake and B. Rogers, Phys. Plasmas 4, 2134 (1997)

Study of SOL in DIII-D tokamak with SOLPS suite of codes.

NASA Astrophysics Data System (ADS)

Pankin, Alexei; Bateman, Glenn; Brennan, Dylan; Coster, David; Hogan, John; Kritz, Arnold; Kukushkin, Andrey; Schnack, Dalton; Snyder, Phil

2005-10-01

The scrape-of-layer (SOL) region in DIII-D tokamak is studied with the SOLPS integrated suite of codes. The SOLPS package includes the 3D multi-species Monte-Carlo neutral code EIRINE and 2D multi-fluid code B2. The EIRINE and B2 codes are cross-coupled through B2-EIRINE interface. The results of SOLPS simulations are used in the integrated modeling of the plasma edge in DIII-D tokamak with the ASTRA transport code. Parameterized dependences for neutral particle fluxes that are computed with the SOLPS code are implemented in a model for the H-mode pedestal and ELMs [1] in the ASTRA code. The effects of neutrals on the H-mode pedestal and ELMs are studied in this report. [1] A. Y. Pankin, I. Voitsekhovitch, G. Bateman, et al., Plasma Phys. Control. Fusion 47, 483 (2005).

Density Limit due to SOL Convection

NASA Astrophysics Data System (ADS)

D'Ippolito, D. A.; Myra, J. R.; Russell, D. A.

2004-11-01

Recent measurements on C-Mod(M. Greenwald, Plasma Phys. Contr. Fusion 44), R27 (2002). suggest there is a density limit due to rapid convection in the SOL: this region starts in the far SOL but expands inward to the separatrix as the density approaches the Greenwald limit. This idea is supported by a recent analysis(D. A. Russell et al., Lodestar Report LRC-04-99 (2004).) of a 3D BOUT code turbulence simulation(X. Q. Xu et al., Bull. APS 48), 184 (2003), paper KP1-20. with neutral fueling of the X-point region. Our work suggests that rapid outwards convection of plasma by turbulent coherent structures (``blobs'') occurs when the X-point collisionality is sufficiently large. Here, we calculate a density limit due to loss of thermal equilibrium in the edge plasma due to rapid radial convective heat transport. We expect a synergistic effect between blob convection and X-point cooling. The cooling increases the parallel resistivity at the X-point, ``disconnects'' the blobs electrically from the sheaths, and increases their radial velocity,(D.A. D'Ippolito et al., 2004 Sherwood Meeting, paper 1C 43.) which in turn further cools the X-points. Progress on a theoretical model will be reported.

Visualizing and Quantifying Blob Characteristics on NSTX

NASA Astrophysics Data System (ADS)

Davis, William; Zweben, Stewart; Myra, James; D'Ippolito, Daniel; Ko, Matthew

2012-10-01

Understanding the radial motion of blob-filaments in the tokamak edge plasma is important since this motion can affect the width of the heat and particle scrape-off layer (SOL) [1]. High resolution (64x80), high speed (400,000 frames/sec) edge turbulence movies taken of the NSTX outer midplane separatrix region have recently been analyzed for blob motion. Regions of high light emission from gas puff imaging within a 25x30 cm cross-section were used to track blob-filaments in the plasma edge and into the SOL. Software tools have been developed for visualizing blob movement and automatically generating statistics of blob speed, shape, amplitude, size, and orientation; thousands of blobs have been analyzed for dozens of shots. The blob tracking algorithm and resulting database entries are explained in detail. Visualization tools also show how poloidal and radial motion change as blobs move through the scrape-off-layer (SOL), e.g. suggesting the influence of sheared flow. Relationships between blob size and velocity are shown for various types of plasmas and compared with simplified theories of blob motion. This work was supported by DOE Contract DE-AC02-09-CH11466. [4pt] [1] J.R. Myra et al, Phys. Plasmas 18, 012305 (2011)

Universality for 1d Random Band Matrices: Sigma-Model Approximation

NASA Astrophysics Data System (ADS)

Shcherbina, Mariya; Shcherbina, Tatyana

2018-02-01

The paper continues the development of the rigorous supersymmetric transfer matrix approach to the random band matrices started in (J Stat Phys 164:1233-1260, 2016; Commun Math Phys 351:1009-1044, 2017). We consider random Hermitian block band matrices consisting of W× W random Gaussian blocks (parametrized by j,k \\in Λ =[1,n]^d\\cap Z^d ) with a fixed entry's variance J_{jk}=δ _{j,k}W^{-1}+β Δ _{j,k}W^{-2} , β >0 in each block. Taking the limit W→ ∞ with fixed n and β , we derive the sigma-model approximation of the second correlation function similar to Efetov's one. Then, considering the limit β , n→ ∞, we prove that in the dimension d=1 the behaviour of the sigma-model approximation in the bulk of the spectrum, as β ≫ n , is determined by the classical Wigner-Dyson statistics.

Preface: phys. stat. sol. (a) 202/11

NASA Astrophysics Data System (ADS)

Bergonzo, Philippe; Nesládek, Milo

2005-09-01

The present issue of physica status solidi (a) contains a collection of 31 papers presented at the 10th International Workshop on Surface and Bulk Defects in CVD Diamond Films held in Diepenbeek-Hasselt, Belgium, 23-25 February 2005. The 10th anniversary of the meeting proved the success of the concept, which originated in 1996 with the idea of bringing together scientists who are active and innovative in the field of electronic and optical properties of thin film diamond. This year the programme contained 9 invited oral talks, 14 contributed oral talks and 34 posters. 103 Participants from 14 countries (Austria, Belgium, Czech Republic, Finland, France, Germany, Japan, Mexico, Poland, Slovak Republic, Sweden, Switzerland, UK, USA) took part in the meeting. The meeting was traditionally directed towards topics ranging from defects and their characterization as well as electrical transport in CVD diamond towards modern diamond thin film devices including bio-sensing applications. Also, diamond homoepitaxial and heteroepitaxial growth, doping, hydrogen induced surface conductivity and several other topics including defects in boron nitride materials were addressed. Intense and lively discussions were as usual part of this meeting to which the hospitality of the city of Hasselt contributed greatly.The workshop would have not been possible without the support of many people and institutions. We also acknowledge the financial support of the Scientific Research Community of the F.W.O.-Vlaanderen (Belgium) and the University of Hasselt. We also thank the editorial staff of physica status solidi, most notably Stefan Hildebrandt, for their excellent and patient work. Finally, we would like to thank Ken Haenen, whose skills for the successful organization are gratefully acknowledged.August 2005

Preface: phys. stat. sol. (a) 201/5

NASA Astrophysics Data System (ADS)

Avelino Pasa, André

2004-04-01

This issue contains scientific contributions to the 4th German/Brazilian Workshop on Applied Surface Science. The workshop was held in Germany at the beautiful Castle Ringberg conference site of the Max Planck Society, located 60 km from Munich, from 21-26 September 2003. The meeting was attended by about 50 participants, with 21 invited talks and 18 contributed presentations (8 oral and 10 posters) on relevant topics of surface science.As in previous meetings (1995 in Portobello, RJ, Brazil, 1998 in Döllnsee, Berlin, Germany, and 2001 in Itapema, SC, Brazil), a significant number of important questions in surface science were covered from both the theoretical and the experimental point of view. In the field of materials science, emphasis was given to the description of the structural, physical and chemical properties of nanostructures and films of inorganic (metals, alloys and oxides) and organic (polymers and biological molecules) materials.A substantial part of the success of the meeting can be attributed to the relaxed atmosphere at the castle, near the lake Tegernsee, where excellent scientific presentations were mixed with intense discussions among both senior and younger researchers. The event also led to the development of new and ongoing collaborations between partners from Brazil and Germany.The organizers of the Workshop, Israel J. R. Baumvol (Porto Alegre, Brazil), Hajo Freund (Berlin, Germany), Wolfgang H. P. Losch (Natal, Brazil), Horst Niehus (Berlin, Germany), André A. Pasa (Florianópolis, Brazil) and Eberhard Umbach (Würzburg, Germany), are greatly indebted to the following organizations for financial support: Deutsche Forschungsgemeinschaft (DFG), Fritz-Haber-Institut Berlin (FHI), Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Universidade Federal de Santa Catarina (UFSC) and the specially created intergovernmental agreement between CAPES and DFG to promote such meetings.

Preface: phys. stat. sol. (a) 202/7

NASA Astrophysics Data System (ADS)

Pollak, Fred H.; Misiewicz, Jan; Sitarek, Piotr

2005-05-01

We have recently observed a growing interest in using the powerful technique of optical modulation spectroscopy. These applications are related mostly to the characterization of low dimensional semiconductor structures and devices based on them.The International Workshop on Modulation Spectroscopy of Semiconductor Structures (MS3) at the beginning of July 2004 gathered in Wrocaw (in the southwest part of Poland) almost 40 participants, half of them from abroad. The 8 invited and 16 contributed talks were presented by the leaders of research teams from the USA, Japan, Taiwan, Canada, Germany, France, the Netherlands, Sweden, Ireland, Russia, Lithuania and Poland. Part of the MS3 workshop was held at the Laboratory of Advanced Optical Spectroscopy, Institute of Physics, Wrocaw University of Technology, where discussions on technical matter of the modulation spectroscopy were carried out in a relaxing atmosphere over a cup of coffee.The topics of the MS3 workshop included: advantages of photoreflectance, electroreflectance, contactless electroreflectance, thermoreflectance, differential reflectance and wavelength-modulated surface photovoltage spectroscopy. The applications of the above methods to investigate transistor, diode and laser structures including VCSELs, low dimensional structures of both wings of the spectrum, i.e. wide band gap materials like GaN, AlGaN, ZnO and low band gap materials such as GaInN(Sb)As, InAs, InSb, and FeSi2 were demonstrated.It is our great pleasure to publish the most interesting of the MS3 workshop presentations in this issue of physica status solidi (a).The organizers acknowledge Wrocaw University of Technology, the Center of Exellence CEPHONA from the Institute of Electron Technology in Warsaw and the Polish Committee for Scientific Research for financial support of the workshop.

Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, SH.; Ballmann, C.; Quarles, C. A.

2009-03-10

The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixedmore » in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.« less

Erratum to "Solar Sources and Geospace Consequences of Interplanetary Magnetic Clouds Observed During Solar Cycle 23-Paper 1" [J. Atmos. Sol.-Terr. Phys. 70(2-4) (2008) 245-253

NASA Technical Reports Server (NTRS)

Gopalswamy, N.; Akiyama, S.; Yashiro, S.; Michalek, G.; Lepping, R. P.

2009-01-01

One of the figures (Fig. 4) in "Solar sources and geospace consequences of interplanetary magnetic Clouds observed during solar cycle 23 -- Paper 1" by Gopalswamy et al. (2008, JASTP, Vol. 70, Issues 2-4, February 2008, pp. 245-253) is incorrect because of a software error in t he routine that was used to make the plot. The source positions of various magnetic cloud (MC) types are therefore not plotted correctly.

A multispin algorithm for the Kob-Andersen stochastic dynamics on regular lattices

NASA Astrophysics Data System (ADS)

Boccagna, Roberto

2017-07-01

The aim of the paper is to propose an algorithm based on the Multispin Coding technique for the Kob-Andersen glassy dynamics. We first give motivations to speed up the numerical simulation in the context of spin glass models [M. Mezard, G. Parisi, M. Virasoro, Spin Glass Theory and Beyond (World Scientific, Singapore, 1987)]; after defining the Markovian dynamics as in [W. Kob, H.C. Andersen, Phys. Rev. E 48, 4364 (1993)] as well as the related interesting observables, we extend it to the more general framework of random regular graphs, listing at the same time some known analytical results [C. Toninelli, G. Biroli, D.S. Fisher, J. Stat. Phys. 120, 167 (2005)]. The purpose of this work is a dual one; firstly, we describe how bitwise operators can be used to build up the algorithm by carefully exploiting the way data are stored on a computer. Since it was first introduced [M. Creutz, L. Jacobs, C. Rebbi, Phys. Rev. D 20, 1915 (1979); C. Rebbi, R.H. Swendsen, Phys. Rev. D 21, 4094 (1980)], this technique has been widely used to perform Monte Carlo simulations for Ising and Potts spin systems; however, it can be successfully adapted to more complex systems in which microscopic parameters may assume boolean values. Secondly, we introduce a random graph in which a characteristic parameter allows to tune the possible transition point. A consistent part is devoted to listing the numerical results obtained by running numerical simulations.

A new biocatalyst: Penicillin G acylase immobilized in sol-gel micro-particles with magnetic properties.

PubMed

Bernardino, Susana M S A; Fernandes, Pedro; Fonseca, Luís P

2009-05-01

The present work focuses on the development and basic characterization of a new magnetic biocatalyst, namely penicillin G acylase (PGA), immobilized in sol-gel matrices with magnetic properties, ultimately aimed for application in cephalexin (CEX) synthesis. A mechanically stable carrier, based on porous xerogels silica matrixes starting from tetramethoxysilane (TMOS), was prepared leading to micro-carriers with medium sized particles of 30 microm, as determined by scanning electron microscopy. An immobilization yield of 95-100% and a recovered activity of 50-65% at 37 degrees C, as determined by penicillin G (PG) hydrolysis (pH STAT method), were observed. These results clearly exceed those reported in a previous work on PGA immobilization in sol-gel, where only 10% of activity was recovered. The values of activity were kept constant for 6 months. Immobilized PGA (682 U/g(dry weight)) retained high specific activity throughout ten consecutive runs for PG hydrolysis, suggesting adequate biocatalyst stability. The CEX synthesis was performed at 14 degrees C, using the free and immobilized PGA in aqueous medium. Phenylglycine methyl ester was used as acyl donor at 90 mM and 7-aminodeacetoxycephalosporanic acid was the limiting substrate at 30 mM. The CEX stoichiometric yield after 1-h reaction was close to 68% (23 mM CEX/h) and 65% (19 mM CEX/h), respectively.

Three-dimensional simulations of plasma turbulence in the RFX-mod scrape-off layer and comparison with experimental measurements

NASA Astrophysics Data System (ADS)

Riva, Fabio; Vianello, Nicola; Spolaore, Monica; Ricci, Paolo; Cavazzana, Roberto; Marrelli, Lionello; Spagnolo, Silvia

2018-02-01

The tokamak scrape-off layer (SOL) plasma dynamics is investigated in a circular limiter configuration with a low edge safety factor. Focusing on the experimental parameters of two ohmic tokamak inner-wall limited plasma discharges in RFX-mod [Sonato et al., Fusion Eng. Des. 74, 97 (2005)], nonlinear SOL plasma simulations are performed with the GBS code [Ricci et al., Plasma Phys. Controlled Fusion 54, 124047 (2012)]. The numerical results are compared with the experimental measurements, assessing the reliability of the GBS model in describing the RFX-mod SOL plasma dynamics. It is found that the simulations are able to quantitatively reproduce the RFX-mod experimental measurements of the electron plasma density, electron temperature, and ion saturation current density (jsat) equilibrium profiles. Moreover, there are indications that the turbulent transport is driven by the same instability in the simulations and in the experiment, with coherent structures having similar statistical properties. On the other hand, it is found that the simulation results are not able to correctly reproduce the floating potential equilibrium profile and the jsat fluctuation level. It is likely that these discrepancies are, at least in part, related to simulating only the tokamak SOL region, without including the plasma dynamics inside the last close flux surface, and to the limits of applicability of the drift approximation. The turbulence drive is then identified from the nonlinear simulations and with the linear theory. It results that the inertial drift wave is the instability driving most of the turbulent transport in the considered discharges.

Ferromagnetism in LaCoO3 nanoparticles

NASA Astrophysics Data System (ADS)

Zhou, Shiming; Shi, Lei; Zhao, Jiyin; He, Laifa; Yang, Haipeng; Zhang, Shangming

2007-11-01

We have investigated the structural and magnetic properties of LaCoO3 nanoparticles prepared by a sol-gel method. A ferromagnetic order with TC˜85K has been observed in the nanoparticles. The infrared spectra give evidence for a stabilizing of higher spin state and a reduced Jahn-Teller distortion in the nanoparticles with respect to the bulk LaCoO3 , which is consistent with the recent reports in the strained films [Phys. Rev. B 75, 144402 (2007)] and proposed to be the possible origin of the observed ferromagnetic order in LaCoO3 .

The Encapsulation of Organic Molecules and Enzymes in Sol-Gel Glasses: Novel Photoactive, Optical, Sensing and Bioactive Materials. A Review

DTIC Science & Technology

1992-01-01

Fr.) 1976,1321. 2. Carturan. G .; Fachin. G4; Gottardi, V .; Guglicmi, M1; Movazio, GJ. Non-Cryst. Solids 1982., 4. 219. 23. Lopez. T.; Lopcz-Gaona. A...1976,44,739. 30. Shtelzer, S; Rappoport, S.; Avnir, D; Ottolenghi, M.; Braun, S., Bitech. Appi. Biochem., submitted 199L 3L Martinek, K, Mozhaev , V . V . Adv...Avnir, D4 Ottolcnighi, IM., J.Phys. C/Wffl. 1989, 93, 7544. & idem, Photrohent. Photobiol. 11ŕ, 54.525. 9. e- g ., (a) Gratzel, M. A"c. Chem. ReS

Oxygen K- and Mn L-Edges of La_xMn_yO_3-d Films

NASA Astrophysics Data System (ADS)

Deleon, Michael; Tyson, Trevor; Qian, Q.; Dubourdieu, C.; Senateur, J. P.; Bosak, A.; Arena, D. A.

2003-03-01

The La_xMn_yO_3-d system holds much interest due to it's wide range of magnetic and transport properties with varying compositions. Oxygen defects and lanthanum deficiencies in the parent compound LaMnO3 induce a mixture of valences at the Mn site which enables transitions to a ferromagnetic metallic state through double exchange [1-5]. We have measured the oxygen K-edges and Mn L-edges for La_xMn_yO_3-d films of varying x deposited on (100) SrTiO3 and x=0.8 on varying thickness deposited on (001) LaAlO_3. These results are interpreted by multiplet structure computations. In addition, band structure results will be used to track changes in unoccupied levels on the Mn and O sites. This work is supported by NSF Career Grant DMR-9733862 and DMR-0209243. [1]A. Gupta, T.R. McGuire, P.R. Duncombe, M. Rupp, J. Z. Sun, W. J. Gallagher, G. Xiao. Appl. Phys. Let. 67, 3494 (1995) [2]P. S. I. P. N. de Silva, F.M. Richards, L. F. Cohen, J. A. Alonso, M. J. Martinez-Lope, M. T. Casais, K. A. Thomas, J. L. MacManus-Driscoll. J. A. Phys. 83, 3394(1998) [3] C. Chen, A. de Lozanne. A. Phys. Let. 73, 3950(1998) [4] S. J. Kim, C. S. Kim, S. Park, B. W. Lee. J. A. Phys. 89, 7416 (2001) [5] J. Topfer, J. B. Goodenough. Sol. St. Ionics 101, 1215 (1997)

Comparative study for highly Al and Mg doped ZnO thin films elaborated by sol gel method for photovoltaic application

NASA Astrophysics Data System (ADS)

El Hallani, G.; Nasih, S.; Fazouan, N.; Liba, A.; Khuili, M.; Sajieddine, M.; Mabrouki, M.; Laanab, L.; Atmani, E. H.

2017-04-01

Transparent conducting oxides such as ZnO doped with Al or Mg are commonly used in solar cells, light emitting diodes, photodetectors, and ultraviolet laser diodes. In our work, we focus on a comparative study of the structural, optical, and electrical properties of ZnO films highly doped with Al (AZO) and Mg (MZO). These films are deposited on glass substrates by the sol-gel spin coating method. The doping concentrations for Al and Mg are fixed to 5%-30%. The XRD spectra indicate that all the samples are polycrystalline with hexagonal wurtzite structures, exhibiting a preferred orientation along the (002) plane. Low degradation in crystallinity was observed for MZO even at a Mg concentration of 30%. The MgO phase started to appear compared to Al-doped layers where smaller grains are formed inducing a deterioration in the films just after doping but no new phase appeared. This result is in agreement with other experimental results [J. K. Rath, Sol. Energy Mater. Sol. Cells 76, 431-487 (2003); Morris et al., J. Appl. Phys. 67, 1079-1087 (1990)]. By AFM analysis, the results indicate a significantly rough surface for MZO compared to AZO films. For equal Al and Mg dopant concentrations, we observe that the transmittance spectra of MZO thin films are wider than those of AZO, indicating a shift toward shorter wavelengths with an optical gap energy equal to 3.67 eV. The electrical measurements of AZO and MZO thin films were made using the I-V characteristic obtained by the four probe method. All the films present an ohmic behavior. The conductivity and the mobility of AZO films were found to be better than those of MZO.

Some connections between importance sampling and enhanced sampling methods in molecular dynamics.

PubMed

Lie, H C; Quer, J

2017-11-21

In molecular dynamics, enhanced sampling methods enable the collection of better statistics of rare events from a reference or target distribution. We show that a large class of these methods is based on the idea of importance sampling from mathematical statistics. We illustrate this connection by comparing the Hartmann-Schütte method for rare event simulation (J. Stat. Mech. Theor. Exp. 2012, P11004) and the Valsson-Parrinello method of variationally enhanced sampling [Phys. Rev. Lett. 113, 090601 (2014)]. We use this connection in order to discuss how recent results from the Monte Carlo methods literature can guide the development of enhanced sampling methods.

Mixing properties of the one-atom maser

NASA Astrophysics Data System (ADS)

Bruneau, Laurent

2014-06-01

We study the relaxation properties of the quantized electromagnetic field in a cavity under repeated interactions with single two-level atoms, so-called one-atom maser. We improve the ergodic results obtained in Bruneau and Pillet (J Stat Phys 134(5-6):1071-1095, 2009) and prove that, whenever the atoms are initially distributed according to the canonical ensemble at temperature , all the invariant states are mixing. Under some non-resonance condition this invariant state is known to be thermal equilibirum at some renormalized temperature and we prove that the mixing is then arbitrarily slow, in other words that there is no lower bound on the relaxation speed.

Some connections between importance sampling and enhanced sampling methods in molecular dynamics

NASA Astrophysics Data System (ADS)

Lie, H. C.; Quer, J.

2017-11-01

In molecular dynamics, enhanced sampling methods enable the collection of better statistics of rare events from a reference or target distribution. We show that a large class of these methods is based on the idea of importance sampling from mathematical statistics. We illustrate this connection by comparing the Hartmann-Schütte method for rare event simulation (J. Stat. Mech. Theor. Exp. 2012, P11004) and the Valsson-Parrinello method of variationally enhanced sampling [Phys. Rev. Lett. 113, 090601 (2014)]. We use this connection in order to discuss how recent results from the Monte Carlo methods literature can guide the development of enhanced sampling methods.

Turbulence, intermittency, and transport in the limiter shadow in LAPD and ET

NASA Astrophysics Data System (ADS)

Carter, Troy

2002-11-01

Turbulence in the scrape-off-layer (SOL) of tokamaks is often found to be intermittent, a tendency which has been attributed to the presence and transport of coherent structures (``blobs''). A recent theory [S.I. Krasheninnikov, shape Phys. Lett. A series 283, 368 (2001)] suggests that transport of these structures is controlled by nabla B and curvature drift driven polarization. I will present a study of turbulence and intermittency in limited discharges in the Large Plasma Device (LAPD) (where rotation may substitute for nabla B drift) and in the Electric Tokamak (ET) at UCLA. In LAPD, strongly intermittent turbulence in the 1-50 kHz range is observed localized to limiter produced gradients. A detailed study of these fluctuations will be presented, focusing on transport, dependencies on magnetic field, plasma density, and the presence of flows or rotation. A comparison with initial probe and imaging measurements of fluctuation characteristics in the SOL of the Electric Tokamak, in discharges with either an axisymmetric belt limiter or a toroidally localized limiter, will also be presented.

Preface: phys. stat. sol. (a) 203/4

NASA Astrophysics Data System (ADS)

Kittler, Martin; Yang, Deren

2006-03-01

This issue of physica status solidi (a) contains the majority of papers presented at the 2nd Sino-German Symposium The Silicon Age which was held at the Lindner Hotel Cottbus, Germany, 19-24 September 2005. This meeting followed the 1st Symposium Progress in Silicon Materials held in June 2002 in Hangzhou, P.R. China. 8 Chinese and 14 German scientists from universities, research institutes and industry were invited to present their views about different aspects of silicon.There was a continuous progress in silicon materials development during the last 40-50 years, driven by the need of the IC industry for better and larger monocrystalline silicon wafers. Moreover, low-cost crystalline silicon now dominates the world's production of solar cells in the photovoltaics industry. Furthermore, there are intensive research activities worldwide for on-chip integration of Si-based photonics in CMOS technology. In addition, new areas being connected with silicon are starting to appear, namely Si-based biochips and nanoelectronics. Silicon, one can reasonably argue, is already the most investigated of all materials. However, there is still a need for continuation of research and development regarding numerous aspects of Si and also SiGe, including related technologies, advanced diagnostics or the role of crystal defects, which are the working fields of many laboratories all over the world. This was also shown by the presentations at the symposium and can be found in the contributions contained in this issue.The organizers would like to thank the participants for their high level contributions and discussions during the symposium. This intensive and open communication allowed the participants to create synergies between the different fields of silicon research and also to build up relationships for cooperation between Chinese and German research groups.Finally, we would like to thank the Sino-German Science Center for the financial support of the symposium.

Self-excitation of single nanomechanical pillars

NASA Astrophysics Data System (ADS)

Kim, Hyun S.; Qin, Hua; Blick, Robert H.

2010-03-01

Self-excitation is a mechanism that is ubiquitous for electromechanical power devices such as electrical generators. This is conventionally achieved by making use of the magnetic field component in electrical generators (Nedic and Lipo 2000 IEEE/IAS Conf. Records (Rome, Italy) vol 1 pp 51-6), a good and widely visible example of which is the wind turbine farm (Muljadi et al 2005 J. Sol. Energy Eng. 127 581-7). In other words, a static force, such as the wind acting on rotor blades, can generate a resonant excitation at a certain mechanical frequency. For nanomechanical systems (Craighead 2000 Science 290 1532-5 Roukes 2001 Phys. World 14 25-31 Cleland 2003 Foundations of Nanomechanics (Berlin: Springer); Ayari et al 2007 Nano Lett. 7 2252-7 Koenig et al 2008 Nat. Nanotechnol. 3 482-4) such a self-excitation (SE) mechanism is also highly desirable, because it can generate mechanical oscillations at radio frequencies by simply applying a dc bias voltage. This is of great importance for low-power signal communication devices and detectors, as well as for mechanical computing elements. For a particular nanomechanical system—the single electron shuttle—this effect was predicted some time ago by Gorelik et al (Phys. Rev. Lett. 80 4526-9). Here, we use a nanoelectromechanical single electron transistor (NEMSET) to demonstrate self-excitation for both the soft and hard regimes, respectively. The ability to use self-excitation in nanomechanical systems may enable the detection of quantum mechanical backaction effects (Naik et al 2006 Nature 443 193-6) in direct tunneling, macroscopic quantum tunneling (Savelev et al 2006 New J. Phys. 8 105-15) and rectification (Pistolesi and Fazio 2005 Phys. Rev. Lett. 94 036806-4). All these effects have so far been overshadowed by the large driving voltages that had to be applied.

Asymmetric spin-wave dispersion in ferromagnetic nanotubes induced by surface curvature

NASA Astrophysics Data System (ADS)

Otálora, Jorge A.; Yan, Ming; Schultheiss, Helmut; Hertel, Riccardo; Kákay, Attila

2017-05-01

We present a detailed analytical derivation of the spin wave (SW) dispersion relation in magnetic nanotubes with magnetization along the azimuthal direction. The obtained formula can be used to calculate the dispersion relation for any longitudinal and azimuthal mode. The obtained dispersion is asymmetric for all azimuthal modes traveling along the axial direction. As reported in our recent publication [Phys. Rev. Lett. 117, 227203 (2016), 10.1103/PhysRevLett.117.227203], the asymmetry is a curvature-induced effect originating from the dipole-dipole interaction. Here, we discuss the asymmetry of the dispersion for azimuthal modes by analyzing the SW asymmetry Δ f (kz) =fn(kz) -fn(-kz) , where fn(kz) is the eigenfrequency of a magnon with a longitudinal and azimuthal wave vectors, kz and n , respectively; and the dependence of the maximum asymmetry with the nanotube radius R . The analytical results are in perfect agreement with micromagnetic simulations. Furthermore, we show that the dispersion relation simplifies to the thin-film dispersion relation with in-plane magnetization when analyzing the three limiting cases: (i) kz=0 , (ii) kz≫1 /R , and (iii) kz≪1 /R . In the first case, for the zeroth-order modes the thin-film Kittel formula is obtained. For modes with higher order the dispersion relation for the Backward-Volume geometry is recovered. In the second case, for the zeroth-order mode the exchange dominated dispersion relation for SW in Damon-Esbach configuration is obtained. For the case kz≪1 /R , we find that the dispersion relation can be reduced to a formula similar to the Kalinikos-Slavin [J. Phys. C: Sol. State Phys. 19, 7013 (1986), 10.1088/0022-3719/19/35/014] type.

Fidelity for kicked atoms with gravity near a quantum resonance.

PubMed

Dubertrand, Rémy; Guarneri, Italo; Wimberger, Sandro

2012-03-01

Kicked atoms under a constant Stark or gravity field are investigated for experimental setups with cold and ultracold atoms. The parametric stability of the quantum dynamics is studied using the fidelity. In the case of a quantum resonance, it is shown that the behavior of the fidelity depends on arithmetic properties of the gravity parameter. Close to a quantum resonance, the long-time asymptotics of the fidelity is studied by means of a pseudoclassical approximation introduced by Fishman et al. [J. Stat. Phys. 110, 911 (2003)]. The long-time decay of fidelity arises from the tunneling out of pseudoclassical stable islands, and a simple ansatz is proposed which satisfactorily reproduces the main features observed in numerical simulations.

Transition point prediction in a multicomponent lattice Boltzmann model: Forcing scheme dependencies

NASA Astrophysics Data System (ADS)

Küllmer, Knut; Krämer, Andreas; Joppich, Wolfgang; Reith, Dirk; Foysi, Holger

2018-02-01

Pseudopotential-based lattice Boltzmann models are widely used for numerical simulations of multiphase flows. In the special case of multicomponent systems, the overall dynamics are characterized by the conservation equations for mass and momentum as well as an additional advection diffusion equation for each component. In the present study, we investigate how the latter is affected by the forcing scheme, i.e., by the way the underlying interparticle forces are incorporated into the lattice Boltzmann equation. By comparing two model formulations for pure multicomponent systems, namely the standard model [X. Shan and G. D. Doolen, J. Stat. Phys. 81, 379 (1995), 10.1007/BF02179985] and the explicit forcing model [M. L. Porter et al., Phys. Rev. E 86, 036701 (2012), 10.1103/PhysRevE.86.036701], we reveal that the diffusion characteristics drastically change. We derive a generalized, potential function-dependent expression for the transition point from the miscible to the immiscible regime and demonstrate that it is shifted between the models. The theoretical predictions for both the transition point and the mutual diffusion coefficient are validated in simulations of static droplets and decaying sinusoidal concentration waves, respectively. To show the universality of our analysis, two common and one new potential function are investigated. As the shift in the diffusion characteristics directly affects the interfacial properties, we additionally show that phenomena related to the interfacial tension such as the modeling of contact angles are influenced as well.

Fluid transport in partially filled porous sol-gel silica glass

NASA Astrophysics Data System (ADS)

D'orazio, Franco; Bhattacharja, Sankar; Halperin, William P.; Gerhardt, Rosario

1990-10-01

Measurements of low-frequency ac electrical conductivity of a porous glass filled with different amounts of a saline solution are compared with the self-diffusion coefficient of water measured in the same sample, reported previously [F. D'Orazio et al., Phys. Rev. Lett. 63, 43 (1989)]. The two transport parameters are consistently related through the Einstein relation under saturation conditions. A more complex picture is revealed for the unsaturated sample, since the presence of a vapor phase enhances the self-diffusion coefficient. Conductivity experiments allow an independent assessment of the contribution to self-diffusion from the liquid phase. However, a comparison between the two experiments indicates that the role of the vapor phase is not well understood.

The Collaborative Heliophysics Events Knowledgebase

NASA Astrophysics Data System (ADS)

Hurlburt, N. E.; Schuler, D.; Cheung, C.

2010-12-01

The Collaborative Heliophysics Events Knowledgebase (CHEK) leverages and integrates the existing resources developed by HEK for SDO (Hurlburt et al. 2010) to provide a collaborative framework for heliophysics researchers. This framework will enable an environment were researches can not only identify and locate relevant data, but can deploy a social network for sharing and expanding knowledge about heliophysical events. CHEK will expand the HEK and key HEK clients into the heliosphere and geospace, and create a heliophysics social network. We describe our design and goals of the CHEK project and discuss its relation to Citizen Science in the heliosphere. Hurlburt, N et al. 2010, “A Heliophysics Event Knowledgebase for Solar Dynamics Observatory,” Sol Phys., in press

Scrape off layer modelling studies for SST-I

NASA Astrophysics Data System (ADS)

Warrier, M.; Jaishankar, S.; Deshpande, S.; Coster, D.; Schneider, R.; Chaturvedi, S.; Srinivasan, R.; Braams, B. J.; SST Team

SOL modelling results for SST-1 (SST Team, Proceedings of the 16th IEEE/NPSS Symposium on Fusion Engineering, Champaign, IL, vol. II, 1995, p. 481) show a sheath limited flow regime. This is due to the low edge densities required by lower hybrid current drive (LHCD), coupled with high power input per unit volume. Coupled plasma-neutral transport studies using B2-Eirene [R. Schneider et al., J. Nucl. Mater. 196-198 (1992) 810] show significantly high charge exchange losses and radiated power from the core. It also shows that the heat flux to the inner divertor is higher than that to the outer divertor due to thinner inner SOL widths. The Monte-Carlo neutral transport code DEGAS [D. Heifitz et al., J. Comput. Phys. 46 (1982) 309] was used to optimise the baffle plate geometry and it was seen that a configuration where the baffle plate shields the main plasma from the divertor strike point results in reduced backflow of neutrals. The divertor erosion code DIVER (M. Warrier et al., SST Divertor Modelling Report, 1996-1997) was used to predict a steady state operating temperature for the SST divertor plate lying in the range 750-1000°C for which the erosion will be minimum.

Computing the multifractal spectrum from time series: an algorithmic approach.

PubMed

Harikrishnan, K P; Misra, R; Ambika, G; Amritkar, R E

2009-12-01

We show that the existing methods for computing the f(alpha) spectrum from a time series can be improved by using a new algorithmic scheme. The scheme relies on the basic idea that the smooth convex profile of a typical f(alpha) spectrum can be fitted with an analytic function involving a set of four independent parameters. While the standard existing schemes [P. Grassberger et al., J. Stat. Phys. 51, 135 (1988); A. Chhabra and R. V. Jensen, Phys. Rev. Lett. 62, 1327 (1989)] generally compute only an incomplete f(alpha) spectrum (usually the top portion), we show that this can be overcome by an algorithmic approach, which is automated to compute the D(q) and f(alpha) spectra from a time series for any embedding dimension. The scheme is first tested with the logistic attractor with known f(alpha) curve and subsequently applied to higher-dimensional cases. We also show that the scheme can be effectively adapted for analyzing practical time series involving noise, with examples from two widely different real world systems. Moreover, some preliminary results indicating that the set of four independent parameters may be used as diagnostic measures are also included.

The universality of nucleosome organization: from yeast to human

NASA Astrophysics Data System (ADS)

Chereji, Razvan

The basic units of DNA packaging are called nucleosomes. Their locations on the chromosomes play an essential role in gene regulation. We study nucleosome positioning in yeast, fly, mouse, and human, and build biophysical models in order to explain the genome-wide nucleosome organization. We show that DNA sequence alone is not able to generate the phased arrays of nucleosomes observed in vivo near the transcription start sites. We discuss simple models which can account for the formation of nucleosome depleted regions and nucleosome phasing at the gene promoters. We show that the same principles apply to different organisms. References: [1] RV Chereji, D Tolkunov, G Locke, AV Morozov - Phys. Rev. E 83, 050903 (2011) [2] RV Chereji, AV Morozov - J. Stat. Phys. 144, 379 (2011) [3] RV Chereji, AV Morozov - Proc. Natl. Acad. Sci. U.S.A. 111, 5236 (2014) [4] RV Chereji, T-W Kan, et al. - Nucleic Acids Res. (2015) doi: 10.1093/nar/gkv978 [5] RV Chereji, AV Morozov - Brief. Funct. Genomics 14, 50 (2015) [6] HA Cole, J Ocampo, JR Iben, RV Chereji, DJ Clark - Nucleic Acids Res. 42, 12512 (2014) [7] D Ganguli, RV Chereji, J Iben, HA Cole, DJ Clark - Genome Res. 24, 1637 (2014)

Classification of Particle Numbers with Unique Heitmann-Radin Minimizer

NASA Astrophysics Data System (ADS)

De Luca, Lucia; Friesecke, Gero

2017-06-01

We show that minimizers of the Heitmann-Radin energy (Heitmann and Radin in J Stat Phys 22(3):281-287, 1980) are unique if and only if the particle number N belongs to an infinite sequence whose first thirty-five elements are 1, 2, 3, 4, 5, 7, 8, 10, 12, 14, 16, 19, 21, 24, 27, 30, 33, 37, 40, 44, 48, 52, 56, 61, 65, 70, 75, 80, 85, 91, 96, 102, 108, 114, 120 (see the paper for a closed-form description of this sequence). The proof relies on the discrete differential geometry techniques introduced in De Luca and Friesecke (Crystallization in two dimensions and a discrete Gauss-Bonnet Theorem, 2016).

A Revision on Classical Solutions to the Cauchy Boltzmann Problem for Soft Potentials

NASA Astrophysics Data System (ADS)

Alonso, Ricardo J.; Gamba, Irene M.

2011-05-01

This short note complements the recent paper of the authors (Alonso, Gamba in J. Stat. Phys. 137(5-6):1147-1165, 2009). We revisit the results on propagation of regularity and stability using L p estimates for the gain and loss collision operators which had the exponent range misstated for the loss operator. We show here the correct range of exponents. We require a Lebesgue's exponent α>1 in the angular part of the collision kernel in order to obtain finiteness in some constants involved in the regularity and stability estimates. As a consequence the L p regularity associated to the Cauchy problem of the space inhomogeneous Boltzmann equation holds for a finite range of p≥1 explicitly determined.

Afterglow luminescence in sol-gel/Pechini grown oxide materials: persistence or phosphorescence process? (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sontakke, Atul; Ferrier, Alban; Viana, Bruno

2017-03-01

Persistent luminescence and phosphorescence, both yields afterglow luminescence, but are completely different mechanisms. Persistent luminescence involves a slow thermal release of trapped electrons stored in defect states, whereas the phosphorescence is caused due to triplet to singlet transition [1,2]. Many persistent luminescence phosphors are based on oxide inorganic hosts, and exhibit long afterglow luminescence after ceasing the excitation. We observed intense and long afterglow luminescence in sol-gel/pechini grown inorganic oxides, and as a first interpretation thought to be due to persistence mechanism. However, some of these materials do not exhibit defect trap centers, and a detailed investigation suggested it is due to phosphorescence, but not the persistence. Phosphorescence is not common in inorganic solids, and that too at room temperature, and therefore usually misinterpreted as persistence luminescence [3]. Here we present a detailed methodology to distinguish phosphorescence from persistence luminescence in inorganic solids, and the process to harvest highly efficient long phosphorescence afterglow at room temperature. 1. Jian Xu, Setsuhisa Tanabe, Atul D. Sontakke, Jumpei Ueda, Appl. Phys. Lett. 107, 081903 (2015) 2. Sebastian Reineke, Marc A. Baldo, Scientific Reports, 4, 3797 (2014) 3. Pengchong Xue, Panpan Wang, Peng Chen, Boqi Yao, Peng Gong, Jiabao Sun, Zhenqi Zhang, Ran Lu, Chem. Sci. (2016) DOI: 10.1039/C5SC03739E

Preface: phys. stat. sol. (c) 1/8

NASA Astrophysics Data System (ADS)

Amann, Markus C.

2004-07-01

In this special issue of physica status solidi (c) we have included 10 invited papers reviewing the current state-of-the-art and the progress achieved in materials science, semiconductor theory, novel physical mechanisms and advanced device concepts in the field of nanostructured electronic and optoelectronic semiconductor devices. All of these papers were written by previous members of the Collaborative Research Centre 348 Nanometer-Halbleiterbauelemente: Grundlagen - Konzepte - Realisierungen (Nanometer Semiconductor Devices: Fundamentals - Concepts - Realisations), which was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) during the period from 1991 to 2003. In these twelve years, the researchers in this programme have carried an intense activity directed towards two main objectives. First of all, Fundamentals and Concepts of nanostructure devices and their technology were explored theoretically and experimentally including the effects of low-dimensional structures on carrier transport, optical properties and spin, as well as the enabling epitaxial and nanostructure technologies such as the cleaved-edge-overgrowth technique and the self-assembled growth of quantum dots. A second field of interest was focused towards the design and development of Novel Semiconductor Devices exploiting nanostructure technology. This comprises optical detectors and memories with nanometer lateral dimensions, microwave detectors and sources up to the 300 GHz regime, innovative tunable and surface-emitting semiconductor lasers for the wavelength range 0.9 to 2 m, and nitride-based resonant tunnelling diodes. Some of the device innovations have meanwhile become commercial products proving also the practical importance of this research area. The articles in this special issue relate to the projects of the last three-years' funding period from 2000 to 2003 and are organized along these two We would like to thank the numerous reviewers for their valuable comments and the editorial staff of physica status solidi (c) for their extremely helpful support. The funding by the German Research Foundation over the full project time and the continued monitoring and advice by its representatives Dr. Klaus Wehrberger and Dr. Peter Heil are gratefully acknowledged by all previous members and co-workers of this Collaborative Research Centre.

Functionalizing graphene by embedded boron clusters

NASA Astrophysics Data System (ADS)

Quandt, Alexander; Kunstmann, Jens; Ozdogan, Cem; Fehske, Holger

2010-03-01

We present results from an ab initio study of B7 clusters implanted into graphene [1,2]. Our model system consists of an alternating chain of quasiplanar B7 clusters. We show that graphene easily accepts these alternating B7-C6 chains and that the implanted boron components may dramatically modify the electronic properties. This suggests that our model system might serve as a blueprint for the controlled layout of graphene based nanodevices, where the semiconducting properties are supplemented by parts of the graphene matrix itself, and the basic metallic wiring is provided by alternating chains of implanted boron clusters. [1] A. Quandt, C. "Ozdogan, J. Kunstmann, and H. Fehske, Nanotechnology 19, 335707 (2008). [2] A. Quandt, C. "Ozdogan, J. Kunstmann, and H. Fehske, phys. stat. solidi (b) 245, 2077 (2008).

Exact solution and precise asymptotics of a Fisher-KPP type front

NASA Astrophysics Data System (ADS)

Berestycki, Julien; Brunet, Éric; Derrida, Bernard

2018-01-01

The present work concerns a version of the Fisher-KPP equation where the nonlinear term is replaced by a saturation mechanism, yielding a free boundary problem with mixed conditions. Following an idea proposed in Brunet and Derrida (2015 J. Stat. Phys. 161 801), we show that the Laplace transform of the initial condition is directly related to some functional of the front position μt . We then obtain precise asymptotics of the front position by means of singularity analysis. In particular, we recover the so-called Ebert and van Saarloos correction (Ebert and van Saarloos 2000 Physica D 146 1), we obtain an additional term of order log t /t in this expansion, and we give precise conditions on the initial condition for those terms to be present.

Heat flow in chains driven by thermal noise

NASA Astrophysics Data System (ADS)

Fogedby, Hans C.; Imparato, Alberto

2012-04-01

We consider the large deviation function for a classical harmonic chain composed of N particles driven at the end points by heat reservoirs, first derived in the quantum regime by Saito and Dhar (2007 Phys. Rev. Lett. 99 180601) and in the classical regime by Saito and Dhar (2011 Phys. Rev. E 83 041121) and Kundu et al (2011 J. Stat. Mech. P03007). Within a Langevin description we perform this calculation on the basis of a standard path integral calculation in Fourier space. The cumulant generating function yielding the large deviation function is given in terms of a transmission Green's function and is consistent with the fluctuation theorem. We find a simple expression for the tails of the heat distribution, which turns out to decay exponentially. We, moreover, consider an extension of a single-particle model suggested by Derrida and Brunet (2005 Einstein Aujourd'hui (Les Ulis: EDP Sciences)) and discuss the two-particle case. We also discuss the limit for large N and present a closed expression for the cumulant generating function. Finally, we present a derivation of the fluctuation theorem on the basis of a Fokker-Planck description. This result is not restricted to the harmonic case but is valid for a general interaction potential between the particles.

The Fourier transforms for the spatially homogeneous Boltzmann equation and Landau equation

NASA Astrophysics Data System (ADS)

Meng, Fei; Liu, Fang

2018-03-01

In this paper, we study the Fourier transforms for two equations arising in the kinetic theory. The first equation is the spatially homogeneous Boltzmann equation. The Fourier transform of the spatially homogeneous Boltzmann equation has been first addressed by Bobylev (Sov Sci Rev C Math Phys 7:111-233, 1988) in the Maxwellian case. Alexandre et al. (Arch Ration Mech Anal 152(4):327-355, 2000) investigated the Fourier transform of the gain operator for the Boltzmann operator in the cut-off case. Recently, the Fourier transform of the Boltzmann equation is extended to hard or soft potential with cut-off by Kirsch and Rjasanow (J Stat Phys 129:483-492, 2007). We shall first establish the relation between the results in Alexandre et al. (2000) and Kirsch and Rjasanow (2007) for the Fourier transform of the Boltzmann operator in the cut-off case. Then we give the Fourier transform of the spatially homogeneous Boltzmann equation in the non cut-off case. It is shown that our results cover previous works (Bobylev 1988; Kirsch and Rjasanow 2007). The second equation is the spatially homogeneous Landau equation, which can be obtained as a limit of the Boltzmann equation when grazing collisions prevail. Following the method in Kirsch and Rjasanow (2007), we can also derive the Fourier transform for Landau equation.

Lattice Boltzmann scheme for mixture modeling: analysis of the continuum diffusion regimes recovering Maxwell-Stefan model and incompressible Navier-Stokes equations.

PubMed

Asinari, Pietro

2009-11-01

A finite difference lattice Boltzmann scheme for homogeneous mixture modeling, which recovers Maxwell-Stefan diffusion model in the continuum limit, without the restriction of the mixture-averaged diffusion approximation, was recently proposed [P. Asinari, Phys. Rev. E 77, 056706 (2008)]. The theoretical basis is the Bhatnagar-Gross-Krook-type kinetic model for gas mixtures [P. Andries, K. Aoki, and B. Perthame, J. Stat. Phys. 106, 993 (2002)]. In the present paper, the recovered macroscopic equations in the continuum limit are systematically investigated by varying the ratio between the characteristic diffusion speed and the characteristic barycentric speed. It comes out that the diffusion speed must be at least one order of magnitude (in terms of Knudsen number) smaller than the barycentric speed, in order to recover the Navier-Stokes equations for mixtures in the incompressible limit. Some further numerical tests are also reported. In particular, (1) the solvent and dilute test cases are considered, because they are limiting cases in which the Maxwell-Stefan model reduces automatically to Fickian cases. Moreover, (2) some tests based on the Stefan diffusion tube are reported for proving the complete capabilities of the proposed scheme in solving Maxwell-Stefan diffusion problems. The proposed scheme agrees well with the expected theoretical results.

An exploration of advanced X-divertor scenarios on ITER

NASA Astrophysics Data System (ADS)

Covele, B.; Valanju, P.; Kotschenreuther, M.; Mahajan, S.

2014-07-01

It is found that the X-divertor (XD) configuration (Kotschenreuther et al 2004 Proc. 20th Int. Conf. on Fusion Energy (Vilamoura, Portugal, 2004) (Vienna: IAEA) CD-ROM file [IC/P6-43] www-naweb.iaea.org/napc/physics/fec/fec2004/datasets/index.html, Kotschenreuther et al 2006 Proc. 21st Int. Conf. on Fusion Energy 2006 (Chengdu, China, 2006) (Vienna: IAEA), CD-ROM file [IC/P7-12] www-naweb.iaea.org/napc/physics/FEC/FEC2006/html/index.htm, Kotschenreuther et al 2007 Phys. Plasmas 14 072502) can be made with the conventional poloidal field (PF) coil set on ITER (Tomabechi et al and Team 1991 Nucl. Fusion 31 1135), where all PF coils are outside the TF coils. Starting from the standard divertor, a sequence of desirable XD configurations are possible where the PF currents are below the present maximum design limits on ITER, and where the baseline divertor cassette is used. This opens the possibility that the XD could be tested and used to assist in high-power operation on ITER, but some further issues need examination. Note that the increased major radius of the super-X-divertor (Kotschenreuther et al 2007 Bull. Am. Phys. Soc. 53 11, Valanju et al 2009 Phys. Plasmas 16 5, Kotschenreuther et al 2010 Nucl. Fusion 50 035003, Valanju et al 2010 Fusion Eng. Des. 85 46) is not a feature of the XD geometry. In addition, we present an XD configuration for K-DEMO (Kim et al 2013 Fusion Eng. Des. 88 123) to demonstrate that it is also possible to attain the XD configuration in advanced tokamak reactors with all PF coils outside the TF coils. The results given here for the XD are far more encouraging than recent calculations by Lackner and Zohm (2012 Fusion Sci. Technol. 63 43) for the Snowflake (Ryutov 2007 Phys. Plasmas 14 064502, Ryutov et al 2008 Phys. Plasmas 15 092501), where the required high PF currents represent a major technological challenge. The magnetic field structure in the outboard divertor SOL (Kotschenreuther 2013 Phys. Plasmas 20 102507) in the recently created XD configurations reproduces what was presented in the earlier XD papers (Kotschenreuther et al 2004 Proc. 20th Int. Conf. on Fusion Energy (Vilamoura, Portugal, 2004) (Vienna: IAEA) CD-ROM file [IC/P6-43] www-naweb.iaea.org/napc/physics/fec/fec2004/datasets/index.html, Kotschenreuther et al 2006 Proc. 21st Int. Conf. on Fusion Energy 2006 (Chengdu, China, 2006) (Vienna: IAEA) CD-ROM file [IC/P7-12] www-naweb.iaea.org/napc/physics/FEC/FEC2006/html/index.htm, Kotschenreuther et al 2007 Phys. Plasmas 14 072502). Consequently, the same advantages accrue, but no close-in PF coils are employed.

Boundary modelling of the stellarator Wendelstein 7-X

NASA Astrophysics Data System (ADS)

Renner, H.; Strumberger, E.; Kisslinger, J.; Nührenberg, J.; Wobig, H.

1997-02-01

To justify the design of the divertor plates in W7-X the magnetic fields of finite-β HELIAS equilibria for the so-called high-mirror case have been computed for various average β-values up to < β > = 0.04 with the NEMEC free-boundary equilibrium code [S.P. Hirshman, W.I. van Rij and W.I. Merkel, Comput. Phys. Commun. 43 (1986) 143] in combination with the newly developed MFBE (magnetic field solver for finite-beta equilibria) code. In a second study the unloading of the target plates by radiation was investigated. The B2 code [B.J. Braams, Ph.D. Thesis, Rijksuniversiteit Utrecht (1986)] was applied for the first time to stellarators to provide of a self-consistent modelling of the SOL including effects of neutrals and impurities.

Vanishing Corrections for the Position in a Linear Model of FKPP Fronts

NASA Astrophysics Data System (ADS)

Berestycki, Julien; Brunet, Éric; Harris, Simon C.; Roberts, Matt

2017-02-01

Take the linearised FKPP equation {partialth = partial2xh + h} with boundary condition h( m( t), t) = 0. Depending on the behaviour of the initial condition h 0( x) = h( x, 0) we obtain the asymptotics—up to a o(1) term r( t)—of the absorbing boundary m( t) such that {ω(x) := lim_{tto∞} h(x + m(t) ,t)} exists and is non-trivial. In particular, as in Bramson's results for the non-linear FKPP equation, we recover the celebrated {-3/2 log t} correction for initial conditions decaying faster than {x^{ν}e^{-x}} for some {ν < -2}. Furthermore, when we are in this regime, the main result of the present work is the identification (to first order) of the r( t) term, which ensures the fastest convergence to {ω(x)}. When h 0( x) decays faster than {x^{ν}e^{-x}} for some {ν < -3}, we show that r( t) must be chosen to be {-3√{π/t}}, which is precisely the term predicted heuristically by Ebert-van Saarloos (Phys. D Nonlin. Phenom. 146(1): 1-99, 2000) in the non-linear case (see also Mueller and Munier Phys Rev E 90(4):042143, 2014, Henderson, Commun Math Sci 14(4):973-985, 2016, Brunet and Derrida Stat Phys 1-20, 2015). When the initial condition decays as {x^{ν}e^{-x}} for some {ν in [-3, -2)}, we show that even though we are still in the regime where Bramson's correction is {-3/2 log t}, the Ebert-van Saarloos correction has to be modified. Similar results were recently obtained by Henderson CommunMath Sci 14(4):973-985, 2016 using an analytical approach and only for compactly supported initial conditions.

Interacting partially directed self-avoiding walk: a probabilistic perspective

NASA Astrophysics Data System (ADS)

Carmona, Philippe; Nguyen, Gia Bao; Pétrélis, Nicolas; Torri, Niccolò

2018-04-01

We review some recent results obtained in the framework of the 2D interacting self-avoiding walk (ISAW). After a brief presentation of the rigorous results that have been obtained so far for ISAW we focus on the interacting partially directed self-avoiding walk (IPDSAW), a model introduced in Zwanzig and Lauritzen (1968 J. Chem. Phys. 48 3351) to decrease the mathematical complexity of ISAW. In the first part of the paper, we discuss how a new probabilistic approach based on a random walk representation (see Nguyen and Pétrélis (2013 J. Stat. Phys. 151 1099–120)) allowed for a sharp determination of the asymptotics of the free energy close to criticality (see Carmona et al (2016 Ann. Probab. 44 3234–90)). Some scaling limits of IPDSAW were conjectured in the physics literature (see e.g. Brak et al (1993 Phys. Rev. E 48 2386–96)). We discuss here the fact that all limits are now proven rigorously, i.e. for the extended regime in Carmona and Pétrélis (2016 Electron. J. Probab. 21 1–52), for the collapsed regime in Carmona et al (2016 Ann. Probab. 44 3234–90) and at criticality in Carmona and Pétrélis (2017b arxiv:1709.06448). The second part of the paper starts with the description of four open questions related to physically relevant extensions of IPDSAW. Among such extensions is the interacting prudent self-avoiding walk (IPSAW) whose configurations are those of the 2D prudent walk. We discuss the main results obtained in Pétrélis and Torri (2016 Ann. Inst. Henri Poincaré D) about IPSAW and in particular the fact that its collapse transition is proven to exist rigorously.

Microscopic origin and macroscopic implications of lane formation in mixtures of oppositely driven particles

NASA Astrophysics Data System (ADS)

Klymko, Katherine; Geissler, Phillip L.; Whitelam, Stephen

2016-08-01

Colloidal particles of two types, driven in opposite directions, can segregate into lanes [Vissers et al., Soft Matter 7, 2352 (2011), 10.1039/c0sm01343a]. This phenomenon can be reproduced by two-dimensional Brownian dynamics simulations of model particles [Dzubiella et al., Phys. Rev. E 65, 021402 (2002), 10.1103/PhysRevE.65.021402]. Here we use computer simulation to assess the generality of lane formation with respect to variation of particle type and dynamical protocol. We find that laning results from rectification of diffusion on the scale of a particle diameter: oppositely driven particles must, in the time taken to encounter each other in the direction of the drive, diffuse in the perpendicular direction by about one particle diameter. This geometric constraint implies that the diffusion constant of a particle, in the presence of those of the opposite type, grows approximately linearly with the Péclet number, a prediction confirmed by our numerics over a range of model parameters. Such environment-dependent diffusion is statistically similar to an effective interparticle attraction; consistent with this observation, we find that oppositely driven nonattractive colloids display features characteristic of the simplest model system possessing both interparticle attractions and persistent motion, the driven Ising lattice gas [Katz, Leibowitz, and Spohn, J. Stat. Phys. 34, 497 (1984), 10.1007/BF01018556]. These features include long-ranged correlations in the disordered regime, a critical regime characterized by a change in slope of the particle current with the Péclet number, and fluctuations that grow with system size. By analogy, we suggest that lane formation in the driven colloid system is a phase transition in the macroscopic limit, but that macroscopic phase separation would not occur in finite time upon starting from disordered initial conditions.

Precision Measurement of the Electron's Electric Dipole Moment Using Trapped Molecular Ions

NASA Astrophysics Data System (ADS)

Cairncross, William B.; Gresh, Daniel N.; Grau, Matt; Cossel, Kevin C.; Roussy, Tanya S.; Ni, Yiqi; Zhou, Yan; Ye, Jun; Cornell, Eric A.

2017-10-01

We describe the first precision measurement of the electron's electric dipole moment (de) using trapped molecular ions, demonstrating the application of spin interrogation times over 700 ms to achieve high sensitivity and stringent rejection of systematic errors. Through electron spin resonance spectroscopy on 180Hf 19F+ in its metastable 3Δ1 electronic state, we obtain de=(0.9 ±7. 7stat±1. 7syst)×10-29 e cm , resulting in an upper bound of |de|<1.3 ×10-28 e cm (90% confidence). Our result provides independent confirmation of the current upper bound of |de|<9.4 ×10-29 e cm [J. Baron et al., New J. Phys. 19, 073029 (2017), 10.1088/1367-2630/aa708e], and offers the potential to improve on this limit in the near future.

Annealed importance sampling with constant cooling rate

NASA Astrophysics Data System (ADS)

Giovannelli, Edoardo; Cardini, Gianni; Gellini, Cristina; Pietraperzia, Giangaetano; Chelli, Riccardo

2015-02-01

Annealed importance sampling is a simulation method devised by Neal [Stat. Comput. 11, 125 (2001)] to assign weights to configurations generated by simulated annealing trajectories. In particular, the equilibrium average of a generic physical quantity can be computed by a weighted average exploiting weights and estimates of this quantity associated to the final configurations of the annealed trajectories. Here, we review annealed importance sampling from the perspective of nonequilibrium path-ensemble averages [G. E. Crooks, Phys. Rev. E 61, 2361 (2000)]. The equivalence of Neal's and Crooks' treatments highlights the generality of the method, which goes beyond the mere thermal-based protocols. Furthermore, we show that a temperature schedule based on a constant cooling rate outperforms stepwise cooling schedules and that, for a given elapsed computer time, performances of annealed importance sampling are, in general, improved by increasing the number of intermediate temperatures.

Light-induced degradation in gallium-doped silicon

NASA Astrophysics Data System (ADS)

Lindroos, Jeanette; Yli-Koski, Marko; Haarahiltunen, Antti; Schubert, Martin C.; Savin, Hele

2012-02-01

Light-induced degradation (LID) is a lifetime-decreasing effect in silicon solar cells attributed to the formation of B-O defect complexes during illumination [1-2]. However, Savin et al. [3] have recently observed degradation similar to LID in B- and P-doped Si contaminated with Cu, suggesting that Cu might be the cause of LID. Since Ga-doped Si is considered a degradation-free option to conventional B-doped Si [2], lifetime stability should also be studied in Cu-contaminated Ga-Si. Hence, in this paper, we intentionally contaminated high-oxygen 0.41 and 10.1 φcm Ga-doped Cz-Si with Cu and subjected the material to illumination. No lifetime degradation was measured with μ-PCD in clean Ga-Si or at low Cu levels, which is in agreement with the previously reported LID-free behavior of Ga-Si [2]. However, at higher Cu levels (20 ppb), a clear lifetime degradation was observed in Ga-Si. This lifetime degradation increased with increasing Cu concentration or with increasing wafer resistivity. [1] J. Schmidt, A.G. Aberle and R. Hezel, 26th IEEE PVSC, Anaheim, CA, USA, p.13-18 (1997). [2] S.W. Glunz, S. Rein, W. Warta, J. Knobloch and W. Wettling. Sol. Energ. Mat. Sol. C. 65, 219-229 (2001). [3] H. Savin, M. Yli-Koski and A. Haarahiltunen. Appl. Phys. Lett. 95, 152111 (2009).

Search for neutral D meson mixing using semileptonic decays

NASA Astrophysics Data System (ADS)

Flood, Kevin T.

Based on a 87 fb-1 dataset, a search for D0-D¯0 mixing is made using the semileptonic decay modes D*+ → pi +D0, D0 → [K/K*]enu (+c.c.) at the B-Factory facility at the Stanford Linear Accelerator Center. These modes offer unambiguous initial and final-state charm flavor tags, and allow the combined use of the D0 lifetime and D*+- D0 mass difference (DeltaM) in a global likelihood fit. The high-statistics sample of reconstructed unmixed semileptonic D0 decays is used to model both the DeltaM distribution and the time-dependence of mixed events directly from the data. Neural networks are used both to select events and to fully reconstruct the D0. A result consistent with no charm mixing has been obtained, Rmix = 0.0023 +/- 0.0012(stat) +/- 0.0004(sys ). This corresponds to an upper limit of Rmix < 0.0047 (95% C.L.) and Rmix < 0.0043 (90% C.L.). The lowest current published limit on semileptonic charm mixing is 0.005 (90% C.L.) (E791, E.M. Aitala et al., Phys.Rev.Lett. 77 2384 (1996)). The current best published limit using any analysis technique on the total rate of charm mixing is 0.0016 (95% C.L.) (Babar Kpi mixing, B. Aubert et al., Phys.Rev.Lett. 91 171801 (2003)).

Relativistic H-theorem and nonextensive kinetic theory

NASA Astrophysics Data System (ADS)

Silva, R.; Lima, J. A. S.

2003-08-01

In 1988 Tsallis proposed a striking generalization of the Boltzmann-Gibbs entropy functional form given by [1] (1) where kB is Boltzmann's constant, pi is the probability of the i-th microstate, and the parameter q is any real number. Nowadays, the q-thermostatistics associated with Sq is being hailed as the possible basis of a theoretical framework appropriate to deal with nonextensive settings. There is a growing body of evidence suggesting that Sq provides a convenient frame for the thermostatistical analysis of many physical systems and processes ranging from the laboratory scale to the astrophysical domain [2]. However, all the basic results, including the proof of the H-theorem has been worked in the classical non-relativistic domain [3]. In this context we discuss the relativistic kinetic foundations of the Tsallis' nonextensive approach through the full Boltzmann's transport equation. Our analysis follows from a nonextensive generalization of the "molecular chaos hypothesis". For q > 0, the q-transport equation satisfies a relativistic H-theorem based on Tsallis entropy. It is also proved that the collisional equilibrium is given by the relativistic Tsallis' q-nonextensive velocity distribution. References [1] C. Tsallis, J. Stat. Phys. 52, 479 (1988). [2] J. A. S. Lima, R. Silva, and J. Santos, Astron. and Astrophys. 396, 309 (2002). [3] J. A. S. Lima, R. Silva, and A. R. Plastino, Phys. Rev. Lett. 86, 2938 (2001).

High harmonic generation in a gas-filled hollow-core photonic crystal fiber

NASA Astrophysics Data System (ADS)

Heckl, O. H.; Baer, C. R. E.; Kränkel, C.; Marchese, S. V.; Schapper, F.; Holler, M.; Südmeyer, T.; Robinson, J. S.; Tisch, J. W. G.; Couny, F.; Light, P.; Benabid, F.; Keller, U.

2009-10-01

High harmonic generation (HHG) of intense infrared laser radiation (Ferray et al., J. Phys. B: At. Mol. Opt. Phys. 21:L31, 1988; McPherson et al., J. Opt. Soc. Am. B 4:595, 1987) enables coherent vacuum-UV (VUV) to soft-X-ray sources. In the usual setup, energetic femtosecond laser pulses are strongly focused into a gas jet, restricting the interaction length to the Rayleigh range of the focus. The average photon flux is limited by the low conversion efficiency and the low average power of the complex laser amplifier systems (Keller, Nature 424:831, 2003; Südmeyer et al., Nat. Photonics 2:599, 2008; Röser et al., Opt. Lett. 30:2754, 2005; Eidam et al., IEEE J. Sel. Top. Quantum Electron. 15:187, 2009) which typically operate at kilohertz repetition rates. This represents a severe limitation for many experiments using the harmonic radiation in fields such as metrology or high-resolution imaging. Driving HHG with novel high-power diode-pumped multi-megahertz laser systems has the potential to significantly increase the average photon flux. However, the higher average power comes at the expense of lower pulse energies because the repetition rate is increased by more than a thousand times, and efficient HHG is not possible in the usual geometry. So far, two promising techniques for HHG at lower pulse energies were developed: external build-up cavities (Gohle et al., Nature 436:234, 2005; Jones et al., Phys. Rev. Lett. 94:193, 2005) and resonant field enhancement in nanostructured targets (Kim et al., Nature 453:757, 2008). Here we present a third technique, which has advantages in terms of ease of HHG light extraction, transverse beam quality, and the possibility to substantially increase conversion efficiency by phase-matching (Paul et al., Nature 421:51, 2003; Ren et al., Opt. Express 16:17052, 2008; Serebryannikov et al., Phys. Rev. E (Stat. Nonlinear Soft Matter Phys.) 70:66611, 2004; Serebryannikov et al., Opt. Lett. 33:977, 2008; Zhang et al., Nat. Phys. 3:270, 2007). The interaction between the laser pulses and the gas occurs in a Kagome-type Hollow-Core Photonic Crystal Fiber (HC-PCF) (Benabid et al., Science 298:399, 2002), which reduces the detection threshold for HHG to only 200 nJ. This novel type of fiber guides nearly all of the light in the hollow core (Couny et al., Science 318:1118, 2007), preventing damage even at intensities required for HHG. Our fiber guided 30-fs pulses with a pulse energy of more than 10 μJ, which is more than five times higher than for any other photonic crystal fiber (Hensley et al., Conference on Lasers and Electro-Optics (CLEO), IEEE Press, New York, 2008).

High-beta steady-state research with integrated modeling in the JT-60 Upgrade

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ozeki, T.

2007-05-15

Improvement of high-beta performance and its long sustainment was obtained with ferritic steel tiles in the JT-60 Upgrade (JT-60U) [T. Fujita et al., Phys. Plasmas 50, 104 (2005)], which were installed inside the vacuum vessel to reduce fast ion loss by decreasing the toroidal field ripple. When a separation between the plasma surface and the wall was small, high-beta plasmas reached the ideal wall stability limit, i.e., the ideal magnetohydrodynamics stability limit with the wall stabilization. A small rotation velocity of 0.3% of the Alfven velocity was found to be effective for suppressing the resistive wall mode. Sustainment of themore » high normalized beta value of {beta}{sub N}=2.3 has been extended to 28.6 s ({approx}15 times the current diffusion time) by improvement of the confinement and increase in the net heating power. Based on the research in JT-60U experiments and first-principle simulations, integrated models of core, edge-pedestal, and scrape-off-layer (SOL) divertors were developed, and they clarified complex features of reactor-relevant plasmas. The integrated core plasma model indicated that the small amount of electron cyclotron (EC) current density of about half the bootstrap current density could effectively stabilize the neoclassical tearing mode by the localized EC current accurately aligned to the magnetic island center. The integrated edge-pedestal model clarified that the collisionality dependence of energy loss due to the edge-localized mode was caused by the change in the width of the unstable mode and the SOL transport. The integrated SOL-divertor model clarified the effect of the exhaust slot on the pumping efficiency and the cause of enhanced radiation near the X-point multifaceted asymmetric radiation from edge. Success in these consistent analyses using the integrated code indicates that it is an effective means to investigate complex plasmas and to control the integrated performance.« less

Extreme current fluctuations in lattice gases: Beyond nonequilibrium steady states

NASA Astrophysics Data System (ADS)

Meerson, Baruch; Sasorov, Pavel V.

2014-01-01

We use the macroscopic fluctuation theory (MFT) to study large current fluctuations in nonstationary diffusive lattice gases. We identify two universality classes of these fluctuations, which we call elliptic and hyperbolic. They emerge in the limit when the deterministic mass flux is small compared to the mass flux due to the shot noise. The two classes are determined by the sign of compressibility of effective fluid, obtained by mapping the MFT into an inviscid hydrodynamics. An example of the elliptic class is the symmetric simple exclusion process, where, for some initial conditions, we can solve the effective hydrodynamics exactly. This leads to a super-Gaussian extreme current statistics conjectured by Derrida and Gerschenfeld [J. Stat. Phys. 137, 978 (2009), 10.1007/s10955-009-9830-1] and yields the optimal path of the system. For models of the hyperbolic class, the deterministic mass flux cannot be neglected, leading to a different extreme current statistics.

Publisher's Note: Branching ratio of the electromagnetic decay of the Σ+(1385) Phys. Rev. D 85, 052004 (2012)

NASA Astrophysics Data System (ADS)

Keller, D.; Hicks, K.; Adhikari, K. P.; Adikaram, D.; Amaryan, M. J.; Anghinolfi, M.; Baghdasaryan, H.; Ball, J.; Battaglieri, M.; Bedlinskiy, I.; Biselli, A. S.; Bookwalter, C.; Boiarinov, S.; Branford, D.; Briscoe, W. J.; Brooks, W. K.; Burkert, V. D.; Carman, D. S.; Celentano, A.; Chandavar, S.; Cole, P. L.; Contalbrigo, M.; Crede, V.; D'Angelo, A.; Daniel, A.; Dashyan, N.; De Vita, R.; De Sanctis, E.; Djalali, C.; Doughty, D.; Dupre, R.; El Alaoui, A.; El Fassi, L.; Elouadrhiri, L.; Eugenio, P.; Fedotov, G.; Gabrielyan, M. Y.; Gevorgyan, N.; Gilfoyle, G. P.; Giovanetti, K. L.; Gohn, W.; Golovatch, E.; Gothe, R. W.; Graham, L.; Griffioen, K. A.; Guidal, M.; Guler, N.; Guo, L.; Hafidi, K.; Hakobyan, H.; Holtrop, M.; Ilieva, Y.; Ireland, D. G.; Ishkhanov, B. S.; Isupov, E. L.; Jo, H. S.; Joo, K.; Khandaker, M.; Khetarpal, P.; Kim, A.; Kim, W.; Klein, F. J.; Kubarovsky, A.; Kubarovsky, V.; Kuleshov, S. V.; Lu, H. Y.; MacGregor, I. J. D.; Mao, Y.; Markov, N.; Mayer, M.; McKinnon, B.; Meyer, C. A.; Mineeva, T.; Mirazita, M.; Mokeev, V.; Moutarde, H.; Munevar, E.; Nadel-Turonski, P.; Nasseripour, R.; Niccolai, S.; Niculescu, G.; Niculescu, I.; Osipenko, M.; Ostrovidov, A. I.; Paolone, M.; Pappalardo, L.; Paremuzyan, R.; Park, K.; Park, S.; Pasyuk, E.; Anefalos Pereira, S.; Pisano, S.; Pogorelko, O.; Pozdniakov, S.; Procureur, S.; Prok, Y.; Protopopescu, D.; Raue, B. A.; Ricco, G.; Rimal, D.; Ripani, M.; Ritchie, B. G.; Rosner, G.; Rossi, P.; Sabatié, F.; Saini, M. S.; Salgado, C.; Schott, D.; Schumacher, R. A.; Seraydaryan, H.; Sharabian, Y. G.; Smith, E. S.; Smith, G. D.; Sober, D. I.; Sokhan, D.; Stepanyan, S. S.; Stepanyan, S.; Stoler, P.; Strauch, S.; Taiuti, M.; Tang, W.; Taylor, C. E.; Tkachenko, S.; Vernarsky, B.; Vineyard, M. F.; Vlassov, A. V.; Voskanyan, H.; Voutier, E.; Watts, D. P.; Wood, M. H.; Zachariou, N.; Zana, L.; Zhao, B.; Zhao, Z. W.

2012-03-01

The CLAS detector was used to obtain the first ever measurement of the electromagnetic decay of the $\\Sigma^{*+}(1385)$ from the reaction $\\gamma p \\to K^0 \\Sigma^{*+}(1385)$. A real photon beam with a maximum energy of 3.8 GeV was incident on a liquid-hydrogen target, resulting in the photoproduction of the kaon and $\\Sigma^*$ hyperon. Kinematic fitting was used to separate the reaction channel from the background processes. The fitting algorithm exploited a new method to kinematically fit neutrons in the CLAS detector, leading to the partial width measurement of $250.0\\pm56.9(stat)^{+34.3}_{-41.2}(sys)$ keV. A U-spin symmetry test using the SU(3) flavor-multiplet representation yields predictions for the $\\Sigma^{*+}(1385)\\to\\Sigma^{+}\\gamma$ and $\\Sigma^{*0}(1385)\\to\\Lambda\\gamma$ partial widths that agree with the experimental measurements.

Precision Measurement of the Electron's Electric Dipole Moment Using Trapped Molecular Ions.

PubMed

Cairncross, William B; Gresh, Daniel N; Grau, Matt; Cossel, Kevin C; Roussy, Tanya S; Ni, Yiqi; Zhou, Yan; Ye, Jun; Cornell, Eric A

2017-10-13

We describe the first precision measurement of the electron's electric dipole moment (d_{e}) using trapped molecular ions, demonstrating the application of spin interrogation times over 700 ms to achieve high sensitivity and stringent rejection of systematic errors. Through electron spin resonance spectroscopy on ^{180}Hf^{19}F^{+} in its metastable ^{3}Δ_{1} electronic state, we obtain d_{e}=(0.9±7.7_{stat}±1.7_{syst})×10^{-29}  e cm, resulting in an upper bound of |d_{e}|<1.3×10^{-28}  e cm (90% confidence). Our result provides independent confirmation of the current upper bound of |d_{e}|<9.4×10^{-29}  e cm [J. Baron et al., New J. Phys. 19, 073029 (2017)NJOPFM1367-263010.1088/1367-2630/aa708e], and offers the potential to improve on this limit in the near future.

13-Moment System with Global Hyperbolicity for Quantum Gas

NASA Astrophysics Data System (ADS)

Di, Yana; Fan, Yuwei; Li, Ruo

2017-06-01

We point out that the quantum Grad's 13-moment system (Yano in Physica A 416:231-241, 2014) is lack of global hyperbolicity, and even worse, the thermodynamic equilibrium is not an interior point of the hyperbolicity region of the system. To remedy this problem, by fully considering Grad's expansion, we split the expansion into the equilibrium part and the non-equilibrium part, and propose a regularization for the system with the help of the new hyperbolic regularization theory developed in Cai et al. (SIAM J Appl Math 75(5):2001-2023, 2015) and Fan et al. (J Stat Phys 162(2):457-486, 2016). This provides us a new model which is hyperbolic for all admissible thermodynamic states, and meanwhile preserves the approximate accuracy of the original system. It should be noted that this procedure is not a trivial application of the hyperbolic regularization theory.

Tightness of the Ising-Kac Model on the Two-Dimensional Torus

NASA Astrophysics Data System (ADS)

Hairer, Martin; Iberti, Massimo

2018-05-01

We consider the sequence of Gibbs measures of Ising models with Kac interaction defined on a periodic two-dimensional discrete torus near criticality. Using the convergence of the Glauber dynamic proven by Mourrat and Weber (Commun Pure Appl Math 70:717-812, 2017) and a method by Tsatsoulis and Weber employed in (arXiv:1609.08447 2016), we show tightness for the sequence of Gibbs measures of the Ising-Kac model near criticality and characterise the law of the limit as the Φ ^4_2 measure on the torus. Our result is very similar to the one obtained by Cassandro et al. (J Stat Phys 78(3):1131-1138, 1995) on Z^2, but our strategy takes advantage of the dynamic, instead of correlation inequalities. In particular, our result covers the whole critical regime and does not require the large temperature/large mass/small coupling assumption present in earlier results.

On iterative algorithms for quantitative photoacoustic tomography in the radiative transport regime

NASA Astrophysics Data System (ADS)

Wang, Chao; Zhou, Tie

2017-11-01

In this paper, we present a numerical reconstruction method for quantitative photoacoustic tomography (QPAT), based on the radiative transfer equation (RTE), which models light propagation more accurately than diffusion approximation (DA). We investigate the reconstruction of absorption coefficient and scattering coefficient of biological tissues. An improved fixed-point iterative method to retrieve the absorption coefficient, given the scattering coefficient, is proposed for its cheap computational cost; the convergence of this method is also proved. The Barzilai-Borwein (BB) method is applied to retrieve two coefficients simultaneously. Since the reconstruction of optical coefficients involves the solutions of original and adjoint RTEs in the framework of optimization, an efficient solver with high accuracy is developed from Gao and Zhao (2009 Transp. Theory Stat. Phys. 38 149-92). Simulation experiments illustrate that the improved fixed-point iterative method and the BB method are competitive methods for QPAT in the relevant cases.

Majority-Vote Model with Heterogeneous Agents on Square Lattice

NASA Astrophysics Data System (ADS)

Lima, F. W. S.

2013-11-01

We study a nonequilibrium model with up-down symmetry and a noise parameter q known as majority-vote model (MVM) of [M. J. Oliveira, J. Stat. Phys.66, 273 (1992)] with heterogeneous agents on square lattice (SL). By Monte Carlo (MC) simulations and finite-size scaling relations, the critical exponents β/ν, γ/ν and 1/ν and points qc and U* are obtained. After extensive simulations, we obtain β/ν = 0.35(1), γ/ν = 1.23(8) and 1/ν = 1.05(5). The calculated values of the critical noise parameter and Binder cumulant are qc = 0.1589(4) and U* = 0.604(7). Within the error bars, the exponents obey the relation 2β/ν + γ/ν = 2 and the results presented here demonstrate that the MVM heterogeneous agents belongs to a different universality class than the nonequilibrium MVM with homogeneous agents on SL.

Theoretical study of some experimentally relevant states of dysprosium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzuba, V. A.; Flambaum, V. V.

2010-05-15

Configuration interaction method is used to calculate transition amplitudes and other properties of the low states of dysprosium which are used in cooling and in the study of the time variation of the fine structure constant and violation of fundamental symmetries. The branching ratio for the cooling state to decay to states other than ground states is found to be smaller than 10{sup -4}. The matrix element of the weak interaction between degenerate states at E=19797.96 cm{sup -1} is about 4 Hz which is consistent with the experimental limit |H{sub W}|=|2.3{+-}2.9(stat.){+-}0.7(syst.)| Hz [A. T. Nguyen, D. Budker, D. DeMille, andmore » M. Zolotorev, Phys. Rev. A 56, 3453 (1997)] and points to feasibility of its experimental measurement. Applications include the search for physics beyond the standard model using the parity nonconservation (PNC) isotopic chain approach.« less

Driven phase space vortices in plasmas with nonextensive velocity distribution

NASA Astrophysics Data System (ADS)

Trivedi, Pallavi; Ganesh, Rajaraman

2017-03-01

The evolution of chirp-driven electrostatic waves in unmagnetized plasmas is numerically investigated by using a one-dimensional (1D) Vlasov-poisson solver with periodic boundary conditions. The initial velocity distribution of the 1D plasma is assumed to be governed by nonextensive q distribution [C. Tsallis, J. Stat. Phys. 52, 479 (1988)]. For an infinitesimal amplitude of an external drive, we investigate the effects of chirp driven dynamics that leads to the formation of giant phase space vortices (PSV) for both Maxwellian (q = 1) and non-Maxwellian ( q ≠ 1 ) plasmas. For non-Maxwellian plasmas, the formation of giant PSV with multiple extrema and phase velocities is shown to be dependent on the strength of "q". Novel features such as "shark"-like and transient "honeycomb"-like structures in phase space are discussed. Wherever relevant, we compare our results with previous work.

Virial Coefficients from Unified Statistical Thermodynamics of Quantum Gases Trapped under Generic Power Law Potential in d Dimension and Equivalence of Quantum Gases

NASA Astrophysics Data System (ADS)

Bahauddin, Shah Mohammad; Mehedi Faruk, Mir

2016-09-01

From the unified statistical thermodynamics of quantum gases, the virial coefficients of ideal Bose and Fermi gases, trapped under generic power law potential are derived systematically. From the general result of virial coefficients, one can produce the known results in d = 3 and d = 2. But more importantly we found that, the virial coefficients of Bose and Fermi gases become identical (except the second virial coefficient, where the sign is different) when the gases are trapped under harmonic potential in d = 1. This result suggests the equivalence between Bose and Fermi gases established in d = 1 (J. Stat. Phys. DOI 10.1007/s10955-015-1344-4). Also, it is found that the virial coefficients of two-dimensional free Bose (Fermi) gas are equal to the virial coefficients of one-dimensional harmonically trapped Bose (Fermi) gas.

Integrability of the odd eight-vertex model with symmetric weights

NASA Astrophysics Data System (ADS)

Martins, M. J.

2018-06-01

In this paper we investigate the integrability properties of a two-state vertex model on the square lattice whose microstates at a vertex always have an odd number of incoming or outcoming arrows. This model was named the odd eight-vertex model by Wu and Kunz (2004 J. Stat. Phys. 116 67) to distinguish it from the well-known eight-vertex model possessing an even number of arrow orientations at each vertex. When the energy weights are invariant under arrow inversion we show that the integrable manifold of the odd eight-vertex model coincides with that of the even eight-vertex model. The form of the -matrix for the odd eight-vertex model is however not the same as that of the respective Lax operator. Altogether we find that these eight-vertex models give rise to a generic sheaf of -matrices satisfying the Yang–Baxter equations resembling intertwiner relations associated to equidimensional representations.

Preface: phys. stat. sol. (a) 201/8

NASA Astrophysics Data System (ADS)

Shin, Sung-Chul

2004-06-01

The KMS/SOMMA Meeting 2003 was held 3-6 December 2003 at Spapia Hotel, Daejeon, Korea. It was the 5th SOMMA (International Symposium on Magnetic Materials and Applications) organized by ReCAMM (Research Center for Advanced Magnetic Materials) of Chungnam National University. Since 2002, the Korean Magnetics Society (KMS) winter conference has been jointly held with SOMMA. This was the second time to have a KMS/SOMMA joint meeting. The main objective of the meeting was to provide an international forum to discuss up-to-date results on magnetism and magnetic materials. The conference brought together 360 participants from 12 countries. Sessions of the meeting were: Theory and Fundamentals, Magnetic Random Access Memory, Spintronics, Information Storage, Nanostructured Materials, Sensors, and Interdisciplinary. In these seven sessions, 325 papers were presented including 66 oral and 259 poster presentations. Since the symposium was held in Korea, this enabled a large number of Asian scientists to attend: 239 from Korea, 41 from Japan, 7 from Taiwan, and 5 from China.The conference program had 25 invited and plenary speakers. They were Y. Ando (Tohoku U.), M. Inoue (Toyohashi U. Tech), H. Kubota (Tohoku U.), K. Mohri (Nagoya U.), M. Sahashi, M. Takahashi, K. Takanashi, M. Tsunoda (Tohoku U.), and H. Yoda (Toshiba) from Japan; A. J. Freeman (Northwestern U.), A. T. Hanbicki (NRL), F. B. Humphrey (Boston U.), and S. Sun (IBM) from the USA; J. D. Boeck (IMEC, Belgium), B. Dieny (CEA, France), N. Garcia (CSIS, Spain), G. Reiss (Bielefeld U., Germany), T. Stobiecki (U. M. & M. Krakow, Poland), and M. Wolfram (Singulus Tech, Germany) from Europe; C. G. Kim, D. J. Kim (CNU), T. W. Kim (SAIT), S. H. Lim (KIST), Sung-Chul Shin (KAIST), and Yoon Hee Chung (POSTEC) from Korea.For the first time, the SOMMA Proceedings appear in physica status solidi. The Editors hope that the Proceedings could provide chances for deeper and wider understanding of the presentations as well as for enhanced relationship between all participants. We deeply appreciate the help of the editorial staff of physica status solidi for their efficient and kind help during the paper preparations and publications.Finally, we would like to take this opportunity to thank all members of the Advisory Committee, Organizing Committee, referees, and KMS staff for their effort before, during, and after the meeting.

Preface: phys. stat. sol. (b) 241/7

NASA Astrophysics Data System (ADS)

Shin, Sung-Chul

2004-06-01

The KMS/SOMMA Meeting 2003 was held 3-6 December 2003 at Spapia Hotel, Daejeon, Korea. It was the 5th SOMMA (International Symposium on Magnetic Materials and Applications) organized by ReCAMM (Research Center for Advanced Magnetic Materials) of Chungnam National University. Since 2002, the Korean Magnetics Society (KMS) winter conference has been jointly held with SOMMA. This was the second time to have a KMS/SOMMA joint meeting.The main objective of the meeting was to provide an international forum to discuss up-to-date results on magnetism and magnetic materials. The conference brought together 360 participants from 12 countries. Sessions of the meeting were: Theory and Fundamentals, Magnetic Random Access Memory, Spintronics, Information Storage, Nanostructured Materials, Sensors, and Interdisciplinary. In these seven sessions, 325 papers were presented including 66 oral and 259 poster presentations. Since the symposium was held in Korea, this enabled a large number of Asian scientists to attend: 239 from Korea, 41 from Japan, 7 from Taiwan, and 5 from China.The conference program had 25 invited and plenary speakers. They were Y. Ando (Tohoku U.), M. Inoue (Toyohashi U. Tech), H. Kubota (Tohoku U.), K. Mohri (Nagoya U.), M. Sahashi, M. Takahashi, K. Takanashi, M. Tsunoda (Tohoku U.), and H. Yoda (Toshiba) from Japan; A. J. Freeman (Northwestern U.), A. T. Hanbicki (NRL), F. B. Humphrey (Boston U.), and S. Sun (IBM) from the USA; J. D. Boeck (IMEC, Belgium), B. Dieny (CEA, France), N. Garcia (CSIS, Spain), G. Reiss (Bielefeld U., Germany), T. Stobiecki (U. M. & M. Krakow, Poland), and M. Wolfram (Singulus Tech, Germany) from Europe; C. G. Kim, D. J. Kim (CNU), T. W. Kim (SAIT), S. H. Lim (KIST), Sung-Chul Shin (KAIST), and Yoon Hee Chung (POSTEC) from Korea.For the first time, the SOMMA Proceedings appear in physica status solidi. The Editors hope that the Proceedings could provide chances for deeper and wider understanding of the presentations as well as for enhanced relationship between all participants. We deeply appreciate the help of the editorial staff of physica status solidi for their efficient and kind help during the paper preparations and publications.Finally, we would like to take this opportunity to thank all members of the Advisory Committee, Organizing Committee, referees, and KMS staff for their effort before, during, and after the meeting.

Blob-hole correlation model for edge turbulence and comparisons with NSTX gas puff imaging data

NASA Astrophysics Data System (ADS)

Myra, J. R.; Zweben, S. J.; Russell, D. A.

2018-07-01

Gas puff imaging (GPI) observations made in NSTX (Zweben et al 2017 Phys. Plasmas 24 102509) have revealed two-point spatial correlations of edge and scrape-off layer (SOL) turbulence in the plane perpendicular to the magnetic field. A common feature is the occurrence of dipole-like patterns with significant regions of negative correlation. In this paper, we explore the possibility that these dipole patterns may be due to blob-hole pairs. Statistical methods are applied to determine the two-point spatial correlation that results from a model of blob-hole pair formation. It is shown that the model produces dipole correlation patterns that are qualitatively similar to the GPI data in several respects. Effects of the reference location (confined surfaces or SOL), a superimposed random background, hole velocity and lifetime, and background sheared flows are explored and discussed with respect to experimental observations. Additional analysis of the experimental GPI dataset is performed to further test this blob-hole correlation model. A time delay two-point spatial correlation study did not reveal inward propagation of the negative correlation structures that were postulated to correspond to holes in the data nor did it suggest that the negative correlation structures are due to neutral shadowing. However, tracking of the highest and lowest values (extrema) of the normalized GPI fluctuations shows strong evidence for mean inward propagation of minima and outward propagation of maxima, in qualitative agreement with theoretical expectations. Other properties of the experimentally observed extrema are discussed.

A Pearson Random Walk with Steps of Uniform Orientation and Dirichlet Distributed Lengths

NASA Astrophysics Data System (ADS)

Le Caër, Gérard

2010-08-01

A constrained diffusive random walk of n steps in ℝ d and a random flight in ℝ d , which are equivalent, were investigated independently in recent papers (J. Stat. Phys. 127:813, 2007; J. Theor. Probab. 20:769, 2007, and J. Stat. Phys. 131:1039, 2008). The n steps of the walk are independent and identically distributed random vectors of exponential length and uniform orientation. Conditioned on the sum of their lengths being equal to a given value l, closed-form expressions for the distribution of the endpoint of the walk were obtained altogether for any n for d=1,2,4. Uniform distributions of the endpoint inside a ball of radius l were evidenced for a walk of three steps in 2D and of two steps in 4D. The previous walk is generalized by considering step lengths which have independent and identical gamma distributions with a shape parameter q>0. Given the total walk length being equal to 1, the step lengths have a Dirichlet distribution whose parameters are all equal to q. The walk and the flight above correspond to q=1. Simple analytical expressions are obtained for any d≥2 and n≥2 for the endpoint distributions of two families of walks whose q are integers or half-integers which depend solely on d. These endpoint distributions have a simple geometrical interpretation. Expressed for a two-step planar walk whose q=1, it means that the distribution of the endpoint on a disc of radius 1 is identical to the distribution of the projection on the disc of a point M uniformly distributed over the surface of the 3D unit sphere. Five additional walks, with a uniform distribution of the endpoint in the inside of a ball, are found from known finite integrals of products of powers and Bessel functions of the first kind. They include four different walks in ℝ3, two of two steps and two of three steps, and one walk of two steps in ℝ4. Pearson-Liouville random walks, obtained by distributing the total lengths of the previous Pearson-Dirichlet walks according to some specified probability law are finally discussed. Examples of unconstrained random walks, whose step lengths are gamma distributed, are more particularly considered.

On The Constitutive Properties Of Strongly Magnetized Matter Observed In A Class Of Solar Ejecta

NASA Astrophysics Data System (ADS)

Berdichevsky, D. B.

2013-12-01

Several studies of the transient events known as magnetic clouds at 1 AU suggest that they possess the ';1/2' anomalous value for its adiabatic, polytropic index, i.e., γ= 1/2, which implies that the temperature of the plasma decreases with increased density[1-3]. Coronal mass ejections commonly observed by missions like The Solar Terrestrial Relations Observatory (STEREO) have been successfully modeled previously by Berdichevsky Stenborg and Vourlidas[4] as magnetic flux-ropes which propagate from the Sun with uniform velocity. Building on this existing analytical three-dimensional magnetohydrodynamic (MHD) model of a magnetic flux-rope, we present an interpretation of the anomalous and somewhat counterintuitive dynamic property mentioned above. Using plasma and magnetic field observations by the Wind spacecraft for the magnetic cloud of June 2, 1998, we argue that this anomalous polytropic index is indeed a consequence of thermodynamic processes in this strongly magnetized matter. We show that the derived models of Berdichevsky et al.[5, 6] easily accommodate a familiar thermodynamic explanation of this property. Such an explanation may shed light also on the evolution of other astrophysical observations such as remnants in nebulae of past super-novae, as well other transient interstellar events. This MHD solution may be a good way to go beyond gas-dynamics in the development of a coherent picture of shock and its driver, as they are becoming a current interpretation. 1Osherovich, V.A., 1997, Proc. 31st, ESLAB Symp. Correlated Phenomena at the Sun, in the Heliosphere and in Geospace. 2Sittler, E.C., and L.F., Burlaga, 1998, J. Geophys. Res., 103, 17447. 3Nieves-Chinchilla T., and A., Figueroa-Viñas, 2008, J. Geophys. Res., 113, DOI: 10.1029/2007JA012703 4Berdichevsky, Stenborg, and Vourlidas, 2011, ApJ, 741, 47. 5Berdichevsky, D.B., R.L., Lepping, C.J., Farrugia, 2003, Phys.Rev. E, 67, DOI: 10.1103/PhysRevE036405. 6Berdichevsky, D.B. , 2012, Sol. Phys., 284, 245.

Vertical profiles for SO2 and SO on Venus from different one-dimensional simulations

NASA Astrophysics Data System (ADS)

Mills, Franklin P.; Jessup, Kandis-Lea; Yung, Yuk

2017-10-01

Sulfur dioxide (SO2) plays many roles in Venus’ atmosphere. It is a precursor for the sulfuric acid that condenses to form the global cloud layers and is likely a precursor for the unidentified UV absorber, which, along with CO2 near the tops of the clouds, appears to be responsible for absorbing about half of the energy deposited in Venus’ atmosphere [1]. Most published simulations of Venus’ mesospheric chemistry have used one-dimensional numerical models intended to represent global-average or diurnal-average conditions [eg, 2, 3, 4]. Observations, however, have found significant variations of SO and SO2 with latitude and local time throughout the mesosphere [eg, 5, 6]. Some recent simulations have examined local time variations of SO and SO2 using analytical models [5], one-dimensional steady-state solar-zenith-angle-dependent numerical models [6], and three-dimensional general circulation models (GCMs) [7]. As an initial step towards a quantitative comparison among these different types of models, this poster compares simulated SO, SO2, and SO/SO2 from global-average, diurnal-average, and solar-zenith-angle (SZA) dependent steady-state models for the mesosphere.The Caltech/JPL photochemical model [8] was used with vertical transport via eddy diffusion set based on observations and observationally-defined lower boundary conditions for HCl, CO, and OCS. Solar fluxes are based on SORCE SOLSTICE and SORCE SIM measurements from 26 December 2010 [9, 10]. The results indicate global-average and diurnal-average models may have significant limitations when used to interpret latitude- and local-time-dependent observations of SO2 and SO.[1] Titov D et al (2007) in Exploring Venus as a Terrestrial Planet, 121-138. [2] Zhang X et al (2012) Icarus, 217, 714-739. [3] Krasnopolsky V A (2012) Icarus, 218, 230-246. [4] Parkinson C D et al (2015) Planet Space Sci, 113-114, 226-236. [5] Sandor B J et al (2010) Icarus, 208, 49-60. [6] Jessup K-L et al (2015) Icarus, 258, 309-336. [7] Stolzenbach A et al (2014) EGU General Assembly 2014, 16, EGU2014-5315. [8] Allen M et al (1981) J Geophys Res, 86, 3617-3627. [9] Harder J W et al (2010) Sol Phys, 263, 3-24. [10] Snow M et al (2005) Sol Phys, 230, 295-324.

77 FR 37779 - Airworthiness Directives; Agusta S.p.A. Helicopters

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-25

... numbers (S[sol]Ns) except S[sol]Ns 31002, 31003, 31004, and 31007. EASA advises that laboratory tests... helicopters, S[sol]Ns 31005 up to S[sol]N 31143, except for S[sol]Ns 31007, 31037, 31038, 31094; S[sol]N 31112; S[sol]Ns 31146 up to S[sol]N 31148; S[sol]N 31155; S[sol]Ns 31201 up to S[sol]N 31218; and S[sol]Ns...

STATs profiling reveals predominantly-activated STAT3 in cholangiocarcinoma genesis and progression.

PubMed

Dokduang, Hasaya; Techasen, Anchalee; Namwat, Nisana; Khuntikeo, Narong; Pairojkul, Chawalit; Murakami, Yoshinori; Loilome, Watcharin; Yongvanit, Puangrat

2014-10-01

We investigated the aberrant expression of the STAT family in humans and liver fluke (Opisthorchis viverrini, Ov)-induced hamster cholangiocarcinoma (CCA) tissues. The expression and phosphorylation of STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 in human hamster CCA tissues were immunohistochemistry-profiled. Localizations of STAT5 in macrophages and lipopolysaccharide (LPS)-induced macrophage-conditioned media mediated STAT3 activation in CCA cells were demonstrated. The expressions of STAT 1-4 and 6 were detected in the cytoplasm of hyperplastic bile ducts and tumor cells, whereas STAT5a and STAT5b were observed in macrophages and connective tissues surrounding tumor, respectively. The expressions of STAT3 and STAT5b were significantly observed in tumors with a poorer histological differentiation. STAT3 expression was significantly associated with shorter survival of CCA patients and was predominately activated in CCA cell lines. In the CCA-hamsters, STATs expression was gradually increased along the carcinogenesis, especially at 30 days post-infection in which the inflammatory response was markedly observed, showing the correlation between the inflammation and STATs activation. Moreover, LPS-induced macrophage-conditioned media could mediate STAT3 activation in CCA cells. STAT3 is the major STAT, which plays roles in the inflammation that contributes to CCA carcinogenesis and progression and may serve as a marker for a poor prognosis of CCA. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

75 FR 70936 - Accreditation and Approval of Inspectorate America Corporation, as a Commercial Gauger and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... laboratories. http:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol]. DATES: The accreditation and approval of Inspectorate America...

75 FR 70935 - Accreditation and Approval of Inspectorate America Corporation, as a Commercial Gauger and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... laboratories. http:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol]. DATES: The accreditation and approval of Inspectorate America...

75 FR 70936 - Accreditation and Approval of Intertek USA, Inc., as a Commercial Gauger and Laboratory

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

.... http:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol] DATES: The accreditation and approval of Intertek USA, Inc., as...

In silico simulations of STAT1 and STAT3 inhibitors predict SH2 domain cross-binding specificity.

PubMed

Szelag, Malgorzata; Sikorski, Krzysztof; Czerwoniec, Anna; Szatkowska, Katarzyna; Wesoly, Joanna; Bluyssen, Hans A R

2013-11-15

Signal transducers and activators of transcription (STATs) comprise a family of transcription factors that are structurally related and which participate in signaling pathways activated by cytokines, growth factors and pathogens. Activation of STAT proteins is mediated by the highly conserved Src homology 2 (SH2) domain, which interacts with phosphotyrosine motifs for specific contacts between STATs and receptors and for STAT dimerization. By generating new models for human (h)STAT1, hSTAT2 and hSTAT3 we applied comparative in silico docking to determine SH2-binding specificity of the STAT3 inhibitor stattic, and of fludarabine (STAT1 inhibitor). Thus, we provide evidence that by primarily targeting the highly conserved phosphotyrosine (pY+0) SH2 binding pocket stattic is not a specific hSTAT3 inhibitor, but is equally effective towards hSTAT1 and hSTAT2. This was confirmed in Human Micro-vascular Endothelial Cells (HMECs) in vitro, in which stattic inhibited interferon-α-induced phosphorylation of all three STATs. Likewise, fludarabine inhibits both hSTAT1 and hSTAT3 phosphorylation, but not hSTAT2, by competing with the highly conserved pY+0 and pY-X binding sites, which are less well-preserved in hSTAT2. Moreover we observed that in HMECs in vitro fludarabine inhibits cytokine and lipopolysaccharide-induced phosphorylation of hSTAT1 and hSTAT3 but does not affect hSTAT2. Finally, multiple sequence alignment of STAT-SH2 domain sequences confirmed high conservation between hSTAT1 and hSTAT3, but not hSTAT2, with respect to stattic and fludarabine binding sites. Together our data offer a molecular basis that explains STAT cross-binding specificity of stattic and fludarabine, thereby questioning the present selection strategies of SH2 domain-based competitive small inhibitors. © 2013 Elsevier B.V. All rights reserved.

75 FR 70934 - U.S. Customs and Border Protection Accreditation and Approval of Intertek USA, Inc., as a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

...:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol]. DATES: The accreditation and approval of Intertek USA, Inc., as commercial gauger...

75 FR 70921 - Simon Property Group, Inc.; Analysis of Proposed Agreement Containing Consent Orders To Aid...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... site, at http:[sol][sol]www.ftc.gov[sol]os[sol]publiccomments.shtm. Because comments will be made.../simonproperty . If this Notice appears at http:[sol][sol]www.regulations.gov[sol]search[sol]index.jsp, you may... regulations.gov forwards to it. You may also visit the FTC Web site at http:[sol][sol]www.ftc.gov[sol] to read...

Roles of unphosphorylated STATs in signaling.

PubMed

Yang, Jinbo; Stark, George R

2008-04-01

The seven members of the signal transducer and activator of transcription (STAT) family of transcription factors are activated in response to many different cytokines and growth factors by phosphorylation of specific tyrosine residues. The STAT1 and STAT3 genes are specific targets of activated STATs 1 and 3, respectively, resulting in large increases in the levels of these unphosphorylated STATs (U-STATs) in response to the interferons (STAT1) or ligands that active gp130, such as IL-6 (STAT3). U-STATs drive gene expression by novel mechanisms distinct from those used by phosphorylated STAT (P-STAT) dimers. In this review, we discuss the roles of U-STATs in transcription and regulation of gene expression.

A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB

PubMed Central

2011-01-01

Background The transcription factor STAT3 (signal transducer and activator of transcription 3) is frequently activated in tumor cells. Activated STAT3 forms homodimers, or heterodimers with other TFs such as NF-κB, which becomes activated. Cytoplasmic STAT3 dimers are activated by tyrosine phosphorylation; they interact with importins via a nuclear localization signal (NLS) one of which is located within the DNA-binding domain formed by the dimer. In the nucleus, STAT3 regulates target gene expression by binding a consensus sequence within the promoter. STAT3-specific decoy oligonucleotides (STAT3-decoy ODN) that contain this consensus sequence inhibit the transcriptional activity of STAT3, leading to cell death; however, their mechanism of action is unclear. Results The mechanism of action of a STAT3-decoy ODN was analyzed in the colon carcinoma cell line SW 480. These cells' dependence on activated STAT3 was verified by showing that cell death is induced by STAT3-specific siRNAs or Stattic. STAT3-decoy ODN was shown to bind activated STAT3 within the cytoplasm, and to prevent its translocation to the nucleus, as well as that of STAT3-associated NF-κB, but it did not prevent the nuclear transfer of STAT3 with mutations in its DNA-binding domain. The complex formed by STAT3 and the STAT3-decoy ODN did not associate with importin, while STAT3 alone was found to co-immunoprecipitate with importin. Leptomycin B and vanadate both trap STAT3 in the nucleus. They were found here to oppose the cytoplasmic trapping of STAT3 by the STAT3-decoy ODN. Control decoys consisting of either a mutated STAT3-decoy ODN or a NF-κB-specific decoy ODN had no effect on STAT3 nuclear translocation. Finally, blockage of STAT3 nuclear transfer correlated with the induction of SW 480 cell death. Conclusions The inhibition of STAT3 by a STAT3-decoy ODN, leading to cell death, involves the entrapment of activated STAT3 dimers in the cytoplasm. A mechanism is suggested whereby this entrapment is due to STAT3-decoy ODN's inhibition of active STAT3/importin interaction. These observations point to the high potential of STAT3-decoy ODN as a reagent and to STAT3 nucleo-cytoplasmic shuttling in tumor cells as a potential target for effective anti-cancer compounds. PMID:21486470

A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation.

PubMed

Zhang, Xiaolei; Sun, Ying; Pireddu, Roberta; Yang, Hua; Urlam, Murali K; Lawrence, Harshani R; Guida, Wayne C; Lawrence, Nicholas J; Sebti, Saïd M

2013-03-15

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding, and transcriptional regulation of downstream target genes. Here, we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation, and malignant transforming activity. Fluorescence polarization assay and molecular modeling suggest that S3I-1757 interacts with the phospho-Y-705-binding site in the SH2 domain and displaces fluorescein-labeled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated hemagglutinin (HA)-tagged STAT3 and FLAG-tagged STAT3 and showed using coimmunoprecipitation and colocalization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor (EGFR) binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analog, S3I-1756, which does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding, and transcriptional activation and suppresses the expression levels of STAT3 target genes, such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1), and matrix metalloproteinase (MMP)-9. Furthermore, S3I-1757, but not S3I-1756, inhibits anchorage-dependent and -independent growth, migration, and invasion of human cancer cells, which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyperactivated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3.

A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation

PubMed Central

Zhang, Xiaolei; Sun, Ying; Pireddu, Roberta; Yang, Hua; Urlam, Murali K.; Lawrence, Harshani R.; Guida, Wayne C.; Lawrence, Nicholas J.; Sebti, Saïd M.

2014-01-01

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding and transcriptional regulation of downstream target genes. Here we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation and malignant transforming activity. Fluorescence polarization assays and molecular modeling suggest that S3I-1757 interacts with the Y-705 binding site in the SH2 domain and displaces fluorescein-labelled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated HA-tagged STAT3 and FLAG-tagged STAT3 and showed using co-immunoprecipitation and co-localization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analogue, S3I-1756, that does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding and transcriptional activation and suppresses the expression levels of STAT3 target genes such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1) and MMP9. Furthermore, S3I-1757 but not S3I-1756 inhibits anchorage-dependent and -independent growth, migration and invasion of human cancer cells which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyper activated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3. PMID:23322008

Three STATs are involved in the regulation of the expression of antimicrobial peptides in the triangle sail mussel, Hyriopsis cumingii.

PubMed

Dai, Yun-Jia; Hui, Kai-Min; Zhang, Ying-Hao; Liu, Yan; Wang, Yu-Qing; Zhao, Li-Juan; Lin, Li; Chai, Lian-Qin; Wei, Shun; Lan, Jiang-Feng

2017-04-01

Janus kinase (Jak) and signal transducers and activators of transcription (STAT) signaling pathway is associated in antiviral and antibacterial immune response. Previous studies primarily investigated the function of STATs in mammals. For most invertebrates, only one STAT was found in each species, such as STAT92E was found in Drosophila melanogaster. The studies, which focus on the functional difference between various STATs in the same species of invertebrate, are limited. In the present study, three STATs (HcSTAT1, HcSTAT2 and HcSTAT3) were identified in triangle shell pearl mussel, Hyriopsis cumingii. Phylogenetic analysis showed that HcSTAT1 and HcSTAT3 were clustered with Homo sapiens STAT5, and HcSTAT2 was clustered with Pinctada fucata STAT and Crassostea gigas STAT6. All three STATs could be detected in all tested tissues (hemocytes, hepatopancreas, gill, mantle and foot), and were induced expression when challenged with Staphylococcus aureus or Aeromonas hydrophilia in hemocytes and hepatopancreas. HcSTAT1 regulated the expression of HcDef, HcWAP, HcThe and HcTNF. The expression of HcWAP and HcTNF was down-regulated in HcSTAT2-RNAi mussel. And HcSTAT3 affected the expression of HcTNF. The study is the first report of different functions in antibacterial immune responses between STATs in mollusks. Copyright © 2017 Elsevier Ltd. All rights reserved.

Alternative activation of STAT1 and STAT3 in response to interferon-gamma.

PubMed

Qing, Yulan; Stark, George R

2004-10-01

Interferon-gamma (IFNgamma) is a pluripotent cytokine whose major biological effects are mediated through a pathway in which STAT1 is the predominant and essential transcription factor. STAT3 can also be activated weakly by IFNgamma, but the mechanism of activation and function of STAT3 as a part of the interferon response are not known. Here we show that STAT3 activation is much stronger and more prolonged in STAT1-null mouse embryo fibroblasts than in wild-type cells. In response to IFNgamma, SRC-family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor-bound kinases JAK1 and JAK2 are required to activate both STATs. Tyrosine 419 of the IFNgamma receptor subunit 1 (IFNGR1) is required to activate both STATs, suggesting that STAT1 and STAT3 compete with each other for the same receptor phosphotyrosine motif. Activated STAT3 can replace STAT1 in STAT1-null cells to drive the transcription of certain genes, for example, socs-3 and c/ebpdelta, which have gamma-activated sequence motifs in their promoters. Work from Ian Kerr's laboratory reveals that the gp130-linked interleukin-6 receptor, which usually activates STAT3 predominantly, activates STAT1 efficiently when STAT3 is absent. Because STAT1 and STAT3 have opposing biological effects (STAT3 is an oncogene, and STAT1 is a tumor suppressor), the reciprocal activation of these two transcription factors in response to IFNgamma or interleukin-6 suggests that their relative abundance, which may vary substantially in different normal cell types, under different conditions or in tumors is likely to have a major impact on how cells behave in response to different cytokines.

Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

PubMed Central

Szelag, Malgorzata; Czerwoniec, Anna; Wesoly, Joanna; Bluyssen, Hans A. R.

2015-01-01

Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. PMID:25710482

STAT inhibitors for cancer therapy

PubMed Central

2013-01-01

Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds. PMID:24308725

Division of Labor Among the Yeast Sol Proteins Implicated in tRNA Nuclear Export and Carbohydrate Metabolism

PubMed Central

Stanford, D. R.; Whitney, M. L.; Hurto, R. L.; Eisaman, D. M.; Shen, W.-C.; Hopper, A. K.

2004-01-01

SOL1, the founding member of the S. cerevisiae SOL family, was previously identified as a multi-copy suppressor of the los1 defect in tRNA-mediated nonsense suppression. Here we report that the four-member SOL family is not essential and that individual family members appear to have distinct functions. SOL1–SOL4 are homologous to genes encoding 6-phosphogluconolactonase (6Pgl) involved in the pentose phosphate pathway. Both Sol3p and Sol4p affect this activity. However, Sol4p does not act as a los1 multi-copy suppressor. In contrast, neither Sol1p nor Sol2p, both of which correct the los1 defect in nonsense suppression, possess detectable 6Pgl activity. Rather, Sol1p and Sol2p appear to function in tRNA nuclear export as sol1 and sol2 mutants possess elevated levels of nuclear tRNA. Members of the Sol protein family appear to have different subcellular distributions. Thus, Sol3p and Sol4p likely function in carbohydrate metabolism, while Sol1p and Sol2p appear to have roles in tRNA function and nuclear export, thereby defining an unusual protein family whose individual members are biochemically distinct and spatially dispersed. PMID:15454531

Division of labor among the yeast Sol proteins implicated in tRNA nuclear export and carbohydrate metabolism.

PubMed

Stanford, D R; Whitney, M L; Hurto, R L; Eisaman, D M; Shen, W-C; Hopper, A K

2004-09-01

SOL1, the founding member of the S. cerevisiae SOL family, was previously identified as a multi-copy suppressor of the los1 defect in tRNA-mediated nonsense suppression. Here we report that the four-member SOL family is not essential and that individual family members appear to have distinct functions. SOL1-SOL4 are homologous to genes encoding 6-phosphogluconolactonase (6Pgl) involved in the pentose phosphate pathway. Both Sol3p and Sol4p affect this activity. However, Sol4p does not act as a los1 multi-copy suppressor. In contrast, neither Sol1p nor Sol2p, both of which correct the los1 defect in nonsense suppression, possess detectable 6Pgl activity. Rather, Sol1p and Sol2p appear to function in tRNA nuclear export as sol1 and sol2 mutants possess elevated levels of nuclear tRNA. Members of the Sol protein family appear to have different subcellular distributions. Thus, Sol3p and Sol4p likely function in carbohydrate metabolism, while Sol1p and Sol2p appear to have roles in tRNA function and nuclear export, thereby defining an unusual protein family whose individual members are biochemically distinct and spatially dispersed.

Direct Measurement of the Mass Difference of 163Ho and 163Dy Solves the Q -Value Puzzle for the Neutrino Mass Determination

NASA Astrophysics Data System (ADS)

Eliseev, S.; Blaum, K.; Block, M.; Chenmarev, S.; Dorrer, H.; Düllmann, Ch. E.; Enss, C.; Filianin, P. E.; Gastaldo, L.; Goncharov, M.; Köster, U.; Lautenschläger, F.; Novikov, Yu. N.; Rischka, A.; Schüssler, R. X.; Schweikhard, L.; Türler, A.

2015-08-01

The atomic mass difference of 163 and 163Dy has been directly measured with the Penning-trap mass spectrometer SHIPTRAP applying the novel phase-imaging ion-cyclotron-resonance technique. Our measurement has solved the long-standing problem of large discrepancies in the Q value of the electron capture in 163Ho determined by different techniques. Our measured mass difference shifts the current Q value of 2555(16) eV evaluated in the Atomic Mass Evaluation 2012 [G. Audi et al., Chin. Phys. C 36, 1157 (2012)] by more than 7 σ to 2833 (30stat)(15sys) eV /c2 . With the new mass difference it will be possible, e.g., to reach in the first phase of the ECHo experiment a statistical sensitivity to the neutrino mass below 10 eV, which will reduce its present upper limit by more than an order of magnitude.

Network-Physics(NP) Bec DIGITAL(#)-VULNERABILITY Versus Fault-Tolerant Analog

NASA Astrophysics Data System (ADS)

Alexander, G. K.; Hathaway, M.; Schmidt, H. E.; Siegel, E.

2011-03-01

Siegel[AMS Joint Mtg.(2002)-Abs.973-60-124] digits logarithmic-(Newcomb(1881)-Weyl(1914; 1916)-Benford(1938)-"NeWBe"/"OLDbe")-law algebraic-inversion to ONLY BEQS BEC:Quanta/Bosons= digits: Synthesis reveals EMP-like SEVERE VULNERABILITY of ONLY DIGITAL-networks(VS. FAULT-TOLERANT ANALOG INvulnerability) via Barabasi "Network-Physics" relative-``statics''(VS.dynamics-[Willinger-Alderson-Doyle(Not.AMS(5/09)]-]critique); (so called)"Quantum-computing is simple-arithmetic(sans division/ factorization); algorithmic-complexities: INtractibility/ UNdecidability/ INefficiency/NONcomputability / HARDNESS(so MIScalled) "noise"-induced-phase-transitions(NITS) ACCELERATION: Cook-Levin theorem Reducibility is Renormalization-(Semi)-Group fixed-points; number-Randomness DEFINITION via WHAT? Query(VS. Goldreich[Not.AMS(02)] How? mea culpa)can ONLY be MBCS "hot-plasma" versus digit-clumping NON-random BEC; Modular-arithmetic Congruences= Signal X Noise PRODUCTS = clock-model; NON-Shor[Physica A,341,586(04)] BEC logarithmic-law inversion factorization:Watkins number-thy. U stat.-phys.); P=/=NP TRIVIAL Proof: Euclid!!! [(So Miscalled) computational-complexity J-O obviation via geometry.

Mutant number distribution in an exponentially growing population

NASA Astrophysics Data System (ADS)

Keller, Peter; Antal, Tibor

2015-01-01

We present an explicit solution to a classic model of cell-population growth introduced by Luria and Delbrück (1943 Genetics 28 491-511) 70 years ago to study the emergence of mutations in bacterial populations. In this model a wild-type population is assumed to grow exponentially in a deterministic fashion. Proportional to the wild-type population size, mutants arrive randomly and initiate new sub-populations of mutants that grow stochastically according to a supercritical birth and death process. We give an exact expression for the generating function of the total number of mutants at a given wild-type population size. We present a simple expression for the probability of finding no mutants, and a recursion formula for the probability of finding a given number of mutants. In the ‘large population-small mutation’ limit we recover recent results of Kessler and Levine (2014 J. Stat. Phys. doi:10.1007/s10955-014-1143-3) for a fully stochastic version of the process.

Kinetic Models for Topological Nearest-Neighbor Interactions

NASA Astrophysics Data System (ADS)

Blanchet, Adrien; Degond, Pierre

2017-12-01

We consider systems of agents interacting through topological interactions. These have been shown to play an important part in animal and human behavior. Precisely, the system consists of a finite number of particles characterized by their positions and velocities. At random times a randomly chosen particle, the follower, adopts the velocity of its closest neighbor, the leader. We study the limit of a system size going to infinity and, under the assumption of propagation of chaos, show that the limit kinetic equation is a non-standard spatial diffusion equation for the particle distribution function. We also study the case wherein the particles interact with their K closest neighbors and show that the corresponding kinetic equation is the same. Finally, we prove that these models can be seen as a singular limit of the smooth rank-based model previously studied in Blanchet and Degond (J Stat Phys 163:41-60, 2016). The proofs are based on a combinatorial interpretation of the rank as well as some concentration of measure arguments.

Entropy Flow Through Near-Critical Quantum Junctions

NASA Astrophysics Data System (ADS)

Friedan, Daniel

2017-05-01

This is the continuation of Friedan (J Stat Phys, 2017. doi: 10.1007/s10955-017-1752-8). Elementary formulas are derived for the flow of entropy through a circuit junction in a near-critical quantum circuit close to equilibrium, based on the structure of the energy-momentum tensor at the junction. The entropic admittance of a near-critical junction in a bulk-critical circuit is expressed in terms of commutators of the chiral entropy currents. The entropic admittance at low frequency, divided by the frequency, gives the change of the junction entropy with temperature—the entropic "capacitance". As an example, and as a check on the formalism, the entropic admittance is calculated explicitly for junctions in bulk-critical quantum Ising circuits (free fermions, massless in the bulk), in terms of the reflection matrix of the junction. The half-bit of information capacity per end of critical Ising wire is re-derived by integrating the entropic "capacitance" with respect to temperature, from T=0 to T=∞.

Motion of a Rigid Body in a Special Lorentz Gas: Loss of Memory Effect

NASA Astrophysics Data System (ADS)

Koike, Kai

2018-06-01

Linear motion of a rigid body in a special kind of Lorentz gas is mathematically analyzed. The rigid body moves against gas drag according to Newton's equation. The gas model is a special Lorentz gas consisting of gas molecules and background obstacles, which was introduced in Tsuji and Aoki (J Stat Phys 146:620-645, 2012). The specular boundary condition is imposed on the resulting kinetic equation. This study complements the numerical study by Tsuji and Aoki cited above—although the setting in this paper is slightly different from theirs, qualitatively the same asymptotic behavior is proved: The velocity V(t) of the rigid body decays exponentially if the obstacles undergo thermal motion; if the obstacles are motionless, then the velocity V(t) decays algebraically with a rate t^{- 5} independent of the spatial dimension. This demonstrates the idea that interaction of the molecules with the background obstacles destroys the memory effect due to recollision.

The limit distribution in the q-CLT for q\\,\\geqslant \\,1 is unique and can not have a compact support

NASA Astrophysics Data System (ADS)

Umarov, Sabir; Tsallis, Constantino

2016-10-01

In a paper by Umarov et al (2008 Milan J. Math. 76 307-28), a generalization of the Fourier transform, called the q-Fourier transform, was introduced and applied for the proof of a q-generalized central limit theorem (q-CLT). Subsequently, Hilhorst illustrated (2009 Braz. J. Phys. 39 371-9 2010 J. Stat. Mech. P10023) that the q-Fourier transform for q\\gt 1, is not invertible in the space of density functions. Indeed, using an invariance principle, he constructed a family of densities with the same q-Fourier transform and noted that ‘as a consequence, the q-CLT falls short of achieving its stated goal’. The distributions constructed there have compact support. We prove now that the limit distribution in the q-CLT is unique and can not have a compact support. This result excludes all the possible counterexamples which can be constructed using the invariance principle and fills the gap mentioned by Hilhorst.

Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs.

PubMed

Klampfer, Lidija

2006-03-01

A family of latent cytoplasmic transcription factors, signal transducers and activators of transcription (STATs), mediates the responsiveness of cells to several cytokines and growth factors. Although mutations of STATs have not been described in human tumors, the activity of several members of the family, such as STAT1, STAT3 and STAT5, is deregulated in a variety of human tumors. STAT3 and STAT5 acquire oncogenic potential through constitutive phosphorylation on tyrosine, and their activity has been shown to be required to sustain a transformed phenotype. Disruption of STAT3 and STAT5 signaling in transformed cells therefore represents an excellent opportunity for targeted cancer therapy. In contrast to STAT3 and STAT5, STAT1 negatively regulates cell proliferation and angiogenesis and thereby inhibits tumor formation. Consistent with its tumor suppressive properties, STAT1 and its downstream targets have been shown to be reduced in a variety of human tumors and STAT1 deficient mice are highly susceptible to tumor formation. In recent years we have gained mechanistic understanding of the pathways whereby STATs convey signals from the cytoplasm to the nucleus. In addition, several endogenous regulators of the JAK/STAT pathway have been described - and their mechanism of action revealed - that profoundly affect signaling by STATs. Both should greatly facilitate the design of drugs with potential to modulate STAT signaling and to restore the homeostasis in tissues where STATs have gone awry.

75 FR 70935 - Accreditation and Approval of Intertek USA, Inc., as a Commercial Gauger and Laboratory

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... below for a complete listing of CBP approved gaugers and accredited laboratories. http:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol]. DATES: The accreditation and approval of Intertek USA, Inc., as commercial gauger and laboratory...

75 FR 70935 - Accreditation and Approval of Intertek USA, Inc., as a Commercial Gauger and Laboratory

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... listed below for a complete listing of CBP approved gaugers and accredited laboratories. http:[sol][sol]cbp.gov[sol]xp[sol]cgov[sol]import[sol]operations-- support[sol]labs--scientific--svcs[sol]commercial--gaugers[sol]. DATES: The accreditation and approval of Intertek USA, Inc., as commercial gauger and...

The Drastic Outcomes from Voting Alliances in Three-Party Democratic Voting (1990 → 2013)

NASA Astrophysics Data System (ADS)

Galam, Serge

2013-04-01

The drastic effect of local alliances in three-party competition is investigated in democratic hierarchical bottom-up voting. The results are obtained analytically using a model which extends a sociophysics frame introduced in 1986 (Galam in J. Math. Phys. 30:426, 1986) and 1990 (Galam in J. Stat. Phys. 61:943, 1990) to study two-party systems and the spontaneous formation of democratic dictatorship. It is worth stressing that the 1990 paper was published in the Journal of Statistical Physics, the first paper of its kind in this journal. It was shown how a minority in power can preserve its leadership using bottom-up democratic elections. However such a bias holds only down to some critical value of minimum support. The results were used latter to explain the sudden collapse of European communist parties in the nineties. The extension to three-party competition reveals the mechanisms by which a very small minority party can get a substantial representation at higher levels of the hierarchy when the other two competing parties are big. Additional surprising results are obtained, which enlighten the complexity of three-party democratic bottom-up voting. In particular, the unexpected outcomes of local voting alliances are singled out. Unbalanced democratic situations are exhibited with strong asymmetries between the actual bottom support of a party and its associated share of power at the top leadership. Subtle strategies are identified for a party to maximize its hold on the top leadership. The results are also valid to describe opinion dynamics with three competing opinions.

Ionic screening and dissociation are crucial for understanding chemical self-propulsion in polar solvents.

PubMed

Brown, Aidan T; Poon, Wilson C K; Holm, Christian; de Graaf, Joost

2017-02-08

Polar solvents like water support the bulk dissociation of themselves and their solutes into ions, and the re-association of these ions into neutral molecules in a dynamic equilibrium, e.g., H 2 O 2 ⇌ H + + HO 2 - . Using continuum theory, we study the influence of these association-dissociation reactions on the self-propulsion of colloids driven by surface chemical reactions (chemical swimmers). We find that association-dissociation reactions should have a strong influence on swimmers' behaviour, and therefore should be included in future modelling. In particular, such bulk reactions should permit charged swimmers to propel electrophoretically even if all species involved in the surface reactions are neutral. The bulk reactions also significantly modify the predicted speed of chemical swimmers propelled by ionic currents, by up to an order of magnitude. For swimmers whose surface reactions produce both anions and cations (ionic self-diffusiophoresis), the bulk reactions produce an additional reactive screening length, analogous to the Debye length in electrostatics. This in turn leads to an inverse relationship between swimmer radius and swimming speed, which could provide an alternative explanation for recent experimental observations on Pt-polystyrene Janus swimmers [S. Ebbens et al., Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2012, 85, 020401]. We also use our continuum theory to investigate the effect of the Debye screening length itself, going beyond the infinitely-thin-screening-length approximation used by previous analytical theories. We identify significant departures from this limiting behaviour for micron-sized swimmers under typical experimental conditions and find that the approximation fails entirely for nanoscale swimmers.

Optical detection of nanometric thermal fluctuations to measure the stiffness of rigid superparamagnetic microrods

PubMed Central

Wang, Yuan

2017-01-01

The rigidity of numerous biological filaments and crafted microrods has been conveniently deduced from the analysis of their thermal fluctuations. However, the difficulty of measuring nanometric displacements with an optical microscope has so far limited such studies to sufficiently flexible rods, of which the persistence length (Lp) rarely exceeds 1 m at room temperature. Here, we demonstrate the possibility to probe 10-fold stiffer rods by a combination of superresolutive optical methods and a statistical analysis of the data based on a recent theoretical model that predicts the amplitude of the fluctuations at any location of the rod [Benetatos P, Frey E (2003) Phys Rev E Stat Nonlin Soft Matter Phys 67(5):051108]. Using this approach, we report measures of Lp up to 0.5 km. We obtained these measurements on recently designed superparamagnetic ∼40-μm-long microrods containing iron-oxide nanoparticles connected by a polymer mesh. Using their magnetic properties, we provide an alternative proof of validity of these thermal measurements: For each individual studied rod, we performed a second measure of its rigidity by deflecting it with a uniform magnetic field. The agreement between the thermal and the magnetoelastic measures was realized with more than a decade of values of Lp from 5.1 m to 129 m, corresponding to a bending modulus ranging from 2.2 to 54 (×10−20 Jm). Despite the apparent homogeneity of the analyzed microrods, their Young modulus follows a broad distribution from 1.9 MPa to 59 MPa and up to 200 MPa, depending on the size of the nanoparticles. PMID:28228530

Identification, gene expression and immune function of the novel Bm-STAT gene in virus-infected Bombyx mori.

PubMed

Zhang, Xiaoli; Guo, Rui; Kumar, Dhiraj; Ma, Huanyan; Liu, Jiabin; Hu, Xiaolong; Cao, Guangli; Xue, Renyu; Gong, Chengliang

2016-02-10

Genes in the signal transducer and activator of transcription (STAT) family are vital for activities including gene expression and immune response. To investigate the functions of the silkworm Bombyx mori STAT (Bm-STAT) gene in antiviral immunity, two Bm-STAT gene isoforms, Bm-STAT-L for long form and Bm-STAT-S for short form, were cloned. Sequencing showed that the open reading frames were 2313 bp encoding 770 amino acid residues for Bm-STAT-L and 2202 bp encoding 734 amino acid residues for Bm-STAT-S. The C-terminal 42 amino acid residues of Bm-STAT-L were different from the last 7 amino acid residues of Bm-STAT-S. Immunofluorescence showed that Bm-STAT was primarily distributed in the nucleus. Transcription levels of Bm-STAT in different tissues were determined by quantitative PCR, and the results revealed Bm-STAT was mainly expressed in testes. Western blots showed two bands with molecular weights of 70 kDa and 130 kDa in testes, but no bands were detected in ovaries by using anti-Bm-STAT antibody as the primary antibody. Expression of Bm-STAT in hemolymph at 48 h post infection with B. mori macula-like virus (BmMLV) was slightly enhanced compared with controls, suggesting a weak response induced by infection with BmMLV. Hemocyte immunofluorescence showed that Bm-STAT expression was elevated in B. mori nucleopolyhedrovirus (BmNPV)-infected cells. Moreover, resistance of BmN cells to BmNPV was reduced by downregulation of Bm-STAT expression and increased by upregulation. Resistance of BmN cells to BmCPV was not significantly improved by upregulating Bm-STAT expression. Therefore, we concluded that Bm-STAT is a newly identified insect gene of the STAT family. The JAK-STAT pathway has a more specialized role in antiviral defense in silkworms, but JAK-STAT pathway is not triggered in response to all viruses. Copyright © 2015 Elsevier B.V. All rights reserved.

Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC).

PubMed

Zheng, Jie; van de Veerdonk, Frank L; Crossland, Katherine L; Smeekens, Sanne P; Chan, Chun M; Al Shehri, Tariq; Abinun, Mario; Gennery, Andrew R; Mann, Jelena; Lendrem, Dennis W; Netea, Mihai G; Rowan, Andrew D; Lilic, Desa

2015-10-01

Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

STATs get their move on.

PubMed

Reich, Nancy C

2013-10-01

Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action. This review presents a synopsis of some of the studies that address the nuclear dynamics of the STAT proteins. Evidence suggests that not all STATs are the same. Nuclear import of STAT1 and STAT4 appears linked to their tyrosine phosphorylation and the formation of parallel dimers via reciprocal phosphotyrosine and Src homology 2 domain interactions. This dimer arrangement generates a conformational nuclear localization signal. STAT2 is imported continually to the nucleus in an unphosphorylated state due to its association with IRF9, but the dominant nuclear export signal of STAT2 shuttles the complex back to the cytoplasm. Following STAT2 tyrosine phosphorylation, it can form dimers with STAT1 to affect nuclear import as the trimeric complex (ISGF3). Distinctly, STAT3, STAT5, and STAT6 are continually imported to the nucleus independent of tyrosine phosphorylation. Mutational studies indicate the nuclear localization signals in these STATs require the conformational structure of their coiled-coil domains. Increases in STAT nuclear accumulation following cytokine stimulation appear coordinate with their ability to bind DNA.

Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chueh, Fu-Yu; Leong, King-Fu; Yu, Chao-Lan, E-mail: chaolan.yu@rosalindfranklin.edu

2010-11-26

Research highlights: {yields} STAT5 interacts with a mitochondrial protein PDC-E2 in a leukemic T cell line LSTRA. {yields} Tyrosine-phosphorylated STAT5, but not STAT3, is present in LSTRA mitochondria. {yields} Cytokines induce mitochondrial translocation of STAT5, but not STAT1 or STAT3. {yields} Cytokine-induced mitochondrial translocation of tyrosine-phosphorylated STAT5 is transient. {yields} Mitochondrial STAT5 binds to a putative STAT5 site in the mitochondrial DNA in vitro. -- Abstract: Signal transducers and activators of transcription (STATs) were first identified as key signaling molecules in response to cytokines. Constitutive STAT activation also has been widely implicated in oncogenesis. We analyzed STAT5-associated proteins in amore » leukemic T cell line LSTRA, which exhibits constitutive tyrosine phosphorylation and activation of STAT5. A cellular protein was found to specifically interact with STAT5 in LSTRA cells by co-immunoprecipitation. Sequencing analysis and subsequent immunoblotting confirmed the identity of this STAT5-associated protein as the E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2). Consistent with this interaction, both subcellular fractionation and immunofluorescence microscopy revealed mitochondrial localization of STAT5 in LSTRA cells. Mitochondrial localization of tyrosine-phosphorylated STAT5 also occurred in cytokine-stimulated cells. A time course experiment further demonstrated the transient kinetics of STAT5 mitochondrial translocation after cytokine stimulation. In contrast, cytokine-induced STAT1 and STAT3 activation did not result in their translocation into mitochondria. Furthermore, we showed that mitochondrial STAT5 bound to the D-loop regulatory region of mitochondrial DNA in vitro. It suggests a potential role of STAT5 in regulating the mitochondrial genome. Proliferative metabolism toward aerobic glycolysis is well known in cancer cells as the Warburg effect and is also observed in cytokine-stimulated cells. Our novel findings of cytokine-induced STAT5 translocation into mitochondria and its link to oncogenesis provide important insights into the underlying mechanisms of this characteristic metabolic shift.« less

The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma

PubMed Central

Ganguly, Debolina; Fan, Meiyun; Yang, Chuan He; Zbytek, Blazej; Finkelstein, David; Roussel, Martine F.; Pfeffer, Lawrence M.

2018-01-01

Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro. Tumorigenesis was rescued by the enforced expression of wild-type STAT3 in cells lacking STAT3. In contrast, GICs were highly addicted to STAT3 and upon STAT3 deletion GICs were non-viable. Moreover, we found that STAT3 was constitutively activated in GICs by phosphorylation on both tyrosine (Y705) and serine (S727) residues. Therefore, to study STAT3 function in GICs we established an inducible system to knockdown STAT3 expression (iSTAT3-KD). Using this approach, we demonstrated that Y705-STAT3 phosphorylation was critical and indispensable for GIC-induced tumor formation. Both phosphorylation sites in STAT3 promoted GIC proliferation in vitro. We further showed that S727-STAT3 phosphorylation was Y705-dependent. Targeted microarray and RNA sequencing revealed that STAT3 activated cell-cycle regulator genes, and downregulated genes involved in the interferon response, the hypoxia response, the TGFβ pathway, and remodeling of the extracellular matrix. Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers. PMID:29774125

STAT3, p-STAT3 and HIF-1α are associated with vasculogenic mimicry and impact on survival in gastric adenocarcinoma

PubMed Central

SONG, YAN-YAN; SUN, LI-DAN; LIU, MIN-LI; LIU, ZHONG-LIANG; CHEN, FEI; ZHANG, YING-ZHE; ZHENG, YAN; ZHANG, JIAN-PING

2014-01-01

Vasculogenic mimicry (VM) formation is important for invasion and metastasis of tumor cells in gastric adenocarcinoma (GAC). The present study aimed to investigate the association between signal transducer and activator of transcription-3 (STAT3), phosphor-STAT3 (p-STAT3), hypoxia-inducible factor-1α (HIF-1α) and VM formation in GAC, and discuss their clinical significance and correlation with the prognosis of patients with GAC. The expression levels of STAT3, p-STAT3, HIF-1α and VM were assessed in 60 cases of patients with GAC and 20 cases of patients with gastritis on tissue microarrays by immunohistochemical methods. The expression levels of STAT3, p-STAT3, HIF-1α and VM were higher in patients with GAC (particularly in poorly differentiated GAC) than in those with gastritis (P<0.05). The expression levels of STAT3, p-STAT3 and HIF-1α were higher in VM tissues compared with non-VM tissues (P<0.05). Positive correlations existed between STAT3, p-STAT3, HIF-1α and VM expression (P<0.05). The expression levels of STAT3, p-STAT3 and HIF-1α, VM, status of lymph node metastasis and tumor differentiation degree were associated with the overall survival time of patients with GAC (P<0.05). However, only p-STAT3 and VM expression were identified as the independent risk factors of GAC OS when analyzed with multivariate analysis. p-STAT3 and VM play a significant role in indicating the prognosis of patients with GAC. STAT3 activation may play a positive role in VM formation of GAC by the STAT3-p-STAT3-HIF-1α-VM effect axis. PMID:24959290

STATs get their move on

PubMed Central

Reich, Nancy C

2013-01-01

Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action. This review presents a synopsis of some of the studies that address the nuclear dynamics of the STAT proteins. Evidence suggests that not all STATs are the same. Nuclear import of STAT1 and STAT4 appears linked to their tyrosine phosphorylation and the formation of parallel dimers via reciprocal phosphotyrosine and Src homology 2 domain interactions. This dimer arrangement generates a conformational nuclear localization signal. STAT2 is imported continually to the nucleus in an unphosphorylated state due to its association with IRF9, but the dominant nuclear export signal of STAT2 shuttles the complex back to the cytoplasm. Following STAT2 tyrosine phosphorylation, it can form dimers with STAT1 to affect nuclear import as the trimeric complex (ISGF3). Distinctly, STAT3, STAT5, and STAT6 are continually imported to the nucleus independent of tyrosine phosphorylation. Mutational studies indicate the nuclear localization signals in these STATs require the conformational structure of their coiled-coil domains. Increases in STAT nuclear accumulation following cytokine stimulation appear coordinate with their ability to bind DNA. PMID:24470978

75 FR 73996 - Approval and Promulgation of State Air Quality Plans for Designated Facilities and Pollutants...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-30

...:[sol][sol]www.regulations.gov, including any personal information provided, unless the comment includes... http:[sol][sol]www.regulations.gov or e-mail. The http:[sol][sol]www.regulations.gov Web site is an... through http:[sol][sol]www.regulations.gov, your e-mail address will be automatically captured and...

Comprehensive meta-analysis of Signal Transducers and Activators of Transcription (STAT) genomic binding patterns discerns cell-specific cis-regulatory modules

PubMed Central

2013-01-01

Background Cytokine-activated transcription factors from the STAT (Signal Transducers and Activators of Transcription) family control common and context-specific genetic programs. It is not clear to what extent cell-specific features determine the binding capacity of seven STAT members and to what degree they share genetic targets. Molecular insight into the biology of STATs was gained from a meta-analysis of 29 available ChIP-seq data sets covering genome-wide occupancy of STATs 1, 3, 4, 5A, 5B and 6 in several cell types. Results We determined that the genomic binding capacity of STATs is primarily defined by the cell type and to a lesser extent by individual family members. For example, the overlap of shared binding sites between STATs 3 and 5 in T cells is greater than that between STAT5 in T cells and non-T cells. Even for the top 1,000 highly enriched STAT binding sites, ~15% of STAT5 binding sites in mouse female liver are shared by other STATs in different cell types while in T cells ~90% of STAT5 binding sites are co-occupied by STAT3, STAT4 and STAT6. In addition, we identified 116 cis-regulatory modules (CRM), which are recognized by all STAT members across cell types defining a common JAK-STAT signature. Lastly, in liver STAT5 binding significantly coincides with binding of the cell-specific transcription factors HNF4A, FOXA1 and FOXA2 and is associated with cell-type specific gene transcription. Conclusions Our results suggest that genomic binding of STATs is primarily determined by the cell type and further specificity is achieved in part by juxtaposed binding of cell-specific transcription factors. PMID:23324445

Tsallis non-additive entropy and natural time analysis of seismicity

NASA Astrophysics Data System (ADS)

Sarlis, N. V.; Skordas, E. S.; Varotsos, P.

2017-12-01

Within the context of Tsallis non-additive entropy [1] statistical mechanics -in the frame of which kappa distributions arise [2,3]- a derivation of the Gutenberg-Richter (GR) law of seismicity has been proposed [4,5]. Such an analysis leads to a generalized GR law [6,7] which is applied here to the earthquakes in Japan and California. These seismic data are also studied in natural time [6] revealing that although some properties of seismicity may be recovered by the non-additive entropy approach, temporal correlations between successive earthquake magnitudes should be also taken into account [6,8]. The importance of such correlations is strengthened by the observation of periods of long range correlated earthquake magnitude time series [9] a few months before all earthquakes of magnitude 7.6 or larger in the entire Japanese area from 1 January 1984 to 11 March 2011 (the day of the magnitude 9.0 Tohoku-Oki earthquake) almost simultaneously with characteristic order parameter variations of seismicity [10]. These variations appear approximately when low frequency abnormal changes of the electric and magnetic field of the Earth (less than around 1Hz) are recorded [11] before strong earthquakes as the magnitude 9.0 Tohoku-Oki earthquake in Japan in 2011 [12]. 1. C Tsallis, J Stat Phys 52 (1988) 479 2. G Livadiotis, and D J McComas, J Geophys Res 114 (2009) A11105 3. G Livadiotis, Kappa Distributions. (Elsevier, Amsterdam) 2017. doi: 10.1016/B978-0-12-804638-8.01001-9 4. O Sotolongo-Costa, A Posadas, Phys Rev Lett 92 (2004) 048501 5. R Silva, G França, C Vilar, J Alcaniz, Phys Rev E 73 (2006) 026102 6. N Sarlis, E Skordas, P Varotsos, Phys Rev E 82 (2010) 021110 7. L Telesca, Bull Seismol Soc Am 102 (2012) 886-891 8. P Varotsos, N Sarlis, E Skordas, Natural Time Analysis: The new view of time. (Springer, Berlin) 2011. doi: 10.1007/978-3-642-16449-1 9. P Varotsos, N Sarlis, E Skordas, J Geophys Res Space Physics 119 (2014) 9192. 10. N Sarlis, E Skordas, P Varotsos, T Nagao, M Kamogawa, H Tanaka, S Uyeda, Proc Natl Acad Sci USA 110 (2013) 13734. 11. P Varotsos, N Sarlis, E Skordas, M Lazaridou-Varotsos, Earthq Sci 30 (2017) doi: 10.1007/s11589-017-0189-0 12. P Varotsos, N Sarlis, E Skordas, Earthq Sci 30 (2017) doi: 10.1007/s11589-017-0182-7

JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimoto, Arata, E-mail: anishimo@yamaguchi-u.ac.jp; Kugimiya, Naruji; Hosoyama, Toru

2013-08-30

Highlights: •JAB1 interacted with unphosphorylated STAT3 in the nucleus. •JAB1 knockdown tended to increase nuclear STAT3 expression. •JAB1 knockdown significantly decreased unphosphorylated STAT3 DNA-binding activity. •JAB1 knockdown significantly decreased MDR1, NANOG, and VEGF expressions. •Nuclear JAB1, but not nuclear STAT3, correlated with STAT3 DNA-binding activity. -- Abstract: Recent studies have revealed that unphosphorylated STAT3 forms a dimer, translocates to the nucleus, binds to the STAT3 binding site, and activates the transcription of STAT3 target genes, thereby playing an important role in oncogenesis in addition to phosphorylated STAT3. Among signaling steps of unphosphorylated STAT3, nuclear translocation and target DNA-binding are themore » critical steps for its activation. Therefore, elucidating the regulatory mechanism of these signaling steps of unphosphorylated STAT3 is a potential step in the discovery of a novel cancer drug. However, the mechanism of unphosphorylated STAT3 binding to the promoter of target genes remains unclear. In this study, we focused on Jun activation domain-binding protein 1 (JAB1) as a candidate protein that regulates unphosphorylated STAT3 DNA-binding activity. Initially, we observed that both unphosphorylated STAT3 and JAB1 existed in the nucleus of human colon cancer cell line COLO205 at the basal state (no cytokine stimulation). On the other hand, phosphorylated STAT3 did not exist in the nucleus of COLO205 cells at the basal state. Immunoprecipitation using nuclear extract of COLO205 cells revealed that JAB1 interacted with unphosphorylated STAT3. To investigate the effect of JAB1 on unphosphorylated STAT3 activity, RNAi studies were performed. Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA-binding activity. Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target genes. Furthermore, the expression level of nuclear JAB1, but not nuclear STAT3, correlated with unphosphorylated STAT3 DNA-binding activity between COLO205 and LoVo cells. Taken together, these results suggest that nuclear JAB1 positively regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cell line COLO205.« less

Alternative Splicing of STAT3 Is Affected by RNA Editing.

PubMed

Goldberg, Lior; Abutbul-Amitai, Mor; Paret, Gideon; Nevo-Caspi, Yael

2017-05-01

A-to-I RNA editing, carried out by adenosine deaminase acting on RNA (ADAR) enzymes, is an epigenetic phenomenon of posttranscriptional modifications on pre-mRNA. RNA editing in intronic sequences may influence alternative splicing of flanking exons. We have previously shown that conditions that induce editing result in elevated expression of signal transducer and activator of transcription 3 (STAT3), preferentially the alternatively-spliced STAT3β isoform. Mechanisms regulating alternative splicing of STAT3 have not been elucidated. STAT3 undergoes A-to-I RNA editing in an intron residing in proximity to the alternatively spliced exon. We hypothesized that RNA editing plays a role in regulating alternative splicing toward STAT3β. In this study we extend our observation connecting RNA editing to the preferential induction of STAT3β expression. We study the involvement of ADAR1 in STAT3 editing and reveal the connection between editing and alternative splicing of STAT3. Deferoaxamine treatment caused the induction in STAT3 RNA editing and STAT3β expression. Silencing ADAR1 caused a decrease in STAT3 editing and expression with a preferential decrease in STAT3β. Cells transfected with a mutated minigene showed preferential splicing toward the STAT3β transcript. Editing in the STAT3 intron is performed by ADAR1 and affects STAT3 alternative splicing. These results suggest that RNA editing is one of the molecular mechanisms regulating the expression of STAT3β.

Different competitive capacities of Stat4- and Stat6-deficient CD4+ T cells during lymphophenia-driven proliferation.

PubMed

Sanchez-Guajardo, Vanesa; Borghans, José A M; Marquez, Maria-Elena; Garcia, Sylvie; Freitas, Antonio A

2005-02-01

The outcome of an immune response relies on the competitive capacities acquired through differentiation of CD4(+) T cells into Th1 or Th2 effector cells. Because Stat4 and Stat6 proteins are implicated in the Th1 vs Th2 generation and maintenance, respectively, we compare in this study the kinetics of Stat4(-/-) and Stat6(-/-) CD4(+) T cells during competitive bone marrow reconstitution and lymphopenia-driven proliferation. After bone marrow transplantation, both populations reconstitute the peripheral T cell pools equally well. After transfer into lymphopenic hosts, wild-type and Stat6(-/-) CD4(+) T cells show a proliferation advantage, which is early associated with the expression of an active phospho-Stat4 and the down-regulation of Stat6. Despite these differences, Stat4- and Stat6-deficient T cells reach similar steady state numbers. However, when both Stat4(-/-) and Stat6(-/-) CD4(+) T cells are coinjected into the same hosts, the Stat6(-/-) cells become dominant and out-compete Stat4(-/-) cells. These findings suggest that cell activation, through the Stat4 pathway and the down-regulation of Stat6, confers to pro-Th1 T cells a slight proliferation advantage that in a competitive situation has major late repercussions, because it modifies the final homeostatic equilibrium of the populations and favors the establishment of Th1 CD4(+) T cell dominance.

Molecular Determinants of Hormone Refractory Prostate Cancer

DTIC Science & Technology

2013-07-01

Chk2 T68 STAT5b Y699 STAT6 Y641 MEK1/2 STAT5a/b… STAT2 Y689 RSK1/2/3 STAT3 Y705 Lck Y394 AMPKa2 T172 STAT1 Y701 AMPKa1 FAK Y397 Fyn Y420 HSP27 S78/S82...p27 T198 STAT5a Y694 STAT3 Y705 AMPKa2 T172 Lck Y394 STAT2 Y689 STAT1 Y701 p70S6K T229 p38a Fyn Y420 HSP27 … c-Jun S63 ranked by AKT1 (>1.5x,ɘ.67x

Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer

PubMed Central

Yeh, Jennifer E.; Kreimer, Simion; Walker, Sarah R.; Emori, Megan M.; Krystal, Hannah; Richardson, Andrea; Ivanov, Alexander R.; Frank, David A.

2015-01-01

Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer. PMID:26000098

An SH2 domain model of STAT5 in complex with phospho-peptides define ``STAT5 Binding Signatures''

NASA Astrophysics Data System (ADS)

Gianti, Eleonora; Zauhar, Randy J.

2015-05-01

The signal transducer and activator of transcription 5 (STAT5) is a member of the STAT family of proteins, implicated in cell growth and differentiation. STAT activation is regulated by phosphorylation of protein monomers at conserved tyrosine residues, followed by binding to phospho-peptide pockets and subsequent dimerization. STAT5 is implicated in the development of severe pathological conditions, including many cancer forms. However, nowadays a few STAT5 inhibitors are known, and only one crystal structure of the inactive STAT5 dimer is publicly available. With a view to enabling structure-based drug design, we have: (1) analyzed phospho-peptide binding pockets on SH2 domains of STAT5, STAT1 and STAT3; (2) generated a model of STAT5 bound to phospho-peptides; (3) assessed our model by docking against a class of known STAT5 inhibitors (Müller et al. in ChemBioChem 9:723-727, 2008); (4) used molecular dynamics simulations to optimize the molecular determinants responsible for binding and (5) proposed unique "Binding Signatures" of STAT5. Our results put in place the foundations to address STAT5 as a target for rational drug design, from sequence, structural and functional perspectives.

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes

PubMed Central

2012-01-01

Introduction Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome. Methods Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models. Results Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome. Conclusions Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials. PMID:23036105

Expression and activation of STAT3 in ischemia-induced retinopathy.

PubMed

Mechoulam, Hadas; Pierce, Eric A

2005-12-01

Signal transducer and activator of transcription protein-3 (STAT3) is a transcription factor that participates in many biological processes, including tumor angiogenesis. The expression and activation of Stat3 in the mouse model of ischemia-induced retinal neovascularization was investigated to evaluate the possible role of STAT3 in retinal vascular disease. Retinal neovascularization was induced in mice pups by exposure to hyperoxia. Gene microarrays were used to identify genes whose expression in the retina is altered at postnatal day (P)12 and P18. The relative levels of Stat3 mRNA were determined by semiquantitative RT-PCR. Stat3 protein levels and the levels of the activated form of Stat3 (pStat3) at P12, P15, P18, and P22 were determined by immunoblot analysis. Stat3 and pStat3 were demonstrated by immunofluorescence in retinal sections at P12, P15, and P18. In a series of microarray experiments, increased Stat3 mRNA levels in the retina were detected at P18. This result was validated by RT-PCR and demonstrated that Stat3 and pStat3 protein levels also increase during the development of neovascularization. Stat3 partially colocalized with blood vessels at the peak of neovascularization. pStat3 colocalized completely with blood vessels in both experimental samples and age-matched controls. pStat3 staining increased notably in the neovascular vessels at P15 and P18 and was more strongly associated with the epiretinal vessels than with inner retinal vessels. It was not detected in larger blood vessels, such as those of the optic nerve. The level of Stat3 expression increased, and pStat3 was observed in association with retinal neovascularization. Activated Stat3 was preferentially localized to neovascular retinal vessels. These data suggest that STAT3 may have a role in proliferative retinopathy.

Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes

PubMed Central

Leibowitz, Michael S.; Filho, Pedro A. Andrade; Ferrone, Soldano; Ferris, Robert L.

2012-01-01

Squamous cell carcinoma of the head and neck (SCCHN) cells can escape recognition by tumor antigen (TA)-specific cytotoxic T lymphocytes (CTL) by downregulation of antigen processing machinery (APM) components, such as the transporter associated with antigen processing (TAP)-1/2 heterodimer. APM component upregulation by interferon gamma (IFN-γ) restores SCCHN cell recognition and susceptibility to lysis by CTL, but the mechanism underlying TAP1/2 downregulation in SCCHN cells is not known. Because IFN-γ activates signal transducer and activator of transcription (STAT)-1, we investigated phosphorylated (p)-STAT1 as a mediator of low basal TAP1/2 expression in SCCHN cells. SCCHN cells were found to express basal total STAT1 but low to undetectable levels of activated STAT1. The association of increased pSTAT1 levels and APM components likely reflects a cause–effect relationship, since STAT1 knockdown significantly reduced both IFN-γ-mediated APM component expression and TA-specific CTL recognition of IFN-γ-treated SCCHN cells. On the other hand, since oncogenic pSTAT3 is overexpressed in SCCHN cells and was found to heterodimerize with pSTAT1, we also tested whether pSTAT3 and pSTAT1:pSTAT3 heterodimers inhibited IFN-γ-induced STAT1 activation and APM component expression. First, STAT3 activation or depletion did not affect basal or IFN-γ-induced expression of pSTAT1 and APM components or recognition of SCCHN cells by TA-specific CTL. Second, pSTAT1:pSTAT3 heterodimers did not interfere with IFN-γ-induced STAT1 binding to the TAP1 promoter or APM protein expression. These findings demonstrate that APM component downregulation is regulated primarily by an IFN-γ-pSTAT1-mediated signaling pathway, independent of oncogenic STAT3 overexpression in SCCHN cells. PMID:21207025

Design of Conditionally Active STATs: Insights into STAT Activation and Gene Regulatory Function

PubMed Central

Milocco, Lawrence H.; Haslam, Jennifer A.; Rosen, Jonathan; Seidel, H. Martin

1999-01-01

The STAT (signal transducer and activator of transcription) signaling pathway is activated by a large number of cytokines and growth factors. We sought to design a conditionally active STAT that could not only provide insight into basic questions about STAT function but also serve as a powerful tool to determine the precise biological role of STATs. To this end, we have developed a conditionally active STAT by fusing STATs with the ligand-binding domain of the estrogen receptor (ER). We have demonstrated that the resulting STAT-ER chimeras are estrogen-inducible transcription factors that retain the functional and biochemical characteristics of the cognate wild-type STATs. In addition, these tools have allowed us to evaluate separately the contribution of tyrosine phosphorylation and dimerization to STAT function. We have for the first time provided experimental data supporting the model that the only apparent role of STAT tyrosine phosphorylation is to drive dimerization, as dimerization alone is sufficient to unmask a latent STAT nuclear localization sequence and induce nuclear translocation, sequence-specific DNA binding, and transcriptional activity. PMID:10082558

[Expressions of VEGF/VEGFRs and activation of STATs in ovarian carcinoma].

PubMed

Chen, Bing-Ya; Ye, Da-Feng; Xie, Xing; Chen, Huai-Zeng; Lü, Wei-Guo

2005-01-01

To study the expressions of VEGF/VEGFRs and activation of STATs in ovarian epithelial carcinoma, and to elucidate direct effect of VEGF on ovarian carcinoma cells. Tissue samples from 42 women with primary ovarian epithelial carcinoma (OVCA), 29 with begnin ovarian tumor (OVBT) and 11 with normal ovarian tissue (NOV) were collected. LSAB immunohistochemical staining was used to determine the expression of VEGF, VEGFR1, VEGFR2 and activated STATS (P-STAT1, P-STAT3, P-STAT5, P-STAT6) proteins. (1) Semi-quantitative scoring showed that VEGF expression in OVCA was significantly higher than that in OVBT and NOV (P < 0.01). Expressions of VEGFR1 and VEGFR2 were significantly elevated in OVCA, including tumor cells and stromal vascular endothelial cells (P < 0.01, compared with OVBT and NOV). There was no difference in VEGFRs expressions between OVBT and NOV. (2) In OVCA, tumor cells and endothelial cells expressed P-STAT3 and P-STAT5 at significantly higher levels than those in OVBT and NOV (P = 0.000). The staining of P-STAT1 and P-STAT6 was weak with no significant differences among OVCA, OVBT and NOV. (3) Expressions of VEGFR1 and VEGFR2 in endothelial cells were significantly correlated with P-STAT5 and P-STAT3, respectively (P = 0.006 and 0.001). In cancer cells, VEGF, VEGFR1 and VEGFR2 were all significantly correlated with P-STAT3 and P-STAT5 (P = 0.000), but not with P-STAT1 or P-STAT6. VEGF affects ovarian carcinoma cells via VEGFRs, and STATs probably participate in intracellular signaling of VEGF.

Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis.

PubMed

Fukushi, S; Yamasaki, K; Aiba, S

2011-11-01

Prurigo nodularis (PN) is a chronic dermatitis characterized by discrete, raised, and firm papulonodules with intense pruritus. The pathogenesis still remains to be elucidated. To clarify the role of Th1 and Th2 cytokines in the pathogenesis of PN. We examined the cytokine signatures, such as phosphorylation of STAT1, STAT3 and STAT6, HLA-DR and hyaluronan accumulation, to reveal the Th1 and Th2 cytokine influence on the lesional epidermis of PN. We first optimized antigen retrieval methods to detect these signatures with antibodies for phospho-STAT1 (pSTAT1), phospho-STAT3 (pSTAT3), phospho-STAT6 (pSTAT6), HLA-DR and hyaluronic acid binding protein (HABP) on the formalin-fixed paraffin-embedded sections of psoriasis, lichen planus and atopic dermatitis biopsy samples. Activation of STAT1 and STAT6 in epidermis by Th1 and Th2 cytokines was further confirmed in a cultured skin equivalent model treated with interferon-γ or interleukin (IL)-4/IL-13. With the relevant immunostaining methods, we examined the cytokine signatures in 22 cases of PN. The results revealed that (i) the entire epidermis of 19 cases was stained with anti-pSTAT6 antibody, (ii) 21 cases demonstrated nuclear staining with anti-pSTAT3 antibody, (iii) the entire epidermis of 21 cases was stained with HABP, (iv) the epidermis of eight cases showed scattered staining with anti-pSTAT1 antibody, and (v) six cases were positive for HLA-DR membrane expression. These data indicated that Th2 cytokines related to STAT6 activation together with some unknown stimuli that activate STAT3 play a principal role in the pathogenesis of PN. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

75 FR 70905 - President's Export Council: Meeting of the President's Export Council

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... Council will convene its next meeting via live webcast on the Internet at http:[sol][sol]whitehouse.gov[sol]live. FOR FURTHER INFORMATION CONTACT: J. Marc Chittum, President's Export Council, Room 4043...'s Export Council Web site at http:[sol][sol]trade.gov[sol]pec[sol]peccomments.asp; or Paper...

Inborn Errors of Human JAKs and STATs

PubMed Central

Casanova, Jean-Laurent; Holland, Steven M.; Notarangelo, Luigi D.

2012-01-01

Inborn errors of the genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described. We review the disorders arising from mutations in these five genes, highlighting the way in which the molecular and cellular pathogenesis of these conditions has been clarified by the discovery of inborn errors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. The phenotypic similarities between mice and humans lacking individual JAK-STAT components suggest that the functions of JAKs and STATs are largely conserved in mammals. However, a wide array of phenotypic differences has emerged between mice and humans carrying bi-allelic null alleles of JAK3, TYK2, STAT1, or STAT5B. Moreover, the high level of allelic heterogeneity at the human JAK3, STAT1, and STAT3 loci has revealed highly diverse immunological and clinical phenotypes, which had not been anticipated. PMID:22520845

Inborn errors of human JAKs and STATs.

PubMed

Casanova, Jean-Laurent; Holland, Steven M; Notarangelo, Luigi D

2012-04-20

Inborn errors of the genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described. We review the disorders arising from mutations in these five genes, highlighting the way in which the molecular and cellular pathogenesis of these conditions has been clarified by the discovery of inborn errors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. The phenotypic similarities between mice and humans lacking individual JAK-STAT components suggest that the functions of JAKs and STATs are largely conserved in mammals. However, a wide array of phenotypic differences has emerged between mice and humans carrying biallelic null alleles of JAK3, TYK2, STAT1, or STAT5B. Moreover, the high degree of allelic heterogeneity at the human JAK3, TYK2, STAT1, and STAT3 loci has revealed highly diverse immunological and clinical phenotypes, which had not been anticipated. Copyright © 2012 Elsevier Inc. All rights reserved.

First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy

PubMed Central

Sen, Malabika; Thomas, Sufi. M.; Kim, Seungwon; Yeh, Joanne I.; Ferris, Robert L.; Johnson, Jonas T.; Duvvuri, Umamaheswar; Lee, Jessica; Sahu, Nivedita; Joyce, Sonali; Freilino, Maria L.; Shi, Haibin; Li, Changyou; Ly, Danith; Rapireddy, Srinivas; Etter, Jonathan P.; Li, Pui-Kai; Wang, Lin; Chiosea, Simion; Seethala, Raja R.; Gooding, William. E.; Chen, Xiaomin; Kaminski, Naftali; Pandit, Kusum; Johnson, Daniel. E.; Grandis, Jennifer R.

2013-01-01

Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable”. We developed a decoy targeting STAT3 and performed a phase 0 trial. Expression levels of STAT3 target genes were decreased in the head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexa-ethyleneglycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. PMID:22719020

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia.

PubMed

Piairo, Paulina; Moura, Rute S; Baptista, Maria João; Correia-Pinto, Jorge; Nogueira-Silva, Cristina

2018-01-01

Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH. © 2018 The Author(s). Published by S. Karger AG, Basel.

Brain STAT5 signaling modulates learning and memory formation.

PubMed

Furigo, Isadora C; Melo, Helen M; Lyra E Silva, Natalia M; Ramos-Lobo, Angela M; Teixeira, Pryscila D S; Buonfiglio, Daniella C; Wasinski, Frederick; Lima, Eliana R; Higuti, Eliza; Peroni, Cibele N; Bartolini, Paolo; Soares, Carlos R J; Metzger, Martin; de Felice, Fernanda G; Donato, Jose

2018-06-01

The signal transducer and activator of transcription 5 (STAT5) is a transcription factor recruited by numerous cytokines. STAT5 is important for several physiological functions, including body and tissue growth, mammary gland development, immune system and lipid metabolism. However, the role of STAT5 signaling for brain functions is still poorly investigated, especially regarding cognitive aspects. Therefore, the objective of the present study was to investigate whether brain STAT5 signaling modulates learning and memory formation. For this purpose, brain-specific STAT5 knockout (STAT5 KO) mice were studied in well-established memory tests. Initially, we confirmed a robust reduction in STAT5a and STAT5b mRNA levels in different brain structures of STAT5 KO mice. STAT5 KO mice showed no significant alterations in metabolism, growth, somatotropic axis and spontaneous locomotor activity. In contrast, brain-specific STAT5 ablation impaired learning and memory formation in the novel object recognition, Barnes maze and contextual fear conditioning tests. To unravel possible mechanisms that might underlie the memory deficits of STAT5 KO mice, we assessed neurogenesis in the hippocampus, but no significant differences were observed between groups. On the other hand, reduced insulin-like growth factor-1 (IGF-1) mRNA expression was found in the hippocampus and hypothalamus of STAT5 KO mice. These findings collectively indicate that brain STAT5 signaling is required to attain normal learning and memory. Therefore, STAT5 is an important downstream cellular mechanism shared by several cytokines to regulate cognitive functions.

STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells.

PubMed

Lin, Li; Jou, David; Wang, Yina; Ma, Haiyan; Liu, Tianshu; Fuchs, James; Li, Pui-Kai; Lü, Jiagao; Li, Chenglong; Lin, Jiayuh

2016-12-01

Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer including pancreatic cancer. Whether STAT3 is activated in stem cell-like pancreatic cancer cells and the effect of STAT3 inhibition, is still unknown. Flow cytometry was used to isolate pancreatic cancer stem-like cells which are identified by both aldehyde dehydrogenase (ALDH)-positive (ALDH+) as well as cluster of differentiation (CD) 44-positive/CD24-positive subpopulations (CD44+/CD24+). STAT3 activation and the effects of STAT3 inhibition by STAT3 inhibitors, LLL12, FLLL32, and Stattic in ALDH+ and CD44+/CD24+ cells were examined. Our results showed that ALDH+ and CD44+/CD24+ pancreatic cancer stem-like cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, compared to ALDH-negative (ALDH-) and CD44-negative/CD24-negative (CD44-/CD24-) pancreatic cancer cells, suggesting that STAT3 is activated in pancreatic cancer stem-like cells. Small molecular STAT3 inhibitors inhibited STAT3 phosphorylation, STAT3 downstream target gene expression, cell viability, and tumorsphere formation in ALDH+ and CD44+/CD24+ cells. Our results indicate that STAT3 is a novel therapeutic target in pancreatic cancer stem-like cells and inhibition of activated STAT3 in these cells by STAT3 inhibitors may offer an effective treatment for pancreatic cancer.

Corrigendum to “Suppression of Υ production in d+Au and Au+Au collisions at √ SNN = 200 GeV" [Phys. Lett. B 735 (2014) 127-137

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adamczyk, L.

We report measurements of Υ meson production in p + p, d + Au, and Au+Au collisions using the STAR detector at RHIC. We compare the Υ yield to the measured cross section in p + p collisions in order to quantify any modifications of the yield in cold nuclear matter using d + Au data and in hot nuclear matter using Au+Au data separated into three centrality classes. Our p + p measurement is based on three times the statistics of our previous result. We obtain a nuclear modification factor for Upsilon (1S + 2S + 3S) in themore » rapidity range |y| < 1 in d + Au collisions of R dAu = 0.79 ± 0.24(stat.) ± 0.03(syst.) ± 0.10(p + p syst.). A comparison with models including shadowing and initial state parton energy loss indicates the presence of additional cold-nuclear matter suppression. Similarly, in the top 10% most-central Au + Au collisions, we measure a nuclear modification factor of R AA = 0.49 ±0.1(stat.) ±0.02(syst.) ±0.06(p + p syst.), which is a larger suppression factor than that seen in cold nuclear matter. Our results are consistent with complete suppression of excited-state Upsilon mesons in Au + Au collisions. The additional suppression in Au + Au is consistent with the level expected in model calculations that include the presence of a hot, deconfined Quark–Gluon Plasma. However, understanding the suppression seen in d + Au is still needed before any definitive statements about the nature of the suppression in Au + Au can be made.« less

Corrigendum to “Suppression of Υ production in d+Au and Au+Au collisions at √ SNN = 200 GeV" [Phys. Lett. B 735 (2014) 127-137

DOE PAGES

Adamczyk, L.

2015-04-01

We report measurements of Υ meson production in p + p, d + Au, and Au+Au collisions using the STAR detector at RHIC. We compare the Υ yield to the measured cross section in p + p collisions in order to quantify any modifications of the yield in cold nuclear matter using d + Au data and in hot nuclear matter using Au+Au data separated into three centrality classes. Our p + p measurement is based on three times the statistics of our previous result. We obtain a nuclear modification factor for Upsilon (1S + 2S + 3S) in themore » rapidity range |y| < 1 in d + Au collisions of R dAu = 0.79 ± 0.24(stat.) ± 0.03(syst.) ± 0.10(p + p syst.). A comparison with models including shadowing and initial state parton energy loss indicates the presence of additional cold-nuclear matter suppression. Similarly, in the top 10% most-central Au + Au collisions, we measure a nuclear modification factor of R AA = 0.49 ±0.1(stat.) ±0.02(syst.) ±0.06(p + p syst.), which is a larger suppression factor than that seen in cold nuclear matter. Our results are consistent with complete suppression of excited-state Upsilon mesons in Au + Au collisions. The additional suppression in Au + Au is consistent with the level expected in model calculations that include the presence of a hot, deconfined Quark–Gluon Plasma. However, understanding the suppression seen in d + Au is still needed before any definitive statements about the nature of the suppression in Au + Au can be made.« less

Conditional Stat1 Ablation Reveals the Importance of Interferon Signaling for Immunity to Listeria monocytogenes Infection

PubMed Central

Kernbauer, Elisabeth; Maier, Verena; Stoiber, Dagmar; Strobl, Birgit; Schneckenleithner, Christine; Sexl, Veronika; Reichart, Ursula; Reizis, Boris; Kalinke, Ulrich; Jamieson, Amanda; Müller, Mathias; Decker, Thomas

2012-01-01

Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naïve animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection. PMID:22719255

Los1p, involved in yeast pre-tRNA splicing, positively regulates members of the SOL gene family.

PubMed

Shen, W C; Stanford, D R; Hopper, A K

1996-06-01

To understand the role of Los1p in pre-tRNA splicing, we sought los1 multicopy suppressors. We found SOL1 that suppresses both point and null LOS1 mutations. Since, when fused to the Ga14p DNA-binding domain, Los1p activates transcription, we tested whether Los1p regulates SOL1. We found that las1 mutants have depleted levels of SOL1 mRNA and Sol1p. Thus, LOS1 appears to positively regulate SOL1. SOL1 belongs to a multigene family with at least two additional members, SOL2 and SOL3. Sol proteins have extensive similarity to an unusual group of glucose-6-phosphate dehydrogenases. As the similarities are restricted to areas separate from the catalytic domain, these G6PDs may have more than one function. The SOL family appears to be unessential since cells with a triple disruption of all three SOL genes are viable. SOL gene disruptions negatively affect tRNA-mediated nonsense suppression and the severity increases with the number of mutant SOL genes. However, tRNA levels do not vary with either multicopy SOL genes or with SOL disruptions. Therefore, the Sol proteins affect tRNA expression/ function at steps other than transcription or splicing. We propose that LOS1 regulates gene products involved in tRNA expression/function as well as pre-tRNA splicing.

The NEPRF (Naval Environmental Prediction Research Facility) Sunglint Pattern Calculation and Display System

DTIC Science & Technology

1989-01-01

CDATE,TN IQNX(1)=IDIFDTG(CIQNX,CDATE) SOL = FLOAT(IQNX(1))/24.DO/365.DO*360.DO*PI/180.DO SOLDEC=23.5DO*DSIN( SOL ) C C FIND THE LONGITUDE OF EQUATOR...CROSSING EQCX=LN IF(LH.EQ.1HW) EQCX=360.DO-EQCX C C FIND THE SOLAR LONGITUDE C READ (CTN,7004) SOL ,AMDA SOL = SOL +AMDA/60.DO SOL =DMOD(540.DO- SOL *15.DO,360.DO...AMDAxEQCX- SOL +360.DO AMDA=DMOD(AMDA, 360.DO) C WRITE (6,6000) IDATE WRITE (6,6001) HT,SIA IQNX(1)wIHE IF(SOL.LT.180.) GO TO 12 SOLz360.DO- SOL IQNX(1

Characterization of two mosquito STATs, AaSTAT and CtSTAT. Differential regulation of tyrosine phosphorylation and DNA binding activity by lipopolysaccharide treatment and by Japanese encephalitis virus infection.

PubMed

Lin, Chang-Chi; Chou, Chih-Ming; Hsu, Ya-Li; Lien, Jih-Ching; Wang, Yu-Ming; Chen, Shui-Tsung; Tsai, Shu-Chuan; Hsiao, Pei-Wen; Huang, Chang-Jen

2004-01-30

Two mosquito STATs, AaSTAT and CtSTAT, have been cloned from Aedes albopictus and Culex tritaeniorhynchus mosquitoes, respectively. These two STATs are more similar to those of Drosophila, Anopheles, and mammalian STAT5 in the DNA binding and Src homology 2 domains. The mRNA transcripts are expressed at all developmental stages, and the proteins are present predominantly at the pupal and adult stages in both mosquitoes. Stimulation with lipopolysaccharide resulted in an increase of tyrosine phosphorylation and DNA binding activity of AaSTAT and CtSTAT as well as an increase of luciferase activity of a reporter gene containing Drosophila STAT binding motif in mosquito C6/36 cells. After being infected with Japanese encephalitis virus, nuclear extracts of C6/36 cells revealed a decrease of tyrosine phosphorylation and DNA binding activity of AaSTAT which could be restored by sodium orthovanadate treatment. Taking all of the data together, this is the first report to clone and characterize two mosquito STATs with 81% identity and to demonstrate a different response of tyrosine phosphorylation and DNA binding of these two STATs by lipopolysaccharide treatment and by Japanese encephalitis virus infection.

Stat3-induced S1PR1 expression is critical for persistent Stat3 activation in tumors

PubMed Central

Lee, Heehyoung; Deng, Jiehui; Kujawski, Maciej; Yang, Chunmei; Liu, Yong; Herrmann, Andreas; Kortylewski, Marcin; Horne, David; Somlo, George; Forman, Stephen; Jove, Richard; Yu, Hua

2011-01-01

IL-6/Jak2 signaling is viewed critical for persistent Stat3 activation in cancer. However, IL-6-induced Stat3 activity is transient in normal physiology. Here we identify a mechanism important for persistent Stat3 activation in tumor cells and the tumor microenvironment. We show that sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor for lysophospholipid sphingosine-1-phosphate (S1P), is elevated in Stat3-positive tumors. Stat3 is a transcription factor for the S1pr1 gene. Enhanced S1pr1 expression activates Stat3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis. Conversely, silencing S1pr1 in tumor cells or immune cells inhibits tumor Stat3 activity, tumor growth and metastasis. S1P/S1PR1-induced Stat3 activation is persistent, in contrast to transient Stat3 activation by IL-6. S1PR1 activates Stat3 in part by upregulating Jak2 tyrosine kinase activity. We demonstrate that Stat3-induced S1pr1 expression, as well as S1P/S1PR1 pathway, is important for persistent Stat3 activation in cancer cells and the tumor microenvironment and for malignant progression. PMID:21102457

Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease.

PubMed

Szelag, Malgorzata; Piaszyk-Borychowska, Anna; Plens-Galaska, Martyna; Wesoly, Joanna; Bluyssen, Hans A R

2016-07-26

Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses.Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors.This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs.

Validation of nuclear STAT6 immunostaining as a diagnostic marker of meningeal solitary fibrous tumor (SFT)/hemangiopericytoma.

PubMed

Berghoff, Anna S; Kresl, Philip; Bienkowski, Michal; Koelsche, Christian; Rajky, Ursula; Hainfellner, Johannes A; Preusser, Matthias

NAB2-STAT6 gene fusion is a molecular characteristic of solitary fibrous tumors (SFT) and hemangiopericytoma, underscoring their definition as one diagnostic entity. NAB2-STAT6 fusion is associated with nuclear relocation of STAT6 protein that can be detected by immunohistochemistry. We evaluated the diagnostic value of STAT6 expression in meningeal tumors. 77 meningeal tumors (17/77 (22.0%) SFT/hemangiopericytoma, 11/77 meningothelial meningioma, 10/77 atypical meningioma 8/77 chordoid meningioma, 9/77 fibroblastic meningioma, 10/77 transitional meningioma, 3/77 rhabdoid meningioma and 9/77 anaplastic meningioma) were included. STAT6 immunohistochemistry was performed on FFPE specimens using a fully automated slide-staining system and anti-STAT6 antibody SC-20:sc621. Two independent observers analyzed all specimens blinded to histological diagnoses, and a third observer was consulted in case of discordancy. STAT6 immunohistochemistry yielded an exclusively nuclear immunostaining signal. 16/17 (94%) SFT/hemangiopericytoma specimens presented with clear-cut, wide-spread, and moderate to strong staining in tumor cell nuclei and were rated as STAT6-positive. In only 1 SFT case with weak and focal nuclear STAT6 immunostaining signal, STAT6 expression was rated discordant (observer 1: STAT6-negative, observers 2 and 3: STAT6-positive). All non-SFT/hemangiopericytoma cases were unanimously rated as STAT6-negative. In 76/77 (98.7%) cases the evaluation of STAT6 immunostaining results was in agreement among observers. STAT6 immunohistochemistry is a robust method to verify diagnosis of SFT/hemangiopericytoma and should therefore be included in the diagnostic work-up of meningeal tumors. In singular cases, weak and focal STAT6 expression may lead to false-negative evaluation and may prompt further molecular work-up.
.

Novel Multiplexed Assay for Identifying SH2 Domain Antagonists of STAT Family Proteins

PubMed Central

Takakuma, Kazuyuki; Ogo, Naohisa; Uehara, Yutaka; Takahashi, Susumu; Miyoshi, Nao; Asai, Akira

2013-01-01

Some of the signal transducer and activator of transcription (STAT) family members are constitutively activated in a wide variety of human tumors. The activity of STAT depends on their Src homology 2 (SH2) domain-mediated binding to sequences containing phosphorylated tyrosine. Thus, antagonizing this binding is a feasible approach to inhibiting STAT activation. We have developed a novel multiplexed assay for STAT3- and STAT5b-SH2 binding, based on amplified luminescent proximity homogeneous assay (Alpha) technology. AlphaLISA and AlphaScreen beads were combined in a single-well assay, which allowed the binding of STAT3- and STAT5b-SH2 to phosphotyrosine peptides to be simultaneously monitored. Biotin-labeled recombinant human STAT proteins were obtained as N- and C-terminal deletion mutants. The spacer length of the DIG-labeled peptide, the reaction time, and the concentration of sodium chloride were optimized to establish a HTS system with Z’ values of greater than 0.6 for both STAT3- and STAT5b-SH2 binding. We performed a HTS campaign for chemical libraries using this multiplexed assay and identified hit compounds. A 2-chloro-1,4-naphthalenedione derivative, Compound 1, preferentially inhibited STAT3-SH2 binding in vitro, and the nuclear translocation of STAT3 in HeLa cells. Initial structure activity relationship (SAR) studies using the multiplexed assay showed the 3-substituent effect on both the activity and selectivity of STAT3 and STAT5b inhibition. Therefore, this multiplexed assay is useful for not only searching for potential lead compounds but also obtaining SAR data for developing new STAT3/STAT5b inhibitors. PMID:23977103

Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus

PubMed Central

Lee, Jae Hee; Kim, Tae Hoon; Oh, Seo Jin; Yoo, Jung-Yoon; Akira, Shizuo; Ku, Bon Jeong; Lydon, John P.; Jeong, Jae-Wook

2013-01-01

Recent studies have shown that activation of the signal transducer and activator of transcription-3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR-A, which is known to be important for uterine development and function, but not with PR-B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR-positive cells (PRcre/+ Stat3f/f; Stat3d/d). Our studies revealed that ovarian function and uterine development of Stat3d/d mice were normal. However, Stat3d/d female mice were infertile due to defective embryo implantation. Unlike Stat3f/f mice, Stat3d/d mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3d/d mice were unable to undergo a well-characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3d/d mice, and PR target genes were significantly down-regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.—Lee, J. H., Kim, T. H., Oh, S. J., Yoo, J.-Y., Akira, S., Ku, B. J., Lydon, J. P., Jeong, J.-W. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. PMID:23531596

Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease

PubMed Central

Szelag, Malgorzata; Piaszyk-Borychowska, Anna; Plens-Galaska, Martyna; Wesoly, Joanna; Bluyssen, Hans A.R.

2016-01-01

Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses. Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors. This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs. PMID:27166190

Novel multiplexed assay for identifying SH2 domain antagonists of STAT family proteins.

PubMed

Takakuma, Kazuyuki; Ogo, Naohisa; Uehara, Yutaka; Takahashi, Susumu; Miyoshi, Nao; Asai, Akira

2013-01-01

Some of the signal transducer and activator of transcription (STAT) family members are constitutively activated in a wide variety of human tumors. The activity of STAT depends on their Src homology 2 (SH2) domain-mediated binding to sequences containing phosphorylated tyrosine. Thus, antagonizing this binding is a feasible approach to inhibiting STAT activation. We have developed a novel multiplexed assay for STAT3- and STAT5b-SH2 binding, based on amplified luminescent proximity homogeneous assay (Alpha) technology. AlphaLISA and AlphaScreen beads were combined in a single-well assay, which allowed the binding of STAT3- and STAT5b-SH2 to phosphotyrosine peptides to be simultaneously monitored. Biotin-labeled recombinant human STAT proteins were obtained as N- and C-terminal deletion mutants. The spacer length of the DIG-labeled peptide, the reaction time, and the concentration of sodium chloride were optimized to establish a HTS system with Z' values of greater than 0.6 for both STAT3- and STAT5b-SH2 binding. We performed a HTS campaign for chemical libraries using this multiplexed assay and identified hit compounds. A 2-chloro-1,4-naphthalenedione derivative, Compound 1, preferentially inhibited STAT3-SH2 binding in vitro, and the nuclear translocation of STAT3 in HeLa cells. Initial structure activity relationship (SAR) studies using the multiplexed assay showed the 3-substituent effect on both the activity and selectivity of STAT3 and STAT5b inhibition. Therefore, this multiplexed assay is useful for not only searching for potential lead compounds but also obtaining SAR data for developing new STAT3/STAT5b inhibitors.

Constitutive STAT5 Activation Correlates With Better Survival in Cervical Cancer Patients Treated With Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Helen H.W.; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Chou, Cheng-Yang

2012-02-01

Purpose: Constitutively activated signal transducers and activators of transcription (STAT) factors, in particular STAT1, STAT3, and STAT5, have been detected in a wide variety of human primary tumors and have been demonstrated to directly contribute to oncogenesis. However, the expression pattern of these STATs in cervical carcinoma is still unknown, as is whether or not they have prognostic significance. This study investigated the expression patterns of STAT1, STAT3, and STAT5 in cervical cancer and their associations with clinical outcomes in patients treated with radical radiation therapy. Methods and Materials: A total of 165 consecutive patients with International Federation of Gynecologymore » and Obstetrics (FIGO) Stages IB to IVA cervical cancer underwent radical radiation therapy, including external beam and/or high-dose-rate brachytherapy between 1989 and 2002. Immunohistochemical studies of their formalin-fixed, paraffin-embedded tissues were performed. Univariate and multivariate analyses were performed to identify and to evaluate the effects of these factors affecting patient survival. Results: Constitutive activations of STAT1, STAT3, and STAT5 were observed in 11%, 22%, and 61% of the participants, respectively. While STAT5 activation was associated with significantly better metastasis-free survival (p < 0.01) and overall survival (p = 0.04), STAT1 and STAT3 activation were not. Multivariate analyses showed that STAT5 activation, bulky tumor ({>=}4 cm), advanced stage (FIGO Stages III and IV), and brachytherapy (yes vs. no) were independent prognostic factors for cause-specific overall survival. None of the STATs was associated with local relapse. STAT5 activation (odds ratio = 0.29, 95% confidence interval = 0.13-0.63) and advanced stage (odds ratio = 2.54; 95% confidence interval = 1.03-6.26) were independent predictors of distant metastasis. Conclusions: This is the first report to provide the overall expression patterns and prognostic significance of specific STATs in cervical carcinoma. Our results indicate that constitutive STAT5 activation correlates with better metastasis-free survival and overall survival in cervical cancer patients who have received radiation therapy.« less

Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer.

PubMed

Lewis, Katherine M; Bharadwaj, Uddalak; Eckols, T Kris; Kolosov, Mikhail; Kasembeli, Moses M; Fridley, Colleen; Siller, Ricardo; Tweardy, David J

2015-11-01

Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically. We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and β) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL). Levels of pSTAT3, STAT3α, and STATβ were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3β, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47-78% reduction in anchorage-dependent and anchorage-independent growth and a 28-45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30 μM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25-60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06 to 52.44 μM and 0.86 to 11.66 μM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins. STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococci

PubMed Central

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2013-01-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 may disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococci, especially Staphylococcus aureus. Here, we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococci. PMID:23040277

Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage

PubMed Central

Cain, Jennifer A.; Xiang, Zhifu; O'Neal, Julie; Kreisel, Friederike; Colson, AnnaLynn; Luo, Hui; Hennighausen, Lothar

2007-01-01

Expression of the constitutively activated TEL/PDGFβR fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGFβR activates multiple signal transduction pathways in cell-culture systems, and expression of the TEL-PDGFRB fusion gene induces myeloproliferative disease (MPD) in mice. We used gene-targeted mice to characterize the contribution of signal transducer and activator of transcription (Stat) and Src family genes to TEL-PDGFRB–mediated transformation in methylcellulose colony and murine bone marrow transduction/transplantation assays. Fetal liver hematopoietic stem and progenitor cells harboring targeted deletion of both Stat5a and Stat5b (Stat5abnull/null) genes were refractory to transformation by TEL-PDGFRB in methylcellulose colony assays. Notably, these cell populations were maintained in Stat5abnull/null fetal livers and succumbed to transformation by c-Myc. Surprisingly, targeted disruption of either Stat5a or Stat5b alone also impaired TEL-PDGFRB–mediated transformation. Survival of TPiGFP→Stat5a−/− and TPiGFP→Stat5a+/− mice was significantly prolonged, demonstrating significant sensitivity of TEL-PDGFRB–induced MPD to the dosage of Stat5a. TEL-PDGFRB–mediated MPD was incompletely penetrant in TPiGFP→Stat5b−/− mice. In contrast, Src family kinases Lyn, Hck, and Fgr and the Stat family member Stat1 were dispensable for TEL-PDGFRB disease. Together, these data demonstrate that Stat5a and Stat5b are dose-limiting mediators of TEL-PDGFRB–induced myeloproliferation. PMID:17218386

STAT3 Oligonucleotide Inhibits Tumor Angiogenesis in Preclinical Models of Squamous Cell Carcinoma

PubMed Central

Klein, Jonah D.; Sano, Daisuke; Sen, Malabika; Myers, Jeffrey N.; Grandis, Jennifer R.; Kim, Seungwon

2014-01-01

Purpose Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis. Experimental Design A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models. Results STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1. Conclusions The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies. PMID:24404126

STAT1 in cancer: friend or foe?

PubMed

Zhang, Ying; Liu, Zhaoyong

2017-08-01

The first STAT family member, STAT1, is an essential component of interferon (IFN)-signaling, which mediates several cellular functions in response to stimulation by cytokines, growth factors, and hormones, such as the IFNs and IL-6. The role and significance of STAT1 in cancer biology have been studied for a decade. The majority of evidence shows that activating STAT1 plays a tumor suppressor role in cancer cells. Nevertheless, results from some experiments and clinical studies suggest that STAT1 also exerts tumor promoter effects under specific conditions. In some malignant phenotypes, STAT1 can function either as an oncoprotein or tumor suppressor in the same cell type, depending on the specific genetic background. Thus, the function of STAT1 in cancer biology remains a mystery. In this review, we discuss both the "friend" and "foe" features of STAT1 by summarizing its tumor suppressor or oncogenic functions and mechanisms. To explain how STAT1 may mediate its tumor suppressor effects, we discuss several possible mechanisms, one of which is linked to the role of STAT1β, an isoform of STAT1.

Acanthamoeba castellanii STAT protein.

PubMed

Kicinska, Anna; Leluk, Jacek; Jarmuszkiewicz, Wieslawa

2014-01-01

STAT (signal transducers and activators of transcription) proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. We described the presence of STAT protein in a unicellular, free-living amoebae with a simple life cycle, Acanthamoeba castellanii. A. castellanii is the only, studied to date, Amoebozoan that does not belong to Mycetozoa but possesses STATs. A sequence of the A. castellanii STAT protein includes domains similar to those of the Dictyostelium STAT proteins: a coiled coil (characteristic for Dictyostelium STAT coiled coil), a STAT DNA-binding domain and a Src-homology domain. The search for protein sequences homologous to A. castellanii STAT revealed 17 additional sequences from lower eukaryotes. Interestingly, all of these sequences come from Amoebozoa organisms that belong to either Mycetozoa (slime molds) or Centramoebida. We showed that there are four separated clades within the slime mold STAT proteins. The A. castellanii STAT protein branches next to a group of STATc proteins from Mycetozoa. We also demonstrate that Amoebozoa form a distinct monophyletic lineage within the STAT protein world that is well separated from the other groups.

The Sizing and Optimization Language, (SOL): Computer language for design problems

NASA Technical Reports Server (NTRS)

Lucas, Stephen H.; Scotti, Stephen J.

1988-01-01

The Sizing and Optimization Language, (SOL), a new high level, special purpose computer language was developed to expedite application of numerical optimization to design problems and to make the process less error prone. SOL utilizes the ADS optimization software and provides a clear, concise syntax for describing an optimization problem, the OPTIMIZE description, which closely parallels the mathematical description of the problem. SOL offers language statements which can be used to model a design mathematically, with subroutines or code logic, and with existing FORTRAN routines. In addition, SOL provides error checking and clear output of the optimization results. Because of these language features, SOL is best suited to model and optimize a design concept when the model consits of mathematical expressions written in SOL. For such cases, SOL's unique syntax and error checking can be fully utilized. SOL is presently available for DEC VAX/VMS systems. A SOL package is available which includes the SOL compiler, runtime library routines, and a SOL reference manual.

Toward a new STATe: The role of STATs in mitochondrial function

PubMed Central

Meier, Jeremy A.; Larner, Andrew C.

2014-01-01

Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease. PMID:24434063

STAT3 selectively interacts with Smad3 to antagonize TGF-β signaling

PubMed Central

Wang, Gaohang; Yu, Yi; Sun, Chuang; Liu, Ting; Liang, Tingbo; Zhan, Lixing; Lin, Xia; Feng, Xin-Hua

2015-01-01

Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates TGF-β-induced responses through a direct Smad3-STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3-Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3-Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. PMID:26616859

Opposite nuclear level and binding activity of STAT5B and STAT3 proteins with rat haptoglobin gene under normal and turpentine induced acute phase conditions.

PubMed

Grigorov, I; Lazić, T; Cvetković, I; Milosavljević, T; Petrović, M

2001-01-01

Transcription of the rat gene encoding haptoglobin (Hp) is highly induced during acute phase (AP) response which has been previously shown to be mediated by inducible STAT3 member of the Signal Transducer and Activators of Transcription (STATs) family proteins. In this study, we observed that under normal but not in the turpentine induced AP conditions, another member of the STAT family proteins, STAT5b is expressed and binds to the hormone regulatory element (HRE) of the rat Hp gene. We found that the nuclear amounts of constitutively active STAT5b in rat liver decreased significantly with time of turpentine treatment as opposed to that of cytosol STAT5b, suggesting possible export of constitutive STAT5b from the nucleus. Nuclear accumulation and binding of inducible STAT3 proteins to the rat Hp gene HRE following turpentine treatment implicated that STAT5b negatively regulates Hp gene expression during normal conditions.

Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling

PubMed Central

Kuusanmäki, Heikki; Dufva, Olli; Parri, Elina; van Adrichem, Arjan J.; Rajala, Hanna; Majumder, Muntasir M.; Yadav, Bhagwan; Parsons, Alun; Chan, Wing C.; Wennerberg, Krister; Mustjoki, Satu; Heckman, Caroline A.

2017-01-01

Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3. PMID:29228628

Los1p, involved in yeast pre-tRNA splicing, positively regulates members of the SOL gene family

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, W.C.; Stanford, D.R.; Hopper, A.K.

1996-06-01

To understand the role of Los1p in pre-tRNA splicing, we sought los1 multicopy suppressors. We found SOL1 that suppresses both point and null LOS1 mutations. Since, when fused to the Gal4p DNA-binding domain, Los1p activates transcription, we tested whether Los1p regulates SOL1. We found that los1 mutants have depleted levels of SOL1 mRNA and Sol1p. Thus, LOS1 appears to positively regulate SOL1. SOL1 belongs to a multigene family with at least two additional members, SOL2 and SOL3. Sol proteins have extensive similarity to an unusual group of glucose-6-phosphate dehydrogenases (G6PDs). As the similarities are restricted to areas separate from themore » catalytic domain, these G6PDs may have more than one function. The SOL gene disruptions negatively affect tRNA-mediated nonsense suppression and the severity increases with the number of mutant SOL genes. However, tRNA levels do not vary with either multicopy SOL genes or with SOL disruptions. Therefore, the Sol proteins affect tRNA expression/function at steps other than transcription or splicing. We propose that LOS1 regulates gene products involved in tRNA expression/function as well as pre-tRNA splicing. 64 refs., 6 figs., 6 tabs.« less

Signaling by STATs.

PubMed

Ivashkiv, Lionel B; Hu, Xiaoyu

2004-01-01

A variety of cytokines and growth factors use the Janus kinase (Jak)-STAT signaling pathway to transmit extracellular signals to the nucleus. STATs (signal transducers and activators of transcription) are latent cytoplasmic transcription factors. There are seven mammalian STATs and they have critical, nonredundant roles in mediating cellular transcriptional responses to cytokines. The physiological roles of STATs have been elucidated by analysis of mice rendered deficient in STAT genes. STAT activation is regulated and can be modulated in a positive or negative fashion; it can be reprogrammed to drive different cellular responses. Several auto-regulatory and signaling crosstalk mechanisms for regulating Jak-STAT signaling have been described. Understanding and manipulation of the function of STATs will help in the development of therapeutic strategies for diseases that are regulated by cytokines.

75 FR 57956 - Draft Revision of the Federalwide Assurance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-23

...:[sol][sol]www.hhs.gov/ohrp/assurances/assurances_index.html. OHRP will consider comments received...:[sol][sol]www.regulations.gov. Enter the above docket ID number in the ``Enter Keyword or ID'' field... received, including any personal information, will be posted without change to http:[sol][sol]www...

77 FR 30439 - Proposed Establishment of Class E Airspace; Apopka, FL

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-23

... through the Internet at http:[sol][sol]www.regulations.gov. FOR FURTHER INFORMATION CONTACT: John Fornito...:[sol][sol]www.regulations.gov. Persons wishing the FAA to acknowledge receipt of their comments on this... http:[sol][sol]www.regulations.gov. Recently published rulemaking documents can also be accessed...

76 FR 38585 - Proposed Establishment of Class E Airspace; Wilkes-Barre, PA

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... may also submit and review received comments through the Internet at http:[sol][sol]www.regulations... submit comments through the Internet at http:[sol][sol]www.regulations.gov. Annotators wishing the FAA to... downloaded from and comments submitted through http:[sol][sol]www.regulations.gov. Recently published...

75 FR 73015 - Proposed Amendment of Class E Airspace; Newport, VT

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-29

... comments through the Internet at http:[sol][sol]www.regulations.gov. FOR FURTHER INFORMATION CONTACT...:[sol][sol]www.regulations.gov. Commenters wishing the FAA to acknowledge receipt of their comments on... submitted through http:[sol][sol]www.regulations.gov. Recently published rulemaking documents can also be...

78 FR 32212 - Proposed Amendment of Class E Airspace; Factoryville, PA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

... received comments through the Internet at http:[sol][sol]www.regulations.gov. FOR FURTHER INFORMATION... comments through the Internet at http:[sol][sol]www.regulations.gov. Persons wishing the FAA to acknowledge... from and comments submitted through http:[sol][sol]www.regulations.gov. Recently published rulemaking...

75 FR 62024 - Metal and Nonmetal Dams

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-07

... the following methods: (1) Federal Rulemaking Portal: http:[sol][sol]www.regulations.gov. Follow the... receptionist's desk on the 21st floor. (6) Docket: Comments can be accessed electronically at http:[sol][sol... publishes rulemaking documents in the Federal Register. To subscribe, go to http:[sol][sol]www.msha.gov...

76 FR 52297 - Defense Federal Acquisition Regulation Supplement; Safeguarding Unclassified DoD Information

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-22

...: http:[sol][sol]www.regulations.gov. Follow the instructions for submitting comments. [cir] E-mail... without change to http:[sol][sol]www.regulations.gov, including any personal information provided. To confirm receipt of your comment, please check http:[sol][sol]www.regulations.gov approximately two to...

78 FR 32213 - Proposed Amendment of Class E Airspace; Bedford, PA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

... at http:[sol][sol]www.regulations.gov. FOR FURTHER INFORMATION CONTACT: John Fornito, Operations... for address and phone number). You may also submit comments through the Internet at http:[sol][sol]www...:[sol][sol]www.regulations.gov. Recently published rulemaking documents can also be accessed through the...

75 FR 73016 - Proposed Establishment of Class E Airspace; Kenbridge, VA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-29

... the Internet at http:[sol][sol]www.regulations.gov. FOR FURTHER INFORMATION CONTACT: Richard Horrocks...:[sol][sol]www.regulations.gov. Comments wishing the FAA to acknowledge receipt of their comments on... comments submitted through http:[sol][sol]www.regulations.gov. Recently published rulemaking documents can...

STAT6 is amplified in a subset of dedifferentiated liposarcoma.

PubMed

Doyle, Leona A; Tao, Derrick; Mariño-Enríquez, Adrián

2014-09-01

A recurrent intrachromosomal rearrangement on chromosome 12q in solitary fibrous tumor leads to the formation of a NAB2-STAT6 fusion oncogene. As a result, nuclear expression of the cytoplasmic transcription factor STAT6 is found in solitary fibrous tumor and serves as a useful diagnostic marker. STAT6 is located in 12q13, a region containing well-characterized oncogenes that are commonly amplified in dedifferentiated liposarcoma; we have previously reported that STAT6 is expressed in a subset of dedifferentiated liposarcoma. The aim of this study was to determine the frequency of STAT6 expression in dedifferentiated liposarcoma and the underlying genetic mechanism. STAT6 protein expression was analyzed by immunohistochemistry in a well-characterized series of 35 previously unpublished cases of dedifferentiated liposarcoma, all with nuclear MDM2 and/or CDK4 expression by immunohistochemistry and/or cytogenetic features of dedifferentiated liposarcoma. FISH for STAT6 was performed in all cases with STAT6 expression, and a subset of control cases without STAT6 expression. In total 4/35 cases (11%) showed STAT6 expression (three with multifocal staining of moderate to strong intensity and one with weak focal staining). FISH demonstrated amplification of STAT6 in all cases positive for STAT6 by immunohistochemistry; in contrast, FISH performed on four STAT6-negative dedifferentiated liposarcomas demonstrated no STAT6 amplification (P=0.0286). Of the four STAT6 amplified cases, three patients were male and one was female, ranging in age from 51 to 76 years. Tumors were located in the mediastinum (n=2), paratesticular soft tissue (n=1), and perirenal soft tissue (n=1). Three patients received pre-operative chemotherapy +/- radiation therapy. In conclusion, STAT6 is amplified in a subset of dedifferentiated liposarcoma, resulting in STAT6 protein expression that can be detected by immunohistochemistry and may be a potential pitfall in the differential diagnosis of dedifferentiated liposarcoma and solitary fibrous tumor. These findings suggest a role for STAT6-mediated transcriptional activity in some cases of dedifferentiated liposarcoma and highlight the genomic complexity and heterogeneity of dedifferentiated liposarcoma.

Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma.

PubMed

Arzt, Lisa; Halbwedl, Iris; Gogg-Kamerer, Margit; Popper, Helmut H

2017-07-01

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is still increasing in Europe and the prognosis remains poor. We investigated the oncogenic function of signal transducer and activator of transcription 1 (STAT1) in MPM in more detail. A miRNA profiling was performed on 52 MPM tissue samples. Upregulated miRNAs (targeting SOCS1/3) were knocked-down using miRNA inhibitors. mRNA expression levels of STAT1/3, SOCS1/3 were detected in MPM cell lines. STAT1 has been knocked-down using siRNA and qPCR was used to detect mRNA expression levels of all JAK/STAT family members and genes that regulate them. An immunohistochemical staining was performed to detect the expression of caspases. STAT1 was upregulated and STAT3 was downregulated, SOCS1/3 protein was not detected but it was possible to detect SOCS1/3 mRNA in MPM cell lines. The upregulated miRNAs were successfully knocked-down, however the expected effect on SOCS1 expression was not detected. STAT1 knock-down had different effects on STAT3/5 expression. Caspase 3a and 8 expression was found to be increased after STAT1 knock-down. The physiologic regulation of STAT1 via SOCS1 is completely lost in MPM and it does not seem that the miRNAs identified by now, do inhibit the expression of SOCS1. MPM cell lines compensate STAT1 knock-down by increasing the expression of STAT3 or STAT5a, two genes which are generally considered to be oncogenes. And much more important, STAT1 knock-down induces apoptosis in MPM cell lines and STAT1 might therefore be a target for therapeutic intervention.

Stat1-independent regulation of gene expression in response to IFN-γ

PubMed Central

Ramana, Chilakamarti V.; Gil, M. Pilar; Han, Yulong; Ransohoff, Richard M.; Schreiber, Robert D.; Stark, George R.

2001-01-01

Although Stat1 is essential for cells to respond fully to IFN-γ, there is substantial evidence that, in the absence of Stat1, IFN-γ can still regulate the expression of some genes, induce an antiviral state and affect cell growth. We have now identified many genes that are regulated by IFN-γ in serum-starved Stat1-null mouse fibroblasts. The proteins induced by IFN-γ in Stat1-null cells can account for the substantial biological responses that remain. Some genes are induced in both wild-type and Stat1-null cells and thus are truly Stat1-independent. Others are subject to more complex regulation in response to IFN-γ, repressed by Stat1 in wild-type cells and activated in Stat1-null cells. Many genes induced by IFN-γ in Stat1-null fibroblasts also are induced by platelet-derived growth factor in wild-type cells and thus are likely to be involved in cell proliferation. In mouse cells expressing the docking site mutant Y440F of human IFN-γ receptor subunit 1, the mouse Stat1 is not phosphorylated in response to human IFN-γ, but c-myc and c-jun are still induced, showing that the Stat1 docking site is not required for Stat1-independent signaling. PMID:11390994

Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Yun; Zhou, Lin; Xie, Haiyang

2015-06-05

Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between themore » two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.« less

Toward a new STATe: the role of STATs in mitochondrial function.

PubMed

Meier, Jeremy A; Larner, Andrew C

2014-02-01

Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

75 FR 70956 - Post Office Closing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... electronically via the Commission's Filing Online system at http:[sol][sol]www.prc.gov. Those who cannot submit... supporting material on its Web site at http:[sol][sol]www.prc.gov. Additional filings in this case and...) pursuant to Commission rules 9(a) and 10(a) at the Commission's Web site, http:[sol][sol]www.prc.gov...

75 FR 70965 - Petition for Exemption; Summary of Petition Received

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... rulemaking Web site: Go to http:[sol][sol]www.regulations.gov and follow the instructions for sending your.... Privacy: We will post all comments we receive, without change, to http:[sol][sol]www.regulations.gov... 19477-78). Docket: To read background documents or comments received, go to http:[sol][sol]www...

Altered expression and activation of signal transducers and activators of transcription (STATs) in hepatitis C virus infection: in vivo and in vitro studies.

PubMed

Larrea, E; Aldabe, R; Molano, E; Fernandez-Rodriguez, C M; Ametzazurra, A; Civeira, M P; Prieto, J

2006-08-01

Signal transducers and activators of transcription (STATs) play a critical role in antiviral defence. STAT3 is also important in cell protection against inflammatory damage. STAT proteins are activated by interferons and by hepatoprotective cytokines of the interleukin 6 superfamily, including cardiotrophin 1. We analysed the status of STATs in hepatitis C virus (HCV) infected livers and the relationship between expression and activation of STATs and HCV replication in Huh7 cells transfected with HCV genomic replicon. STAT3alpha expression was reduced in HCV infected livers showing an inverse correlation with serum alanine aminotransferase. In patients with HCV infection, nuclear staining for phosphorylated STAT3 was faint in parenchymal cells (although conspicuous in infiltrating leucocytes), in contrast with strong nuclear staining in hepatocytes from control livers. Expression and activation of STAT1 (a factor activated by both interferon (IFN)-alpha and IFN-gamma) were increased in HCV infected livers, particularly in those with high inflammatory activity. Conversely, phosphorylated STAT2 (a factor selectively activated by IFN-alpha) was undetectable in livers with HCV infection, a finding that was associated with marked downregulation of the two functional subunits of the IFN-alpha receptor. HCV replication in Huh7 cells caused STAT3alpha downregulation and blocked STAT3 phosphorylation by either IFN-alpha or cardiotrophin 1. HCV replication in Huh7 cells also inhibited STAT1 and STAT2 activation by IFN-alpha while there was no impairment of STAT1 phosphorylation by the proinflammatory cytokine IFN-gamma. STAT3 is downregulated in HCV infected livers and in Huh7 cells bearing the full length HCV replicon. HCV replication is associated with impaired Jak-STAT signalling by antiviral and cytoprotective cytokines. These effects may favour viral replication while facilitating the progression of liver disease.

Signaling by STATs

PubMed Central

Ivashkiv, Lionel B; Hu, Xiaoyu

2004-01-01

A variety of cytokines and growth factors use the Janus kinase (Jak)–STAT signaling pathway to transmit extracellular signals to the nucleus. STATs (signal transducers and activators of transcription) are latent cytoplasmic transcription factors. There are seven mammalian STATs and they have critical, nonredundant roles in mediating cellular transcriptional responses to cytokines. The physiological roles of STATs have been elucidated by analysis of mice rendered deficient in STAT genes. STAT activation is regulated and can be modulated in a positive or negative fashion; it can be reprogrammed to drive different cellular responses. Several auto-regulatory and signaling crosstalk mechanisms for regulating Jak–STAT signaling have been described. Understanding and manipulation of the function of STATs will help in the development of therapeutic strategies for diseases that are regulated by cytokines. PMID:15225360

Identification of STAT target genes in adipocytes

PubMed Central

Zhao, Peng; Stephens, Jacqueline M.

2013-01-01

Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. Studies in the last two decades have identified the hormones and cytokines that activate specific STATs in adipocytes in vitro and in vivo. Five of the seven STAT family members are expressed in adipocyte (STATs 1, 3, 5A, 5B and 6). Many transcription factors, including STATs, have been shown to play an important role in adipose tissue development and function. This review will summarize the importance of adipocytes, indicate the cytokines and hormones that utilize the JAK-STAT signaling pathway in fat cells and focus on the identification of STAT target genes in mature adipocytes. To date, specific target genes have been identified for STATs, 1, 5A and 5B, but not for STATs 3 and 6. PMID:24058802

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species.

PubMed

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2012-11-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.

PubMed

Liu, Luyan; Okada, Satoshi; Kong, Xiao-Fei; Kreins, Alexandra Y; Cypowyj, Sophie; Abhyankar, Avinash; Toubiana, Julie; Itan, Yuval; Audry, Magali; Nitschke, Patrick; Masson, Cécile; Toth, Beata; Flatot, Jérome; Migaud, Mélanie; Chrabieh, Maya; Kochetkov, Tatiana; Bolze, Alexandre; Borghesi, Alessandro; Toulon, Antoine; Hiller, Julia; Eyerich, Stefanie; Eyerich, Kilian; Gulácsy, Vera; Chernyshova, Ludmyla; Chernyshov, Viktor; Bondarenko, Anastasia; Grimaldo, Rosa María Cortés; Blancas-Galicia, Lizbeth; Beas, Ileana Maria Madrigal; Roesler, Joachim; Magdorf, Klaus; Engelhard, Dan; Thumerelle, Caroline; Burgel, Pierre-Régis; Hoernes, Miriam; Drexel, Barbara; Seger, Reinhard; Kusuma, Theresia; Jansson, Annette F; Sawalle-Belohradsky, Julie; Belohradsky, Bernd; Jouanguy, Emmanuelle; Bustamante, Jacinta; Bué, Mélanie; Karin, Nathan; Wildbaum, Gizi; Bodemer, Christine; Lortholary, Olivier; Fischer, Alain; Blanche, Stéphane; Al-Muhsen, Saleh; Reichenbach, Janine; Kobayashi, Masao; Rosales, Francisco Espinosa; Lozano, Carlos Torres; Kilic, Sara Sebnem; Oleastro, Matias; Etzioni, Amos; Traidl-Hoffmann, Claudia; Renner, Ellen D; Abel, Laurent; Picard, Capucine; Maródi, László; Boisson-Dupuis, Stéphanie; Puel, Anne; Casanova, Jean-Laurent

2011-08-01

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Novel function of STAT1beta in B cells: induction of cell death by a mechanism different from that of STAT1alpha.

PubMed

Najjar, Imen; Schischmanoff, Pierre Olivier; Baran-Marszak, Fanny; Deglesne, Pierre-Antoine; Youlyouz-Marfak, Ibtissam; Pampin, Mathieu; Feuillard, Jean; Bornkamm, Georg W; Chelbi-Alix, Mounira K; Fagard, Remi

2008-12-01

Alternate splicing of STAT1 produces two isoforms: alpha, known as the active form, and beta, previously shown to act as a dominant-negative factor. Most studies have dealt with STAT1alpha, showing its involvement in cell growth control and cell death. To examine the specific function of either isoform in cell death, a naturally STAT1-deficient human B cell line was transfected to express STAT1alpha or STAT1beta. STAT1alpha, expressed alone, enhanced cell death, potentiated the fludarabine-induced apoptosis, and enhanced the nuclear location, the phosphorylation, and the transcriptional activity of p53. Unexpectedly, STAT1beta, expressed alone, induced cell death through a mechanism that was independent of the nuclear function of p53. Indeed, in STAT1beta-expressing B cells, p53 was strictly cytoplasmic where it formed clusters, and there was no induction of the transcriptional activity of p53. These data reveal a novel role of STAT1beta in programmed cell death, which is independent of p53.

The preliminary SOL (Sizing and Optimization Language) reference manual

NASA Technical Reports Server (NTRS)

Lucas, Stephen H.; Scotti, Stephen J.

1989-01-01

The Sizing and Optimization Language, SOL, a high-level special-purpose computer language has been developed to expedite application of numerical optimization to design problems and to make the process less error-prone. This document is a reference manual for those wishing to write SOL programs. SOL is presently available for DEC VAX/VMS systems. A SOL package is available which includes the SOL compiler and runtime library routines. An overview of SOL appears in NASA TM 100565.

Expression of JAKs/STATs pathway molecules in rat model of rapid focal segmental glomerulosclerosis.

PubMed

Liang, Yaojun; Jin, Yu; Li, Yuning

2009-09-01

The objective of this study was to investigate the role of the Janus kinase-signal transducers and activators of transcription (JAKs/STATs) pathway in focal segmental glomerulosclerosis. Sixty specific pathogen-free male Wistar rats were randomly divided into two groups: a model group (MG) and a control group (CG). In the MG group, nephropathy was induced by unilateral nephrectomy and a single tail vein injection of adriamycin (5 mg/kg). Ten rats were sacrificed every 2 weeks in each group. The expressions of smooth muscle alpha actin (alpha-SMA), collagen (COL)-IV, STAT1, and STAT3 were examined using histochemical techniques, and Western blotting was used to examine the protein levels of STAT1, STAT3, phosphorylated (P)-STAT1, P-STAT3, and transforming growth factor beta1 (TGFbeta(1)). The expressions of JAK1, JAK2, STAT1, STAT3, suppressors of cytokine signaling (SOCS)1, SOCS3, protein inhibitors of activated STAT (PIAS)1, and PIAS3 were also measured by real-time quantitative reverse transcriptase-PCR. A steady and significant increase in the expressions of alpha-SMA, COL-IV and TGFbeta(1) were observed in MG rats over the whole experimental course. Increased STAT1 and P-STAT1 levels in MG rats were observed by week 6, whereas increased levels of STAT3 and P-STAT3 were noted by week 2. At the mRNA levels, JAK1, STAT1, and PIAS1 were significantly increased in MG rats in week 2, whereas JAK2 mRNA showed a significant decrease by weeks 2 and 4, followed by an significant increase in week 6. Significantly increased STAT3 levels were noted in week 2, followed by a steady and significant decrease in weeks 4 and 6. Significantly reduced levels of SOCS1, SOCS3, and PIAS3 mRNA were noted at all time points. We conclude that the JAKs/STATs signaling pathway may play an important role in the pathological process of rapid focal segmental glomerulosclerosis in the rat model.

77 FR 22328 - Guidance for Industry on the Judicious Use of Medically Important Antimicrobial Drugs in Food...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-13

... electronic comments on the guidance to http:[sol][sol]www.regulations.gov. Submit written comments to the... at either http:[sol][sol]www.fda.gov/AnimalVeterinary/ GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm or http:[sol][sol]www.regulations.gov. Dated: April 5, 2012. David Dorsey, Acting...

76 FR 38340 - Revisions to the California State Implementation Plan, San Joaquin Valley Unified Air Pollution...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-30

...: http:[sol][sol]www.regulations.gov. Follow the on-line instructions. 2. E-mail: [email protected] docket without change and may be made available online at http:[sol][sol]www.regulations.gov, including... otherwise protected should be clearly identified as such and should not be submitted through http:[sol][sol...

77 FR 35703 - Collection of Information Under Review by Office of Management and Budget

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-14

... the docket on the Internet at http:[sol][sol] www.regulations.gov . A copy of the ICR is available through the docket on the Internet at http:[sol][sol] www.regulations.gov . Additionally, copies are... be received by July 16, 2012. We will post all comments received, without change, to http:[sol][sol...

75 FR 32533 - WTO Dispute Settlement Proceeding Regarding United States-Anti-Dumping Measures on Certain Shrimp...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-08

... should be submitted electronically to http:[sol][sol] www.regulations.gov , docket number USTR-2010-0008. If you are unable to submit comments using http:[sol][sol] www.regulations.gov , please contact Sandy.... Persons may submit public comments electronically to http:[sol][sol] www.regulations.gov docket number...

Tissue-Specific Autoregulation of the stat3 Gene and Its Role in Interleukin-6-Induced Survival Signals in T Cells

PubMed Central

Narimatsu, Masahiro; Maeda, Hisoka; Itoh, Shousaku; Atsumi, Toru; Ohtani, Takuya; Nishida, Keigo; Itoh, Motoyuki; Kamimura, Daisuke; Park, Sung-Joo; Mizuno, Katsunori; Miyazaki, Jun-ichi; Hibi, Masahiko; Ishihara, Katsuhiko; Nakajima, Koichi; Hirano, Toshio

2001-01-01

Signal transducer and activator of transcription 3 (STAT3) mediates signals of various growth factors and cytokines, including interleukin-6 (IL-6). In certain IL-6-responsive cell lines, the stat3 gene is autoregulated by STAT3 through a composite IL-6 response element in its promoter that contains a STAT3-binding element (SBE) and a cyclic AMP-responsive element. To reveal the nature and roles of the stat3 autoregulation in vivo, we generated mice that harbor a mutation in the SBE (stat3mSBE). The intact SBE was crucial for IL-6-induced stat3 gene activation in the spleen, especially in the red pulp region, the kidney, and both mature and immature T lymphocytes. The SBE was not required, however, for IL-6-induced stat3 gene activation in hepatocytes. T lymphocytes from the stat3mSBE/mSBE mice were more susceptible to apoptosis despite the presence of IL-6 than those from wild-type mice. Consistent with this, IL-6-dependent activation of the Pim-1 and junB genes, direct target genes for STAT3, was attenuated in T lymphocytes of the stat3mSBE/mSBE mice. Thus, the tissue-specific autoregulation of the stat3 gene operates in vivo and plays a role in IL-6-induced antiapoptotic signaling in T cells. PMID:11533249

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α.

PubMed

Yamauchi, Shota; Takeuchi, Kenji; Chihara, Kazuyasu; Honjoh, Chisato; Kato, Yuji; Yoshiki, Hatsumi; Hotta, Hak; Sada, Kiyonao

2016-12-08

Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway.

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

PubMed Central

Yamauchi, Shota; Takeuchi, Kenji; Chihara, Kazuyasu; Honjoh, Chisato; Kato, Yuji; Yoshiki, Hatsumi; Hotta, Hak; Sada, Kiyonao

2016-01-01

Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway. PMID:27929099

Molecular cloning, subcelluar location and expression profile of signal transducer and activator of transcription 2 (STAT2) from turbot, Scophthalmus maximus.

PubMed

Wang, Na; Wang, Xian-Li; Yang, Chang-Geng; Chen, Song-Lin

2013-10-01

Signal transducer and activator of transcription 2 (STAT2) is an important molecule involved in the type I interferon signalling pathway. To date, little STAT2 homologue is available in fish except Atlantic salmon and goldfish. In this paper, STAT2 was firstly cloned and characterized from turbot, a marine flatfish with high economic value. Briefly, turbot STAT2 cDNA is 3206 bp in length encoding a predicted protein of 793 amino acids. The phylogenetic tree shows that turbot STAT2 protein shared the closest relationship with Atlantic salmon. Analysis of subcellular distribution indicates that STAT2 is mainly present in the cytoplasm of TK cells. Stat2 mRNA is constitutively expressed in widespread tissues and induced by several folds in turbot tissues and TK cells after stimulation with Vibrio anguillarum and lymphocystis disease virus (LCDV). Unlike the higher vertebrate STAT2, turbot STAT2 nuclear export signal (NES) exists not in the C-terminal 79 amino acids but in N-terminal 137-312 amino acids (STAT_alpha domain). The nuclear translocation of turbot STAT2 after Poly(I:C) treatment proved its transcription activity in TK cells. All these results suggested that STAT2 may be involved in the immune response in turbot as a transcription factor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Transcription co-activator SAYP mediates the action of STAT activator.

PubMed

Panov, Vladislav V; Kuzmina, Julia L; Doronin, Semen A; Kopantseva, Marina R; Nabirochkina, Elena N; Georgieva, Sofia G; Vorobyeva, Nadezhda E; Shidlovskii, Yulii V

2012-03-01

Jak/STAT is an important signaling pathway mediating multiple events in development. We describe participation of metazoan co-activator SAYP/PHF10 in this pathway downstream of STAT. The latter, via its activation domain, interacts with the conserved core of SAYP. STAT is associated with the SAYP-containing co-activator complex BTFly and recruits BTFly onto genes. SAYP is necessary for stimulating STAT-driven transcription of numerous genes. Mutation of SAYP leads to maldevelopments similar to those observed in STAT mutants. Thus, SAYP is a novel co-activator mediating the action of STAT.

STATs MEDIATE FIBROBLAST GROWTH FACTOR INDUCED VASCULAR ENDOTHELIAL MORPHOGENESIS

PubMed Central

Yang, Xinhai; Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas

2009-01-01

The fibroblast growth factors (FGFs) play diverse roles in development, wound healing and angiogenesis. The intracellular signal transduction pathways which mediate these pleiotropic activities remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STATs) in mouse microvascular endothelial cells. Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type where FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel endothelial cell nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain endothelial cells, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain endothelial cell mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both appear to be involved in the activation of STAT5, as their inhibition reduces FGF2 and FGF8b induced STAT5 phosphorylation and endothelial cell tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations demonstrate that FGFs utilize distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway. PMID:19176400

Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor

PubMed Central

McCann, Georgia A.; Naidu, Shan; Rath, Kellie S.; Bid, Hemant K.; Tierney, Brent J.; Suarez, Adrian; Varadharaj, Saradhadevi; Zhang, Jianying; Hideg, Kálmán; Houghton, Peter; Kuppusamy, Periannan; Cohn, David E.; Selvendiran, Karuppaiyah

2014-01-01

Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. In this study, we demonstrate the level of pSTAT3 Tyr705 is increased in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens, as determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. In addition, we show that S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. STAT3-target proteins Bcl-xL, cyclin D2 and VEGF showed similar decreases in HO-3867 treated cells. Taken together, these findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. PMID:25594014

Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Xiaopeng; Du, Jie; Hua, Song

Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly,more » combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.« less

Defective interleukin-4/Stat6 activity correlates with increased constitutive expression of negative regulators SOCS-3, SOCS-7, and CISH in colon cancer cells.

PubMed

Liu, Xiao Hong; Xu, Shuang Bing; Yuan, Jia; Li, Ben Hui; Zhang, Yan; Yuan, Qin; Li, Pin Dong; Li, Feng; Zhang, Wen Jie

2009-12-01

Interleukin-4 (IL-4)-induced Stat6 activities (phenotypes) vary among human cancer cells, of which the HT-29 cell line carries an active Stat6(high) phenotype, while Caco-2 carries a defective Stat6(null) phenotype, respectively. Cancer cells with Stat6(high) show resistance to apoptosis and exaggerated metastasis, suggesting the clinical significance of Stat6 phenotypes. We previously showed that Stat6(high) HT-29 cells exhibited low constitutive expression of Stat6-negative regulators SOCS-1 and SHP-1 because of gene hypermethylation. This study further examined the constitutive expression of other closely related SOCS family numbers including SOCS-3, SOCS-5, SOCS-7, and CISH using RT-PCR. Similar to SOCS-1 and SHP-1, Stat6(high) HT-29 cells expressed low constitutive mRNA of SOCS-3, SOCS-7, and CISH than Stat6(null) Caco-2 cells. Interestingly, DNA demethylation using 5-aza-2'-deoxycytidine in HT-29 cells up-regulated mRNA expression of the above genes, indicating a hypermethylation status, which was confirmed by methylation-specific sequencing in selected SOCS-3 gene. Furthermore, defective Stat6(null) Caco-2 exhibited impaired phosphorylation of Stat6 after IL-4 stimulation by flow cytometry, in keeping with the notion of an over-performed negative regulation. The findings that IL-4/Stat6 phenotypes show differential expression of multiple negative regulators suggest a model that a collective force of powerful negative regulators, directly and indirectly, acts on Stat6 activation, which may result in differential Stat6 phenotypes.

Protein tyrosine phosphatases as wardens of STAT signaling

PubMed Central

Böhmer, Frank-D; Friedrich, Karlheinz

2014-01-01

Signaling by signal transducers and activators of transcription (STATs) is controlled at many levels of the signaling cascade. Protein tyrosine phosphatases (PTPs) regulate STAT activation at several layers, including direct pSTAT dephosphorylation in both cytoplasm and nucleus. Despite the importance of this regulation mode, many aspects are still incompletely understood, e.g., the identity of PTPs acting on certain members of the STAT family. After a brief introduction into the STAT and PTP families, we discuss here the current knowledge on PTP mediated regulation of STAT activity, focusing on the interaction of individual STATs with specific PTPs. Finally, we highlight open questions and propose important tasks of future research. PMID:24778927

STATs in cancer inflammation and immunity: a leading role for STAT3.

PubMed

Yu, Hua; Pardoll, Drew; Jove, Richard

2009-11-01

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

STAT1 is Constitutively Activated in the T/C28a2 Immortalized Juvenile Human Chondrocyte Line and Stimulated by IL-6 Plus Soluble IL-6R.

PubMed

Meszaros, Evan C; Malemud, Charles J

2015-04-01

T/C28a2 immortalized juvenile human chondrocytes were employed to determine the extent to which activation of Signal Transducers and Activators of Transcription-1 (STAT1) occurred in response to recombinant human interleukin-6 (rhIL-6) or rhIL-6 in combination with the soluble IL-6 receptor (sIL-6R). Two forms of STAT1, STAT1A and STAT1B, were identified on SDS-PAGE and western blotting with anti-STAT1 antibody. Western blotting revealed that STAT1 was constitutively phosphorylated (p-STAT1). Although incubation of T/C28a2 chondrocytes with rhIL-6 (50 ng/ml) increased p-STAT1A by Δ=22.3% after 30 min, this percent difference failed to reach significance by Chi-square analysis. Similarly, no effect of rhIL-6 (Δ=+10.7%) on p-STAT1B was seen at 30 min. In contrast, although the combination of rhIL-6 plus sIL-6R had no effect on p-STAT1A, rhIL-6 plus sIL-6R increased p-STAT1B by Δ=73.3% (p<0.0001) after 30 min compared to the control group and by Δ=56.7% (p<0.0001) compared to rhIL-6 alone. Janex-1, a Janus kinase-3-specific inhibitor (100 μM) partially reduced the effect of rhIL-6 on p-STAT1B by Δ=27.7% (p<0.05). The results of this study showed that STAT1A/STAT1B was constitutively activated in T/C28a2 chondrocytes. Although rhIL-6 increased p-STAT1B to a small extent, the combination of rhIL-6 plus sIL-6R was far more effective in stimulating STAT1B phosphorylation compared to controls or rhIL-6 alone. These data support the likelihood that although JAK3-mediated activation of STAT1 in T/C28a2 chondrocytes may involve the IL-6/IL-6R/gp130 pathway, these results indicated that STAT1 activation in response to IL-6 preferentially involved IL-6 trans -signaling via sIL-6R.

The JAK-STAT signaling pathway: input and output integration.

PubMed

Murray, Peter J

2007-03-01

Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.

Intracellular staining for analysis of the expression and phosphorylation of signal transducers and activators of transcription (STATs) in NK cells.

PubMed

Miyagi, Takuya; Lee, Seung-Hwan; Biron, Christine A

2010-01-01

Cytokines stimulate biological responses by activating intracellular signaling pathways. We have been adapting flow cytometric techniques to measure the levels of expression and activation of signaling molecules within mixed populations containing NK cells and to characterize their differences within NK cell subpopulations. Approaches for evaluating the total levels of the signal transducers and activators of transcription STAT1 and STAT4, of STAT1 in cells expressing IFNgamma, and of the type 1 interferon (type 1 IFN) activation by phosphorylation, i.e., induction of pSTAT1 and pSTAT4, have been developed. The results of experiments using these techniques have demonstrated that an unusual feature of NK cells is high basal expression of STAT4 but reduced STAT1 levels. The condition predisposes for pSTAT4 activation by type 1 IFNs. The work has also shown, however, that total STAT1 levels are induced during viral infections as a result of IFN exposure, and that this change acts to promote the activation of STAT1 but limit both the activation of STAT4 and IFNgamma expression. The intracellular staining approaches used for the studies described here have utility in characterizing other mechanisms regulating cytokine-mediated signaling, and defining additional pathways shaping cellular responses to cytokines.

Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.

PubMed

Rivera, L E; Kraiselburd, E; Meléndez, L M

2016-10-01

Cystatin B is a cysteine protease inhibitor that induces HIV replication in monocyte-derived macrophages (MDM). This protein interacts with signal transducer and activator of transcription (STAT-1) factor and inhibits the interferon (IFN-β) response in Vero cells by preventing STAT-1 translocation to the nucleus. Cystatin B also decreases the levels of tyrosine-phosphorylated STAT-1 (STAT-1PY). However, the mechanisms of cystatin B regulation on STAT-1 phosphorylation in MDM are unknown. We hypothesized that cystatin B inhibits IFN-β antiviral responses and induces HIV replication in macrophage reservoirs through the inhibition of STAT-1 phosphorylation. Macrophages were transfected with cystatin B siRNA prior to interferon-β treatment or infected with HIV-ADA to determine the effect of cystatin B modulation in STAT-1 localization and activation using immunofluorescence and proximity ligation assays. Cystatin B decreased STAT-1PY and its transportation to the nucleus, while HIV infection retained unphosphorylated STAT (USTAT-1) in the nucleus avoiding its exit to the cytoplasm for eventual phosphorylation. In IFN-β-treated MDM, cystatin B inhibited the nuclear translocation of both, USTAT-1 and STAT-1PY. These results demonstrate that cystatin B interferes with the STAT-1 signaling and IFN-β-antiviral responses perpetuating HIV in macrophage reservoirs.

IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Benhui; Yang Xianzi; Department of Medical Oncology, Taihe Hospital, Yunyang Medical College, Shiyan, Hubei 442000

2008-05-02

IL-4-induced Stat6 signaling is active in a variety of cell types and plays a role in cell proliferation/growth and resistance to apoptosis. Using EMSA, we identified differential IL-4/Stat6 activities in colorectal cancer cell lines, HT-29 being active Stat6{sup high} phenotype and Caco-2 being defective Stat6{sup null} phenotype, respectively. Active Stat6{sup high} HT-29 cells exhibited resistance to apoptosis by flowcytometry and aggressive metastasis by Transwell assay compared with defective Stat6{sup null} Caco-2 cells. Comparing one another using RT-PCR, Stat6{sup high} HT-29 cells expressed more mRNA of anti-apoptotic and pro-metastatic genes Survivin, MDM2, and TMPRSS4, while Stat6{sup null} Caco-2 cells expressed moremore » mRNA of pro-apoptotic and anti-metastatic genes BAX, CAV1, and P53, respectively. This is the first study describing correlations of IL-4/Stat6 activities with apoptosis and metastasis in colon cancer. These findings, together with the observation of constitutive Stat6 activation in many human malignancies, suggest that Stat6 activities could be a biomarker for cancer cell's invasive/metastatic capability.« less

75 FR 70897 - Notice of Request for Extension of Approval of an Information Collection; South American Cactus...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... either of the following methods: Federal eRulemaking Portal: Go to http:[sol][sol]www.regulations.gov[sol]fdmspublic[sol]component[sol]main ?main=DocketDetail&d=APHIS-2010-0106 to submit or view comments and to view supporting and related materials available electronically. Postal Mail[sol]Commercial Delivery: Please send...

77 FR 34032 - American River Power III, LLC; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-08

... Commission's Web site http:[sol][sol]www.ferc.gov/docs-filing/efiling.asp. Commenters can submit brief comments up to 6,000 characters, without prior registration, using the eComment system at http:[sol][sol... on the ``eLibrary'' link of Commission's Web site at http:[sol][sol]www.ferc.gov/docs-filing...

76 FR 12958 - Amnor Hydro West Inc.; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

... http:[sol][sol]www.ferc.gov/docs-filing/efiling.asp. Commenters can submit brief comments up to 6,000 characters, without prior registration, using the eComment system at http:[sol][sol]www.ferc.gov/docs-filing...Library'' link of Commission's Web site at http:[sol][sol]www.ferc.gov/docs-filing/ elibrary.asp. Enter...

78 FR 22275 - Collection of Information under Review by Office of Management and Budget

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-15

... following means: (1) Online: (a) To Coast Guard docket at http:[sol][sol] www.regulations.gov . (b) To OIRA... Federal holidays. You may also find the docket on the Internet at http:[sol][sol] www.regulations.gov . Copies of the ICRs are available through the docket on the Internet at http:[sol][sol] www.regulations...

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

PubMed Central

Liu, Luyan; Okada, Satoshi; Kong, Xiao-Fei; Kreins, Alexandra Y.; Cypowyj, Sophie; Abhyankar, Avinash; Toubiana, Julie; Itan, Yuval; Audry, Magali; Nitschke, Patrick; Masson, Cécile; Toth, Beata; Flatot, Jérome; Migaud, Mélanie; Chrabieh, Maya; Kochetkov, Tatiana; Bolze, Alexandre; Borghesi, Alessandro; Toulon, Antoine; Hiller, Julia; Eyerich, Stefanie; Eyerich, Kilian; Gulácsy, Vera; Chernyshova, Ludmyla; Chernyshov, Viktor; Bondarenko, Anastasia; María Cortés Grimaldo, Rosa; Blancas-Galicia, Lizbeth; Madrigal Beas, Ileana Maria; Roesler, Joachim; Magdorf, Klaus; Engelhard, Dan; Thumerelle, Caroline; Burgel, Pierre-Régis; Hoernes, Miriam; Drexel, Barbara; Seger, Reinhard; Kusuma, Theresia; Jansson, Annette F.; Sawalle-Belohradsky, Julie; Belohradsky, Bernd; Jouanguy, Emmanuelle; Bustamante, Jacinta; Bué, Mélanie; Karin, Nathan; Wildbaum, Gizi; Bodemer, Christine; Lortholary, Olivier; Fischer, Alain; Blanche, Stéphane; Al-Muhsen, Saleh; Reichenbach, Janine; Kobayashi, Masao; Rosales, Francisco Espinosa; Lozano, Carlos Torres; Kilic, Sara Sebnem; Oleastro, Matias; Etzioni, Amos; Traidl-Hoffmann, Claudia; Renner, Ellen D.; Abel, Laurent; Picard, Capucine; Maródi, László; Boisson-Dupuis, Stéphanie

2011-01-01

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity. PMID:21727188

STAT proteins: from normal control of cellular events to tumorigenesis.

PubMed

Calò, Valentina; Migliavacca, Manuela; Bazan, Viviana; Macaluso, Marcella; Buscemi, Maria; Gebbia, Nicola; Russo, Antonio

2003-11-01

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis. On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis.

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production

PubMed Central

Matsui, Futoshi; Babitz, Stephen A.; Rhee, Audrey; Hile, Karen L.; Zhang, Hongji

2017-01-01

STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson’s trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production. PMID:27760767

Pyruvate dehydrogenase complex (PDC) subunits moonlight as interaction partners of phosphorylated STAT5 in adipocytes and adipose tissue.

PubMed

Richard, Allison J; Hang, Hardy; Stephens, Jacqueline M

2017-12-01

STAT5 proteins play a role in adipocyte development and function, but their specific functions are largely unknown. To this end, we used an unbiased MS-based approach to identify novel STAT5-interacting proteins. We observed that STAT5A bound the E1β and E2 subunits of the pyruvate dehydrogenase complex (PDC). Whereas STAT5A typically localizes to the cytosol or nucleus, PDC normally resides within the mitochondrial matrix where it converts pyruvate to acetyl-CoA. We employed affinity purification and immunoblotting to validate the interaction between STAT5A and PDC subunits in murine and human cultured adipocytes, as well as in adipose tissue. We found that multiple PDC subunits interact with hormone-activated STAT5A in a dose- and time-dependent manner that coincides with tyrosine phosphorylation of STAT5. Using subcellular fractionation and immunofluorescence microscopy, we observed that PDC-E2 is present within the adipocyte nucleus where it associates with STAT5A. Because STAT5A is a transcription factor, we used chromatin immunoprecipitation (ChIP) to assess PDC's ability to interact with STAT5 DNA-binding sites. These analyses revealed that PDC-E2 is bound to a STAT5-binding site in the promoter of the STAT5 target gene c ytokine- i nducible SH 2-containing protein ( cish ). We have demonstrated a compelling interaction between STAT5A and PDC subunits in adipocytes under physiological conditions. There is previous evidence that PDC localizes to cancer cell nuclei where it plays a role in histone acetylation. On the basis of our ChIP data and these previous findings, we hypothesize that PDC may modulate STAT5's ability to regulate gene expression by controlling histone or STAT5 acetylation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Assessing the Role of STAT3 in DC Differentiation and Autologous DC Immunotherapy in Mouse Models of GBM

PubMed Central

Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah; Sofroniew, Michael; Doherty, Robert; Zamler, Daniel; Lowenstein, Pedro R.; Castro, Maria G.

2014-01-01

Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM-CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFα were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors. PMID:24806510

Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM.

PubMed

Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah; Sofroniew, Michael; Doherty, Robert; Zamler, Daniel; Lowenstein, Pedro R; Castro, Maria G

2014-01-01

Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM-CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFα were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors.

Prognostic significance of signal transducer and activator of transcription 5 and 5b expression in Epstein-Barr virus-positive patients with chronic lymphocytic leukemia.

PubMed

Diamantopoulos, Panagiotis T; Sofotasiou, Maria; Georgoussi, Zafiroula; Giannakopoulou, Nefeli; Papadopoulou, Vasiliki; Galanopoulos, Athanasios; Kontandreopoulou, Elina; Zervakis, Panagiotis; Pallaki, Paschalina; Kalala, Fani; Kyrtsonis, Marie-Christine; Dimitrakopoulou, Aglaia; Vassilakopoulos, Theodoros; Angelopoulou, Maria; Spanakis, Nikolaos; Viniou, Nora-Athina

2016-09-01

Signal transducer and activator of transcription (STAT) proteins have been intensively studied in hematologic malignancies, and the efficacy of agents against STATs in lymphomas is already under research. We investigated the expression of total STAT5 and STAT5b in peripheral blood samples of patients with chronic lymphocytic leukemia (CLL) in correlation with the presence of Epstein-Barr Virus (EBV) and its major oncoprotein (latent membrane protein 1, LMP1). The EBV load was measured in the peripheral blood by real-time PCR for the BXLF1 gene and the levels of LMP1 by PCR and ELISA. Western blotting was performed for total STAT5 and STAT5b in protein extracts. STAT5b was only expressed in patients (not in healthy subjects) and STAT5 but particularly STAT5b expression was correlated with the presence of the virus (77.3% vs. 51.2%, P = 0.006 for STAT5b) and to the expression of LMP1 (58.3% vs. 21.6%, P = 0.011 for STAT5b). Moreover, the expression of STAT5b and the presence of EBV and LMP1 were strongly negatively correlated with the overall survival of the patients (log-rank test P = 0.011, 0.015, 0.006, respectively). Double positive (for EBV and STAT5b) patients had the lowest overall survival (log-rank test P = 0.013). This is the first report of a survival disadvantage of EBV+ patients with CLL, and the first time that STAT5b expression is correlated with survival. The correlation of STAT5 expression with the presence of the virus, along with our survival correlations defines a subgroup of patients with CLL that may benefit from anti-STAT agents. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators

PubMed Central

Lo, Hui-Wen; Cao, Xinyu; Zhu, Hu; Ali-Osman, Francis

2009-01-01

Purpose The goals of this study are to elucidate the relationship of the oncogenic transcription factor signal transducer and activator of transcription 3(STAT3) with glioma aggressiveness and to understand the role of high STAT3 activity in the resistance of malignant gliomas and medulloblastomas to chemotherapy. Experimental Design Immunohistochemical staining and biochemical methods were used to examine the extent of STAT3 activation and EGFR expression in primary specimens and cell lines, respectively. Cellular response to drug treatments was determined using cell cytotoxicity and clonogenic growth assays. Results We found STAT3 to be constitutively activated in 60% of primary high-grade/malignant gliomas and the extent of activation correlated positively with glioma grade. High levels of activated/phosphorylated STAT3 were also present in cultured human malignant glioma and medulloblastoma cells. Three STAT3-activating kinases, Janus-activated kinase 2 (JAK2), EGFR, and EGFRvIII, contributed to STAT3 activation. An inhibitor toJAK2/STAT3, JSI-124, significantly reduced expression of STAT3 target genes, suppressed cancer cell growth, and induced apoptosis. Furthermore, we found that STAT3 constitutive activation coexisted with EGFR expression in 27.2% of primary high-grade/malignant gliomas and such coexpression correlated positively with glioma grade. Combination of an anti-EGFR agent Iressa and a JAK2/STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII. JSI-124 also sensitized malignant glioma and medulloblastoma cells to temozolomide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and cisplatin in which a synergism existed between JSI-124 and cisplatin. Conclusion STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents. PMID:18829483

Current Fluctuations in One Dimensional Diffusive Systems with a Step Initial Density Profile

NASA Astrophysics Data System (ADS)

Derrida, Bernard; Gerschenfeld, Antoine

2009-12-01

We show how to apply the macroscopic fluctuation theory (MFT) of Bertini, De Sole, Gabrielli, Jona-Lasinio, and Landim to study the current fluctuations of diffusive systems with a step initial condition. We argue that one has to distinguish between two ways of averaging (the annealed and the quenched cases) depending on whether we let the initial condition fluctuate or not. Although the initial condition is not a steady state, the distribution of the current satisfies a symmetry very reminiscent of the fluctuation theorem. We show how the equations of the MFT can be solved in the case of non-interacting particles. The symmetry of these equations can be used to deduce the distribution of the current for several other models, from its knowledge (Derrida and Gerschenfeld in J. Stat. Phys. 136, 1-15, 2009) for the symmetric simple exclusion process. In the range where the integrated current Qt˜sqrt{t} , we show that the non-Gaussian decay exp [- Q {/t 3}/ t] of the distribution of Q t is generic.

Decay of a linear pendulum in a collisional gas: Spatially one-dimensional case

NASA Astrophysics Data System (ADS)

Tsuji, Tetsuro; Aoki, Kazuo

2014-05-01

An infinitely wide plate, subject to an external force in its normal direction obeying Hooke's law, is placed in an infinite expanse of a rarefied gas. When the plate is displaced from its equilibrium position and released, it starts in general an oscillatory motion in its normal direction. This is the one-dimensional setting of a linear pendulum considered previously for a collisionless gas and a special Lorentz gas by the present authors [T. Tsuji and K. Aoki, J. Stat. Phys. 146, 620 (2012), 10.1007/s10955-011-0412-7]. The motion decays as time proceeds because of the drag force on the plate exerted by the surrounding gas. The long-time behavior of the unsteady motion of the gas caused by the motion of the plate is investigated numerically on the basis of the Bhatnagar-Gross-Krook (BGK) model of the Boltzmann equation with special interest in the rate of the decay of the oscillatory motion of the plate. The result provides numerical evidence that the displacement of the plate decays in proportion to an inverse power of time for large time.

Decay of a linear pendulum in a collisional gas: spatially one-dimensional case.

PubMed

Tsuji, Tetsuro; Aoki, Kazuo

2014-05-01

An infinitely wide plate, subject to an external force in its normal direction obeying Hooke's law, is placed in an infinite expanse of a rarefied gas. When the plate is displaced from its equilibrium position and released, it starts in general an oscillatory motion in its normal direction. This is the one-dimensional setting of a linear pendulum considered previously for a collisionless gas and a special Lorentz gas by the present authors [T. Tsuji and K. Aoki, J. Stat. Phys. 146, 620 (2012)]. The motion decays as time proceeds because of the drag force on the plate exerted by the surrounding gas. The long-time behavior of the unsteady motion of the gas caused by the motion of the plate is investigated numerically on the basis of the Bhatnagar-Gross-Krook (BGK) model of the Boltzmann equation with special interest in the rate of the decay of the oscillatory motion of the plate. The result provides numerical evidence that the displacement of the plate decays in proportion to an inverse power of time for large time.

Generalized canonical ensembles and ensemble equivalence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Costeniuc, M.; Ellis, R.S.; Turkington, B.

2006-02-15

This paper is a companion piece to our previous work [J. Stat. Phys. 119, 1283 (2005)], which introduced a generalized canonical ensemble obtained by multiplying the usual Boltzmann weight factor e{sup -{beta}}{sup H} of the canonical ensemble with an exponential factor involving a continuous function g of the Hamiltonian H. We provide here a simplified introduction to our previous work, focusing now on a number of physical rather than mathematical aspects of the generalized canonical ensemble. The main result discussed is that, for suitable choices of g, the generalized canonical ensemble reproduces, in the thermodynamic limit, all the microcanonical equilibriummore » properties of the many-body system represented by H even if this system has a nonconcave microcanonical entropy function. This is something that in general the standard (g=0) canonical ensemble cannot achieve. Thus a virtue of the generalized canonical ensemble is that it can often be made equivalent to the microcanonical ensemble in cases in which the canonical ensemble cannot. The case of quadratic g functions is discussed in detail; it leads to the so-called Gaussian ensemble.« less

STAT Overview and SCENIC Functional Concept

NASA Technical Reports Server (NTRS)

Welch, Bryan

2016-01-01

This is an overview of the guiding principles of STAT derivation from back in early 2012. This includes a functional view of STAT operations, a STAT demonstration, as well as how the STAT functional view is an excellent model, in my perspective, how the necessary functional view for the SCENIC Analysis Tool.

43 CFR Appendix A to Subpart A of... - Appendix A to Subpart A of Part 17

Code of Federal Regulations, 2012 CFR

2012-10-01

.... Pittman-Robertson Act (50 Stat. 917, as amended, 16 U.S.C. 669). 2. Dingell-Johnson Act (64 Stat. 430, 16... Outdoor Recreation (77 Stat. 49, 16 U.S.C. 460l). 5. Revised Organic Act of the Virgin Islands (68 Stat... Act (39 Stat. 954, 48 U.S.C. 748). 2. Virgin Islands Corporation Act (63 Stat. 350, as amended, 48 U.S...

43 CFR Appendix A to Subpart A of... - Appendix A to Subpart A of Part 17

Code of Federal Regulations, 2014 CFR

2014-10-01

.... Pittman-Robertson Act (50 Stat. 917, as amended, 16 U.S.C. 669). 2. Dingell-Johnson Act (64 Stat. 430, 16... Outdoor Recreation (77 Stat. 49, 16 U.S.C. 460l). 5. Revised Organic Act of the Virgin Islands (68 Stat... Act (39 Stat. 954, 48 U.S.C. 748). 2. Virgin Islands Corporation Act (63 Stat. 350, as amended, 48 U.S...

43 CFR Appendix A to Subpart A of... - Appendix A to Subpart A of Part 17

Code of Federal Regulations, 2011 CFR

2011-10-01

.... Pittman-Robertson Act (50 Stat. 917, as amended, 16 U.S.C. 669). 2. Dingell-Johnson Act (64 Stat. 430, 16... Outdoor Recreation (77 Stat. 49, 16 U.S.C. 460l). 5. Revised Organic Act of the Virgin Islands (68 Stat... Act (39 Stat. 954, 48 U.S.C. 748). 2. Virgin Islands Corporation Act (63 Stat. 350, as amended, 48 U.S...

43 CFR Appendix A to Subpart A of... - Appendix A to Subpart A of Part 17

Code of Federal Regulations, 2013 CFR

2013-10-01

.... Pittman-Robertson Act (50 Stat. 917, as amended, 16 U.S.C. 669). 2. Dingell-Johnson Act (64 Stat. 430, 16... Outdoor Recreation (77 Stat. 49, 16 U.S.C. 460l). 5. Revised Organic Act of the Virgin Islands (68 Stat... Act (39 Stat. 954, 48 U.S.C. 748). 2. Virgin Islands Corporation Act (63 Stat. 350, as amended, 48 U.S...

43 CFR Appendix A to Subpart A of... - Appendix A to Subpart A of Part 17

Code of Federal Regulations, 2010 CFR

2010-10-01

.... Pittman-Robertson Act (50 Stat. 917, as amended, 16 U.S.C. 669). 2. Dingell-Johnson Act (64 Stat. 430, 16... Outdoor Recreation (77 Stat. 49, 16 U.S.C. 460l). 5. Revised Organic Act of the Virgin Islands (68 Stat... Act (39 Stat. 954, 48 U.S.C. 748). 2. Virgin Islands Corporation Act (63 Stat. 350, as amended, 48 U.S...

SFK-STAT pathway: an alternative and important way to malignancies.

PubMed

Hayakawa, Fumihiko; Naoe, Tomoki

2006-11-01

Signal transducers and activators of transcription (STAT) proteins play a crucial role in mediating signals from a diverse spectrum of cytokine receptors. STAT is thought to be activated by JAK family kinases (JFK) in many cytokine receptor signal pathways; however, recent studies have demonstrated an alternative pathway to activate STAT by Src family kinases (SFK) in growth factor receptor signal. We also observed STAT5 phosphorylation by Lyn, a member of SFK, in our two recent studies. We introduce these studies and review the literature of STAT activation by SFK and aberrant activation of STAT by oncogenic signals.

Transcription co-activator SAYP mediates the action of STAT activator

PubMed Central

Panov, Vladislav V.; Kuzmina, Julia L.; Doronin, Semen A.; Kopantseva, Marina R.; Nabirochkina, Elena N.; Georgieva, Sofia G.; Vorobyeva, Nadezhda E.; Shidlovskii, Yulii V.

2012-01-01

Jak/STAT is an important signaling pathway mediating multiple events in development. We describe participation of metazoan co-activator SAYP/PHF10 in this pathway downstream of STAT. The latter, via its activation domain, interacts with the conserved core of SAYP. STAT is associated with the SAYP-containing co-activator complex BTFly and recruits BTFly onto genes. SAYP is necessary for stimulating STAT-driven transcription of numerous genes. Mutation of SAYP leads to maldevelopments similar to those observed in STAT mutants. Thus, SAYP is a novel co-activator mediating the action of STAT. PMID:22123744

Unphosphorylated STATs go nuclear.

PubMed

Brown, Stephen; Zeidler, Martin P

2008-10-01

The JAK/STAT signal transduction pathway has traditionally been viewed as a cytokine-stimulated activator of gene expression consisting of a straightforward receptor/JAK kinase/STAT transcription factor cascade. Recent studies in Drosophila, have, however consistently identified a range of chromatin-remodelling factors as regulators of in vivo JAK/STAT signalling. Now, the detailed analysis of one of these, heterochromatin protein 1 (HP1), has provided an insight into an unexpected non-canonical in vivo role for STAT. In this model, unphosphorylated STATs associate with and maintain the stability of transcriptionally repressed heterochromatin--an effect countered by the recruitment of STAT to the canonical pathway. We examine the background of this new model and its implications for JAK/STAT pathway requirements in stem cell maintenance and cancer.

STAT3 inhibition as a therapeutic strategy for leukemia.

PubMed

Kanna, Rubashruti; Choudhary, Gaurav; Ramachandra, Nandini; Steidl, Ulrich; Verma, Amit; Shastri, Aditi

2017-11-22

Leukemia is characterized by selective overgrowth of malignant hematopoietic stem cells (HSC's) that interfere with HSC differentiation. Cytoreductive chemotherapy can kill rapidly dividing cancerous cells but cannot eradicate the malignant HSC pool leading to relapses. Leukemic stem cells have several dysregulated pathways and the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) pathway are prominent among them. STAT3 is an important transcription factor that regulates cell growth, proliferation, and inhibits apoptosis. High STAT3 expression in leukemia has been associated with an increased risk for relapse and decreased overall survival. Multiple strategies for interfering with STAT3 activity in leukemic cells include inhibition of STAT3 phosphorylation, interfering with STAT3 interactions, preventing nuclear transfer, inhibiting transcription and causing interference in STAT: DNA binding. A better understanding of key interactions and upstream mediators of STAT3 activity will help facilitate the development of effective cancer therapies and may result in durable remissions.

Identification of STAT3 and STAT5 proteins in the rat suprachiasmatic nucleus and the Day/Night difference in astrocytic STAT3 phosphorylation in response to lipopolysaccharide.

PubMed

Moravcová, Simona; Červená, Kateřina; Pačesová, Dominika; Bendová, Zdeňka

2016-01-01

Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night. © 2015 Wiley Periodicals, Inc.

The JAK2 Inhibitor, AZD1480, Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

PubMed Central

Hedvat, Michael; Huszar, Dennis; Herrmann, Andreas; Gozgit, Joseph M.; Schroeder, Anne; Sheehy, Adam; Buettner, Ralf; Proia, David; Kowolik, Claudia M.; Xin, Hong; Armstrong, Brian; Bebernitz, Geraldine; Weng, Shaobu; Wang, Lin; Ye, Minwei; McEachern, Kristen; Chen, Huawei; Morosini, Deborah; Bell, Kirsten; Alimzhanov, Marat; Ioannidis, Stephanos; McCoon, Patricia; Cao, Zhu A.; Yu, Hua; Jove, Richard; Zinda, Michael

2009-01-01

Summary Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor, AZD1480, suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using shRNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis. PMID:19962667

Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.

PubMed

Bauer, K; Kretzschmar, A K; Cvijic, H; Blumert, C; Löffler, D; Brocke-Heidrich, K; Schiene-Fischer, C; Fischer, G; Sinz, A; Clevenger, C V; Horn, F

2009-08-06

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis.

PubMed

Yu, Jing; Wu, Yimei; Wang, Lu; Zhang, Wen; Xu, Man; Song, Jiayu; Fu, Yu; Cui, Yiyun; Gong, Wei; Li, Shuzhen; Xia, Weiwei; Huang, Songming; Zhang, Aihua; Jia, Zhanjun

2017-11-01

We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.

The role of STATs in transcriptional control and their impact on cellular function.

PubMed

Bromberg, J; Darnell, J E

2000-05-15

The STAT proteins (Signal Transducers and Activators of Transcription), were identified in the last decade as transcription factors which were critical in mediating virtually all cytokine driven signaling. These proteins are latent in the cytoplasm and become activated through tyrosine phosphorylation which typically occurs through cytokine receptor associated kinases (JAKs) or growth factor receptor tyrosine kinases. Recently a number of non-receptor tyrosine kinases (for example src and abl) have been found to cause STAT phosphorylation. Phosphorylated STATs form homo- or hetero-dimers, enter the nucleus and working coordinately with other transcriptional co-activators or transcription factors lead to increased transcriptional initiation. In normal cells and in animals, ligand dependent activation of the STATs is a transient process, lasting for several minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently at the heart of cellular transformation, the STAT proteins (in particular Stats 1, 3 and 5) are persistently tyrosine phosphorylated or activated. The importance of STAT activation to growth control in experiments using anti-sense molecules or dominant negative STAT protein encoding constructs performed in cell lines or studies in animals lacking specific STATs strongly indicate that STATs play an important role in controlling cell cycle progression and apoptosis. Stat1 plays an important role in growth arrest, in promoting apoptosis and is implicated as a tumor suppressor; while Stats 3 and 5 are involved in promoting cell cycle progression and cellular transformation and preventing apoptosis. Many questions remain including: (1) a better understanding of how the STAT proteins through association with other factors increase transcription initiation; (2) a more complete definition of the sets of genes which are activated by different STATs and (3) how these sets of activated genes differ as a function of cell type. Finally, in the context of many cancers, where STATs are frequently persistently activated, an understanding of the mechanisms leading to their constitutive activation and defining the potential importance of persistent STAT activation in human tumorigenesis remains. Oncogene (2000).

Non-genomic STAT5-dependent effects at the endoplasmic reticulum and Golgi apparatus and STAT6-GFP in mitochondria

PubMed Central

Sehgal, Pravin B

2013-01-01

STAT protein species are well-known as transcription factors that regulate nuclear gene expression. Recent novel lines of research suggest new non-genomic functions of STAT5A/B and STAT6. It was discovered in human pulmonary arterial endothelial cells that STAT5A, including STAT5A-GFP, constitutively associated with the Golgi apparatus, and both STAT5A and B with the endoplasmic reticulum. Acute siRNA-mediated knockdown of STAT5A/B led to the rapid development of a dramatic cystic change in the endoplasmic reticulum (ER) characterized by deposition of the ER structural protein reticulon-4 (RTN4; also called Nogo-B) and the ER-resident GTPase atlastin-3 (ATL3) along cyst membranes and cyst-zone boundaries, accompanied by Golgi fragmentation. Functional consequences included reduced anterograde trafficking, an ER stress response (increased GRP78/BiP) and eventual mitochondrial fragmentation. This phenotype was “non-genomic” in that it was elicited in enucleated cytoplasts. In cross-immunopanning assays STAT5A and B species associated with ATL3, and the ER-lumen spacer CLIMP63 (also called cytoskeleton-associated protein 4, CKAP4) but not RTN4. From a disease significance perspective we posit that STAT5, which is known to be affected by estradiol-17β and prolactin, represents the gender-sensitive determinant in the pathogenesis of idiopathic pulmonary hypertension (IPAH), a disease which includes ER/Golgi dysfunctions but with a 2- to 4-fold higher prevalence in postpubertal women. A separate line of recent research produced evidence for the association of STAT6-GFP, but not STAT3-GFP, STAT3-DsRed, or STAT3-Flag, with mitochondria in live-cell, immunofluorescence, and immunoelectron microscopy. An N-terminal truncation of STAT6-GFP (1–459), which lacked the SH2 domain and Tyr-phosphorylation site, constitutively associated with mitochondria. Thus, the emergent new of biology STAT proteins includes non-genomic roles—structurally and functionally—in the three closely related membrane organelles consisting of the endoplasmic reticulum, Golgi apparatus, and mitochondria. PMID:24470974

Essential role of Stat5 for IL-5-dependent IgH switch recombination in mouse B cells.

PubMed

Horikawa, K; Kaku, H; Nakajima, H; Davey, H W; Hennighausen, L; Iwamoto, I; Yasue, T; Kariyone, A; Takatsu, K

2001-11-01

IL-5 stimulation of CD38-activated murine splenic B cells induces mu-gamma1 CSR at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent mu-gamma1 CSR. Although some of the postreceptor signaling events initiated by IL-5 in activated B cells have been characterized, the involvement of Stat in IL-5 signaling has not been thoroughly evaluated. In this study, we examined the activation of Stat5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells by IL-5. The role of Stat5a and Stat5b in IL-5-induced mu-gamma1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a(-/-) and Stat5b(-/-) mice. Expression levels of CD38-induced germline gamma1 transcripts and AID in Stat5a(-/-) and Stat5b(-/-) B cells upon IL-5 stimulation were comparable to those of wild-type B cells. The impaired mu-gamma1 CSR by Stat5b(-/-) B cells, but not by Stat5a(-/-) B cells, was rescued in part by IL-4, as the addition of IL-4 to the culture of CD38- and IL-5-stimulated B cells induced mu-gamma1 CSR leading to IgG1 production. Analysis of cell division cycle number of wild-type B cells revealed that mu-gamma1 CSR was observed after five or six cell divisions. Stat5a(-/-) and Stat5b(-/-) B cells showed similar cell division cycles, but they did not undergo mu-gamma1 CSR. Our data support the notion that both Stat5a and Stat5b are essential for IL-5-dependent mu;-gamma1 CSR and Ig secretion; however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.

Response of brain oxygenation and metabolism to deep hypothermic circulatory arrest in newborn piglets: comparison of pH-stat and alpha-stat strategies.

PubMed

Markowitz, Scott D; Mendoza-Paredes, Alberto; Liu, Huiping; Pastuszko, Peter; Schultz, Steven P; Schears, Gregory J; Greeley, William J; Wilson, David F; Pastuszko, Anna

2007-07-01

To determine the effect of pH-stat as compared with alpha-stat management on brain oxygenation, level of striatal extracellular dopamine, phosphorylation, and levels of protein kinase B (Akt) and cyclic adenosine 3', 5'-monophosphate response element-binding protein (CREB), and levels of extracellular signal-regulated kinase (ERK)1/2, Bcl-2, and Bax in a piglet model of deep hypothermic circulatory arrest (DHCA). The piglets were placed on cardiopulmonary bypass (CPB), cooled with pH-stat or alpha-stat to 18 degrees C, subjected to 90 minutes of DHCA, rewarmed, weaned from CPB, and maintained for two hours recovery. The cortical oxygen was measured by: quenching of phosphorescence; dopamine by microdialysis; phosphorylation of CREB (p-CREB), ERK (p-ERK) 1/2, Akt (p-Akt), and level of Bcl-2, Bax by Western blots. Oxygen pressure histograms for the microvasculature of the cortex show substantially higher oxygen levels during cooling and during the oxygen depletion period after cardiac arrest (up to 15 minutes) when using pH-stat compared with alpha-stat management. Significant increases in dopamine occurred at 45 minutes and 60 minutes of DHCA in the alpha-stat and pH-stat groups, respectively. The p-CREB and p-Akt in the pH-stat group were significantly higher than in the alpha-stat group (140 +/- 9%, p < 0.05 and 125 +/- 6%, p < 0.05, respectively). There was no significant difference in p-ERK1/2 and Bax. The Bcl-2 increased in the pH-stat group to 121 +/- 4% (p < 0.05) compared with the alpha-stat group. The ratio Bcl-2:Bax increased in the pH-stat group compared with the alpha-stat group. The increase in p-CREB, p-Akt, Bcl-2, Bcl-2/Bax, and delay in increase of dopamine indicated that pH-stat, in the piglet model, prolongs "safe" time of DHCA and provides some brain protection against ischemic injury.

77 FR 21761 - Alice Falls Corporation, Alice Falls Hydro, LLC; Notice of Application for Transfer of License...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-11

... under http:[sol][sol]www.ferc.gov/docs-filing/efiling.asp. Commenters can submit brief comments up to 6,000 characters, without prior registration, using the eComment system at http:[sol][sol]www.ferc.gov... printed on the eLibrary link of Commission's Web site at http:[sol][sol]www.ferc.gov/docs-filing/elibrary...

76 FR 72699 - KC Hydro LLC of New Hampshire; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-25

....2001(a)(1)(iii) and the instructions on the Commission's Web site http:[sol][sol]www.ferc.gov/docs... registration, using the eComment system at http:[sol][sol]www.ferc.gov/docs-filing/ecomment.asp. You must... http:[sol][sol]www.ferc.gov/docs-filing/ elibrary.asp. Enter the docket number (P-14248-000) in the...

So, Why Sol-Mi? American Music Education

ERIC Educational Resources Information Center

Bennett, Peggy D.

2005-01-01

Walk into any primary grade music class in the U.S., and you will likely hear teacher and students singing a musical greeting, such as "Good morning boys and girls" (sol-mi-mi-sol-sol-mi) and the response "Good morning Miss Purdy" (sol-mi-mi-sol-mi-mi). Since about the 1970s, teachers have been beginning and ending music class for young children…

Composition gradient optimization and electrical characterization of (Pb, Ca)TiO3 thin films

NASA Astrophysics Data System (ADS)

Bao, Dinghua; Mizutani, Nobuyasu; Zhang, Liangying; Yao, Xi

2001-01-01

Compositionally graded (Pb, Ca)TiO3 thin films were prepared by a monoethanolamine-modified sol-gel technique on platinum-coated silicon substrates at the annealing temperature of 600 °C. The composition gradient of the films was greatly improved by a modified annealing method. The dielectric constants, for up-graded and down-graded films annealed at 600 °C for 60 min, were found to be 469 and 355, respectively. Both were larger than those reported for conventional (Pb, Ca)TiO3 thin films. The compositionally graded films had large polarization offsets in hysteresis loops when excited by an alternating electric field. The more smooth the composition gradient of the graded film, the larger the polarization offset. This was consistent with a theoretical model reported previously by Mantese and coworkers [Appl. Phys. Lett. 71, 2047 (1997)]. The magnitude of polarization offset displayed a power-law dependence on the electric field, and the direction of the offset depended on the direction of the composition gradient with respect to the substrate. Both up-graded and down-graded films had good leakage current characteristics.

STAT5A and STAT5B have opposite correlations with drug response gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamba, V., E-mail: vlamba@ufl.edu; Jia, B.; Liang, F.

Introduction: STAT5A and STAT5B are important transcription factors that play a key role in regulation of several important physiological processes including proliferation, survival, mediation of responses to cytokines and in regulating gender differences in drug response genes such as the hepatic cytochrome P450s (CYPs) that are responsible for a large majority of drug metabolism reactions in the human body. STAT5A and STAT5b have a high degree of sequence homology and have been reported to have largely similar functions. Recent studies have, however, indicated that they can also often have distinct and unique roles in regulating gene expression. Objective: In thismore » study, we evaluated the association of STAT5A and STAT5B mRNA expression levels with those of several key hepatic cytochrome P450s (CYPs) and hepatic transcription factors (TFs) and evaluated the potential roles of STAT5A and 5b in mediating gender differences in these CYPs and TFs. Methods: Expression profiling for major hepatic CYP isoforms and transcription factors was performed using RNA sequencing (RNA-seq) in 102 human liver samples (57 female, 45 male). Real time PCR gene expression data for selected CYPs and TFs was available on a subset of 50 human liver samples (25 female, 25 male) and was used to validate the RNA-seq findings. Results: While STAT5A demonstrated significant negative correlation with expression levels of multiple hepatic transcription factors (including NR1I2 and HNF4A) and DMEs such as CYP3A4 and CYP2C19, STAT5B expression was observed to demonstrate positive associations with several CYPs and TFs analyzed. As STAT5A and STAT5B have been shown to be important in regulation of gender differences in CYPs, we also analyzed STAT5A and 5b associations with CYPs and TFs separately in males and females and observed gender dependent differential associations of STATs with several CYPs and TFs. Results from the real time PCR validation largely supported our RNA-seq findings. Conclusions: Using both RNA sequencing and real time PCR, we examined the association of STAT5A and STAT5B mRNA expression with CYP and TF gene expression. While STAT5A demonstrated significant negative correlations with expression levels of multiple hepatic TFs (including NR1I2 and HNF4α) and CYPs (eg. CYP3A4, CYP2C19), STAT5B expression was observed to demonstrate positive association with most of the CYPs/TFs analyzed suggesting that STAT5A and STAT5b have potentially different and distinct roles in regulating expression of hepatic drug response genes. Further studies are needed to elucidate the potential roles of STAT5A and 5b in regulation of CYPs/TFs and the potential implications of these findings.« less

Developmental expression of STATs, nuclear factor-κB and inflammatory genes in the jejunum of piglets during weaning.

PubMed

Yi, Hongbo; Jiang, Denghu; Zhang, Lin; Xiong, Haitao; Han, Feifei; Wang, Yizhen

2016-07-01

The signal transducer and activator of transcription (STAT) proteins play essential roles in apoptosis, proliferation and survival. However, the role of STATs in intestinal inflammation during weaning is unclear. This study aimed to investigate developmental expression of STATs, nuclear factor-κB (NF-κB) and inflammatory genes in the jejunum of piglets during weaning. Thirty-two piglets were weaned at 21d and sacrificed at 0, 1, 7, or 14d (n=8) after weaning. Villus height and the villus height/crypt depth ratio were decreased, whereas crypt depth was increased in the jejunum at 7 and 14d after weaning. In addition, the mRNA levels of interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), IL-6, IL-8, IL-12 and IL-22 were increased in the jejunum at 7 and 14d after weaning, whereas transforming growth factor-β (TGF-β), suppressor of cytokine signaling 3 (SCOS3) and arginase-1 was decreased. Neutrophil infiltration was increased in the mucosa of the jejunum after weaning. Moreover, phosphorylation of IκB-α, NF-κB, AKT and STAT-3 was increased. However, the phosphorylation of STAT-1 (at 7 and 14d) and STAT-6 (at 1 and 7d) was suppressed in the jejunum after weaning. Treatment of porcine jejunal epithelial (IPEC-J2) cells with the STAT inhibitors fludarabine, niclosamide and teriflunomide, which inhibit the phosphorylation of STAT-1, STAT-3 and STAT-6, respectively, weakened the defense capacity of these cells against bacterial infection. In conclusion, weaning caused severe inflammation associated with activation of the NF-κB and STAT-3 pathways and suppression of STAT-1 and STAT-6 in the jejunum of piglets. Copyright © 2016 Elsevier B.V. All rights reserved.

High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer

PubMed Central

Wallbillich, John J.; Josyula, Srirama; Saini, Uksha; Zingarelli, Roman A.; Dorayappan, Kalpana Deepa Priya; Riley, Maria K.; Wanner, Ross A.; Cohn, David E.; Selvendiran, Karuppaiyah

2017-01-01

Objectives STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin. Methods In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin. Results Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins. Conclusions These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin. PMID:28114390

Multidimensional Single Cell Based STAT Phosphorylation Profiling Identifies a Novel Biosignature for Evaluation of Systemic Lupus Erythematosus Activity

PubMed Central

Huang, Xinfang; Guo, Yanzhi; Bao, Chunde; Shen, Nan

2011-01-01

Introduction Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE), a complex autoimmune disease. Comprehensively quantifying basal STATs phosphorylation and their signaling response to cytokines should help us to better understand the etiology of SLE. Methods Phospho-specific flow cytometry was used to measure the basal STAT signaling activation in three immune cell types of peripheral-blood mononuclear cells from 20 lupus patients, 9 rheumatoid arthritis (RA) patients and 13 healthy donors (HDs). A panel of 27 cytokines, including inflammatory cytokines, was measured with Bio-Plex™ Human Cytokine Assays. Serum Prolactin levels were measured with an immunoradiometric assay. STAT signaling responses to inflammatory cytokines (interferon α [IFNα], IFNγ, interleukin 2 [IL2], IL6, and IL10) were also monitored. Results We observed the basal activation of STAT3 in SLE T cells and monocytes, and the basal activation of STAT5 in SLE T cells and B cells. The SLE samples clustered into two main groups, which were associated with the SLE Disease Activity Index 2000, their erythrocyte sedimentation rate, and their hydroxychloroquine use. The phosphorylation of STAT5 in B cells was associated with cytokines IL2, granulocyte colony-stimulating factor (G-CSF), and IFNγ, whereas serum prolactin affected STAT5 activation in T cells. The responses of STAT1, STAT3, and STAT5 to IFNα were greatly reduced in SLE T cells, B cells, and monocytes, except for the STAT1 response to IFNα in monocytes. The response of STAT3 to IL6 was reduced in SLE T cells. Conclusions The basal activation of STATs signaling and reduced response to cytokines may be helpful us to identify the activity and severity of SLE. PMID:21799742

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production.

PubMed

Matsui, Futoshi; Babitz, Stephen A; Rhee, Audrey; Hile, Karen L; Zhang, Hongji; Meldrum, Kirstan K

2017-01-01

STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 10 6 /rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Copyright © 2017 the American Physiological Society.

JAK/Stat signaling regulates heart precursor diversification in Drosophila

PubMed Central

Johnson, Aaron N.; Mokalled, Mayssa H.; Haden, Tom N.; Olson, Eric N.

2011-01-01

Intercellular signal transduction pathways regulate the NK-2 family of transcription factors in a conserved gene regulatory network that directs cardiogenesis in both flies and mammals. The Drosophila NK-2 protein Tinman (Tin) was recently shown to regulate Stat92E, the Janus kinase (JAK) and Signal transducer and activator of transcription (Stat) pathway effector, in the developing mesoderm. To understand whether the JAK/Stat pathway also regulates cardiogenesis, we performed a systematic characterization of JAK/Stat signaling during mesoderm development. Drosophila embryos with mutations in the JAK/Stat ligand upd or in Stat92E have non-functional hearts with luminal defects and inappropriate cell aggregations. Using strong Stat92E loss-of-function alleles, we show that the JAK/Stat pathway regulates tin expression prior to heart precursor cell diversification. tin expression can be subdivided into four phases and, in Stat92E mutant embryos, the broad phase 2 expression pattern in the dorsal mesoderm does not restrict to the constrained phase 3 pattern. These embryos also have an expanded pericardial cell domain. We show the E(spl)-C gene HLHm5 is expressed in a pattern complementary to tin during phase 3 and that this expression is JAK/Stat dependent. In addition, E(spl)-C mutant embryos phenocopy the cardiac defects of Stat92E embryos. Mechanistically, JAK/Stat signals activate E(spl)-C genes to restrict Tin expression and the subsequent expression of the T-box transcription factor H15 to direct heart precursor diversification. This study is the first to characterize a role for the JAK/Stat pathway during cardiogenesis and identifies an autoregulatory circuit in which tin limits its own expression domain. PMID:21965617

Method of making ionic liquid mediated sol-gel sorbents

DOEpatents

Malik, Abdul; Shearrow, Anne M.

2017-01-31

Ionic liquid (IL)-mediated sol-gel hybrid organic-inorganic materials present enormous potential for effective use in analytical microextraction. One obstacle to materializing this prospect arises from high viscosity of ILs significantly slowing down sol-gel reactions. A method was developed which provides phosphonium-based, pyridinium-based, and imidazolium-based IL-mediated advanced sol-gel organic-inorganic hybrid materials for capillary microextraction. Scanning electron microscopy results demonstrate that ILs can serve as porogenic agents in sol-gel reactions. IL-mediated sol-gel coatings prepared with silanol-terminated polymers provided up to 28 times higher extractions compared to analogous sol-gel coatings prepared without any IL in the sol solution. This study shows that IL-generated porous morphology alone is not enough to provide effective extraction media: careful choice of the organic polymer and the precursor with close sol-gel reactivity must be made to ensure effective chemical bonding of the organic polymer to the created sol-gel material to be able to provide the desired sorbent characteristics.

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia.

PubMed

Jiang, Xuechao; Zha, Bingbing; Liu, Xiaoming; Liu, Ronghua; Liu, Jun; Huang, Enyu; Qian, Tingting; Liu, Jiajing; Wang, Zhiming; Zhang, Dan; Wang, Luman; Chu, Yiwei

2016-12-01

Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD.

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

PubMed Central

Jiang, Xuechao; Zha, Bingbing; Liu, Xiaoming; Liu, Ronghua; Liu, Jun; Huang, Enyu; Qian, Tingting; Liu, Jiajing; Wang, Zhiming; Zhang, Dan; Wang, Luman; Chu, Yiwei

2016-01-01

Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD. PMID:27906181

Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells.

PubMed

Chung, Seyung S; Wu, Yong; Okobi, Quincy; Adekoya, Debbie; Atefi, Mohammad; Clarke, Orette; Dutta, Pranabananda; Vadgama, Jaydutt V

2017-01-01

There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF- α , activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF- α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF- κ B physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF- α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF- α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF- α -induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF- κ B interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.

Stat3 phosphorylation is required for embryonic stem cells ground state maintenance in 2i culture media.

PubMed

Wang, Dan; Sang, Hui; Zhang, Kaiyue; Nie, Yan; Zhao, Shuang; Zhang, Yan; He, Ningning; Wang, Yuebing; Xu, Yang; Xie, Xiaoyan; Li, Zongjin; Liu, Na

2017-05-09

Embryonic stem cells (ES cells) can be maintained its undifferentiated state with feeder cells or LIF, which can activate Jak/Stat3 pathway. Recently, it has been reported a new culture condition comprising serum-free medium with ERK and GSK3β inhibitors (2i) could drive ES cells into a state of pluripotency more like inner cell mass (ICM) in mouse blastocysts called ground state. However, although 2i could sustain ES cells self-renewal, LIF is routinely added. The roles of Stat3 activation are still unclear now. Here we investigated whether Jak/Stat3 might also contribute to the induction of ground state pluripotency. We introduced a lentiviral construct with 7-repeat Stat3-binding sequence to drive Renilla luciferase into ES cells, which can be used as a reporter to detect Stat3 activation by noninvasive bioluminescence imaging. Using this ES cells, we investigated the role of Stat3 activation in ground state maintenance. The results showed that Stat3 could be activated by 2i. Stattic, a chemical inhibitor of Stat3 phosphorylation, could effectively inhibit Stat3 activation in ES cells. When Stat3 activation was suppressed, ground state related genes were down regulated, and ES cells could not be maintained the ground state pluripotency even in 2i medium. All of these results indicate Stat3 activation is required in ground state maintenance.

Identification, expression, and immuno-reactivity of Sol i 2 & Sol i 4 venom proteins of queen red imported fire ants, Solenopsis invicta Buren (Hymenoptera: Formicidae).

PubMed

Lockwood, Stephanie A; Haghipour-Peasley, Jilla; Hoffman, Donald R; Deslippe, Richard J

2012-10-01

We report on two low-molecular weight proteins that are stored in the venom of queen red imported fire ants (Solenopsis invicta). Translated amino acid sequences identified one protein to have 74.8% identity with the Sol i 2w worker allergen, and the other protein was found to have 96/97% identity with Sol i 4.01w/4.02w worker allergens. Both Sol i 2 and Sol i 4 queen and worker proteins were expressed using pEXP1-DEST vector in SHuffle™ T7 Express lysY Escherichia coli. Proteins were expressed at significant concentrations, as opposed to the μg/ml amounts by our previous expression methods, enabling further study of these proteins. Sol i 2q protein bound weakly to human IgE, sera pooled from allergic patients, whereas Sol i 2w, Sol i 4.01w, and Sol i 4q proteins bound strongly. Despite Sol i 2w and Sol i 2q proteins having 74.8% identity, the queen protein is less immuno-reactive than the worker allergen. This finding is consistent with allergic individuals being less sensitive to queen than worker venom. Copyright © 2012 Elsevier Ltd. All rights reserved.

28 CFR 51.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Voting Rights Act of 1965, 79 Stat. 437, as amended by the Civil Rights Act of 1968, 82 Stat. 73, the Voting Rights Act Amendments of 1970, 84 Stat. 314, the District of Columbia Delegate Act, 84 Stat. 853, the Voting Rights Act Amendments of 1975, 89 Stat. 400, the Voting Rights Act Amendments of 1982, 96...

28 CFR 51.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Voting Rights Act of 1965, 79 Stat. 437, as amended by the Civil Rights Act of 1968, 82 Stat. 73, the Voting Rights Act Amendments of 1970, 84 Stat. 314, the District of Columbia Delegate Act, 84 Stat. 853, the Voting Rights Act Amendments of 1975, 89 Stat. 400, and the Voting Rights Act Amendments of 1982...

Phosphorylation of Stats at Ser727 in renal proximal tubular epithelial cells exposed to cadmium.

PubMed

Nakagawa, Junko; Nishitai, Gen; Inageda, Kiyoshi; Matsuoka, Masato

2007-11-01

The effects of cadmium exposure on serine phosphorylation of signal transducers and activators of transcription (Stats) and an upstream kinase were examined in renal proximal tubular cells. In porcine LLC-PK1 cells treated with cadmium, Stat1 and Stat3 proteins were phosphorylated at Ser727 without changing total Stat protein levels. While phosphorylated forms of the members of mitogen-activated protein kinases (MAPKs) increased in response to cadmium exposure, treatment with a p38 inhibitor, SB203580 reduced Ser727 phosphorylation of Stat1 and Stat3 markedly in LLC-PK1 cells. The expression of human matrix metalloproteinase-3 (MMP-3), a Stats-inducible gene, was found to be up-regulated in human HK-2 cells exposed to cadmium, and suppressed by preincubation with SB203580. These results suggest that cadmium might induce the phosphorylation of Stat1 and Stat3 at Ser727 via the p38 pathway at least in part, and modulate gene expression in these proximal tubular cells. Copyright © 2007 Elsevier B.V. All rights reserved.

Interferon-γ biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells

PubMed Central

Satou, Ryousuke; Miyata, Kayoko; Gonzalez-Villalobos, Romer A.; Ingelfinger, Julie R.; Navar, L. Gabriel; Kobori, Hiroyuki

2012-01-01

Renal inflammation modulates angiotensinogen (AGT) production in renal proximal tubular cells (RPTCs) via inflammatory cytokines, including interleukin-6, tumor necrosis factor α, and interferon-γ (IFN-γ). Among these, the effects of IFN-γ on AGT regulation in RPTCs are incompletely delineated. This study aimed to elucidate mechanisms by which IFN-γ regulates AGT expression in RPTCs. RPTCs were incubated with or without IFN-γ up to 48 h. AGT expression, STAT1 and STAT3 activities, and SOCS1 expression were evaluated. RNA interference studies against STAT1, SOCS1, and STAT3 were performed to elucidate a signaling cascade. IFN-γ decreased AGT expression at 6 h (0.61±0.05, ratio to control) and 12 h (0.47±0.03). In contrast, longer exposure for 24 and 48 h increased AGT expression (1.76±0.18, EC50=3.4 ng/ml, and 1.45±0.08, respectively). IFN-γ treatment for 6 h strongly induced STAT1 phosphorylation and SOCS1 augmentation, and decreased STAT3 activity. However, STAT1 phosphorylation and SOCS1 augmentation waned at 24 h, while STAT3 activity increased. RNA interference studies revealed that activation of STAT1-SOCS1 axis decreased STAT3 activity. Thus, IFN-γ biphasically regulates AGT expression in RPTCs via STAT3 activity modulated by STAT1-SOCS1 axis, suggesting the STAT1-SOCS1 axis is important in IFN-γ-induced activation of the intrarenal renin-angiotensin system.—Satou, R., Miyata, K., Gonzalez-Villalobos, R. A., Ingelfinger, J. R., Navar, L. G., Kobori, H. Interferon-γ biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells. PMID:22302831

Activation of the STAT3 Signaling Pathway Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP

PubMed Central

Huang, Xin; Meng, Bin; Iqbal, Javeed; Ding, B. Belinda; Perry, Anamarija M.; Cao, Wenfeng; Smith, Lynette M.; Bi, Chengfeng; Jiang, Chunsun; Greiner, Timothy C.; Weisenburger, Dennis D.; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Gascoyne, Randy D.; Cook, James R.; Tubbs, Raymond R.; Jaffe, Elaine S.; Armitage, James O.; Vose, Julie M.; Staudt, Louis M.; McKeithan, Timothy W.; Chan, Wing C.; Ye, B. Hilda; Fu, Kai

2013-01-01

Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non–germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype. PMID:24220563

Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2V617F in mice

PubMed Central

Walz, Christoph; Ahmed, Wesam; Lazarides, Katherine; Betancur, Monica; Patel, Nihal; Hennighausen, Lothar; Zaleskas, Virginia M.

2012-01-01

STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2V617F in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1–induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2V617F failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2V617F, and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs. PMID:22234689

Nuclear relocation of STAT6 reliably predicts NAB2-STAT6 fusion for the diagnosis of solitary fibrous tumour.

PubMed

Koelsche, Christian; Schweizer, Leonille; Renner, Marcus; Warth, Arne; Jones, David T W; Sahm, Felix; Reuss, David E; Capper, David; Knösel, Thomas; Schulz, Birte; Petersen, Iver; Ulrich, Alexis; Renker, Eva Kristin; Lehner, Burkhard; Pfister, Stefan M; Schirmacher, Peter; von Deimling, Andreas; Mechtersheimer, Gunhild

2014-11-01

Nuclear relocation of STAT6 has been shown in tumours with NAB2-STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT. A total of 689 formalin-fixed paraffin-embedded tumours comprising 35 pleural SFTs and 654 other mesenchymal tumours were investigated for STAT6 expression using immunohistochemistry. Nine dedifferentiated liposarcomas (DDLSs) and five SFTs were also examined for the presence of NAB2-STAT6 fusion at the protein level using the proximity ligation assay (PLA), and for copy number variants (CNVs) with the Illumina Infinium Human Methylation450 array. Thirty-four of 35 SFTs showed strong nuclear STAT6 expression. Furthermore, five of 68 DDLSs, two of 130 undifferentiated pleomorphic sarcomas and one of 63 cases of nodular fasciitis showed moderate to strong nuclear STAT6 expression. The PLA indicated the presence of NAB2-STAT6 fusion protein in SFTs, but signal was also detected in some DDLSs. Copy number analysis showed an overall low frequency of chromosomal imbalances in SFTs, but complex karyotypes in DDLSs, including amplification of STAT6 and MDM2 loci. The detection of nuclear relocation of STAT6 with immunohistochemistry is a characteristic of SFTs, and may serve as a diagnostic marker that indicates NAB2-STAT6 fusion and helps to discriminate SFTs from histological mimics. © 2014 John Wiley & Sons Ltd.

STAT3 in Cancer—Friend or Foe?

PubMed Central

Zhang, Hai-Feng; Lai, Raymond

2014-01-01

The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and shapes many malignant phenotypes in cancer cells. Nevertheless, results from more recent experimental and clinicopathologic studies have suggested that STAT3 also can exert tumor suppressor effects under specific conditions. Importantly, some of these studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects. Thus, in the context of cancer biology, STAT3 can be a friend or foe. In the first half of this review, we will highlight the “evil” features of STAT3 by summarizing its oncogenic functions and mechanisms. The differences between the canonical and non-canonical pathway will be highlighted. In the second half, we will summarize the evidence supporting that STAT3 can function as a tumor suppressor. To explain how STAT3 may mediate its tumor suppressor effects, we will discuss several possible mechanisms, one of which is linked to the role of STAT3β, one of the two STAT3 splicing isoforms. Taken together, it is clear that the roles of STAT3 in cancer are multi-faceted and far more complicated than one appreciated previously. The new knowledge has provided us with new approaches and strategies when we evaluate STAT3 as a prognostic biomarker or therapeutic target. PMID:24995504

PTP1B is a negative regulator of interleukin 4–induced STAT6 signaling

PubMed Central

Lu, Xiaoqing; Malumbres, Raquel; Shields, Benjamin; Jiang, Xiaoyu; Sarosiek, Kristopher A.; Natkunam, Yasodha

2008-01-01

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed enzyme shown to negatively regulate multiple tyrosine phosphorylation-dependent signaling pathways. PTP1B can modulate cytokine signaling pathways by dephosphorylating JAK2, TYK2, and STAT5a/b. Herein, we report that phosphorylated STAT6 may serve as a cytoplasmic substrate for PTP1B. Overexpression of PTP1B led to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B knockdown or deficiency augmented IL-4–induced STAT6 signaling. Pretreatment of these cells with the PTK inhibitor staurosporine led to sustained STAT6 phosphorylation consistent with STAT6 serving as a direct substrate of PTP1B. Furthermore, PTP1B-D181A “substrate-trapping” mutants formed stable complexes with phosphorylated STAT6 in a cellular context and endogenous PTP1B and STAT6 interacted in an interleukin 4 (IL-4)–inducible manner. We delineate a new negative regulatory loop of IL-4–JAK-STAT6 signaling. We demonstrate that IL-4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase–dependent manner and enhances PTP1B protein stability to suppress IL-4–induced STAT6 signaling. Finally, we show that PTP1B expression may be preferentially elevated in activated B cell–like diffuse large B-cell lymphomas. These observations identify a novel regulatory loop for the regulation of IL-4–induced STAT6 signaling that may have important implications in both neoplastic and inflammatory processes. PMID:18716132

Nipah Virus V Protein Evades Alpha and Gamma Interferons by Preventing STAT1 and STAT2 Activation and Nuclear Accumulation

PubMed Central

Rodriguez, Jason J.; Parisien, Jean-Patrick; Horvath, Curt M.

2002-01-01

Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V proteins. The V proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V protein escapes IFN by a distinct mechanism involving direct inhibition of STAT protein function. Nipah virus V protein differs from other paramyxovirus V proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT protein subcellular distribution in the steady state, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V protein. As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-α and IFN-γ. PMID:12388709

STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues.

PubMed

Tahara, Teruyuki; Streit, Ursula; Pelish, Henry E; Shair, Matthew D

2017-04-07

Signal transducer and activator of transcription 3 (STAT3) is a component of the JAK/STAT pathway. Therapeutic inhibition of STAT3 has been of high interest, as its aberrant activation has been linked to cancer, inflammation, and other human diseases. The withanolide family natural product withaferin A (1) inhibits STAT3 activation. We designed, synthesized, and evaluated simplified withanolide analogues SLW1 (3) and SLW2 (4), and found that SLW1 retained the STAT3 inhibitory activity of withaferin A.

Metal-silica sol-gel materials

NASA Technical Reports Server (NTRS)

Stiegman, Albert E. (Inventor)

2002-01-01

The present invention relates to a single phase metal-silica sol-gel glass formed by the co-condensation of a transition metal with silicon atoms where the metal atoms are uniformly distributed within the sol-gel glass as individual metal centers. Any transition metal may be used in the sol-gel glasses. The present invention also relates to sensor materials where the sensor material is formed using the single phase metal-silica sol-gel glasses. The sensor materials may be in the form of a thin film or may be attached to an optical fiber. The present invention also relates to a method of sensing chemicals using the chemical sensors by monitoring the chromatic change of the metal-silica sol-gel glass when the chemical binds to the sensor. The present invention also relates to oxidation catalysts where a metal-silica sol-gel glass catalyzes the reaction. The present invention also relates to a method of performing oxidation reactions using the metal-silica sol-gel glasses. The present invention also relates to organopolymer metal-silica sol-gel composites where the pores of the metal-silica sol-gel glasses are filled with an organic polymer polymerized by the sol-gel glass.

Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma

PubMed Central

Yco, Lisette P; Mocz, Gabor; Opoku-Ansah, John; Bachmann, André S

2014-01-01

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM. PMID:25452693

The measles virus phosphoprotein interacts with the linker domain of STAT1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devaux, Patricia, E-mail: devaux.patricia@mayo.edu; Priniski, Lauren; Cattaneo, Roberto

2013-09-15

The measles virus (MV) phosphoprotein (P) and V proteins block the interferon (IFN) response by impeding phosphorylation of the signal transducer and activator of transcription 1 (STAT1) by the Janus kinase 1 (JAK1). We characterized how STAT1 mutants interact with P and JAK1 phosphorylation. Certain mutants of the linker, the Src-homology 2 domain (SH2), or the transactivation domain had reduced or abolished phosphorylation through JAK1 after IFN treatment. Other mutants, mainly localized in the linker, failed to interact with P as documented by the lack of interference with nuclear translocation. Thus the functional footprint of P on STAT1 localizes mainlymore » to the linker domain; there is also some overlap with the STAT1 phosphorylation functional footprint on the SH2 domain. Based on these observations, we discuss how the MV-P might operate to inhibit the JAK/STAT pathway. - Highlights: • Residue in the linker and SH2 domains of STAT1 are important for MV-P interaction. • Residue in the linker and SH2 domains of STAT1 are important for STAT1 phosphorylation. • Residues interferring with both functions have similar location on STAT1. • The viral P and V proteins may operate in concert to inhibit the JAK/STAT pathway.« less

STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

PubMed

Mizowaki, Takashi; Sasayama, Takashi; Tanaka, Kazuhiro; Mizukawa, Katsu; Takata, Kumi; Nakamizo, Satoshi; Tanaka, Hirotomo; Nagashima, Hiroaki; Nishihara, Masamitsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

2015-09-01

Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

Clustered localization of STAT3 during the cell cycle detected by super-resolution fluorescence microscopy

NASA Astrophysics Data System (ADS)

Gao, Jing; Chen, Junling; Cai, Mingjun; Xu, Haijiao; Jiang, Junguang; Tong, Ti; Wang, Hongda

2017-06-01

Signal transducer and activator of transcription 3 (STAT3) plays a key role in various cellular processes such as cell proliferation, differentiation, apoptosis and immune responses. In particular, STAT3 has emerged as a potential molecular target for cancer therapy. The functional role and standard activation mechanism of STAT3 have been well studied, however, the spatial distribution of STAT3 during the cell cycle is poorly known. Therefore, it is indispensable to study STAT3 spatial arrangement and nuclear-cytoplasimic localization at the different phase of cell cycle in cancer cells. By direct stochastic optical reconstruction microscopy imaging, we find that STAT3 forms various number and size of clusters at the different cell-cycle stage, which could not be clearly observed by conventional fluorescent microscopy. STAT3 clusters get more and larger gradually from G1 to G2 phase, during which time transcription and other related activities goes on consistently. The results suggest that there is an intimate relationship between the clustered characteristic of STAT3 and the cell-cycle behavior. Meanwhile, clustering would facilitate STAT3 rapid response to activating signals due to short distances between molecules. Our data might open a new door to develop an antitumor drug for inhibiting STAT3 signaling pathway by destroying its clusters.

Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma.

PubMed

Yco, Lisette P; Mocz, Gabor; Opoku-Ansah, John; Bachmann, André S

2014-01-01

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)-mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM.

Stat5 Signaling Specifies Basal versus Stress Erythropoietic Responses through Distinct Binary and Graded Dynamic Modalities

PubMed Central

Porpiglia, Ermelinda; Hidalgo, Daniel; Koulnis, Miroslav; Tzafriri, Abraham R.; Socolovsky, Merav

2012-01-01

Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a “knocked-in” EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and graded modalities combine to generate high-fidelity Stat5 signaling over the entire basal and stress Epo range. They suggest that dynamic behavior may encode information during STAT signal transduction. PMID:22969412

Intramolecular hydrophobic interactions are critical mediators of STAT5 dimerization

NASA Astrophysics Data System (ADS)

Fahrenkamp, Dirk; Li, Jinyu; Ernst, Sabrina; Schmitz-van de Leur, Hildegard; Chatain, Nicolas; Küster, Andrea; Koschmieder, Steffen; Lüscher, Bernhard; Rossetti, Giulia; Müller-Newen, Gerhard

2016-10-01

STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins. We identified a novel intramolecular interaction mediated through F706, adjacent to the phosphotyrosine motif, and a unique hydrophobic interface on the surface of the SH2 domain. Analysis of corresponding STAT5 mutants revealed that this interaction is dispensable for Epo receptor-mediated phosphorylation of STAT5 but essential for dimer formation and subsequent nuclear accumulation. Moreover, the herein presented model clarifies molecular mechanisms of recently discovered leukemic STAT5 mutants and will help to guide future drug development.

Intramolecular hydrophobic interactions are critical mediators of STAT5 dimerization

PubMed Central

Fahrenkamp, Dirk; Li, Jinyu; Ernst, Sabrina; Schmitz-Van de Leur, Hildegard; Chatain, Nicolas; Küster, Andrea; Koschmieder, Steffen; Lüscher, Bernhard; Rossetti, Giulia; Müller-Newen, Gerhard

2016-01-01

STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins. We identified a novel intramolecular interaction mediated through F706, adjacent to the phosphotyrosine motif, and a unique hydrophobic interface on the surface of the SH2 domain. Analysis of corresponding STAT5 mutants revealed that this interaction is dispensable for Epo receptor-mediated phosphorylation of STAT5 but essential for dimer formation and subsequent nuclear accumulation. Moreover, the herein presented model clarifies molecular mechanisms of recently discovered leukemic STAT5 mutants and will help to guide future drug development. PMID:27752093

STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Li, E-mail: lin.796@osu.edu; Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030; Fuchs, James

2011-12-16

Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existencemore » of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower IC50 in colon cancer stem-like cells. In summary, our results indicate that STAT3 is a novel therapeutic target in colon cancer stem-like cells and inhibition of STAT3 in cancer stem-like cells may offer a potential treatment for colorectal cancer.« less

IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer

PubMed Central

2013-01-01

Background Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial–mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. Methods STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. Results Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27–treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. Conclusion IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1–dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27. PMID:24274066

Regulation of STATs by polycystin-1 and their role in polycystic kidney disease.

PubMed

Weimbs, Thomas; Olsan, Erin E; Talbot, Jeffrey J

2013-04-01

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disease caused by mutations in the gene coding for polycystin-1 (PC1). PC1 can regulate STAT transcription factors by a novel, dual mechanism. STAT3 and STAT6 are aberrantly activated in renal cysts. Genetic and pharmacological approaches to inhibit STAT3 or STAT6 have led to promising results in ADPKD mouse models. Here, we review current findings that lead to a model of PC1 as a key regulator of STAT signaling in renal tubule cells. We discuss how PC1 may orchestrate appropriate epithelial responses to renal injury, and how this system may lead to aberrant STAT activation in ADPKD thereby causing inappropriate activation of tissue repair programs that culminate in renal cyst growth and fibrosis.

Sophoraflavanone G induces apoptosis of human cancer cells by targeting upstream signals of STATs.

PubMed

Kim, Byung-Hak; Won, Cheolhee; Lee, Yun-Han; Choi, Jung Sook; Noh, Kum Hee; Han, Songhee; Lee, Haeri; Lee, Chang Seok; Lee, Dong-Sup; Ye, Sang-Kyu; Kim, Myoung-Hwan

2013-10-01

Aberrantly activated signal transducer and activator of transcription (STAT) proteins are implicated with human cancers and represent essential roles for cancer cell survival and proliferation. Therefore, the development of small-molecule inhibitors of STAT signaling bearing pharmacological activity has therapeutic potential for the treatment of human cancers. In this study, we identified sophoraflavanone G as a novel small-molecule inhibitor of STAT signaling in human cancer cells. Sophoraflavanone G inhibited tyrosine phosphorylation of STAT proteins in Hodgkin's lymphoma and tyrosine phosphorylation of STAT3 in solid cancer cells by inhibiting phosphorylation of the Janus kinase (JAK) proteins, Src family tyrosine kinases, such as Lyn and Src, Akt, and ERK1/2. In addition, sophoraflavanone G inhibited STAT5 phosphorylation in murine-bone-marrow-derived pro-B cells transfected with translocated Ets Leukemia (TEL)-JAKs and cytokine-induced rat pre-T lymphoma cells, as well as STAT5b reporter activity in TEL-JAKs and STAT5b reporter systems. Sophoraflavanone G also inhibited nuclear factor-κB (NF-κB) signaling in multiple myeloma cells. Furthermore, sophoraflavanone G inhibited cancer cell proliferation and induced apoptosis by regulating the expression of apoptotic and anti-apoptotic proteins. Our data suggest that sophoraflavanone G is a novel small-molecule inhibitor of STAT signaling by targeting upstream signals of STATs that may have therapeutic potential for cancers caused by persistently activated STAT proteins. Copyright © 2013 Elsevier Inc. All rights reserved.

Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells

PubMed Central

Okobi, Quincy; Adekoya, Debbie; Atefi, Mohammad; Clarke, Orette; Dutta, Pranabananda; Vadgama, Jaydutt V.

2017-01-01

There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer. PMID:28676732

STAT3 Activation Promotes Oncolytic HSV1 Replication in Glioma Cells

PubMed Central

Okemoto, Kazuo; Wagner, Benjamin; Meisen, Hans; Haseley, Amy; Kaur, Balveen; Chiocca, Ennio Antonio

2013-01-01

Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy. PMID:23936533

Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling

PubMed Central

Kim, Byung Hak; Min, Yun Sook; Choi, Jung Sook; Baeg, Gyeong-Hun; Kim, Youngsoo; Shin, Jong Wook; Kim, Tae-Yoon

2011-01-01

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma. PMID:21499010

Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.

PubMed

Kim, Byung Hak; Min, Yun Sook; Choi, Jung Sook; Baeg, Gyeong Hun; Kim, Young Soo; Shin, Jong Wook; Kim, Tae Yoon; Ye, Sang Kyu

2011-05-31

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.

The role of signal transducer and activator of transcription 3 in Rift Valley fever virus infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pinkham, Chelsea; An, Soyeon; Lundberg, Lindsay

Rift Valley fever (RVF) is a zoonotic disease that can cause severe illness in humans and livestock, triggering spontaneous abortion in almost 100% of pregnant ruminants. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3) is phosphorylated on its conserved tyrosine residue (Y705) following RVFV infection. This phosphorylation was dependent on a major virulence factor, the viral nonstructural protein NSs. Loss of STAT3 had little effect on viral replication, but rather resulted in cells being more susceptible to RVFV-induced cell death. Phosphorylated STAT3 translocated to the nucleus, coinciding with inhibition of fos, jun, and nr4a2more » gene expression, and the presence of STAT3 and NSs at the nr4a2 promoter. NSs was found predominantly in the cytoplasm of STAT3 null cells, indicating that STAT3 influences NSs nuclear localization. Collectively, these data demonstrate that STAT3 functions in a pro-survival capacity through modulation of NSs localization. - Highlights: • STAT3 is phosphorylated on tyrosine residue 705 following RVFV infection. • Phosphorylation of STAT3 was dependent on the viral protein NSs. • STAT3 -/- MEFs were more susceptible to RVFV-induced cell death. • Loss of STAT3 led to an increase in pro-apoptotic gene expression. • STAT3 functions in a pro-survival capacity by modulation of NSs localization.« less

Sol concentration effect on ZnO nanofibers photocatalytic activity synthesized by sol-gel dip coating method

NASA Astrophysics Data System (ADS)

Toubane, M.; Tala-Ighil, R.; Bensouici, F.; Bououdina, M.; Souier, M.; Liu, S.; Cai, W.; Iratni, A.

2017-03-01

ZnO thin films were deposited onto glass substrate by sol-gel dip coating method. The initial sol concentrations were varied from 0.2 to 0.5 M. Zinc acetate dihydrate, ethanol and Diethanolamine (DEA) were used as staring material, solvent and stabilizer respectively. The evolution of structural, optical properties and methylene blue (MB) photodegradation of the as-deposited films on sol concentration was investigated. Rietveld refinements of x-ray patterns reveal that all the as-prepared thin films have a Zincite-type structure with grain orientation along to c-axis. The strongest sol concentration is favorable for the highest crystallization quality. However, the high preferred orientation factor (POF) occurs for 0.3 M sol concentration. The field emission scanning electron microscopy observations reveals nanofibrous morphology with different lengths. The nanofibers density increases with increasing sols concentrations until forming a flower-like morphology. The EDS analysis confirms the high purity of the as-deposited ZnO films. It is found that all films present good transparency greater than 95% in the visible range; the optical band gap is slightly reduced with the increase in sol concentration. The photocatalytic degradation is enhanced by 90% with the sol concentration. The K app rate reaction increased with increasing sol concentration. The films stability is found to slightly decrease after the third cycle, especially for 0.5 M sol concentration.

STAT2-dependent immune responses ensure host survival despite the presence of a potent viral antagonist.

PubMed

Le-Trilling, Vu Thuy Khanh; Wohlgemuth, Kerstin; Rückborn, Meike U; Jagnjic, Andreja; Maaßen, Fabienne; Timmer, Lejla; Katschinski, Benjamin; Trilling, Mirko

2018-05-09

Pathogen encounter induces interferons which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, host and pathogens are situated in a continuous arms race which shapes host evolution towards optimized immune responses and the pathogens towards enhanced immune evasive properties.Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2 which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lacking M27 and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pair in vitro and in vivo In contrast to wt-MCMV, ΔM27-MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g. liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection.Taken together, our study reveals the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary stand-off situation with fatal consequences when the equilibrium is disturbed. IMPORTANCE The host limits viral replication by interferons which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g. cytomegaloviruses, Zika virus, Dengue virus, and several paramyxoviruses). We analyzed infections of mouse CMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate their importance for host and virus in vitro and in vivo The inability to counteract STAT2 directly translates into exaggerated IFN susceptibility in vitro and pronounced attenuation in vivo Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus. Copyright © 2018 Le-Trilling et al.

Desensitization of the growth hormone-induced Janus kinase 2 (Jak 2)/signal transducer and activator of transcription 5 (Stat5)-signaling pathway requires protein synthesis and phospholipase C.

PubMed

Fernández, L; Flores-Morales, A; Lahuna, O; Sliva, D; Norstedt, G; Haldosén, L A; Mode, A; Gustafsson, J A

1998-04-01

Signal transducers and activators of transcription (Stat) proteins are latent cytoplasmic transcription factors that are tyrosine phosphorylated by Janus kinases (Jak) in response to GH and other cytokines. GH activates Stat5 by a mechanism that involves tyrosine phosphorylation and nuclear translocation. However, the mechanisms that turn off the GH-activated Jak2/Stat5 pathway are unknown. Continuous exposure to GH of BRL-4 cells, a rat hepatoma cell line stably transfected with rat GH receptor, induces a rapid but transient activation of Jak2 and Stat5. GH-induced Stat5 DNA-binding activity was detected after 2 min and reached a maximum at 10 min. Continued exposure to GH resulted in a desensitization characterized by 1) a rapid decrease in Stat5 DNA-binding activity. The rate of decrease of activity was rapid up to 1 h of GH treatment, and the remaining activity declined slowly thereafter. The activity of Stat5 present after 5 h is still higher than the control levels and almost 10-20% with respect to maximal activity at 10 min; and 2) the inability of further GH treatment to reinduce activation of Stat5. In contrast, with transient exposures of BRL-4 cells to GH, Stat5 DNA-binding activity could repeatedly be induced. GH-induced Jak2 and Stat5 activities were independent of ongoing protein synthesis. However, Jak2 tyrosine phosphorylation and Stat5 DNA-binding activity were prolonged for at least 4 h in the presence of cycloheximide, which suggests that the maintenance of desensitization requires ongoing protein synthesis. Furthermore, inhibition of protein synthesis potentiated GH-induced transcriptional activity in BRL-4 cells transiently transfected with SPIGLE1CAT, a reporter plasmid activated by Stat5. GH-induced Jak2 and Stat5 activation were not affected by D609 or mepacrine, both inhibitors of phospholipase C. However, in the presence of D609 and mepacrine, GH maintained prolonged Jak2 and Stat5 activation. Transactivation of SPIGLE1 by GH was potentiated by mepacrine and D609 but not by the phospholipase A2 inhibitor AACOCF3. Thus, a regulatory circuit of GH-induced transcription through the Jak2/Stat5-signaling pathway includes a prompt GH-induced activation of Jak2/Stat5 followed by a negative regulatory response; ongoing protein synthesis and intracellular signaling pathways, where phospholipase C activity is involved, play a critical role to desensitize the GH-activated Jak2/Stat5-signaling pathway.

Thickening compositions containing xanthomonas gum and hydroxyalkyl ether of guar gum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jordan, W.A.

1973-07-24

Natural and synthetic gums have been used as thickeners for foods, coatings, paints, dyes, explosive slurries, oil-well fluids, and many other applications. Thickening compositions are described which consist of xanthomonas gum and hydroxyalkyl ether of guar gum and are suitable for use in explosive slurries. Aqueous sols of xanthomonas gum are plastic in nature and exhibit higher gel strengths than sols of other gums. Aqueous sols of hydroxyalkyl ether of guar are almost Newtonian and exhibit little or no gel strength. Aqueous sols of the thickening compositions of the present invention are plastic in character. At certain concentrations of themore » thickening compositions in aqueous sols, the sols have higher gel strengths than can be obtained from xanthomonas gum alone. At certain concentrations, the aqueous sols containing the thickening compositions exhibit greater viscosity differentials than do sols containing xanthomonas gum alone. In addition, the aqueous sols exhibit a greater drop in viscosity as the thickening composition concentration is reduced than do aqueous sols of xanthomonas gum alone.(5 claims)« less

STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation.

PubMed

Lee, Chien-kuo; Raz, Regina; Gimeno, Ramon; Gertner, Rachel; Wistinghausen, Birte; Takeshita, Kenichi; DePinho, Ronald A; Levy, David E

2002-07-01

STAT3 has been described as an essential component of G-CSF-driven cell proliferation and granulopoiesis. This notion was tested by conditional gene ablation in transgenic mice. Contrary to expectation, granulocytes developed from STAT3 null bone marrow progenitors, and STAT3 null neutrophils displayed mature effector functions. Rather than a deficit in granulopoiesis, mice lacking STAT3 in their hematopoietic progenitors developed neutrophilia, and bone marrow cells were hyperresponsive to G-CSF stimulation. These studies provide direct evidence for STAT3-independent granulopoiesis and suggest that STAT3 directs a negative feedback loop necessary for controlling neutrophil numbers, possibly through induced expression of the signaling inhibitor, SOCS3.

Kobuvirus VP3 protein restricts the IFN-β-triggered signaling pathway by inhibiting STAT2-IRF9 and STAT2-STAT2 complex formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Qianqian; Lan, Xi; Wang, Chen

Emerged porcine kobuvirus (PKV) has adversely affected the global swine industry since 2008, but the etiological biology of PKV is unclear. Screening PKV-encoded structural and non-structural proteins with a type I IFN-responsive luciferase reporter showed that PKV VP3 protein inhibited the IFN-β-triggered signaling pathway, resulting in the decrease of VSV-GFP replication. QPCR data showed that IFN-β downstream cytokine genes were suppressed without cell-type specificity as well. The results from biochemical experiments indicated that PKV VP3 associated with STAT2 and IRF9, and interfered with the formation of the STAT2-IRF9 and STAT2-STAT2 complex, impairing nuclear translocation of STAT2 and IRF9. Taken together,more » these data reveal a new mechanism for immune evasion of PKV. - Highlights: •PKV VP3 inhibits the IFN-β-triggered signaling pathway. •VP3 associates with STAT2 and IRF9. •VP3 blocks the STAT2-IRF9 nuclear translocation. •VP3 utilizes a novel strategy for innate immune evasion.« less

Revealing the cellular localization of STAT1 during the cell cycle by super-resolution imaging

PubMed Central

Gao, Jing; Wang, Feng; Liu, Yanhou; Cai, Mingjun; Xu, Haijiao; Jiang, Junguang; Wang, Hongda

2015-01-01

Signal transducers and activators of transcription (STATs) can transduce cytokine signals and regulate gene expression. The cellular localization and nuclear trafficking of STAT1, a representative of the STAT family with multiple transcriptional functions, is tightly related with transcription process, which usually happens in the interphase of the cell cycle. However, these priority questions regarding STAT1 distribution and localization at the different cell-cycle stages remain unclear. By using direct stochastic optical reconstruction microscopy (dSTORM), we found that the nuclear expression level of STAT1 increased gradually as the cell cycle carried out, especially after EGF stimulation. Furthermore, STAT1 formed clusters in the whole cell during the cell cycle, with the size and the number of clusters also increasing significantly from G1 to G2 phase, suggesting that transcription and other cell-cycle related activities can promote STAT1 to form more and larger clusters for fast response to signals. Our work reveals that the cellular localization and clustering distribution of STAT1 are associated with the cell cycle, and further provides an insight into the mechanism of cell-cycle regulated STAT1 signal transduction. PMID:25762114

Modulation of the caveolin-3 localization to caveolae and STAT3 to mitochondria by catecholamine-induced cardiac hypertrophy in H9c2 cardiomyoblasts

PubMed Central

Jeong, Kyuho; Kwon, Hayeong; Min, Chanhee

2009-01-01

We investigated the effect of phenylephrine (PE)- and isoproterenol (ISO)-induced cardiac hypertrophy on subcellular localization and expression of caveolin-3 and STAT3 in H9c2 cardiomyoblast cells. Caveolin-3 localization to plasma membrane was attenuated and localization of caveolin-3 to caveolae in the plasma membrane was 24.3% reduced by the catecholamine-induced hypertrophy. STAT3 and phospho-STAT3 were up-regulated but verapamil and cyclosporin A synergistically decreased the STAT3 and phospho-STAT3 levels in PE- and ISO-induced hypertrophic cells. Both expression and activation of STAT3 were increased in the nucleus by the hypertrophy. Immunofluorescence analysis revealed that the catecholamine-induced hypertrophy promoted nuclear localization of pY705-STAT3. Of interest, phosphorylation of pS727-STAT3 in mitochondria was significantly reduced by catecholamine-induced hypertrophy. In addition, mitochondrial complexes II and III were greatly down-regulated in the hypertrophic cells. Our data suggest that the alterations in nuclear and mitochondrial activation of STAT3 and caveolae localization of caveolin-3 are related to the development of the catecholamine-induced cardiac hypertrophy. PMID:19299911

Targeted Blockage of Signal Transducer and Activator of Transcription 5 Signaling Pathway with Decoy Oligodeoxynucleotides Suppresses Leukemic K562 Cell Growth

PubMed Central

Wang, Xiaozhong; Zeng, Jianming; Shi, Mei; Zhao, Shiqiao; Bai, Weijun; Cao, Weixi; Tu, Zhiguang; Huang, Zonggan

2011-01-01

The protein signal transducer and activator of transcription 5 (STAT5) of the JAK/STAT pathway is constitutively activated because of its phosphorylation by tyrosine kinase activity of fusion protein BCR-ABL in chronic myelogenous leukemia (CML) cells. This study investigated the potential therapeutic effect of STAT5 decoy oligodeoxynucleotides (ODN) using leukemia K562 cells as a model. Our results showed that transfection of 21-mer-long STAT5 decoy ODN into K562 cells effectively inhibited cell proliferation and induced cell apoptosis. Further, STAT5 decoy ODN downregulated STAT5 targets bcl-xL, cyclinD1, and c-myc at both mRNA and protein levels in a sequence-specific manner. Collectively, these data demonstrate the therapeutic effect of blocking the STAT5 signal pathway by cis-element decoy for cancer characterized by constitutive STAT5 activation. Thus, our study provides support for STAT5 as a potential target downstream of BCR-ABL for CML treatment and helps establish the concept of targeting STAT5 by decoy ODN as a novel therapy approach for imatinib-resistant CML. PMID:21091189

SOL - SIZING AND OPTIMIZATION LANGUAGE COMPILER

NASA Technical Reports Server (NTRS)

Scotti, S. J.

1994-01-01

SOL is a computer language which is geared to solving design problems. SOL includes the mathematical modeling and logical capabilities of a computer language like FORTRAN but also includes the additional power of non-linear mathematical programming methods (i.e. numerical optimization) at the language level (as opposed to the subroutine level). The language-level use of optimization has several advantages over the traditional, subroutine-calling method of using an optimizer: first, the optimization problem is described in a concise and clear manner which closely parallels the mathematical description of optimization; second, a seamless interface is automatically established between the optimizer subroutines and the mathematical model of the system being optimized; third, the results of an optimization (objective, design variables, constraints, termination criteria, and some or all of the optimization history) are output in a form directly related to the optimization description; and finally, automatic error checking and recovery from an ill-defined system model or optimization description is facilitated by the language-level specification of the optimization problem. Thus, SOL enables rapid generation of models and solutions for optimum design problems with greater confidence that the problem is posed correctly. The SOL compiler takes SOL-language statements and generates the equivalent FORTRAN code and system calls. Because of this approach, the modeling capabilities of SOL are extended by the ability to incorporate existing FORTRAN code into a SOL program. In addition, SOL has a powerful MACRO capability. The MACRO capability of the SOL compiler effectively gives the user the ability to extend the SOL language and can be used to develop easy-to-use shorthand methods of generating complex models and solution strategies. The SOL compiler provides syntactic and semantic error-checking, error recovery, and detailed reports containing cross-references to show where each variable was used. The listings summarize all optimizations, listing the objective functions, design variables, and constraints. The compiler offers error-checking specific to optimization problems, so that simple mistakes will not cost hours of debugging time. The optimization engine used by and included with the SOL compiler is a version of Vanderplatt's ADS system (Version 1.1) modified specifically to work with the SOL compiler. SOL allows the use of the over 100 ADS optimization choices such as Sequential Quadratic Programming, Modified Feasible Directions, interior and exterior penalty function and variable metric methods. Default choices of the many control parameters of ADS are made for the user, however, the user can override any of the ADS control parameters desired for each individual optimization. The SOL language and compiler were developed with an advanced compiler-generation system to ensure correctness and simplify program maintenance. Thus, SOL's syntax was defined precisely by a LALR(1) grammar and the SOL compiler's parser was generated automatically from the LALR(1) grammar with a parser-generator. Hence unlike ad hoc, manually coded interfaces, the SOL compiler's lexical analysis insures that the SOL compiler recognizes all legal SOL programs, can recover from and correct for many errors and report the location of errors to the user. This version of the SOL compiler has been implemented on VAX/VMS computer systems and requires 204 KB of virtual memory to execute. Since the SOL compiler produces FORTRAN code, it requires the VAX FORTRAN compiler to produce an executable program. The SOL compiler consists of 13,000 lines of Pascal code. It was developed in 1986 and last updated in 1988. The ADS and other utility subroutines amount to 14,000 lines of FORTRAN code and were also updated in 1988.

A novel mechanism of skin tumor promotion involving interferon-gamma (IFNγ)/signal transducer and activator of transcription-1 (Stat1) signaling.

PubMed

Bozeman, Ronald; Abel, Erika L; Macias, Everardo; Cheng, Tianyi; Beltran, Linda; DiGiovanni, John

2015-08-01

The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.

STAT3 and importins are novel mediators of early molecular and cellular responses in experimental duodenal ulceration.

PubMed

Khomenko, Tetyana; Deng, Xiaoming; Ahluwalia, Amrita; Tarnawski, Andrzej; Patel, Khushin N; Sandor, Zsuzsanna; Szabo, Sandor

2014-02-01

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers. We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses. We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and β in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or β, and STAT3/DNA binding than wild-type mice in response to cysteamine. Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.

Radiosensitization by inhibiting STAT1 in renal cell carcinoma.

PubMed

Hui, Zhouguang; Tretiakova, Maria; Zhang, Zhongfa; Li, Yan; Wang, Xiaozhen; Zhu, Julie Xiaohong; Gao, Yuanhong; Mai, Weiyuan; Furge, Kyle; Qian, Chao-Nan; Amato, Robert; Butler, E Brian; Teh, Bin Tean; Teh, Bin S

2009-01-01

Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10(-8) for clear cell; and p = 3.6 x 10(-4) for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

PubMed

Al Khatib, Shadi; Keles, Sevgi; Garcia-Lloret, Maria; Karakoc-Aydiner, Elif; Reisli, Ismail; Artac, Hasibe; Camcioglu, Yildiz; Cokugras, Haluk; Somer, Ayper; Kutukculer, Necil; Yilmaz, Mustafa; Ikinciogullari, Aydan; Yegin, Olcay; Yüksek, Mutlu; Genel, Ferah; Kucukosmanoglu, Ercan; Baki, Ali; Bahceciler, Nerin N; Rambhatla, Anupama; Nickerson, Derek W; McGhee, Sean; Barlan, Isil B; Chatila, Talal

2009-08-01

The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. To elucidate mechanisms underlying different forms of HIES. A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

STAT4 deficiency reduces the development of atherosclerosis in mice.

PubMed

Taghavie-Moghadam, Parésa L; Gjurich, Breanne N; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H; Dobrian, Anca D; Nadler, Jerry L; Galkina, Elena V

2015-11-01

Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent

PubMed Central

Cardiff, Robert D.; Trott, Josephine F.; Hovey, Russell C.; Hubbard, Neil E.; Engelberg, Jesse A.; Tepper, Clifford G.; Willis, Brandon J.; Khan, Imran H.; Ravindran, Resmi K.; Chan, Szeman R.; Schreiber, Robert D.; Borowsky, Alexander D.

2015-01-01

Female 129:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment. PMID:26075897

Activation of Stat3 in renal tumors.

PubMed

Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan

2009-02-28

Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target.

Activation of Stat3 in renal tumors

PubMed Central

Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan

2009-01-01

Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target. PMID:19956438

Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation.

PubMed

Ahn, H J; Tomura, M; Yu, W G; Iwasaki, M; Park, W R; Hamaoka, T; Fujiwara, H

1998-12-01

While IL-12 is known to activate JAK2 and TYK2 and induce the phosphorylation of STAT4 and STAT3, little is known regarding how the activation of these signaling molecules is related to the biologic effects of IL-12. Using an IL-12-responsive T cell clone (2D6), we investigated their requirements for proliferation and IFN-gamma production of 2D6 cells. 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 lines maintained with IL-12 (2D6(IL-12)) or IL-2 (2D6(IL-2)) exhibited comparable levels of proliferation, but produced large or only small amounts of IFN-gamma, respectively, when restimulated with IL-12 after starvation of either cytokine. 2D6(IL-12) induced TYK2 and STAT4 phosphorylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL-2-containing medium. 2D6(IL-12) and 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation. JAK2 was associated with STAT5, and IL-12-induced STAT5 phosphorylation was elicited in the absence of JAK3 activation. These results indicate that IL-12 has the capacity to induce/maintain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correlate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphorylation/cellular proliferation, respectively.

Ultrasound Targeted Microbubble Destruction-Mediated Delivery of a Transcription Factor Decoy Inhibits STAT3 Signaling and Tumor Growth

PubMed Central

Kopechek, Jonathan A.; Carson, Andrew R.; McTiernan, Charles F.; Chen, Xucai; Hasjim, Bima; Lavery, Linda; Sen, Malabika; Grandis, Jennifer R.; Villanueva, Flordeliza S.

2015-01-01

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble destruction (UTMD) has been shown to enhance image-guided local delivery of molecular therapeutics to a target site. The objective of this study was to deliver STAT3 decoy to squamous cell carcinoma (SCC) tumors using UTMD to disrupt STAT3 signaling and inhibit tumor growth. Studies performed demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles inhibited STAT3 signaling in SCC cells in vitro. Studies performed in vivo demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles induced significant tumor growth inhibition (31-51% reduced tumor volume vs. controls, p < 0.05) in mice bearing SCC tumors. Furthermore, expression of STAT3 downstream target genes (Bcl-xL and cyclin D1) was significantly reduced (34-39%, p < 0.05) in tumors receiving UTMD treatment with STAT3 decoy-loaded microbubbles compared to controls. In addition, the quantity of radiolabeled STAT3 decoy detected in tumors eight hours after treatment was significantly higher with UTMD treatment compared to controls (70-150%, p < 0.05). This study demonstrates that UTMD can increase delivery of a transcription factor decoy to tumors in vivo and that the decoy can inhibit STAT3 signaling and tumor growth. These results suggest that UTMD treatment holds potential for clinical use to increase the concentration of a transcription factor signaling inhibitor in the tumor. PMID:26681983

STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice

PubMed Central

Ernst, Matthias; Najdovska, Meri; Grail, Dianne; Lundgren-May, Therese; Buchert, Michael; Tye, Hazel; Matthews, Vance B.; Armes, Jane; Bhathal, Prithi S.; Hughes, Norman R.; Marcusson, Eric G.; Karras, James G.; Na, Songqing; Sedgwick, Jonathon D.; Hertzog, Paul J.; Jenkins, Brendan J.

2008-01-01

Deregulated activation of STAT3 is frequently associated with many human hematological and epithelial malignancies, including gastric cancer. While exaggerated STAT3 signaling facilitates an antiapoptotic, proangiogenic, and proproliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 hyperactivation remain poorly understood. Using the gp130Y757F/Y757F mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130Y757F/Y757F mice, when compared with unaffected gastric tissue in wild-type mice, while gp130Y757F/Y757F mice lacking the IL-11 ligand–binding receptor subunit (IL-11Rα) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130Y757F/Y757F mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130Y757F/Y757F mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1. PMID:18431520

Interferon-gamma regulates nucleoside transport systems in macrophages through signal transduction and activator of transduction factor 1 (STAT1)-dependent and -independent signalling pathways.

PubMed Central

Soler, Concepció; Felipe, Antonio; García-Manteiga, José; Serra, Maria; Guillén-Gómez, Elena; Casado, F Javier; MacLeod, Carol; Modolell, Manuel; Pastor-Anglada, Marçal; Celada, Antonio

2003-01-01

The expressions of CNT and ENT (concentrative and equilibrative nucleoside transporters) in macrophages are differentially regulated by IFN-gamma (interferon-gamma). This cytokine controls gene expression through STAT1-dependent and/or -independent pathways (where STAT1 stands for signal transduction and activator of transcription 1). In the present study, the role of STAT1 in the response of nucleoside transporters to IFN-gamma was studied using macrophages from STAT1 knockout mice. IFN-gamma triggered an inhibition of ENT1-related nucleoside transport activity through STAT1-dependent mechanisms. Such inhibition of macrophage growth and ENT1 activity by IFN-gamma is required for DNA synthesis. Interestingly, IFN-gamma led to an induction of the CNT1- and CNT2-related nucleoside transport activities independent of STAT1, thus ensuring the supply of extracellular nucleosides for the STAT1-independent RNA synthesis. IFN-gamma up-regulated CNT2 mRNA and CNT1 protein levels and down-regulated ENT1 mRNA in both wild-type and STAT1 knockout macrophages. This is consistent with a STAT1-independent, long-term-mediated, probably transcription-dependent, regulation of nucleoside transporter genes. Moreover, STAT1-dependent post-transcriptional mechanisms are implicated in the regulation of ENT1 activity. Although nitric oxide is involved in the regulation of ENT1 activity in B-cells at a post-transcriptional level, our results show that STAT1-dependent induction of nitric oxide by IFN-gamma is not implicated in the regulation of ENT1 activity in macrophages. Our results indicate that both STAT1-dependent and -independent pathways are involved in the regulation of nucleoside transporters by IFN-gamma in macrophages. PMID:12868960

The Ying and Yang of STAT3 in Human Disease.

PubMed

Vogel, Tiphanie P; Milner, Joshua D; Cooper, Megan A

2015-10-01

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

75 FR 39710 - Postal Classification Change

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-12

.... ADDRESSES: Submit comments electronically via the Commission's Filing Online system at http:[sol][sol]www... the Commission's Web site (http:[sol][sol]www.prc.gov). Proposed edits to the draft Mail...

STAT3 activation in monocytes accelerates liver cancer progression.

PubMed

Wu, Wen-Yong; Li, Jun; Wu, Zheng-Sheng; Zhang, Chang-Le; Meng, Xiang-Ling

2011-12-05

Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.

Nuclear translocation of phosphorylated STAT3 regulates VEGF-A-induced lymphatic endothelial cell migration and tube formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okazaki, Hideki; Tokumaru, Sho; Hanakawa, Yasushi

2011-09-02

Highlights: {yields} VEGF-A enhanced lymphatic endothelial cell migration and increased tube formation. {yields} VEGF-A treated lymphatic endothelial cell showed activation of STAT3. {yields} Dominant-negative STAT3 inhibited VEGF-A-induced lymphatic endothelial cell migration and tube formation. -- Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific growth factor that regulates endothelial functions, and signal transducers and activators of transcription (STATs) are known to be important during VEGF receptor signaling. The aim of this study was to determine whether STAT3 regulates VEGF-induced lymphatic endothelial cell (LEC) migration and tube formation. VEGF-A (33 ng/ml) enhanced LEC migration by 2-fold and increased tube lengthmore » by 25% compared with the control, as analyzed using a Boyden chamber and Matrigel assay, respectively. Western blot analysis and immunostaining revealed that VEGF-A induced the nuclear translocation of phosphorylated STAT3 in LECs, and this translocation was blocked by the transfection of LECs with an adenovirus vector expressing a dominant-negative mutant of STAT3 (Ax-STAT3F). Transfection with Ax-STAT3F also almost completely inhibited VEGF-A-induced LEC migration and tube formation. These results indicate that STAT3 is essential for VEGF-A-induced LEC migration and tube formation and that STAT3 regulates LEC functions.« less

GPR30 mediates anorectic estrogen-induced STAT3 signaling in the hypothalamus.

PubMed

Kwon, Obin; Kang, Eun Seok; Kim, Insook; Shin, Sora; Kim, Mijung; Kwon, Somin; Oh, So Ra; Ahn, Young Soo; Kim, Chul Hoon

2014-11-01

Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine(705)-phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo. Effect of GPR30 activation on eating behavior was analyzed in vivo. E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus. Copyright © 2014 Elsevier Inc. All rights reserved.

Astaxanthin Inhibits JAK/STAT-3 Signaling to Abrogate Cell Proliferation, Invasion and Angiogenesis in a Hamster Model of Oral Cancer

PubMed Central

Kowshik, J.; Baba, Abdul Basit; Giri, Hemant; Deepak Reddy, G.; Dixit, Madhulika; Nagini, Siddavaram

2014-01-01

Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention. PMID:25296162

Genome-wide STAT3 binding analysis after histone deacetylase inhibition reveals novel target genes in dendritic cells

PubMed Central

Sun, Yaping; Iyer, Matthew; McEachin, Richard; Zhao, Meng; Wu, Yi-Mi; Cao, Xuhong; Oravecz-Wilson, Katherine; Zajac, Cynthia; Mathewson, Nathan; Wu, Shin-Rong Julia; Rossi, Corinne; Toubai, Tomomi; Qin, Zhaohui S.; Chinnaiya, Arul M.; Reddy, Pavan

2016-01-01

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP-seq coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of non-canonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of pro-inflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition. PMID:27866206

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

PubMed Central

Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-01-01

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer. PMID:25327561

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression.

PubMed

Li, Guangchao; Zhao, Likun; Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-09-30

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.

Biologic consequences of Stat1-independent IFN signaling

PubMed Central

Gil, M. Pilar; Bohn, Erwin; O'Guin, Andrew K.; Ramana, Chilakamarti V.; Levine, Beth; Stark, George R.; Virgin, Herbert W.; Schreiber, Robert D.

2001-01-01

Although Stat1 is required for many IFN-dependent responses, recent work has shown that IFNγ functions independently of Stat1 to affect the growth of tumor cells or immortalized fibroblasts. We now demonstrate that both IFNγ and IFNα/β regulate proliferative responses in cells of the mononuclear phagocyte lineage derived from Stat1-null mice. Using both representational difference analysis and gene arrays, we show that IFNγ exerts its Stat1-independent actions on mononuclear phagocytes by regulating the expression of many genes. This result was confirmed by monitoring changes in expression and function of the corresponding gene products. Regulation of the expression of these genes requires the IFNγ receptor and Jak1. The physiologic relevance of IFN-dependent, Stat1-independent signaling was demonstrated by monitoring antiviral responses in Stat1-null mice. Thus, the IFN receptors engage alternative Stat1-independent signaling pathways that have important physiological consequences. PMID:11390995

Cross-talk between KLF4 and STAT3 regulates axon regeneration

NASA Astrophysics Data System (ADS)

Qin, Song; Zou, Yuhua; Zhang, Chun-Li

2013-10-01

Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.

Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice.

PubMed

Takeda, K; Kamanaka, M; Tanaka, T; Kishimoto, T; Akira, S

1996-10-15

IL-13 shares many biologic responses with IL-4. In contrast to well-characterized IL-4 signaling pathways, which utilize STAT6 and 4PS/IRS2, IL-13 signaling pathways are poorly understood. Recent studies performed with STAT6-deficient mice have demonstrated that STAT6 plays an essential role in IL-4 signaling. In this study, the functions of peritoneal macrophages of STAT6-deficient mice in response to IL-13 were analyzed. In STAT6-deficient mice, neither morphologic changes nor augmentation of MHC class II expression in response to IL-13 was observed. In addition, IL-13 did not decrease the nitric oxide production by activated macrophages. Taken together, these results suggest that the macrophage functions in response to IL-13 were impaired in STAT6-deficient mice, indicating that IL-13 and IL-4 share the signaling pathway via STAT6.

Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

PubMed

Lee, Hsueh-Te; Xue, Jianfei; Chou, Ping-Chieh; Zhou, Aidong; Yang, Phillip; Conrad, Charles A; Aldape, Kenneth D; Priebe, Waldemar; Patterson, Cam; Sawaya, Raymond; Xie, Keping; Huang, Suyun

2015-04-30

Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain.

PubMed

Tammineni, Prasad; Anugula, Chandrashekhar; Mohammed, Fareed; Anjaneyulu, Murari; Larner, Andrew C; Sepuri, Naresh Babu Venkata

2013-02-15

The signal transducer and activator of transcription 3 (STAT3), a nuclear transcription factor, is also present in mitochondria and regulates cellular respiration in a transcriptional-independent manner. The mechanism of STAT3 import into mitochondria remains obscure. In this report we show that mitochondrial-localized STAT3 resides in the inner mitochondrial membrane. In vitro import studies show that the gene associated with retinoid interferon induced cell mortality 19 (GRIM-19), a complex I subunit that acts as a chaperone to recruit STAT3 into mitochondria. In addition, GRIM-19 enhances the integration of STAT3 into complex I. A S727A mutation in STAT3 reduces its import and assembly even in the presence of GRIM-19. Together, our studies unveil a novel chaperone function for GRIM-19 in the recruitment of STAT3 into mitochondria.

17β-Estradiol and ICI182,780 Differentially Regulate STAT5 Isoforms in Female Mammary Epithelium, With Distinct Outcomes

PubMed Central

Jallow, Fatou; Brockman, Jennifer L; Helzer, Kyle T; Rugowski, Debra E; Goffin, Vincent; Alarid, Elaine T; Schuler, Linda A

2018-01-01

Abstract Prolactin (PRL) and estrogen cooperate in lobuloalveolar development of the mammary gland and jointly regulate gene expression in breast cancer cells in vitro. Canonical PRL signaling activates STAT5A/B, homologous proteins that have different target genes and functions. Although STAT5A/B are important for physiological mammary function and tumor pathophysiology, little is known about regulation of their expression, particularly of STAT5B, and the consequences for hormone action. In this study, we examined the effect of two estrogenic ligands, 17β-estradiol (E2) and the clinical antiestrogen, ICI182,780 (ICI, fulvestrant) on expression of STAT5 isoforms and resulting crosstalk with PRL in normal and tumor murine mammary epithelial cell lines. In all cell lines, E2 and ICI significantly increased protein and corresponding nascent and mature transcripts for STAT5A and STAT5B, respectively. Transcriptional regulation of STAT5A and STAT5B by E2 and ICI, respectively, is associated with recruitment of estrogen receptor alpha and increased H3K27Ac at a common intronic enhancer 10 kb downstream of the Stat5a transcription start site. Further, E2 and ICI induced different transcripts associated with differentiation and tumor behavior. In tumor cells, E2 also significantly increased proliferation, invasion, and stem cell-like activity, whereas ICI had no effect. To evaluate the role of STAT5B in these responses, we reduced STAT5B expression using short hairpin (sh) RNA. shSTAT5B blocked ICI-induced transcripts associated with metastasis and the epithelial mesenchymal transition in both cell types. shSTAT5B also blocked E2-induced invasion of tumor epithelium without altering E2-induced transcripts. Together, these studies indicate that STAT5B mediates a subset of protumorigenic responses to both E2 and ICI, underscoring the need to understand regulation of its expression and suggesting exploration as a possible therapeutic target in breast cancer. PMID:29594259

Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway

PubMed Central

Lee, Mi-Heon; Kachroo, Puja; Pagano, Paul C; Yanagawa, Jane; Wang, Gerald; Walser, Tonya C; Krysan, Kostyantyn; Sharma, Sherven; John, Maie St.; Dubinett, Steven M; Lee, Jay M

2015-01-01

Background The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway. Objective The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling. Methods and Results Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, β-and γ-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment. Conclusion Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in human lung cancer cells through a STAT1 dominant pathway. PMID:26523208

The SOL-2/Neto Auxiliary Protein Modulates the Function of AMPA-Subtype Ionotropic Glutamate Receptors

PubMed Central

Wang, Rui; Mellem, Jerry E.; Jensen, Michael; Brockie, Penelope J.; Walker, Craig S.; Hoerndli, Frédéric J.; Madsen, David M.; Maricq, Andres V.

2012-01-01

Summary The neurotransmitter glutamate mediates excitatory synaptic transmission by gating ionotropic glutamate receptors (iGluRs). AMPA receptors (AMPARs), a subtype of iGluR, are strongly implicated in synaptic plasticity, learning and memory. We previously discovered two classes of AMPAR auxiliary proteins in C. elegans that modify receptor kinetics and thus change synaptic transmission. Here, we have identified another auxiliary protein, SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR. In sol-2 mutants, behaviors dependent on glutamatergic transmission are disrupted, GLR-1-mediated currents are diminished, and GLR-1 desensitization and pharmacology are modified. Remarkably, a secreted variant of SOL-1 delivered in trans can rescue sol-1 mutants and this rescue depends on in cis expression of SOL-2. Finally, we demonstrate that SOL-1 and SOL-2 have an ongoing role in the adult nervous system to control AMPAR-mediated currents. PMID:22958824

The SOL-2/Neto auxiliary protein modulates the function of AMPA-subtype ionotropic glutamate receptors.

PubMed

Wang, Rui; Mellem, Jerry E; Jensen, Michael; Brockie, Penelope J; Walker, Craig S; Hoerndli, Frédéric J; Hauth, Linda; Madsen, David M; Maricq, Andres V

2012-09-06

The neurotransmitter glutamate mediates excitatory synaptic transmission by gating ionotropic glutamate receptors (iGluRs). AMPA receptors (AMPARs), a subtype of iGluR, are strongly implicated in synaptic plasticity, learning, and memory. We previously discovered two classes of AMPAR auxiliary proteins in C. elegans that modify receptor kinetics and thus change synaptic transmission. Here, we have identified another auxiliary protein, SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR. In sol-2 mutants, behaviors dependent on glutamatergic transmission are disrupted, GLR-1-mediated currents are diminished, and GLR-1 desensitization and pharmacology are modified. Remarkably, a secreted variant of SOL-1 delivered in trans can rescue sol-1 mutants, and this rescue depends on in cis expression of SOL-2. Finally, we demonstrate that SOL-1 and SOL-2 have an ongoing role in the adult nervous system to control AMPAR-mediated currents. Copyright © 2012 Elsevier Inc. All rights reserved.

Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030

PubMed Central

Lin, L; Liu, Y; Li, H; Li, P-K; Fuchs, J; Shibata, H; Iwabuchi, Y; Lin, J

2011-01-01

Background: Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown. Methods: Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH+/CD133+). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined. Results: Our results observed that ALDH+/CD133+ colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model. Conclusion: Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer. PMID:21694723

Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030.

PubMed

Lin, L; Liu, Y; Li, H; Li, P-K; Fuchs, J; Shibata, H; Iwabuchi, Y; Lin, J

2011-07-12

Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown. Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH(+)/CD133(+)). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined. Our results observed that ALDH(+)/CD133(+) colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model. Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer.

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells.

PubMed

Wang, Guansong; Qian, Pin; Jackson, Fannie R; Qian, Guisheng; Wu, Guangyu

2008-01-01

Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxia-promoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNA-binding activity of STAT3 were also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK-STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

Utilization of stat test priority in the clinical laboratory: a College of American Pathologists q-probes study of 52 institutions.

PubMed

Volmar, Keith E; Wilkinson, David S; Wagar, Elizabeth A; Lehman, Christopher M

2013-02-01

Utilization of stat testing priority is a balance between safe, efficient patient management and resource expenditure. To determine the rate of stat testing, compare rates among institutions, and determine the distribution of turnaround time expectations for different turnaround time priorities. During a 7-day period, participants prospectively determined the total number of chemistry, hematology, and coagulation billable tests from inpatients and emergency department patients. Among these, the total numbers of billable tests performed stat were identified. Laboratories also reported the levels of test priority they offered and turnaround expectations for each level of test priority. Fifty institutions submitted data for the study, with 2 additional participants submitting partial results. Participants identified 639 589 chemistry, hematology, and coagulation billable tests, with 229 896 (35.9%) performed stat. The stat rate varied from 21.3% at the 10th percentile to 55.4% at the 90th percentile, with a median of 37.0% of participants' tests performed stat. Laboratories include a mean of 206 tests in chemistry, hematology, and coagulation test menus, with 67% of these tests offered stat. The fraction of the test menu offered stat varied from 29.0% at the 10th percentile to 97.8% at the 90th percentile, with a median of 73.3% of tests on the menu offered stat. The most common number of testing priorities offered by participating laboratories was 3 (44.2%). Among the 52 participating laboratories, the median stat testing rate was 37.0% and a median 73.3% of the test menu was offered stat.

The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway.

PubMed

Pinz, Sophia; Unser, Samy; Brueggemann, Susanne; Besl, Elisabeth; Al-Rifai, Nafisah; Petkes, Hermina; Amslinger, Sabine; Rascle, Anne

2014-01-01

Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies.

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia.

PubMed

Bonetto, Andrea; Aydogdu, Tufan; Jin, Xiaoling; Zhang, Zongxiu; Zhan, Rui; Puzis, Leopold; Koniaris, Leonidas G; Zimmers, Teresa A

2012-08-01

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C(2)C(12) myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia

PubMed Central

Bonetto, Andrea; Aydogdu, Tufan; Jin, Xiaoling; Zhang, Zongxiu; Zhan, Rui; Puzis, Leopold; Koniaris, Leonidas G.

2012-01-01

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C2C12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. PMID:22669242

Survival response of hippocampal neurons under low oxygen conditions induced by Hippophae rhamnoides is associated with JAK/STAT signaling.

PubMed

Manickam, Manimaran; Tulsawani, Rajkumar

2014-01-01

Janus activated kinase/signal transducers and activators of transcription (JAK/STATs) pathway are associated with various neuronal functions including cell survival and inflammation. In the present study, it is hypothesized that protective action of aqueous extract of Hippophae rhamnoides in hippocampal neurons against hypoxia is mediated via JAK/STATs. Neuronal cells exposed to hypoxia (0.5% O2) display higher reactive oxygen species with compromised antioxidant status compared to unexposed control cells. Further, these cells had elevated levels of pro-inflammatory cytokines; tumor necrosis factor α and interleukin 6 and nuclear factor κappa B. Moreover, the expression of JAK1 was found to be highly expressed with phosphorylation of STAT3 and STAT5. Cells treated with JAK1, STAT3 and STAT5 specific inhibitors resulted in more cell death compared to hypoxic cells. Treatment of cells with extract prevented oxidative stress and inflammatory response associated with hypoxia. The extract treated cells had more cell survival than hypoxic cells with induction of JAK1 and STAT5b. Cells treated with extract having suppressed JAK1 or STAT3 or STAT5 expression showed reduced cell viability than the cell treated with extract alone. Overall, the findings from these studies indicate that the aqueous extract of Hippophae rhamnoides treatment inhibited hypoxia induced oxidative stress by altering cellular JAK1, STAT3 and STAT5 levels thereby enhancing cellular survival response to hypoxia and provide a basis for possible use of aqueous extract of Hippophae rhamnoides in facilitating tolerance to hypoxia.

Survival Response of Hippocampal Neurons under Low Oxygen Conditions Induced by Hippophae rhamnoides is Associated with JAK/STAT Signaling

PubMed Central

Manickam, Manimaran; Tulsawani, Rajkumar

2014-01-01

Janus activated kinase/signal transducers and activators of transcription (JAK/STATs) pathway are associated with various neuronal functions including cell survival and inflammation. In the present study, it is hypothesized that protective action of aqueous extract of Hippophae rhamnoides in hippocampal neurons against hypoxia is mediated via JAK/STATs. Neuronal cells exposed to hypoxia (0.5% O2) display higher reactive oxygen species with compromised antioxidant status compared to unexposed control cells. Further, these cells had elevated levels of pro-inflammatory cytokines; tumor necrosis factor α and interleukin 6 and nuclear factor κappa B. Moreover, the expression of JAK1 was found to be highly expressed with phosphorylation of STAT3 and STAT5. Cells treated with JAK1, STAT3 and STAT5 specific inhibitors resulted in more cell death compared to hypoxic cells. Treatment of cells with extract prevented oxidative stress and inflammatory response associated with hypoxia. The extract treated cells had more cell survival than hypoxic cells with induction of JAK1 and STAT5b. Cells treated with extract having suppressed JAK1 or STAT3 or STAT5 expression showed reduced cell viability than the cell treated with extract alone. Overall, the findings from these studies indicate that the aqueous extract of Hippophae rhamnoides treatment inhibited hypoxia induced oxidative stress by altering cellular JAK1, STAT3 and STAT5 levels thereby enhancing cellular survival response to hypoxia and provide a basis for possible use of aqueous extract of Hippophae rhamnoides in facilitating tolerance to hypoxia. PMID:24516559

Contribution of chaperones to STAT pathway signaling

PubMed Central

Bocchini, Claire E; Kasembeli, Moses M; Roh, Soung-Hun; Tweardy, David J

2014-01-01

Aberrant STAT signaling is associated with the development and progression of many cancers and immune related diseases. Recent findings demonstrate that proteostasis modulators under clinical investigation for cancer therapy have a significant impact on STAT signaling, which may be critical for mediating their anti-cancer effects. Chaperones are critical for protein folding, stability and function and, thus, play an essential role in the maintenance of proteostasis. In this review we discuss the role of chaperones in STAT and tyrosine kinase (TK) protein folding, modulation of STAT and TK activity, and degradation of TKs. We highlight the important role of chaperones in STAT signaling, and how this knowledge has provided a framework for the development of new therapeutic avenues of targeting STAT signaling related pathologies. PMID:26413421

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamitani, Shinya; Ohbayashi, Norihiko; Ikeda, Osamu

Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation, and survival in immune responses, hematopoiesis, neurogenesis, and other biological processes. Recently, we showed that KAP1 is a novel STAT-binding partner that regulates STAT3-mediated transactivation. KAP1 is a universal co-repressor protein for the KRAB zinc finger protein superfamily of transcriptional repressors. In this study, we found KAP1-dependent repression of interferon (IFN)/STAT1-mediated signaling. We also demonstrated that endogenous KAP1 associates with endogenous STAT1 in vivo. Importantly, a small-interfering RNA-mediated reduction in KAP1 expression enhanced IFN-induced STAT1-dependent IRF-1 gene expression. These results indicate that KAP1 may act as an endogenous regulatormore » of the IFN/STAT1 signaling pathway.« less

Molecular cloning, transcriptional profiling, and subcellular localization of signal transducer and activator of transcription 2 (STAT2) ortholog from rock bream, Oplegnathus fasciatus.

PubMed

Bathige, S D N K; Umasuthan, Navaneethaiyer; Priyathilaka, Thanthrige Thiunuwan; Thulasitha, William Shanthakumar; Jayasinghe, J D H E; Wan, Qiang; Nam, Bo-Hye; Lee, Jehee

2017-08-30

Signal transducer and activator of transcription 2 (STAT2) is a key element that transduces signals from the cell membrane to the nucleus via the type I interferon-signaling pathway. Although the structural and functional aspects of STAT proteins are well studied in mammals, information on teleostean STATs is very limited. In this study, a STAT paralog, which is highly homologous to the STAT2 members, was identified from a commercially important fish species called rock bream and designated as RbSTAT2. The RbSTAT2 gene was characterized at complementary DNA (cDNA) and genomic sequence levels, and was found to possess structural features common with its mammalian counterparts. The complete cDNA sequence was distributed into 24 exons in the genomic sequence. The promoter proximal region was analyzed and found to contain potential transcription factor binding sites to regulate the transcription of RbSTAT2. Phylogenetic studies and comparative genomic structure organization revealed the distinguishable evolution for fish and other vertebrate STAT2 orthologs. Transcriptional quantification was performed by SYBR Green quantitative real-time PCR (qPCR) and the ubiquitous expression of RbSTAT2 transcripts was observed in all tissues analyzed from healthy fish, with a remarkably high expression in blood cells. Significantly (P<0.05) altered transcription of RbSTAT2 was detected after immune challenge experiments with viral (rock bream irido virus; RBIV), bacterial (Edwardsiella tarda and Streptococcus iniae), and immune stimulants (poly I:C and LPS). Antiviral potential was further confirmed by WST-1 assay, by measuring the viability of rock bream heart cells treated with RBIV. In addition, results of an in vitro challenge experiment signified the influence of rock bream interleukin-10 (RbIL-10) on transcription of RbSTAT2. Subcellular localization studies by transfection of pEGFP-N1/RbSTAT2 into rock bream heart cells revealed that the RbSTAT2 was usually located in the cytoplasm and translocated near to the nucleus upon poly I:C administration. Altogether, these findings suggest that RbSTAT2 is involved in various biologically crucial mechanisms, and provides immune protection to the rock bream. Copyright © 2017 Elsevier B.V. All rights reserved.

Silica- and germania-based dual-ligand sol-gel organic-inorganic hybrid sorbents combining superhydrophobicity and π-π interaction. The role of inorganic substrate in sol-gel capillary microextraction.

PubMed

Seyyal, Emre; Malik, Abdul

2017-04-29

Principles of sol-gel chemistry were utilized to create silica- and germania-based dual-ligand surface-bonded sol-gel coatings providing enhanced performance in capillary microextraction (CME) through a combination of ligand superhydrophobicity and π-π interaction. These organic-inorganic hybrid coatings were prepared using sol-gel precursors with bonded perfluorododecyl (PF-C 12 ) and phenethyl (PhE) ligands. Here, the ability of the PF-C 12 ligand to provide enhanced hydrophobic interaction was advantageously combined with π-π interaction capability of the PhE moiety to attain the desired sorbent performance in CME. The effect of the inorganic sorbent component on microextraction performance of was explored by comparing microextraction characteristics of silica- and germania-based sol-gel sorbents. The germania-based dual-ligand sol-gel sorbent demonstrated superior CME performance compared to its silica-based counterpart. Thermogravimetric analysis (TGA) of the created silica- and germania-based dual-ligand sol-gel sorbents suggested higher carbon loading on the germania-based sorbent. This might be indicative of more effective condensation of the organic ligand-bearing sol-gel-active chemical species to the germania-based sol-gel network (than to its silica-based counterpart) evolving in the sol solution. The type and concentration of the organic ligands were varied in the sol-gel sorbents to fine-tune extraction selectivity toward different classes of analytes. Specific extraction (SE) values were used for an objective comparison of the prepared sol-gel CME sorbents. The sorbents with higher content of PF-C 12 showed remarkable affinity for aliphatic hydrocarbons. Compared to their single-ligand sol-gel counterparts, the dual-ligand sol-gel coatings demonstrated significantly superior CME performance in the extraction of alkylbenzenes, providing up to ∼65.0% higher SE values. The prepared sol-gel CME coatings provided low ng L -1 limit of detections (LOD) (4.2-26.3 ng L -1 ) for environmentally important analytes including polycyclic aromatic hydrocarbons, ketones and aliphatic hydrocarbons. In CME-GC experiments (n = 5), the capillary-to-capillary RSD value was ∼2.1%; such a low RSD value is indicative of excellent reproducibility of the sol-gel method used for the preparation of these CME coatings. The dual-ligand sol-gel coating provided stable performance in capillary microextraction of analytes from saline samples. Copyright © 2017 Elsevier B.V. All rights reserved.

77 FR 1127 - Open Meeting of the President's Council on Jobs and Competitiveness (PCJC)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-09

... live webcast at http:[sol][sol]www.whitehouse.gov/live. DATES: The meeting will be held on January 17..., DC 20220. In general, all statements will be posted on the White House Web site (http:[sol][sol]www... 2 p.m. Eastern Time. The meeting will be broadcast on the internet via live webcast at http:[sol...

75 FR 70923 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... be conducted virtually only. Dial into the meeting: 1-877-705-6006; webcast: http:[sol][sol]altarum..., and the background material will be posted on ONC's Web site after the meeting, at http:[sol][sol... committed to the orderly conduct of its advisory committee meetings. Please visit our Web site at http:[sol...

[Basic Studies on Locoregional Injection of a Newly Designed Chitin Sol].

PubMed

Chiba, Takehiro; Sugitachi, Akio; Kume, Kouhei; Segawa, Takenori; Nishinari, Yutaka; Ishida, Kaoru; Noda, Hironobu; Nishizuka, Satoshi; Kimura, Yusuke; Koeda, Keisuke; Sasaki, Akira

2015-11-01

Systemic chemotherapy in advanced cancer cases often provokes serious adverse events. We aimed to examine the fundamental properties and efficacy of a novel chitin sol, an anti-cancer agent with minor side effects designed to avoid the adverse effects of chemotherapy and enhance the QOL and ADL of patients. DAC-70 was used to create the novel agent termed DAC-70 sol. The anti-proliferative activity was assayed by the WST method using different types of cell lines. The anti-cancer efficacy of the novel agent was examined using cancer-bearing mice. DAC-70 sol was easily injectable through a 21-G needle. The sol suppressed proliferation of the cells in vitro. Intra-tumor injection of DAC-70 sol inhibited the rapid growth of solid tumors in the mice. CDDP-loaded DAC-70 sol, CDDP/DAC-70 sol, successfully controlled malignant ascites in the mice (p<0.05). Neither recurrence nor severe complications were encountered in these animals. These basic data strongly suggest that locoregional administration of our newly designed DAC-70 sol and CDDP/DAC-70 sol is clinically useful as novel cancer chemotherapy for advanced cases. This warrants further clinical studies in cancer chemotherapy.

Hybrid organic-inorganic sol-gel materials and components for integrated optoelectronics

NASA Astrophysics Data System (ADS)

Lu, Dong

On the technical platform of hybrid organic-inorganic sol-gel, the integrated optoelectronics in the forms of heterogeneous integration between the hybrid sol-gel waveguide and the high refractive index semiconductors and the nonlinear functional doping of disperse red chromophore into hybrid sol-gel is developed. The structure of hybrid sol-gel waveguide on high index semiconductor substrate is designed with BPM-CAD software. A hybrid sol-gel based on MAPTMS and TEOS suitable for lower cladding for the waveguide is developed. The multi-layer hybrid sol-gel waveguide with good mode confinement and low polarization dependence is fabricated on Si and InP. As proof of concept, a 1 x 12 beam splitter based on multimode interference is fabricated on silicon substrate. The device shows excess loss below 0.65 dB and imbalance below 0.28 dB for both TE and TM polarization. A nonlinear active hybrid sol-gel doped with disperse red 13 has been developed by simple co-solvent method. It permits high loading concentration and has low optical loss at 1550 nm. The second-order nonlinear property of the active sol-gel is induced with corona poling and studied with second harmonic generation. A 3-fold of enhancement in the poling efficiency is achieved by blue light assisted corona poling. The chromophore alignment stability is improved by reducing the free volume of the formed inorganic network from the sol-gel condensation reaction. An active sol-gel channel waveguide has been fabricated using active and passive hybrid sol-gel materials by only photopatterning and spin-coating. An amplitude modulator based on the active sol-gel containing 30 wt.% of DR13 shows an electro-optic coefficient of 14 pm/V at 1550 nm and stable operation within the observation time of 24 days.

StreamStats in Georgia: a water-resources web application

USGS Publications Warehouse

Gotvald, Anthony J.; Musser, Jonathan W.

2015-07-31

StreamStats is being implemented on a State-by-State basis to allow for customization of the data development and underlying datasets to address their specific needs, issues, and objectives. The USGS, in cooperation with the Georgia Environmental Protection Division and Georgia Department of Transportation, has implemented StreamStats for Georgia. The Georgia StreamStats Web site is available through the national StreamStats Web-page portal at http://streamstats.usgs.gov. Links are provided on this Web page for individual State applications, instructions for using StreamStats, definitions of basin characteristics and streamflow statistics, and other supporting information.

[Study on the correlation between EGFR-STAT3 signal pathway and laryngeal papilloma].

PubMed

Wang, Xinhua; Sun, Jingwu

2009-09-01

To explore the relationship between the expression of EGFR and STAT3 in human laryngeal papilloma and its biological behavior. Reverse transcription polymerase chain reaction(RT-PCR), immunohistochemical staining and Western blot were used to evaluate the mRNA and protein expression of EGFR and STAT3 (p-STAT3) in 42 laryngeal papilloma tissues and 15 samples of normal laryngeal tissue, and the relationship between the protein expression of them and clinic pathological parameters was also analyzed. The mRNA expression levels of EGFR and STAT3 in laryngeal papilloma tissue were significantly higher than that in normal laryngeal tissue (P < 0.05, P < 0.01). Protein positive expression of EGFR and p-STAT3 were also detected in a significantly greater proportion of laryngeal papilloma than normal laryngeal tissue by immunohistochemistry and western blot (P < 0.01, P < 0.05). There was relationship between EGFR and p-STAT3 overexpression in laryngeal papilloma (P < 0.05). The expression p-STAT3 was correlated with the recurrence and canceration of laryngeal papilloma (P < 0.05). The EGFR-STAT3 signal transduction pathway may be involved in the pathogenesis of laryngeal papilloma,, and the persistent activation of STAT3 gene plays an important role in the recurrence and canceration of laryngeal papilloma.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations

PubMed Central

Vogel, Tiphanie P.; Forbes, Lisa; Ma, Chi A.; Stray-Pedersen, Asbjørg; Niemela, Julie E.; Lyons, Jonathan J.; Engelhardt, Karin R.; Zhang, Yu; Topcagic, Nermina; Roberson, Elisha D. O.; Matthews, Helen; Verbsky, James W.; Dasu, Trivikram; Vargas-Hernandez, Alexander; Varghese, Nidhy; McClain, Kenneth L.; Karam, Lina B.; Nahmod, Karen; Makedonas, George; Mace, Emily M.; Sorte, Hanne S.; Perminow, Gøri; Rao, V. Koneti; O’Connell, Michael P.; Price, Susan; Su, Helen C.; Butrick, Morgan; McElwee, Joshua; Hughes, Jason D.; Willet, Joseph; Swan, David; Xu, Yaobo; Santibanez-Koref, Mauro; Slowik, Voytek; Dinwiddie, Darrell L.; Ciaccio, Christina E.; Saunders, Carol J.; Septer, Seth; Kingsmore, Stephen F.; White, Andrew J.; Cant, Andrew J.; Hambleton, Sophie

2015-01-01

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. PMID:25359994

Mumps Virus V Protein Antagonizes Interferon without the Complete Degradation of STAT1

PubMed Central

Kubota, Toru; Yokosawa, Noriko; Yokota, Shin-ichi; Fujii, Nobuhiro; Tashiro, Masato; Kato, Atsushi

2005-01-01

Mumps virus (MuV) has been shown to antagonize the antiviral effects of interferon (IFN) through proteasome-mediated complete degradation of STAT1 by using the viral V protein (T. Kubota et al., Biochem. Biophys. Res. Commun. 283:255-259, 2001). However, we found that MuV could inhibit IFN signaling and the generation of a subsequent antiviral state long before the complete degradation of cellular STAT1 in infected cells. In MuV-infected cells, nuclear translocation and phosphorylation of STAT1 and STAT2 tyrosine residue (Y) at 701 and 689, respectively, by IFN-β were significantly inhibited but the phosphorylation of Jak1 and Tyk2 was not inhibited. The transiently expressed MuV V protein also inhibited IFN-β-induced Y701-STAT1 and Y689-STAT2 phosphorylation, suggesting that the V protein could block IFN-β-induced signal transduction without the aid of other viral components. Finally, a substitution of an alanine residue in place of a cysteine residue in the C-terminal V-unique region known to be required for STAT1 degradation and inhibition of anti-IFN signaling resulted in the loss of V protein function to inhibit the Y701-STAT1 and Y689-STAT2 phosphorylation. PMID:15767445

Curiosity Rock or Soil Sampling Sites on Mars, Through November 2016

NASA Image and Video Library

2016-12-13

nal Caption Released with Image: This graphic maps locations of the sites where NASA's Curiosity Mars rover collected its first 19 rock or soil samples for analysis by laboratory instruments inside the vehicle. It also presents images of the drilled holes where 15 rock-powder samples were acquired. Curiosity scooped two soil samples at each of the other two sites: Rocknest and Gobabeb. The diameter of each drill hole is about 0.6 inch (1.6 centimeters), slightly smaller than a U.S. dime. The images used here are raw color, as recorded by the rover's Mars Hand Lens Imager (MAHLI) camera. Notice the differences in color of the material at different drilling sites. For the map, north is toward the upper left corner. The scale bar represents 2 kilometers (1.2 miles). The base map is from the High Resolution Imaging Science Experiment (HiRISE) camera on NASA's Mars Reconnaissance Orbiter. The latest sample site included is "Sebina,"where Curiosity drilled into bedrock of the Murray formation on Oct. 20, 2016, during the 1,495th Martian day, or sol, of the mission. Curiosity landed in August 2012 on the plain (named Aeolis Palus) near Mount Sharp (or Aeolis Mons). The drilling dates for the first 13 rock samples collected are, by location: "John Klein" on Feb. 8, 2013 (Sol 182); "Cumberland" on May 19, 2013 (Sol 279); "Windjana" on May 5, 2014 (Sol 621); "Confidence Hills" on Sept. 24, 2014 (Sol 759); "Mojave" on Jan. 29, 2015 (Sol 882); "Telegraph Peak" on Feb. 24, 2015 (Sol 908); "Buckskin" on July 30, 2015 (Sol 1060); "Big Sky" on Sept. 29, 2015 (Sol 1119); "Greenhorn" on Oct. 18, 2015 (Sol 1137); "Lubango" on April 23, 2016 (Sol 1320); "Okoruso" on May 5, 2016 (Sol 1332); "Oudam" on June 4, 2016 (Sol 1361); "Quela" on Sept. 18, 2016 (Sol 1464). http://photojournal.jpl.nasa.gov/catalog/PIA21254

Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3

PubMed Central

Subramaniam, Aruljothi; Shanmugam, Muthu K; Ong, Tina H; Li, Feng; Perumal, Ekambaram; Chen, Luxi; Vali, Shireen; Abbasi, Taher; Kapoor, Shweta; Ahn, Kwang Seok; Kumar, Alan Prem; Hui, Kam M; Sethi, Gautam

2013-01-01

BACKGROUND AND PURPOSE Aberrant activation of STAT3 is frequently encountered and promotes proliferation, survival, metastasis and angiogenesis in hepatocellular carcinoma (HCC). Here, we have investigated whether emodin mediates its effect through interference with the STAT3 activation pathway in HCC. EXPERIMENTAL APPROACH The effect of emodin on STAT3 activation, associated protein kinases and apoptosis was investigated using various HCC cell lines. Additionally, we also used a predictive tumour technology to analyse the effects of emodin. The in vivo effects of emodin were assessed in an orthotopic mouse model of HCC. KEY RESULTS Emodin suppressed STAT3 activation in a dose- and time-dependent manner in HCC cells, mediated by the modulation of activation of upstream kinases c-Src, JAK1 and JAK2. Vanadate treatment reversed emodin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase and emodin induced the expression of the tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, silencing of the SHP-1 gene by siRNA abolished the ability of emodin to inhibit STAT3 activation. Finally, when administered i.p., emodin inhibited the growth of human HCC orthotopic tumours in male athymic nu/nu mice and STAT3 activation in tumour tissues. CONCLUSIONS AND IMPLICATIONS Emodin mediated its effects predominantly through inhibition of the STAT3 signalling cascade and thus has a particular potential for the treatment of cancers expressing constitutively activated STAT3. PMID:23848338

Increased expression of activated pSTAT3 and PIM-1 in the pulmonary vasculature of experimental congenital diaphragmatic hernia.

PubMed

Hofmann, Alejandro D; Takahashi, Toshiaki; Duess, Johannes; Gosemann, Jan-Hendrik; Puri, Prem

2015-06-01

Signal transducer and activator of transcription (STAT) protein family (STAT1-6) regulates diverse cellular processes. Recently, the isoform STAT3 has been implicated to play a central role in the pathogenesis of pulmonary hypertension (PH). In human PH activated STAT3 (pSTAT3) was shown to directly trigger expression of the provirus integration site for Moloney murine leukemia virus (Pim-1), which promotes proliferation and resistance to apoptosis in SMCs. We designed this study to investigate the hypothesis that pSTAT3 and Pim-1 pulmonary vascular expression is increased in nitrofen-induced CDH. Pregnant rats were exposed to nitrofen or vehicle on D9.5. Fetuses were sacrificed on D21 and divided into nitrofen (n=16) and control group (n=16). QRT-PCR, western blotting, and confocal-immunofluorescence were performed to determine pulmonary gene and protein expression levels of pSTAT3 and Pim-1. Pulmonary Pim-1 gene expression was significantly increased in the CDH group compared to controls. Western blotting and confocal-microscopy confirmed increased pulmonary protein expression of Pim-1 and increased activation of pSTAT3 in CDH lungs compared to controls. Markedly increased gene and protein expression of Pim-1 and activated pSTAT3 in the pulmonary vasculature of nitrofen-induced CDH lungs suggest that pSTAT3 and Pim-1 are important mediators of PH in nitrofen-induced CDH. Copyright © 2015. Published by Elsevier Inc.

Upregulated STAT3 and RhoA signaling in colorectal cancer (CRC) regulate the invasion and migration of CRC cells.

PubMed

Zhang, G-Y; Yang, W-H; Chen, Z

2016-05-01

We aimed to reveal the expression and activation of signal transducers and activators of transcription 3 (STAT3) and RhoA/Rho-associated coiled-coil forming kinase 1 (ROCK1) signaling in CRC tissues, and to investigate the regulatory role of STAT3 and RhoA signaling in the invasion and migration of colorectal cancer cells. We examined the expression of STAT3, RhoA and ROCK1 in CRC tissues with real-time PCR and Western blotting methods. And then we examined the interaction between STAT3 and RhoA/ROCK1 signaling in CRC HT-29 cells with gain-of-function and loss-of-function strategies. In addition, we determined the regulation by STAT3 and RhoA/ROCK1 on the invasion and migration of CRC HT-29 cells. Our study demonstrated a significant upregulation of RhoA and ROCK1 expression and STAT3-Y705 phosphorylation in 32 CRC specimens, compared to the 17 normal CRC tissues. Further study demonstrated there was a coordination between STAT3 and RhoA/Rock signaling in the HT-29 cells. Moreover, STAT3 knockdown or RhoA knockdown significantly repressed the migration and invasion in HT-29 cells and vice versa. STAT3 and RhoA signaling regulate the invasion and migration of CRC cells, implying the orchestrated and oncogenic roles of STAT3 and RhoA/ROCK1 signaling in CRC.

Curcumin interacts directly with the Cysteine 259 residue of STAT3 and induces apoptosis in H-Ras transformed human mammary epithelial cells.

PubMed

Hahn, Young-Il; Kim, Su-Jung; Choi, Bu-Young; Cho, Kyung-Cho; Bandu, Raju; Kim, Kwang Pyo; Kim, Do-Hee; Kim, Wonki; Park, Joon Sung; Han, Byung Woo; Lee, Jeewoo; Na, Hye-Kyung; Cha, Young-Nam; Surh, Young-Joon

2018-04-23

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Ras transformed breast epithelial cells (H-Ras MCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-Ras MCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.

Clinicopathological significance and prognostic role of p-STAT3 in patients with hepatocellular carcinoma.

PubMed

Liang, Chaojie; Xu, Yingchen; Ge, Hua; Li, Guangming; Wu, Jixiang

2018-01-01

Constitutive activation of STAT3 through its phosphorylation (p-STAT3) plays a key role in the development and progression of various cancers. However, the relationship between p-STAT3 expression and the clinicopathological features and prognostic value in patients with hepatocellular carcinoma (HCC) remains controversial. We conducted a meta-analysis to evaluate the role of p-STAT3 in HCC. The PubMed, Cochrane Library, Web of Science, EMBASE, Chinese CNKI, and Chinese Wanfang databases were searched using the appropriate terms to find the relevant studies on p-STAT3 and HCC. The relationship between p-STAT3 expression and clinicopathological characteristics and prognostic value was established. Pool odds ratios (ORs) and hazard ratios (HRs) with 95% CIs were calculated using the STATA 14.2 software. The eight articles included in this meta-analysis comprised 752 patients. Expression of p-STAT3 was associated with incidence, age, liver cirrhosis, tumor size, vascular invasion, and TNM stage of HCC, but it was not related to gender, alpha-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), number of tumors, and tumor differentiation. Additionally, the expression of p-STAT3 was related to a poor 3- and 5-year overall survival rate and disease-free survival rate. Expression of p-STAT3 was associated with the incidence, age, liver cirrhosis, tumor size, vascular invasion, and TNM stage. Thus, p-STAT3 can be a reliable prognostic biomarker for HCC. Further high-quality studies with larger numbers of patients are needed.

75 FR 63865 - National Science Board; Sunshine Act Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-18

... the National Science Board Web site http:[sol][sol]www.nsf.gov/nsb for additional information and schedule updates (time, place, subject matter or status of meeting) may be found at http:[sol][sol]www.nsf...

76 FR 79168 - U.S. Department of Energy Audit Guidance: For-Profit Recipients

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-21

... Federal eRulemaking Portal at http:[sol][sol]www.regulations.gov. Follow the instructions for submitting... access the guidance at: http:[sol][sol]energy.gov/management/downloads/ draft-profit-audit-guidance-fy...

The regulation of inflammation by interferons and their STATs.

PubMed

Rauch, Isabella; Müller, Mathias; Decker, Thomas

2013-01-01

Interferons (IFN) are subdivided into type I IFN (IFN-I, here synonymous with IFN-α/β), type II (IFN-γ) and type III IFN (IFN-III/IFN-λ) that reprogram nuclear gene expression through STATs 1 and 2 by forming STAT1 dimers (mainly IFN-γ) or the ISGF3 complex, a STAT1-STAT2-IRF9 heterotrimer (IFN-I and IFN-III). Dominant IFN activities in the immune system are to protect cells from viral replication and to activate macrophages for enhanced effector function. However, the impact of IFN and their STATs on the immune system stretches far beyond these activities and includes the control of inflammation. The goal of this review is to give an overview of the different facets of the inflammatory process that show regulatory input by IFN/STAT.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unterberger, Claudia; Hanson, Steven; Department of Infection, Immunity and Inflammation, University of Leicester, University Road, Leicester LE1 9HN

Little is known about determinants regulating expression of Mannan-binding lectin associated serine protease-2 (MASP-2), the effector component of the lectin pathway of complement activation. Comparative bioinformatic analysis of the MASP2 promoter regions in human, mouse, and rat, revealed conservation of two putative Stat binding sites, termed StatA and StatB. Site directed mutagenesis specific for these sites was performed. Transcription activity was decreased 5-fold when StatB site was mutated in the wildtype reporter gene construct. Gel retardation and competition assays demonstrated that proteins contained in the nuclear extract prepared from HepG2 specifically bound double-stranded StatB oligonucleotides. Supershift analysis revealed Stat3 tomore » be the major specific binding protein. We conclude that Stat3 binding is important for MASP2 promoter activity.« less

Enhanced clearance of herpes simplex virus type 1 and reduced herpetic eye disease in STAT6 knockout mice is associated with increased IL-2.

PubMed

Ghiasi, Homayon; Osorio, Yanira; Nesburn, Anthony B; Wechsler, Steven L

2002-10-25

STAT6 (signal transducers and activators of transcription 6)-deficient (STAT6-/-) mice have defects in IL-4- and IL-13-mediated functions and thus have a reduced T(H)2-mediated immune response. Conversely, they have elevated levels of IL-2 and thus an increased T(H)1-mediated immune response. To assess the relative impact of reduced T(H)2- and elevated T(H)1-dependent immune responses on HSV-1 infection, vaccinated and mock-vaccinated STAT6-/- mice were challenged ocularly with HSV-1. Mock-vaccinated STAT6-/- mice were as susceptible to lethal HSV-1 infection as parental BALB/c mice. Mock-vaccinated STAT6-/- mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Furthermore, mock-vaccinated STAT6-/- mice had significantly less corneal scarring than their BALB/c counterparts. Vaccination induced significantly higher serum-neutralizing antibody titers in STAT6-/- mice compared to BALB/c mice, while completely protecting both types of mice against HSV-1-induced death and corneal scarring. Vaccinated STAT6-/- mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Lymphocytes from both vaccinated and mock-vaccinated STAT6-/- mice secreted higher amounts of IL-2 than lymphocytes from BALB/c mice, in the presence or absence of stimulation with UV-inactivated HSV-1. Finally, depletion of IL-2 increased ocular virus replication in STAT6-/- mice to levels similar to that measured in BALB/c mice. Our results suggest that in the absence of the STAT6 pathway, IL-2-mediated immune responses are up-regulated. This, in turn, leads to faster viral clearance and, consequently, lower levels of eye disease.

Altered STAT4 Isoform Expression in Patients with Inflammatory Bowel Disease.

PubMed

Jabeen, Rukhsana; Miller, Lucy; Yao, Weiguo; Gupta, Sandeep; Steiner, Steven; Kaplan, Mark H

2015-10-01

Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel disease, and pathogenesis involves a complex interplay among genetic, environmental, and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. We collected biopsy samples from both patients newly diagnosed with CD and with UC. We further collected blood samples from patients newly diagnosed with CD and with UC as well as from patients who had a flare-up after being in clinical remission, and we examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms, we measured the expression of the cytokines TNFα, IFNγ, granulocyte macrophage-colony stimulating factor, and IL-17 using polymerase chain reaction of biopsy samples and multiplex analysis of patient serum samples. Ratios of STAT4β/STAT4α were increased in specific gastrointestinal tract segments in both patients with CD and those with UC that correlate with the location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from patients with eosinophilic esophagitis. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of patients with UC and those with CD, compared with healthy controls. Ratios were normalized after patients were treated with steroids. Collectively, these data indicate that STAT4 isoforms could be an important noninvasive biomarker in the diagnosis and treatment of inflammatory bowel disease and that expression of these isoforms might provide further insight into the pathogenesis of IBD.

NF-κB-Induced IL-6 Ensures STAT3 Activation and Tumor Aggressiveness in Glioblastoma

PubMed Central

McFarland, Braden C.; Hong, Suk W.; Rajbhandari, Rajani; Twitty, George B.; Gray, G. Kenneth; Yu, Hao; Benveniste, Etty N.; Nozell, Susan E.

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness. PMID:24244348

NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma.

PubMed

McFarland, Braden C; Hong, Suk W; Rajbhandari, Rajani; Twitty, George B; Gray, G Kenneth; Yu, Hao; Benveniste, Etty N; Nozell, Susan E

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness.

The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

PubMed Central

Brueggemann, Susanne; Besl, Elisabeth; Al-Rifai, Nafisah; Petkes, Hermina; Amslinger, Sabine; Rascle, Anne

2014-01-01

Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2′,3,4,4′-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies. PMID:24595334

Vaccinia Virus Blocks Stat1-Dependent and Stat1-Independent Gene Expression Induced by Type I and Type II Interferons

PubMed Central

Mann, Brandon A.; Huang, Julia He; Li, Ping; Chang, Hua-Chen; Slee, Roger B.; O'Sullivan, Audrey; Mathur, Anita; Yeh, Norman; Klemsz, Michael J.; Brutkiewicz, Randy R.; Blum, Janice S.

2008-01-01

Blocking the function of Stat (signal transducer and activator of transcription) proteins, which are critical for antiviral responses, has evolved as a common mechanism for pathogen immune evasion. The poxvirus-encoded phosphatase H1 is critical for viral replication, and may play an additional role in the evasion of host defense by dephosphorylating Stat1 and blocking interferon (IFN)-stimulated innate immune responses. Vaccinia virus (VACV) H1 can inhibit the phosphorylation of the transcription factor Stat1 after IFN-γ stimulation of epithelial cells, greatly attenuating IFN-induced biological functions. In this study, we demonstrate that VACV infection is capable of inhibiting the phosphorylation of Stat1 and Stat2 after stimulation of fibroblasts or bone marrow-derived macrophages with either type I or type II IFNs, but did not inhibit the activation of Stat3 or Stat5 in either cell type. By using recombinant proteins for in vitro assays, we observe that variola virus H1 is more active than VACV H1, although it has similar selectivity for Stat targets. Differential effects of VACV infection were observed on the induction of IFN-stimulated genes, with complete inhibition of some genes by VACV infection, while others were less affected. Despite the IFN-γ-induced expression of some genes in VACV-infected cells, IFN-γ was unable to rescue the VACV-mediated inhibition of MHC class II antigen presentation. Moreover, VACV infection can affect the IFN-induced expression of Stat1-dependent and Stat1-independent genes, suggesting that the virus may target additional IFN-activated pathways. Thus, VACV targets multiple signaling pathways in the evasion of antiviral immune responses. PMID:18593332

Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor.

PubMed

Klover, Peter; Chen, Weiping; Zhu, Bing-Mei; Hennighausen, Lothar

2009-09-01

In skeletal muscle, STAT5a/b transcription factors are critical for normal postnatal growth, whole-animal glucose homeostasis, and local IGF-1 production. These observations have led us to hypothesize that STAT5a/b are critical for maintenance of normal muscle mass and function. To investigate this, mice with a skeletal muscle-specific deletion of the Stat5a/b genes (Stat5MKO) were used. Stat5MKO mice displayed reduced muscle mass, altered fiber-type distribution and reduced activity. On a molecular level, gene expression in skeletal muscle of Stat5MKO and control mice was analyzed by microarrays and real-time PCR, both in the presence and absence of growth hormone (GH) stimulation. Expression of several genes involved in muscle growth and fiber type were significantly changed. Specifically, in the quadriceps, a muscle almost exclusively composed of type II fibers, the absence of STAT5a/b led to increased expression of several genes associated with type I fibers and the de novo appearance of type I fibers. In addition, it is shown here that expression of the androgen receptor gene (Ar) is controlled by GH through STAT5a/b. The link between STAT5a/b and Ar gene is likely through direct transcriptional regulation, as chromatin immunoprecipitaion of the Ar promoter region in C2C12 myoblasts was accomplished by antibodies against STAT5a. These experiments demonstrate an important role for STAT5a/b in skeletal muscle physiology, and they provide a direct link to androgen signaling.

Development and Validation of a Bilingual Stroke Preparedness Assessment Instrument.

PubMed

Skolarus, Lesli E; Mazor, Kathleen M; Sánchez, Brisa N; Dome, Mackenzie; Biller, José; Morgenstern, Lewis B

2017-04-01

Stroke preparedness interventions are limited by the lack of psychometrically sound intermediate end points. We sought to develop and assess the reliability and validity of the video-Stroke Action Test (video-STAT) an English and a Spanish video-based test to assess people's ability to recognize and react to stroke signs. Video-STAT development and testing was divided into 4 phases: (1) video development and community-generated response options, (2) pilot testing in community health centers, (3) administration in a national sample, bilingual sample, and neurologist sample, and (4) administration before and after a stroke preparedness intervention. The final version of the video-STAT included 8 videos: 4 acute stroke/emergency, 2 prior stroke/nonemergency, 1 nonstroke/emergency, and 1 nonstroke/nonemergency. Acute stroke recognition and action response were queried after each vignette. Video-STAT scoring was based on the acute stroke vignettes only (score range 0-12 best). The national sample consisted of 598 participants, 438 who took the video-STAT in English and 160 who took the video-STAT in Spanish. There was adequate internal consistency (Cronbach α=0.72). The average video-STAT score was 5.6 (SD=3.6), whereas the average neurologist score was 11.4 (SD=1.3). There was no difference in video-STAT scores between the 116 bilingual video-STAT participants who took the video-STAT in English or Spanish. Compared with baseline scores, the video-STAT scores increased after a stroke preparedness intervention (6.2 versus 8.9, P <0.01) among a sample of 101 black adults and youth. The video-STAT yields reliable scores that seem to be valid measures of stroke preparedness. © 2017 American Heart Association, Inc.

STAT1 Activation is Enhanced by Cisplatin and Variably Affected by EGFR Inhibition in HNSCC Cells

PubMed Central

Schmitt, Nicole C.; Trivedi, Sumita; Ferris, Robert L.

2015-01-01

Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGFR inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at serine (S727) or tyrosine (Y701) residues. Cisplatin consistently increased the levels of p-S727-STAT1, and STAT1 siRNA knockdown attenuated cisplatin-induced cell death. EGFR stimulation also activated p-S727-STAT1 and p-Y701-STAT1 in a subset of cell lines, whereas EGFR inhibitors alone decreased levels of p-S727-STAT1 and p-Y701-STAT1 in these cells. Contrary to our hypothesis, EGFR inhibitors added to cisplatin treatment caused variable effects among cell lines, with attenuation of p-S727-STAT1 and enhancement of cisplatin-induced cell death in some cells and minimal effect in other cells. Using HNSCC tumor specimens from a clinical trial of adjuvant cisplatin plus the anti-EGFR antibody panitumumab, higher intratumoral p-S727-STAT1 appeared to correlate with worse survival. Together, these results suggest that cisplatin-induced cell death is associated with STAT1 phosphorylation, and the addition of anti-EGFR therapy to cisplatin has variable effects on STAT1 and cell death in HNSCC. PMID:26141950

Cytokine-Induction of Tumor Necrosis Factor Receptor 2 (TNFR2) is Mediated by STAT3 in Colon Cancer Cells

PubMed Central

Hamilton, Kathryn E.; Simmons, James G.; Ding, Shengli; Van Landeghem, Laurianne; Lund, P. Kay

2011-01-01

The IL-6/STAT3 and TNFα/NFκB pathways are emerging as critical mediators of inflammation-associated colon cancer. TNFR2 expression is increased in inflammatory bowel diseases, the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer, and by combined IL-6 and TNFα. The molecular mechanisms that regulate TNFR2 remain undefined. This study used colon cancer cell lines to test the hypothesis that IL-6 and TNFα induce TNFR2 via STAT3 and/or NFκB. Basal and IL-6 + TNFα-induced TNFR2 were decreased by pharmacological STAT3 inhibition. NFκB inhibition had little effect on IL-6 + TNFα-induced TNFR2, but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFα alone. Chromatin immunoprecipitation (ChIP) revealed cooperative effects of IL-6 + TNFα to induce STAT3 binding to a -1578 STAT response element in the TNFR2 promoter, but no effect on NFκB binding to consensus sites. Constitutively active STAT3 was sufficient to induce TNFR2 expression. Over-expression of SOCS3, a cytokine-inducible STAT3 inhibitor, which reduces tumorigenesis in preclinical models of colitis-associated cancer, decreased cytokine-induced TNFR2 expression and STAT3 binding to the -1578 STAT response element. SOCS3 over-expression also decreased proliferation of colon cancer cells and dramatically decreased anchorage-independent growth of colon cancer cells, even cells over-expressing TNFR2. Collectively, these studies demonstrate that IL-6 and TNFα-induced TNFR2 expression in colon cancer cells is mediated primarily by STAT3, and provide evidence that TNFR2 may contribute to the tumor-promoting roles of STAT3. PMID:21994466

Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3.

PubMed

Denson, Lee A; Held, Matthew A; Menon, Ram K; Frank, Stuart J; Parlow, Albert F; Arnold, Dodie L

2003-04-01

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-alpha suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling (Socs) genes are upregulated by TNF-alpha and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH +/- LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-alpha and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages.

PubMed

Williams, Lynn; Bradley, Laura; Smith, Alexandra; Foxwell, Brian

2004-01-01

The signaling mechanism by which the anti-inflammatory cytokine IL-10 mediates suppression of proinflammatory cytokine synthesis remains largely unknown. Macrophage-specific STAT3-null mice have demonstrated that STAT3 plays a critical role in the suppression of LPS-induced TNF-alpha release, although the mechanism by which STAT3 mediates this inhibition is still not clear. Using an adenoviral system, we have expressed a dominant negative (DN) STAT3 in human macrophages to broaden the investigation to determine the role of STAT3 in IL-10-mediated anti-inflammatory signaling and gene expression. Overexpression of STAT3 DN completely inhibited IL-10-induced suppressor of cytokine signaling 3, tissue inhibitor of MMP-1, TNF receptor expression, and the recently identified IL-10-inducible genes, T cell protein tyrosine phosphatase and signaling lymphocyte activation molecule. STAT3 DN also blocked IL-10-mediated inhibition of MHC class II and COX2 expression. In agreement with the studies in STAT3-null mice, overexpression of the STAT3 DN completely reversed the ability of IL-10 to inhibit LPS-mediated TNF-alpha and IL-6 production. However, real-time PCR analysis showed that STAT3 DN expression did not affect immediate suppression of TNF-alpha mRNA, but did reverse the suppression observed at later time points, suggesting a biphasic regulation of TNF-alpha mRNA levels by IL-10. In conclusion, although STAT3 does appear to be the dominant mediator of the majority of IL-10 functions, there are elements of its anti-inflammatory activity that are STAT3 independent.

The potency of STAT (signal transducers and activators of transcription) 3 protein as growth promoter for chicken

NASA Astrophysics Data System (ADS)

Ma'ruf, Anwar; Iswati, Sri; Hidajati, Nove; Damayanti, Ratna

2017-09-01

The long-term objective of this study was to produce STAT synthetic protein in chicken during growth period resulting from the increase of growth hormone (GH) as growth promoter. This study used ten male chicken Lohman from PT. Multibreeder Indonesia. The chicken were kept within batteried cage, with a capacity of one chicken in each cage. The chickens were fed twice a day, at 6 a.m. and 6 p.m. with the amount of feed 10% less than standard. On day 21 the chicken were slaughtered to obtain the samples, i.e., adipose, liver and muscles for the following examinations (1) isolation of STAT-3 signaling protein from adipose, liver and muscles of the chicken, (2) analysis of STAT-3 signaling protein using SDS-PAGE method, and (3) identification of STAT-3 signaling protein using Western blot method by means of protein detection using electrophoresis with polyacrylamide gels. Results of examination on protein in hepatic, muscle and adipose of chickens in growth period revealed that STAT protein was positively present in those tissues. This finding was followed-up with SDS-PAGE examination, from which we found the presence of protein band between the markers of 116 kDa and 14.4 kDa. The protein band was supposedly the STAT-3 protein. To prove that protein band formed was the STAT-3, Western blot examination was conducted using rabbit polyclonal antibody STAT-3. The result showed the formation of the protein band, indicating the presence of reaction between antigen (STAT-3 protein) and STAT-3 protein antibody. In conclusion, STAT-3 protein is present in hepatic, muscular, and adipose tissues, with molecular weight of 59.4 kDa.

Development and Validation of a Bilingual Stroke Preparedness Assessment Instrument

PubMed Central

Skolarus, Lesli E.; Mazor, Kathleen M.; Sánchez, Brisa N.; Dome, Mackenzie; Biller, José; Morgenstern, Lewis B.

2017-01-01

Background and Purpose Stroke preparedness interventions are limited by the lack of psychometrically sound intermediate endpoints. We sought to develop and assess the reliability and validity of the video-Stroke Action Test, video-STAT, an English and Spanish video-based test to assess people’s ability to recognize and react to stroke signs. Methods Video-STAT development and testing was divided into four phases: 1) video development and community-generated response options; 2) pilot testing in community health centers; 3) administration in a national sample, bilingual sample and neurologist sample; and 4) administration before and after a stroke preparedness intervention. Results The final version of the video-STAT included 8 videos: 4 acute stroke/emergency, 2 prior stroke/non-emergency, 1 non-stroke/emergency, 1 non-stroke/non-emergency. Acute stroke recognition and action response were queried after each vignette. Video-STAT scoring was based on the acute stroke vignettes only (score range 0–12 best). The national sample consisted of 598 participants, 438 who took the video-STAT in English and 160 who took the video-STAT in Spanish. There was adequate internal consistency (Cronbach’s alpha=0.72). The average video-STAT score was 5.6 (sd=3.6) while the average neurologist score was 11.4 (sd=1.3). There was no difference in video-STAT scores between the 116 bilingual video-STAT participants who took the video-STAT in English or Spanish. Compared to baseline scores, the video-STAT scores increased following a stroke preparedness intervention (6.2 vs. 8.9, p<0.01) among a sample of 101 African American adults and youth. Conclusion The video-STAT yields reliable scores that appear to be valid measures of stroke preparedness. PMID:28250199

Systemic Administration of a Cyclic Signal Transducer and Activator of Transcription 3 (STAT3) Decoy Oligonucleotide Inhibits Tumor Growth without Inducing Toxicological Effects

PubMed Central

Sen, Malabika; Paul, Kathleen; Freilino, Maria L; Li, Hua; Li, Changyou; Johnson, Daniel E; Wang, Lin; Eiseman, Julie; Grandis, Jennifer R

2014-01-01

Hyperactivation of signal transducer and activator of transcription 3 (STAT3) has been linked to tumorigenesis in most malignancies, including head and neck squamous cell carcinoma. Intravenous delivery of a chemically modified cyclic STAT3 decoy oligonucleotide with improved serum and thermal stability demonstrated antitumor efficacy in conjunction with downmodulation of STAT3 target gene expression such as cyclin D1 and Bcl-XL in a mouse model of head and neck squamous cell carcinoma. The purpose of the present study was to determine the toxicity and dose-dependent antitumor efficacy of the cyclic STAT3 decoy after multiple intravenous doses in Foxn1 nu mice in anticipation of clinical translation. The two doses (5 and 10 mg/kg) of cyclic STAT3 decoy demonstrated a significant decrease in tumor volume compared with the control groups (mutant cyclic STAT3 decoy or saline) in conjunction with downmodulation of STAT3 target gene expression. There was no dose-dependent effect of cyclic STAT3 decoy on tumor volume or STAT3 target gene expression. There were no significant changes in body weights between the groups during the dosing period, after the dosing interval or on the day of euthanasia. No hematology or clinical chemistry parameters suggested toxicity of the cyclic STAT3 decoy compared with saline control. No gross or histological pathological abnormalities were noted at necropsy in any of the animals. These findings suggest a lack of toxicity of intravenous administration of a cyclic STAT3 decoy oligonucleotide. In addition, comparable antitumor effects indicate a lack of dose response at the two dose levels investigated. PMID:24395569

Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response.

PubMed

Jayakumar, Asha; Bothwell, Alfred L M

2017-08-01

Intestinal tumorigenesis in the ApcMin/+ model is initiated by aberrant activation of Wnt pathway. Increased IL-4 expression in human colorectal cancer tissue and growth of colon cancer cell lines implied that IL-4-induced Stat6-mediated tumorigenic signaling likely contributes to intestinal tumor progression in ApcMin/+ mice. Stat6 also appears to promote expansion of myeloid-derived suppressor cells (MDSCs) cells. MDSCs promote polyp formation in the ApcMin/+ model. Hence, Stat6 could have a broad role in coordinating both polyp cell proliferation and MDSC expansion. We found that IL-4-induced Stat6-mediated proliferation of intestinal epithelial cells is augmented by platelet-derived growth factor-BB, a tumor-promoting growth factor. To determine whether polyp progression in ApcMin/+ mice is dependent on Stat6 signaling, we disrupted Stat6 in this model. Total polyps in the small intestine were fewer in ApcMin/+ mice lacking Stat6. Furthermore, proliferation of polyp epithelial cells was reduced, indicating that Stat6 in part controlled polyp formation. Stat6 also promoted expansion of MDSCs in the spleen and lamina propria of ApcMin/+ mice, implying regulation of antitumor T-cell response. More CD8 cells and reduced PD-1 expression on CD4 cells correlated with reduced polyps. In addition, a strong CD8-mediated cytotoxic response led to killing of tumor cells in Stat6-deficient ApcMin/+ mice. Therefore, these findings show that Stat6 has an oncogenic role in intestinal tumorigenesis by promoting polyp cell proliferation and immunosuppressive mediators, and preventing an active cytotoxic process. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis.

PubMed

Kataoka, Ken; Kim, Dae Joon; Carbajal, Steve; Clifford, John L; DiGiovanni, John

2008-06-01

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been found in a variety of human malignancies and has been suggested to play an important role in carcinogenesis. Recently, our laboratory demonstrated that Stat3 is required for the development of skin tumors via two-stage carcinogenesis using skin-specific loss-of-function transgenic mice. To investigate further the role of Stat3 in each stage of chemical carcinogenesis in mouse skin, i.e. initiation and promotion stages, we generated inducible Stat3-deficient mice (K5.Cre-ER(T2) x Stat3(fl/fl)) that show epidermal-specific disruption of Stat3 following topical treatment with 4-hydroxytamoxifen (TM). The epidermis of inducible Stat3-deficient mice treated with TM showed a significant increase in apoptosis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and reduced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate. In two-stage skin carcinogenesis assays, inducible Stat3-deficient mice treated with TM during the promotion stage showed a significant delay of tumor development and a significantly reduced number of tumors compared with control groups. Inducible Stat3-deficient mice treated with TM before initiation with DMBA also showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups. Finally, treatment of inducible Stat3-deficient mice that had existing skin tumors generated by the two-stage carcinogenesis protocol with TM (by intraperitoneal injection) led to inhibition of tumor growth compared with tumors formed in control groups. Collectively, these results directly demonstrate that Stat3 is required for skin tumor development during both the initiation and promotion stages of skin carcinogenesis in vivo.

The assessment of stat laboratory test ordering practice and impact of targeted individual feedback in an urban teaching hospital.

PubMed

Sorita, Atsushi; Steinberg, Daniel I; Leitman, Michael; Burger, Alfred; Husk, Gregg; Sivaprasad, Latha

2014-01-01

Overuse of inpatient stat laboratory orders ("stat" is an abbreviation of the Latin word "statim," meaning immediately, without delay) is a major problem in the modern healthcare system. To understand patterns of stat laboratory ordering practices at our institution and to assess the effectiveness of individual feedback in reducing these orders. Medicine and General Surgery residents were given a teaching session about appropriate stat ordering practice in January 2010. Individual feedback was given to providers who were the highest utilizers of stat laboratory orders by their direct supervisors from February through June of 2010. The proportion of stat orders out of total laboratory orders per provider was the main outcome measure. All inpatient laboratory orders from September 2009 to June 2010 were analyzed. The median proportion of stat orders out of total laboratory orders was 41.6% for nontrainee providers (N = 500), 38.7% for Medicine residents (N = 125), 80.2% for General Surgery residents (N = 32), and 24.2% for other trainee providers (N = 150). Among 27 providers who received feedback (7 nontrainees, 16 Medicine residents, and 4 General Surgery residents), the proportion of stat laboratory orders per provider decreased by 15.7% (95% confidence interval: 5.6%-25.9%, P = 0.004) after feedback, whereas the decrease among providers who were high utilizers but did not receive feedback (N = 39) was not significant (4.5%; 95% confidence interval: 2.1%-11.0%, P = 0.18). Monthly trends showed reduction in the proportion of stat orders among Medicine and General Surgery residents, but not among other trainee providers. The frequency of stat ordering was highly variable among providers. Individual feedback to the highest utilizers of stat orders was effective in decreasing these orders. © 2013 Society of Hospital Medicine.

Epidemiological aspects of self-reported sleep onset latency in Japanese junior high school children.

PubMed

Alexandru, Gaina; Michikazu, Sekine; Shimako, Hamanishi; Xiaoli, Chen; Hitomi, Kanayama; Takashi, Yamagami; Robert, Williams W; Sadanobu, Kagamimori

2006-09-01

The purpose of this study was to investigate the relationships between sleep onset latency (SOL) and other sleep-wake patterns and media use habits in Japanese schoolchildren. A total of 9,718 junior high school children responded (12.8 years) and 9199 questionnaires were used in the present analyses. The questionnaire assessed sleep-wake patterns, TV viewing and videogame habits. Overall, 72.1% of the subjects reported short SOL (20 min) were strongly associated with disturbed sleep manifested especially by increased risk of night awakenings, decreased sleep depth, and bad sleep in general (overall sleep quality). Prolonged SOL was also associated with daytime sleepiness, difficulties in falling asleep, bad morning feeling and sleep insufficiency. We found a U-shaped relationship between sleep period and SOL. Increase in bedtime was accompanied by increased risk of prolonged SOL. The impact of ultra-short and ultra-long SOL (or=40 min) was also analysed. Long durations of watching television and playing videogame were significantly associated with prolonged SOL. After adjustment for sex, girls presented significantly higher risk of prolonged SOL. Body mass index adjustment did not reveal any significant results. SOL presents a significant component of sleep-wake habits; poor sleep hygiene and insufficient sleep time significantly increase SOL. Parents, healthcare practitioners and children themselves should be aware of the potentially negative influence of prolonged SOL. Additionally, the optimal coherent sleep-wake schedule must be promoted in parallel with the limitation on the viewing TV and game practices.

Curiosity First 14 Rock or Soil Sampling Sites on Mars

NASA Image and Video Library

2016-06-13

This graphic maps locations of the first 14 sites where NASA's Curiosity Mars rover collected rock or soil samples for analysis by laboratory instruments inside the vehicle. It also presents images of the drilled holes where 12 rock-powder samples were acquired. At the other two sites -- Rocknest and Gobabeb -- Curiosity scooped soil samples. The diameter of each drill hole is about 0.6 inch (1.6 centimeters), slightly smaller than a U.S. dime. The images used here are raw color, as recorded by the rover's Mars Hand Lens Imager (MAHLI) camera. Notice the differences in color of the material at different drilling sites. The latest sample site included is "Oudam," where Curiosity drilled into mudstone of the "Murray formation" on June 4, during the 1,361th Martian day, or sol, of the mission. Curiosity landed in August 2012 on the plain (named Aeolis Palus) near Mount Sharp (or Aeolis Mons). Dates when the first 11 drilled-rock samples were collected are: "John Klein" on Feb. 8, 2013 (Sol 182); "Cumberland" on May 19, 2013 (Sol 279); "Windjana" on May 5, 2014 (Sol 621); "Confidence Hills" on Sept. 24, 2014 (Sol 759); "Mojave" on Jan. 29, 2015 (Sol 882); "Telegraph Peak" on Feb. 24, 2015 (Sol 908); "Buckskin" on July 30, 2015 (Sol 1060); "Big Sky" on Sept. 29, 2015 (Sol 1119); "Greenhorn" on Oct. 18, 2015 (Sol 1137); "Lubango" on April 23, 2016 (Sol 1320); and "Okoruso" on May 5, 2016 (Sol 1332). http://photojournal.jpl.nasa.gov/catalog/PIA20748

Regulation of PSMB5 Protein and β Subunits of Mammalian Proteasome by Constitutively Activated Signal Transducer and Activator of Transcription 3 (STAT3)

PubMed Central

Vangala, Janakiram Reddy; Dudem, Srikanth; Jain, Nishant; Kalivendi, Shasi V.

2014-01-01

The ubiquitin-proteasome system facilitates the degradation of ubiquitin-tagged proteins and performs a regulatory role in cells. Elevated proteasome activity and subunit expression are found in several cancers. However, the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome. This study was initiated to elucidate the mechanisms involved in the regulation of β subunits of the mammalian proteasome. Suppression of STAT3 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β subunits of the 20 S core complex in DU145 cells. Notably, PSMB5, a molecular target of bortezomib, was shown to be a target of STAT3. Knockdown of STAT3 decreased PSMB5 protein. Inhibition of phospho-STAT3 substantially reduced PSMB5 protein levels in cells expressing constitutively active-STAT3. Accumulation of activated STAT3 resulted in the induction of PSMB5 promoter and protein levels. In addition, a direct correlation was observed between the endogenous levels of PSMB5 and constitutively active STAT3. PSMB5 and STAT3 protein levels remained unaltered following the inhibition of proteasome activity. The EGF-induced concerted increase of β subunits was blocked by inhibition of the EGF receptor or STAT3 but not by the PI3K/AKT or MEK/ERK pathways. Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in STAT3-inhibited cells. Combined treatments with bortezomib and inhibitor of STAT3 abrogated proteasome activity and enhanced cellular apoptosis. Overall, we demonstrate that aberrant activation of STAT3 regulates the expression of β subunits, in particular PSMB5, and the catalytic activity of the proteasome. PMID:24627483

p-STAT3 in luminal breast cancer: Integrated RNA-protein pooled analysis and results from the BIG 2-98 phase III trial.

PubMed

Sonnenblick, Amir; Salgado, Roberto; Brohée, Sylvain; Zahavi, Tamar; Peretz, Tamar; Van den Eynden, Gert; Rouas, Ghizlane; Salmon, Asher; Francis, Prudence A; Di Leo, Angelo; Crown, John P A; Viale, Giuseppe; Daly, Laura; Javdan, Bahar; Fujisawa, Sho; De Azambuja, Evandro; Lieveke, Ameye; Piccart, Martine J; Bromberg, Jacqueline F; Sotiriou, Christos

2018-02-01

In the present study, in order to investigate the role of signal transducer and activator of transcription 3 (STAT3) in estrogen receptor (ER)-positive breast cancer prognosis, we evaluated the phosphorylated STAT3 (p-STAT3) status and investigated its effect on the outcome in a pooled analysis and in a large prospective adjuvant trial. By using the TCGA repository, we developed gene signatures that reflected the level of p-STAT3. Using pooled analysis of the expression data from luminal breast cancer patients, we assessed the effects of the p-STAT3 expression signature on prognosis. We further validated the p-STAT3 prognostic effect using immunohistochemistry (IHC) and immunofluorescence staining of p-STAT3 tissue microarrays from a large randomised prospective trial. Our analysis demonstrated that p-STAT3 expression was elevated in luminal A-type breast cancer (Kruskal-Wallis test, P<10e-10) and was significantly associated with a good prognosis (log-rank, P<10e-10). Notably, the p-STAT3 expression signature identified patients with a good prognosis irrespective of the luminal subtype (log-rank: luminal A, P=0.026; luminal B, P=0.006). p-STAT3 staining by IHC in the stroma or tumour was detected in 174 out of 610 ER-positive samples (28.5%) from the BIG 2-98 randomised trial. With a median follow-up of 10.1 years, p-STAT3 was associated with a reduced risk of recurrence in ER-positive/HER2-negative breast cancer (Cox univariate HR, 0.66; 95% CI, 0.44-0.98; P=0.04). On the whole, our data indicate that p-STAT3 is associated with an improved outcome in ER-positive breast cancer.

Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein.

PubMed

Schweizer, Leonille; Koelsche, Christian; Sahm, Felix; Piro, Rosario M; Capper, David; Reuss, David E; Pusch, Stefan; Habel, Antje; Meyer, Jochen; Göck, Tanja; Jones, David T W; Mawrin, Christian; Schittenhelm, Jens; Becker, Albert; Heim, Stephanie; Simon, Matthias; Herold-Mende, Christel; Mechtersheimer, Gunhild; Paulus, Werner; König, Rainer; Wiestler, Otmar D; Pfister, Stefan M; von Deimling, Andreas

2013-05-01

Non-central nervous system hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) are considered by pathologists as two variants of a single tumor entity now subsumed under the entity SFT. Recent detection of frequent NAB2-STAT6 fusions in both, HPC and SFT, provided additional support for this view. On the other hand, current neuropathological practice still distinguishes between HPC and SFT. The present study set out to identify genes involved in the formation of meningeal HPC. We performed exome sequencing and detected the NAB2-STAT6 fusion in DNA of 8/10 meningeal HPC thereby providing evidence of close relationship of these tumors with peripheral SFT. Due to the considerable effort required for exome sequencing, we sought to explore surrogate markers for the NAB2-STAT6 fusion protein. We adopted the Duolink proximity ligation assay and demonstrated the presence of NAB2-STAT6 fusion protein in 17/17 HPC and the absence in 15/15 meningiomas. More practical, presence of the NAB2-STAT6 fusion protein resulted in a strong nuclear signal in STAT6 immunohistochemistry. The nuclear reallocation of STAT6 was detected in 35/37 meningeal HPC and 25/25 meningeal SFT but not in 87 meningiomas representing the most important differential diagnosis. Tissues not harboring the NAB2-STAT6 fusion protein presented with nuclear expression of NAB2 and cytoplasmic expression of STAT6 proteins. In conclusion, we provide strong evidence for meningeal HPC and SFT to constitute variants of a single entity which is defined by NAB2-STAT6 fusion. In addition, we demonstrate that this fusion can be rapidly detected by STAT6 immunohistochemistry which shows a consistent nuclear reallocation. This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms.

JAK-STAT signalling and the atrial fibrillation promoting fibrotic substrate

PubMed Central

Chen, Yu; Surinkaew, Sirirat; Naud, Patrice; Qi, Xiao-Yan; Gillis, Marc-Antoine; Shi, Yan-Fen; Tardif, Jean-Claude; Dobrev, Dobromir; Nattel, Stanley

2017-01-01

Aims Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis. Methods and results LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control. Conclusions HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention. PMID:28158495

76 FR 3180 - National Science Board; Sunshine Act Meetings; Notice

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-19

... Board Web site http:[sol][sol]www.nsf.gov/nsb for additional information and schedule updates (time, place, subject matter or status of meeting) may be found at http:[sol][sol]www.nsf.gov/nsb/notices...

STATs: An Old Story, Yet Mesmerizing.

PubMed

Abroun, Saeid; Saki, Najmaldin; Ahmadvand, Mohammad; Asghari, Farahnaz; Salari, Fatemeh; Rahim, Fakher

2015-01-01

Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that have a key role in cell fate. STATs, a protein family comprised of seven members, are proteins which are latent cytoplasmic transcription factors that convey signals from the cell surface to the nucleus through activation by cytokines and growth factors. The signaling pathways have diverse biological functions that include roles in cell differentiation, proliferation, development, apoptosis, and inflammation which place them at the center of a very active area of research. In this review we explain Janus kinase (JAK)/STAT signaling and focus on STAT3, which is transient from cytoplasm to nucleus after phosphorylation. This procedure controls fundamental biological processes by regulating nuclear genes controlling cell proliferation, survival, and development. In some hematopoietic disorders and cancers, overexpression and activation of STAT3 result in high proliferation, suppression of cell differentiation and inhibition of cell maturation. This article focuses on STAT3 and its role in malignancy, in addition to the role of microRNAs (miRNAs) on STAT3 activation in certain cancers.

Application of the docking program SOL for CSAR benchmark.

PubMed

Sulimov, Alexey V; Kutov, Danil C; Oferkin, Igor V; Katkova, Ekaterina V; Sulimov, Vladimir B

2013-08-26

This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy. An important SOL feature is the single- or multi-processor performance for up to hundreds of CPUs. DISCORE improves the binding energy scoring by the local energy optimization of the ligand docked pose and a simple linear regression on the base of available experimental data. The docking program SOL has demonstrated a good ability for correct ligand positioning in the active sites of the tested proteins in most cases of CSAR exercises. SOL and DISCORE have not demonstrated very exciting results on the protein-ligand binding free energy estimation. Nevertheless, for some target proteins, SOL and DISCORE were among the first in prediction of inhibition activity. Ways to improve SOL and DISCORE are discussed.

Infrared and Raman spectra of triacetoxyvinylsilane, aqueous sol-gel and xerogel

NASA Astrophysics Data System (ADS)

Li, Ying-Sing; Ba, Abdul; Mahmood, Maleeha S.

2009-04-01

Triacetoxyvinylsilane (TAVS) has been used as a precursor to prepare sol-gel under aqueous conditions. The sol-gel product has been applied for the surface treatment of aluminum. Infrared and Raman spectra have been collected for TAVS and for TAVS sol-gel, xerogel and sol-gel-coated aluminum. Vibrational analyses have been suggested for the recorded spectra based essentially on the group frequencies and the spectral variation with the change of the sol-gel product states and the vibrational assignments of similar molecules. From the recorded infrared and Raman spectra of the sol-gel and xerogel, it is found that the sol-gel produced in the process with TAVS is essentially the same as that prepared from vinyltriethoxysilane. Thermo-gravimetric analysis (TGA) of TAVS xerogel has been conducted, and an explanation has been given in coordination with the results obtained from IR spectroscopic study of the xerogels cured at different temperatures. The study has demonstrated the thermal effect on the condensation of the sol-gel process and on the vinyl decomposition of TAVS xerogel.

[Knockdown of STAT3 inhibits proliferation and migration of HepG2 hepatoma cells induced by IFN1].

PubMed

Li, Xiaofang; Wang, Yuqi; Yan, Ben; Fang, Peipei; Ma, Chao; Xu, Ning; Fu, Xiaoyan; Liang, Shujuan

2018-02-01

Objective To prepare lentiviruses expressing shRNA sequences targeting human signal transducer and activator of transcription 3 (STAT3) and detect the effect of STAT3 knockdown on type I interferon (IFN1)-induced proliferation and migration in HepG2 cells. Methods Four STAT3-targeting shRNA sequences (shRNA1-shRNA4) and one control sequence (Ctrl shRNA) were selected and cloned respectively into pLKO.1-sp6-pgk-GFP to construct shRNA-expressing vectors. Along with backbone psPAX2 and pMD2.G vectors, they were separately transfected into HEK293T cells to prepare lentiviruses. HepG2 cells were infected with the lentiviruses. Cytoplastic STAT3 level was detected by Western blotting to screen effective shRNA sequence(s) targeting STAT3. Proliferation and migration of HepG2 cells were analyzed by CCK-8 assay and Transwell TM migration and scratching assay, respectively. To detect the effect of IFN1 on cell proliferation and migration of HepG2 cells, the cells were treated with 2000 U/mL IFNα2b for indicated time and the activation of IFN-triggered STAT1 signal transduction was assayed by Western blotting. Results Two most effective STAT3-targeting shRNA sequences shRNA1 and shRNA2 were selected, and the expression of both STAT3 shRNA significantly decreased proliferation and migration of HepG2 cells. When treated with IFNα2b, 2000 U/mL of IFN1 showed more competent in attenuating growth and migration of HepG2 cells. Our data further proved that knockdown of STAT3 increased the phosphorylation of STAT1, and IFNα2b further enhanced the activation of STAT1 signaling in HepG2 cells. Conclusion Knockdown of STAT3 inhibits cell migration and growth, and rescues IFN response through up-regulating STAT1 signal transduction in HepG2 hepatoma cells.

JAK/STAT signaling pathway-mediated immune response in silkworm (Bombyx mori) challenged by Beauveria bassiana.

PubMed

Geng, Tao; Lv, Ding-Ding; Huang, Yu-Xia; Hou, Cheng-Xiang; Qin, Guang-Xing; Guo, Xi-Jie

2016-12-20

Innate immunity was critical in insects defensive system and able to be induced by Janus kinase/signal transducer and activator of transcription cascade transduction (JAK/STAT) signaling pathway. Currently, it had been identified many JAK/STAT signaling pathway-related genes in silkworm, but little function was known on insect innate immunity. To explore the roles of JAK/STAT pathway in antifungal immune response in silkworm (Bombyx mori) against Beauveria bassiana infection, the expression patterns of B. mori C-type lectin 5 (BmCTL5) and genes encoding 6 components of JAK/STAT signaling pathway in silkworm challenged by B. bassiana were analyzed using quantitative real time PCR. Meanwhile the activation of JAK/STAT signaling pathway by various pathogenic micro-organisms and the affect of JAK/STAT signaling pathway inhibitors on antifungal activity in silkworm hemolymph was also detected. Moreover, RNAi assay of BmCTL5 and the affect on expression levels of signaling factors were also analyzed. We found that JAK/STAT pathway could be obviously activated in silkworm challenged with B. bassiana and had no response to bacteria and B. mori cytoplasmic polyhedrosis virus (BmCPV). However, the temporal expression patterns of JAK/STAT signaling pathway related genes were significantly different. B. mori downstream receptor kinase (BmDRK) might be a positive regulator of JAK/STAT signaling pathway in silkworm against B. bassiana infection. Moreover, antifungal activity assay showed that the suppression of JAK/STAT signaling pathway by inhibitors could significantly inhibit the antifungal activity in hemolymph and resulted in increased sensitivity of silkworm to B. bassiana infection, indicating that JAK/STAT signaling pathway might be involved in the synthesis and secretion of antifungal substances. The results of RNAi assays suggested that BmCTL5 might be one pattern recognition receptors for JAK/STAT signaling pathway in silkworm. These findings yield insights for better understand the molecular mechanisms of JAK/STAT signaling pathway in antifungal immune response in silkworm. Copyright © 2016 Elsevier B.V. All rights reserved.

Integrity of the LXXLL motif in Stat6 is required for the inhibition of breast cancer cell growth and enhancement of differentiation in the context of progesterone

PubMed Central

2014-01-01

Background Progesterone is essential for the proliferation and differentiation of mammary gland epithelium. Studies of breast cancer cells have demonstrated a biphasic progesterone response consisting of an initial proliferative burst followed by sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the effects of progesterone on mammary cell growth and differentiation remain to be determined. Recently, it was demonstrated that signal transducer and activator of transcription 6 (Stat6) is a cell growth suppressor. Similar to progesterone-bound PR, Stat6 acts by inducing the expression of the G1 cyclin-dependent kinase inhibitors p21 and p27. The possible interaction between Stat6 and progesterone pathways in mammary cells was therefore investigated in the present study. Methods ChIP and luciferase were assayed to determine whether Stat6 induces p21 and p27 expression by recruitment at the proximal Sp1-binding sites of the gene promoters. Immunoprecipitation and Western blotting were performed to investigate the interaction between Stat6 and PR-B. The cellular DNA content and cell cycle distribution in breast cancer cells were analyzed by FACS. Results We found that Stat6 interacts with progesterone-activated PR in T47D cells. Stat6 synergizes with progesterone-bound PR to transactivate the p21 and p27 gene promoters at the proximal Sp1-binding sites. Moreover, Stat6 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. Stat6 knockdown also abolished the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. In addition, knockdown of Stat6 expression prevented the induction of breast cell differentiation markers, previously identified as progesterone target genes. Finally, Stat6 gene expression levels increased following progesterone treatment, indicating a positive auto-regulatory loop between PR and Stat6. Conclusions Taken together, these data identify Stat6 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells. PMID:24401087

BrightStat.com: free statistics online.

PubMed

Stricker, Daniel

2008-10-01

Powerful software for statistical analysis is expensive. Here I present BrightStat, a statistical software running on the Internet which is free of charge. BrightStat's goals, its main capabilities and functionalities are outlined. Three different sample runs, a Friedman test, a chi-square test, and a step-wise multiple regression are presented. The results obtained by BrightStat are compared with results computed by SPSS, one of the global leader in providing statistical software, and VassarStats, a collection of scripts for data analysis running on the Internet. Elementary statistics is an inherent part of academic education and BrightStat is an alternative to commercial products.

Therapeutic modulators of STAT signalling for human diseases

PubMed Central

Miklossy, Gabriella; Hilliard, Tyvette S.; Turkson, James

2014-01-01

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

Temporal regulation of Stat5 activity in determination of cell differentiation program

PubMed Central

Hoshino, Akemi; Fujii, Hodaka

2007-01-01

Although Stat5 is activated by various cytokines, only ethrytopoietin (Epo) and a small number of cytokines induce Stat5-dependent erythroid differentiation. Here, by using a reporter gene system to monitor transcriptional activity of Stat5, we showed that Epo but not interleukin (IL)-3 supports sustained activation of Stat5, which induces globin gene expression. IL-3 or IL-2 stimulation inhibits Epo-induced globin gene expression. The acidic region of the IL-2 receptor β chain was essential for this inhibition. These results underscore the importance of temporal regulation of Stat activity for regulation of cytokine-specific cell differentiation. PMID:17511959

Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis.

PubMed

Silva, Corinne M

2004-10-18

The signal transducers and activators of transcription (STATs) were originally identified in the signaling pathway activated by the nontyrosine kinase containing cytokine receptors. The role of these STATs in hematopoietic cell signaling has been well described. In the case of cytokine receptors, activation of STAT tyrosine phosphorylation occurs through ligand-induced recruitment, and activation of the intracellular JAK kinases. However, STATs can also be activated by growth factor receptors, particularly the EGFR; as well as by members of the Src Family of Kinases (SFKs), particularly c-Src. In many cases, there is a differential activation of the STATs by these tyrosine kinases as compared to activation by the cytokine receptors. This difference provides for the potential of unique actions of STATs in response to growth factor receptor and SFK activation. Since there are many cancers in which SFKs and c-Src in particular, are co-overexpressed with growth factor receptors, it is not surprising that STATs play an important role in the tumorigenesis process induced by c-Src. The activation paradigm and role of STATs in these cancers, with particular emphasis on breast cancer models, is discussed.

Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism

PubMed Central

Nan, Yuchen; Wu, Chunyan; Zhang, Yan-Jin

2017-01-01

Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism. PMID:29312301

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation.

PubMed

Chaudhary, Vidyanath; Zhang, Shuo; Yuen, Kit-San; Li, Chuan; Lui, Pak-Yin; Fung, Sin-Yee; Wang, Pei-Hui; Chan, Chi-Ping; Li, Dexin; Kok, Kin-Hang; Liang, Mifang; Jin, Dong-Yan

2015-11-01

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen causing significant morbidity and mortality in Asia. NSs protein of SFTSV is known to perturb type I IFN induction and signalling, but the mechanism remains to be fully understood. Here, we showed the suppression of both type I and type III IFN signalling by SFTSV NSs protein is mediated through inhibition of STAT1 phosphorylation and activation. Infection with live SFTSV or expression of NSs potently suppressed IFN-stimulated genes but not NFkB activation. NSs was capable of counteracting the activity of IFN-α1, IFN-β, IFN-λ1 and IFN-λ2. Mechanistically, NSs associated with STAT1 and STAT2, mitigated IFN-β-induced phosphorylation of STAT1 at S727, and reduced the expression and activity of STAT1 protein in IFN-β-treated cells, resulting in the inhibition of STAT1 and STAT2 recruitment to IFNstimulated promoters. Taken together, SFTSV NSs protein is an IFN antagonist that suppresses phosphorylation and activation of STAT1.

Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice.

PubMed

Mackenzie, Gerardo G; Huang, Liqun; Alston, Ninche; Ouyang, Nengtai; Vrankova, Kvetoslava; Mattheolabakis, George; Constantinides, Panayiotis P; Rigas, Basil

2013-01-01

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

Bioluminescent Imaging Reveals Divergent Viral Pathogenesis in Two Strains of Stat1-Deficient Mice, and in αßγ Interferon Receptor-Deficient Mice

PubMed Central

Pasieka, Tracy Jo; Collins, Lynne; O'Connor, Megan A.; Chen, Yufei; Parker, Zachary M.; Berwin, Brent L.; Piwnica-Worms, David R.; Leib, David A.

2011-01-01

Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1−/− and IFNαßγR−/− mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1−/− mice and in IFNαßγR−/− mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1−/− (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNαßγR−/− mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1−/− and IFNαßγR−/− mice, we infected an additional Stat1−/− strain deleted in the DNA-binding domain (129Stat1−/− (DBD)). These 129Stat1−/− (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNαßγR−/− mice. This lethal pattern was also observed when 129Stat1−/− (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1−/− (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1−/− mouse strains. The data are consistent with the hypothesis that Stat1−/− (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection. PMID:21915277

Sol-gel processing to form doped sol-gel monoliths inside hollow core optical fiber and sol-gel core fiber devices made thereby

NASA Technical Reports Server (NTRS)

Shaw, Harry C. (Inventor); Ott, Melanie N. (Inventor); Manuel, Michele V. (Inventor)

2002-01-01

A process of fabricating a fiber device includes providing a hollow core fiber, and forming a sol-gel material inside the hollow core fiber. The hollow core fiber is preferably an optical fiber, and the sol-gel material is doped with a dopant. Devices made in this manner includes a wide variety of sensors.

Sol-gel layers for ceramic microsystems application

NASA Astrophysics Data System (ADS)

Czok, Mateusz; Golonka, Leszek

2016-11-01

This paper describes research on sol-gel solutions preparation process. Utilize of a sol-gel layers in the LTCC technology for reduction of surface roughness and influence on the ceramics properties is examined and described. The influence of sol-gel layer on possible sedimentation of dyes or biological substances in channels, mixers or chambers of ceramic microfluidic structures was investigated. Moreover, properties of sol-gel coated surfaces have been precisely examined and described. Finally, positive results of conducted experiments made it possible to design and manufacture a simple microfluidic ceramic structure, with embedded protective layer of sol-gel, for fluorescence measurements.

Fabrication of piezoelectric ceramic fibers by extrusion of PZT powder and PZT sol mixture

NASA Astrophysics Data System (ADS)

Kobayashi, Yoshimasa; Um, Tae Y.; Qiu, Jinhao; Tani, Junji; Takahashi, Hirofumi

2001-07-01

This study aims to fabricate Pb(Zr,Ti)O3 (PZT) piezoelectric ceramic fibers by extrusion with mixture of PZT powder and PZT sol. The added PZT sol in this study played a role as a binder; the sol changed into PZT crystalline during sintering, and removal process of additives before sintering was not required. To obtain PZT fibers, the condition of sol viscosity adjustment, the mixture ratio of powder and sol for fiber extrusion, and the sintering condition for obtaining polycrystalline fibers were investigated. PZT precursor solution was synthesized from lead acetate trihydrate, zirconium n-propoxide and titanium isopropoxide by reflux at 120 degree(s)C for 3 hours with 2-methoxyethanol. The appropriate adjustment of spinnable sol was achieved by the addition of acetic acid for suppressing the hydrolysis reaction and the curing sol at 80 degree(s)C for promoting the condensation of sol. Green fibers with diameter of about 300micrometers were successfully extruded from the mixture of PZT powder and sol. The extruded fibers sintered at 1200 degree(s)C had the microstructure with 2-6micrometers grains and had no pores or cracks. From the result of displacement behavior measurement, PZT fibers fabricated by firing at 1200 degree(s)C in this study were considered to have desired piezoelectric properties.

A homolog of teleostean signal transducer and activator of transcription 3 (STAT3) from rock bream, Oplegnathus fasciatus: Structural insights, transcriptional modulation, and subcellular localization.

PubMed

Bathige, S D N K; Thulasitha, William Shanthakumar; Umasuthan, Navaneethaiyer; Jayasinghe, J D H E; Wan, Qiang; Nam, Bo-Hye; Lee, Jehee

2017-04-01

Signal transducer and activator of transcription 3 (STAT3) is one of the crucial transcription factors in the Janus kinase (JAK)/STAT signaling pathway, and it was previously considered as acute phase response factor. A number of interleukins (ILs) such as IL-5, IL-6, IL-9, IL-10, IL-12, and IL-22 are known to be involved in activation of STAT3. In addition, various growth factors and pathogenic or oxidative stresses mediate the activation of a wide range of functions via STAT3. In this study, a STAT3 homolog was identified and functionally characterized from rock bream (RbSTAT3), Oplegnathus fasciatus. In silico characterization revealed that the RbSTAT3 amino acid sequence shares highly conserved common domain architectural features including N-terminal domain, coiled coil domain, DNA binding domain, linker domain, and Src homology 2 (SH2) domains. In addition, a fairly conserved transcriptional activation domain (TAD) was located at the C-terminus. Comparison of RbSTAT3 with other counterparts revealed higher identities (>90%) with fish orthologs. The genomic sequence of RbSTAT3 was obtained from a bacterial artificial chromosome (BAC) library, and was identified as a multi-exonic gene (24 exons), as found in other vertebrates. Genomic structural comparison and phylogenetic studies have showed that the evolutionary routes of teleostean and non-teleostean vertebrates were distinct. Quantitative real time PCR (qPCR) analysis revealed that the spatial distribution of RbSTAT3 mRNA expression was ubiquitous and highly detectable in blood, heart, and liver tissues. Transcriptional modulation of RbSTAT3 was examined in blood and liver tissues after challenges with bacteria (Edwardsiella tarda and Streptococcus iniae), rock bream irido virus (RBIV), and immune stimulants (LPS and poly (I:C)). Significant changes in RbSTAT3 transcription were also observed in response to tissue injury. In addition, the transcriptional up-regulation of RbSTAT3 was detected in rock bream heart cells upon recombinant rock bream IL-10 (rRbIL-10) treatment. Subcellular localization and nuclear translocation of rock bream STAT3 following poly (I:C) treatment were also demonstrated. Taken together, the results of the current study provide important evidence for potential roles of rock bream STAT3 in the immune system and wound healing processes. Copyright © 2017 Elsevier B.V. All rights reserved.

Baicalein reduces lipopolysaccharide-induced inflammation via suppressing JAK/STATs activation and ROS production.

PubMed

Qi, Zhilin; Yin, Fei; Lu, Lina; Shen, Lei; Qi, Shimei; Lan, Lei; Luo, Lan; Yin, Zhimin

2013-09-01

To investigate the precise molecular mechanisms by which baicalein exerts beneficial biochemical activities in RAW264.7 macrophages treated with LPS. RAW264.7 cells were cultured in the absence or presence of baicalein together with or without LPS. iNOS and COX-2 expression were measured by western blot and RT-PCR analyses. TNF-α, IL-1β, and IL-6 were determined by using double-antibody sandwich ELISA. Phosphorylations of JAK1 and JAK2, and of STAT1 and STAT3 were detected by western blotting. Nuclear translocation of STAT1 and STAT3 was visualized by confocal microscopy. ROS production was detected by ROS assay. Baicalein significantly reduced the phosphorylation of STAT1 and STAT3 and the phosphorylation of JAK1 and JAK2, but without affecting MAPKs phosphorylation in LPS-stimulated RAW264.7 cells. Baicalein suppressed the nuclear translocation of STAT1 and STAT3 and inhibited production of iNOS upon LPS-stimulation, resulting in the inhibition of releases of NO and pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, in a dose-dependent manner. In addition, we found that baicalein reduced the LPS-induced accumulation of ROS, confirming that baicalein serves as an antioxidant. Our results suggested that suppressing JAK/STATs activation and interfering with ROS production might contribute to the anti-inflammatory action of baicalein in macrophages.

The regulation of inflammation by interferons and their STATs

PubMed Central

Rauch, Isabella; Müller, Mathias; Decker, Thomas

2013-01-01

Interferons (IFN) are subdivided into type I IFN (IFN-I, here synonymous with IFN-α/β), type II (IFN-γ) and type III IFN (IFN-III/IFN-λ) that reprogram nuclear gene expression through STATs 1 and 2 by forming STAT1 dimers (mainly IFN-γ) or the ISGF3 complex, a STAT1-STAT2-IRF9 heterotrimer (IFN-I and IFN-III). Dominant IFN activities in the immune system are to protect cells from viral replication and to activate macrophages for enhanced effector function. However, the impact of IFN and their STATs on the immune system stretches far beyond these activities and includes the control of inflammation. The goal of this review is to give an overview of the different facets of the inflammatory process that show regulatory input by IFN/STAT. PMID:24058799

Role of STAT3 in Cancer Metastasis and Translational Advances

PubMed Central

Patil, Prachi; Gude, Rajiv P.

2013-01-01

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. PMID:24199193

Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events.

PubMed

Quintanilla-Martinez, Leticia; Kremer, Marcus; Specht, Katja; Calzada-Wack, Julia; Nathrath, Michaela; Schaich, Robert; Höfler, Heinz; Fend, Falko

2003-05-01

The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three groups in terms of proliferation rate or expression of anti-apoptotic proteins. However, cyclin D1+ cases were always well differentiated and were more likely to show a lymphoplasmocytoid differentiation (chi-square = 9.55). Overall, constitutive activation of Stat 3 was found in almost half (48%) of the investigated MM cases. However, this does not seem to have a major impact on the expression of anti-apoptotic proteins and proliferation. We showed that cyclin D1 overexpression and Stat 3 activation are, mutually exclusive events in MM (P = 0.0066). The universal expression of Mcl-1, independent of activated Stat 3, suggests that its expression is constitutive and that it might play an important role in the pathogenesis of MM.

Expression of STATs and their inhibitors SOCS and PIAS in brain tumors. In vitro and in vivo study.

PubMed

Ehrmann, J; Strakova, N; Vrzalikova, K; Hezova, R; Kolar, Z

2008-01-01

Proteins of STAT family belongs to the transcription factors. Through their binding to the DNA specific sites and consequent regulation of transcription of various genes, these signaling proteins play an important role in many cell functions. Recent studies demonstrated persistent activation of STATs and loss of their natural inhibitors SOCS and PIAS in various human cancers. There is also evidence that experimental pharmacologic or genetic modulation of their function mignt by a new approach in anticancer treatment. The aim of this study was in vitro assesment and analysis of expression of STATs, SOCS and PIAS in glioblastoma cell lines undergoing treatment by PPARgamma agonists/antagonists because PPARgamma and STATs are tightly regulated by an overlapping set of nuclear regulatory proteins. We further analysed immunohistochemical expression of these proteins in vivo, with its correlation to grading in various brain tumors. The results of in vitro study showed decreased expression of phosphorylated form of STAT3 and increase of its inhibitors SOCS3 and PIAS3 in glioblastoma cell lines after treatment with IC50 of PPARgamma agonist ciglitazone. In vivo study failed to reveal changes in STAT3 and SOCS3 expression in either low and high grade astrocytomas, however we detect lower expression of STAT2 in low grade astrocytomas when comparing with high grade astrocytomas and lower expression of STAT3 in ependymomas when comparing with anaplastic ones. The results showed existing relationship between STAT and PPARgamma signaling in glial tumors and further suppport expected important role of STATs in regulation of growth and differentiation in these tumors.

Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings.

PubMed

Pan, Chih-Ming; Wang, Mong-Lien; Chiou, Shih-Hwa; Chen, Hsiao-Yun; Wu, Cheng-Wen

2016-09-13

Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM-mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1-dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells.

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells.

PubMed

Schauwecker, Suzanne M; Kim, J Julie; Licht, Jonathan D; Clevenger, Charles V

2017-02-10

The hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the up-regulation of numerous genes implicated in breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces chromatin decompaction at promoter DNA, corresponding with STAT5 binding. The chromatin-modifying protein high mobility group nucleosomal binding domain 2 (HMGN2) specifically promotes STAT5 accessibility at promoter DNA by facilitating the dissociation of the linker histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker histone H1 prevents STAT5 binding at promoter DNA, and the PRL-induced dissociation of H1 mediated by HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of sites of STAT3 action in the female reproductive tract through conditional gene deletion.

PubMed

Robker, Rebecca L; Watson, Laura N; Robertson, Sarah A; Dunning, Kylie R; McLaughlin, Eileen A; Russell, Darryl L

2014-01-01

The STAT3 transcription factor is a pleiotropic transducer of signalling by hormones, growth factors and cytokines that has been identified in the female reproductive tract from oocytes and granulosa cells of the ovary to uterine epithelial and stromal cells. In the present study we used transgenic models to investigate the importance of STAT3 for reproductive performance in these different tissues. The Cre-LoxP system was used to delete STAT3 in oocytes by crossing Stat3fl/fl with Zp3-cre+ mice, or in ovarian granulosa cells and uterine stroma by crossing with Amhr2-Cre+ mice. Surprisingly, deletion of STAT3 in oocytes had no effect on fertility indicating that the abundance of STAT3 protein in maturing oocytes and fertilized zygotes is not essential to these developmental stages. In Stat3fl/fl;Amhr2-cre+ females impaired fertility was observed through significantly fewer litters and smaller litter size. Ovulation rate, oocyte fertilization and development to blastocyst were unaffected in this line; however, poor recombination efficiency in granulosa cells had yielded no net change in STAT3 protein abundance. In contrast, uteri from these mice showed STAT3 protein depletion selectively from the stomal compartment. A significant reduction in number of viable fetuses on gestational day 18, increased fetal resorptions and disrupted placental morphology were evident causes of the reduced fertility. In conclusion, this study defines an important role for STAT3 in uterine stromal cells during embryo implantation and the development of a functional placenta.

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells*

PubMed Central

Schauwecker, Suzanne M.; Kim, J. Julie; Licht, Jonathan D.; Clevenger, Charles V.

2017-01-01

The hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the up-regulation of numerous genes implicated in breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces chromatin decompaction at promoter DNA, corresponding with STAT5 binding. The chromatin-modifying protein high mobility group nucleosomal binding domain 2 (HMGN2) specifically promotes STAT5 accessibility at promoter DNA by facilitating the dissociation of the linker histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker histone H1 prevents STAT5 binding at promoter DNA, and the PRL-induced dissociation of H1 mediated by HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling. PMID:28035005

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

PubMed

Zerbe, Christa S; Marciano, Beatriz E; Katial, Rohit K; Santos, Carah B; Adamo, Nick; Hsu, Amy P; Hanks, Mary E; Darnell, Dirk N; Quezado, Martha M; Frein, Cathleen; Barnhart, Lisa A; Anderson, Victoria L; Uzel, Gulbu; Freeman, Alexandra F; Lisco, Andrea; Nath, Avindra; Major, Eugene O; Sampaio, Elizabeth P; Holland, Steven M

2016-04-15

Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

pSTAT3 Levels Have Divergent Expression Patterns and Associations with Survival in Squamous Cell Carcinoma and Adenocarcinoma of the Oesophagus.

PubMed

O' Sullivan, Katie E; Michielsen, Adriana J; O' Regan, Esther; Cathcart, Mary C; Moore, Gillian; Breen, Eamon; Segurado, Ricardo; Reynolds, John V; Lysaght, Joanne; O' Sullivan, Jacintha

2018-06-10

Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) ( n = 116) or squamous cell carcinoma (SCC) ( n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266⁻32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574⁻0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

PubMed

Patel, Zubin; Lu, Xiaoming; Miller, Daniel; Forney, Carmy R; Lee, Joshua; Lynch, Arthur; Schroeder, Connor; Parks, Lois; Magnusen, Albert F; Chen, Xiaoting; Pujato, Mario; Maddox, Avery; Zoller, Erin E; Namjou, Bahram; Brunner, Hermine I; Henrickson, Michael; Huggins, Jennifer L; Williams, Adrienne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Glenn, Stuart B; Adler, Adam; Shen, Nan; Nath, Swapan K; Stevens, Anne M; Freedman, Barry I; Pons-Estel, Bernardo A; Tsao, Betty P; Jacob, Chaim O; Kamen, Diane L; Brown, Elizabeth E; Gilkeson, Gary S; Alarcón, Graciela S; Martin, Javier; Reveille, John D; Anaya, Juan-Manuel; James, Judith A; Sivils, Kathy L; Criswell, Lindsey A; Vilá, Luis M; Petri, Michelle; Scofield, R Hal; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Bang, So-Young; Lee, Hye-Soon; Bae, Sang-Cheol; Boackle, Susan A; Cunninghame Graham, Deborah; Vyse, Timothy J; Merrill, Joan T; Niewold, Timothy B; Ainsworth, Hannah C; Silverman, Earl D; Weisman, Michael H; Wallace, Daniel J; Raj, Prithvi; Guthridge, Joel M; Gaffney, Patrick M; Kelly, Jennifer A; Alarcón-Riquelme, Marta E; Langefeld, Carl D; Wakeland, Edward K; Kaufman, Kenneth M; Weirauch, Matthew T; Harley, John B; Kottyan, Leah C

2018-04-18

Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Activation of an IL-6:STAT3-dependent Transcriptome in Pediatric-onset Inflammatory Bowel Disease

PubMed Central

Carey, Rebecca; Jurickova, Ingrid; Ballard, Edgar; Bonkowski, Erin; Han, Xiaonan; Xu, Huan; Denson, Lee A.

2008-01-01

Background: While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation. Methods: Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies. Results: Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3+/CD4+ lymphocytes, and affected colon biopsies of IBD patients. The frequency of pSTAT3+PB granulocytes and colon epithelial and lamina propria cells was highly correlated with the degree of mucosal inflammation. Microarray and Ingenuity Systems bioinformatics analysis identified IL-6:STAT3-dependent biological networks upregulated in IBD patients which control leukocyte recruitment, HLA expression, angiogenesis, and tissue remodeling. Conclusions: A proinflammatory IL6:STAT3 biologic network is upregulated in active pediatric IBD patients at diagnosis and during therapy. Specific targeting of this network may be effective in reducing mucosal inflammation. PMID:18069684

Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells.

PubMed

Ah-Koon, Laurent; Lesage, Denis; Lemadre, Elodie; Souissi, Inès; Fagard, Remi; Varin-Blank, Nadine; Fabre, Emmanuelle E; Schischmanoff, Olivier

2016-10-01

The SN 1 alkylating agents activate the mismatch repair system leading to delayed G2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT1, an anti-proliferative and pro-apoptotic transcription factor is known to potentiate p53 and to affect DNA-damage cellular response. We studied whether STAT1 may modulate cell fate following activation of the mismatch repair system upon exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Using STAT1-proficient or -deficient cell lines, we found that STAT1 is required for: (i) reduction in the extent of DNA lesions, (ii) rapid phosphorylation of T68-CHK2 and of S15-p53, (iii) progression through the G2 /M checkpoint and (iv) long-term survival following treatment with MNNG. Presence of STAT1 is critical for the formation of a p53-DNA complex comprising: STAT1, c-Abl and MLH1 following exposure to MNNG. Importantly, presence of STAT1 allows recruitment of c-Abl to p53-DNA complex and links c-Abl tyrosine kinase activity to MNNG-toxicity. Thus, our data highlight the important modulatory role of STAT1 in the signalling pathway activated by the mismatch repair system. This ability of STAT1 to favour resistance to MNNG indicates the targeting of STAT1 pathway as a therapeutic option for enhancing the efficacy of SN1 alkylating agent-based chemotherapy. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

C/EBPβ Promotes STAT3 Expression and Affects Cell Apoptosis and Proliferation in Porcine Ovarian Granulosa Cells.

PubMed

Yuan, Xiaolong; Zhou, Xiaofeng; He, Yingting; Zhong, Yuyi; Zhang, Ailing; Zhang, Zhe; Zhang, Hao; Li, Jiaqi

2018-06-13

Previous studies suggest that signal transducer and activator of transcription 3 (STAT3) and CCAAT/enhancer binding protein beta (C/EBPβ) play an essential role in ovarian granulosa cells (GCs) for mammalian follicular development. Several C/EBPβ putative binding sites were previously predicted on the STAT3 promoter in mammals. However, the molecular regulation of C/EBPβ on STAT3 and their effects on cell proliferation and apoptosis remain virtually unexplored in GCs. Using porcine GCs as a model, the 5′-deletion, luciferase report assay, mutation, chromatin immunoprecipitation, Annexin-V/PI staining and EdU assays were applied to investigate the molecular mechanism for C/EBPβ regulating the expression of STAT3 and their effects on the cell proliferation and apoptosis ability. We found that over and interfering with the expression of C/EBPβ significantly increased and decreased the messenger RNA (mRNA) and protein levels of STAT3 , respectively. The dual luciferase reporter assay showed that C/EBPβ directly bound at −1397/−1387 of STAT3 to positively regulate the mRNA and protein expressions of STAT3 . Both C/EBPβ and STAT3 were observed to inhibit cell apoptosis and promote cell proliferation. Furthermore, C/EBPβ might enhance the antiapoptotic and pro-proliferative effects of STAT3 . These results would be of great insight in further exploring the molecular mechanism of C/EBPβ and STAT3 on the function of GCs and the development of ovarian follicles in mammals.

Fabrication of piezoelectric ceramic fibers by extrusion of Pb(Zr, Ti)O3 powder and Pb(Zr, Ti)O3 sol mixture

NASA Astrophysics Data System (ADS)

Qiu, Jinhao; Tani, Junji; Kobayashi, Yoshimasa; Um, Tae Young; Takahashi, Hirofumi

2003-06-01

In this study, Pb(Zr, Ti)O3 (PZT) piezoelectric ceramic fibers were fabricated by extrusion from a mixture of PZT powder and PZT sol. The added PZT sol in this study played the role of a binder; the sol changed into crystalline PZT during sintering, and removal of additives before sintering was not required. To obtain the required PZT fibers, the sol viscosity adjustment condition, the mixture ratio of powder and sol for fiber extrusion, and the sintering condition for obtaining polycrystalline fibers were investigated. The PZT precursor solution was synthesized from lead acetate trihydrate, zirconium n-propoxide, and titanium isopropoxide by reflux at 120 °C for 3 h with 2-methoxyethanol. The appropriate adjustment of the spinnable sol was achieved by the addition of acetic acid to suppress the hydrolysis reaction and by curing the sol at 80 °C to promote the condensation of the sol. Green fibers with diameters of about 300µm were successfully extruded from the mixture of PZT powder and sol (powder:sol = 5- 8:1, molar ratio). The extruded fibers, sintered at 1200 °C, had a microstructure with 2- 6µm grains and had no pores or cracks. From the results of displacement behavior measurements, the PZT fibers fabricated by firing at 1200 °C in this study were considered to have the desired piezoelectric properties.

Sol-gel based oxidation catalyst and coating system using same

NASA Technical Reports Server (NTRS)

Leighty, Bradley D. (Inventor); Watkins, Anthony N. (Inventor); Patry, JoAnne L. (Inventor); Schryer, Jacqueline L. (Inventor); Oglesby, Donald M. (Inventor)

2010-01-01

An oxidation catalyst system is formed by particles of an oxidation catalyst dispersed in a porous sol-gel binder. The oxidation catalyst system can be applied by brush or spray painting while the sol-gel binder is in its sol state.

Evaluation of the Special Tertiary Admissions Test (STAT)

ERIC Educational Resources Information Center

Coates, Hamish; Friedman, Tim

2010-01-01

This paper reports findings from the first national Australian study of the predictive validity of the Special Tertiary Admissions Test (STAT). Background on tertiary admissions procedures in Australia is presented, followed by information on STAT and the research methods. The results affirm that STAT, through the provision of baseline and…

Technologies for Genome-Wide Identification of Stat5 Regulated Genes

DTIC Science & Technology

2003-01-01

37 Role of Prl- Jak2 -Stat5 Signaling in Mammary Physiology.......................................... 39 Clinical Implications of Stat5...ROLE OF PRL- JAK2 -STAT5 SIGNALING IN MAMMARY EPITHELIAL CELL DIFFERENTIATION AND GROWTH...Differentiation of HC11 Mouse Mammary Epithelial Cells Correlated With Activation of Tyrosine Kinase Jak2

28 CFR 55.1 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) IMPLEMENTATION OF THE PROVISIONS OF THE VOTING RIGHTS ACT... the Voting Rights Act of 1965, 79 Stat. 437, as amended by the Civil Rights Act of 1968, 82 Stat. 73, the Voting Rights Act Amendments of 1970, 84 Stat. 314, the District of Columbia Delegate Act, 84 Stat...

28 CFR 55.1 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) IMPLEMENTATION OF THE PROVISIONS OF THE VOTING RIGHTS ACT... the Voting Rights Act of 1965, 79 Stat. 437, as amended by the Civil Rights Act of 1968, 82 Stat. 73, the Voting Rights Act Amendments of 1970, 84 Stat. 314, the District of Columbia Delegate Act, 84 Stat...

ZnO-based regenerable sulfur sorbents for fluid-bed/transport reactor applications

DOEpatents

Slimane, Rachid B.; Abbasian, Javad; Williams, Brett E.

2004-09-21

A method for producing regenerable sulfur sorbents in which a support material precursor is mixed with isopropanol and a first portion of deionized water at an elevated temperature to form a sol mixture. A metal oxide precursor comprising a metal suitable for use as a sulfur sorbent is dissolved in a second portion of deionized water, forming a metal salt solution. The metal salt solution and the sol mixture are mixed with a sol peptizing agent while heating and stirring, resulting in formation of a peptized sol mixture. The metal oxide precursor is dispersed substantially throughout the peptized sol mixture, which is then dried, forming a dry peptized sol mixture. The dry peptized sol mixture is then calcined and the resulting calcined material is then converted to particles.

Solvent-resistant sol-gel polydimethyldiphenylsiloxane coating for on-line hyphenation of capillary microextraction with high-performance liquid chromatography.

PubMed

Segro, Scott S; Malik, Abdul

2008-09-26

A sol-gel polydimethyldiphenylsiloxane (PDMDPS) coating was developed for capillary microextraction on-line hyphenated with high-performance liquid chromatography (HPLC). This coating was created using methyltrimethoxysilane (MTMS) as the sol-gel precursor and di-hydroxy-terminated PDMDPS as the sol-gel active polymer. The methyl and phenyl groups on the sol-gel active polymer and the methyl groups on the sol-gel precursor ultimately turned into pendant groups providing the ability to extract non-polar analytes. A 40-cm segment of 0.25 mm I.D. fused silica capillary containing the sol-gel PDMDPS coating was installed as an external sampling loop in an HPLC injection port. Aqueous samples containing polycyclic aromatic hydrocarbons (PAHs), aromatic compounds, ketones, and aldehydes were passed through this capillary wherein the analytes were extracted by the sol-gel coating. The extracted analytes were then transferred to the HPLC column using isocratic or gradient elution with an acetonitrile/water mobile phase. This capillary demonstrated excellent extraction capability for non-polar (e.g., polycyclic aromatic hydrocarbons and aromatic compounds) as well as moderately polar compounds, such as aromatic amines, ketones, and aldehydes. The test results indicate that PDMDPS can be successfully immobilized into a sol-gel network and that the resulting solvent-resistant sol-gel organic-inorganic hybrid coating can be effectively used for on-line hyphenation of capillary microextraction with high-performance liquid chromatography. The test results also indicate that the sol-gel PDMDPS coated capillary is resistant to high-temperature solvents, making it suitable for applications in high-temperature HPLC. To the best of our knowledge, this is the first report on the creation of a silica-based sol-gel PDMDPS coating used in capillary microextraction on-line hyphenated to HPLC.

Sol-gel chemistry-based Ucon-coated columns for capillary electrophoresis.

PubMed

Hayes, J D; Malik, A

1997-07-18

A sol-gel chemistry-based novel approach for the preparation of a Ucon-coated fused-silica capillary column in capillary electrophoresis is presented. In this approach the sol-gel process is carried out inside 25 microm I.D. fused-silica capillaries. The sol solution contained appropriate quantities of an alkoxide-based sol-gel precursor, a polymeric coating material (Ucon), a crosslinking reagent, a surface derivatizing reagent, controlled amounts of water and a catalyst dissolved in a suitable solvent system. The coating procedure involves filling a capillary with the sol solution and allowing the sol-gel process to proceed for an optimum period. Hydrolysis of the alkoxide precursor and polycondensation of the hydrolyzed products with the surface silanol groups and the hydroxy-terminated Ucon molecules lead to the formation of a surface-bonded sol-gel coating on the inner walls of the capillary. The thickness of the coated film can be controlled by varying the reaction time, coating solution composition and experimental conditions. Commercial availability of high purity sol-gel precursors (e.g., TEOS 99.999%), the ease of coating, run-to-run and column-to-column reproducibility, and long column lifetimes make sol-gel coating chemistry very much suitable for being applied in analytical microseparations column technology. Test samples of basic proteins and nucleotides were used to evaluate the column performance. These results show that the sol-gel coating scheme has allowed for the generation of bio-compatible surfaces characterized by high separation efficiencies in CE. For different types of solutes, the sol-gel coated Ucon column consistently provided migration time R.S.D. values of the order of 0.5%.

Epstein-Barr virus-derived EBNA2 regulates STAT3 activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako

The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.

Red cell storage in E-Sol 5 and Adsol additive solutions: paired comparison using mixed and non-mixed study designs.

PubMed

Radwanski, K; Thill, M; Min, K

2014-05-01

If transfusion of older stored red cells is found to negatively affect clinical outcome, one possible alternative to shortened outdate is the use of new additive solutions (AS) that ameliorate the storage lesion. Erythro-Sol (E-Sol), a previously developed next-generation AS, has been reformulated into E-Sol 5, which is compatible with current anticoagulants and AS volumes. The effect of E-Sol 5 on red cells during storage compared to current AS has not been reported. Paired, ABO-matched whole-blood units were collected into CPD anticoagulant, pooled, split and processed into plasma and red cell units with either 110 ml of Adsol or 105 ml of E-Sol 5 within 8 h of collection. In Study 1, paired units in E-Sol 5 and Adsol were sampled on Day 0 and every 7 days up to Day 42 (n = 10). In Study 2, paired units in E-Sol 5 and Adsol were sampled only on Day 0 and Day 42 (n = 10). In Study 1, 2,3 DPG levels were maintained until Day 28 in E-Sol 5 units and Day 14 in Adsol units. ATP levels were higher in E-Sol 5 units until Day 21, after which they were comparable between the two groups. In both studies, metabolic activity was greater in E-Sol 5 units with respect to glucose consumption and lactate production. Morphology scores were higher, and haemolysis and microparticles generated were lower in E-Sol 5 vs. Adsol units. Weekly mixing of units lowered haemolysis and microparticle levels and increased potassium content on Day 42 in both additive solutions. Regardless of whether units are mixed weekly or are stored non-mixed, E-Sol 5 slows the progression of the red cell storage lesion and improves the overall in vitro quality of RBC throughout storage. © 2013 International Society of Blood Transfusion.

Sol-gel approach to in situ creation of high pH-resistant surface-bonded organic-inorganic hybrid zirconia coating for capillary microextraction (in-tube SPME).

PubMed

Alhooshani, Khalid; Kim, Tae-Young; Kabir, Abuzar; Malik, Abdul

2005-01-07

A novel zirconia-based hybrid organic-inorganic sol-gel coating was developed for capillary microextraction (CME) (in-tube SPME). High degree of chemical inertness inherent in zirconia makes it very difficult to covalently bind a suitable organic ligand to its surface. In the present work, this problem was addressed from a sol-gel chemistry point of view. Principles of sol-gel chemistry were employed to chemically bind a hydroxy-terminated silicone polymer (polydimethyldiphenylsiloxane, PDMDPS) to a sol-gel zirconia network in the course of its evolution from a highly reactive alkoxide precursor undergoing controlled hydrolytic polycondensation reactions. A fused silica capillary was filled with a properly designed sol solution to allow for the sol-gel reactions to take place within the capillary for a predetermined period of time (typically 15-30 min). In the course of this process, a layer of the evolving hybrid organic-inorganic sol-gel polymer got chemically anchored to the silanol groups on the capillary inner walls via condensation reaction. At the end of this in-capillary residence time, the unbonded part of the sol solution was expelled from the capillary under helium pressure, leaving behind a chemically bonded sol-gel zirconia-PDMDPS coating on the inner walls. Polycyclic aromatic hydrocarbons, ketones, and aldehydes were efficiently extracted and preconcentrated from dilute aqueous samples using sol-gel zirconia-PDMDPS coated capillaries followed by thermal desorption and GC analysis of the extracted solutes. The newly developed sol-gel hybrid zirconia coatings demonstrated excellent pH stability, and retained the extraction characteristics intact even after continuous rinsing with a 0.1 M NaOH solution for 24 h. To our knowledge, this is the first report on the use of a sol-gel zirconia-based hybrid organic-inorganic coating as an extraction medium in solid phase microextraction (SPME).

Hydrophobicity of hemp shiv treated with sol-gel coatings

NASA Astrophysics Data System (ADS)

Hussain, Atif; Calabria-Holley, Juliana; Schorr, Diane; Jiang, Yunhong; Lawrence, Mike; Blanchet, Pierre

2018-03-01

This is the first time sol-gel technology is used in the treatment of hemp shiv to develop sustainable thermal insulation building materials. The impact on the hydrophobicity of hemp shiv by depositing functionalised sol-gel coatings using hexadecyltrimethoxysilane (HDTMS) has been investigated. Bio-based materials have tendency to absorb large amounts of water due to their hydrophilic nature and highly porous structure. In this work, the influence of catalysts, solvent dilution and HDTMS loading in the silica sols on the hydrophobicity of hemp shiv surface has been reported. The hydrophobicity of sol-gel coated hemp shiv increased significantly when using acid catalysed sols which provided water contact angles of up to 118° at 1% HDTMS loading. Ethanol diluted sol-gel coatings enhanced the surface roughness of the hemp shiv by 36% as observed under 3D optical profilometer. The XPS results revealed that the surface chemical composition of the hemp shiv was altered by the sol-gel coating, blocking the hydroxyl sites responsible for hydrophilicity.

Modified silica sol coatings for surface enhancement of leather.

PubMed

Mahltig, Boris; Vossebein, Lutz; Ehrmann, Andrea; Cheval, Nicolas; Fahmi, Amir

2012-06-01

The presented study reports on differently modified silica sols for coating applications on leather. Silica sols are prepared by acidic hydrolysis of tetraethoxysilane and modified by silane compounds with fluorinated and non-fluorinated alkylgroups. In contrast to many earlier investigations regarding sol-gel applications on leather, no acrylic resin is used together with the silica sols when applying on leather. The modified silica particles are supposed to aggregate after application, forming thus a modified silica coating on the leather substrate. Scanning electron microscopy investigation shows that the applied silica coatings do not fill up or close the pores of the leather substrate. However, even if the pores of the leather are not sealed by this sol-gel coating, an improvement of the water repellent and oil repellent properties of the leather substrates are observed. These improved properties of leather by application of modified silica sols can provide the opportunity to develop sol-gel products for leather materials present in daily life.

Optical properties of Na2O-TiO2-SiO2 glass films prepared by the sol-gel method

NASA Astrophysics Data System (ADS)

Barton, Ivo; Matejec, Vlastimil; Mrazek, Jan; Predoana, Luminita; Zaharescu, Maria

2017-12-01

Layers based on TiO2-SiO2 systems fabricated by sol-gel method have been investigated for the preparation of planar waveguides, antireflective coatings, Bragg mirrors, etc. However, at high titania contents such materials exhibit high viscosities and tendency to phase separation. In this paper we present optical properties of films containing TiO2 which are prepared via a novel approach sol-gel on the basis of ternary Na2O-TiO2-SiO2 glasses and which can exhibit lower viscosities. Films of Na2O-TiO2-SiO2 systems were prepared from input sols mixed of silica, titania and sodium oxide sols. The silica sol was prepared from tetraethyl orthosilicate (TEOS), ethanol, hydrochloric acid and water, with a TEOS c= 2 mol/l and water/alkoxide ratio 1.75. The titania sol was mixed from titanium tetraisopropoxide (TiPr), propan-2-ol, nitric acid and water, c= 0.5 mol/l, RW= 0.42. The sodium oxide sols with c= 0.474 mol/l were prepared from sodium ethoxide and ethanol. Input sols were prepared by mixing the silica and titania sols first and then the sodium sol was added. The input sols were aged for one hour. Stable input sols were obtained. The input sols were deposited on glass and silica slides by dip-coating technique at a withdrawing speeds of 200 mm/min. Applied gel layers were thermally treated at temperatures of 450 and 900°C. Layers containing sodium oxide and titania in concentration ranges of 0-20 mol.% and 0-30 mol.% respectively have been fabricated. Optical properties of layers were determined by UV-VIS-NIR transmission and reflection spectrophotometry. Refractive indices of layers were determined by spectral ellipsometry and from transmission spectra. Optical properties were correlated with results of XRD spectroscopy, optical microscopy, and atomic force microscopy. Transparent homogenous films with a maximum refractive index of 1.61 at a wavelength of 600 nm have been obtained.

Editorial: phys. stat. sol. (b) 241/5

NASA Astrophysics Data System (ADS)

Stutzmann, Martin

2004-04-01

Physica status solidi was founded in 1961 by a number of eminent solid state physicists as an attempt to overcome the iron curtain, which then separated East and West, at least in the field of science. Since that time our world has changed quite a bit, and so have the boundary conditions of science publishing. However, one thing has not changed: then as now, the general policy and development of a respectable scientific journal should be determined by a board of independent scientists, who volunteer to assume responsibility for the scientific content of the journal, to assure a fair and critical peer review process for all submitted manuscripts, and, in cases of conflict, to finally decide which papers will be published and which will not.As a matter of fact, an international Board of Editors which consists of scientists coming from different countries and continents, with a good reputation in their respective community, and without any conflict of interest with the Publisher of the journal is, in my opinion, these days more important than ever. As our daily scientific work becomes increasingly specialized, but at the same time also increasingly interdisciplinary, we are more and more forced to trust the quality and reliability of published scientific results in the literature, without really having a chance to come to an independent opinion on our own. This is one of the reasons why the many recent cases of plagiarism, scientific misconduct, or outright fraud have caused such a high level of public awareness. It is quite clear that without a serious peer review there would be an even larger number of such cases in the literature, and that without the responsible action taken by concerned Journal Editors, many of the revealed cases probably would have remained under the carpet.It is, therefore, a particular pleasure for me to introduce to you on the following pages the current Editorial Board of physica status solidi (b) in the form of a brief curriculum vitae, a photograph, and an e-mail address (in case you want to contact our Editors directly!). Of course, since 1961 the Editorial Board of our journal has undergone many changes and will continue to do so, but we always have attempted to maintain a good balance between the different areas of solid state physics, between theory and experiment, and between different countries. And although nothing is perfect, I hope that you will find at least one or two board members, who are known to you through their contributions to the literature in solid state physics.For me, this is the perfect occasion to thank all Members of the Editorial Board, past and present, for their advice, continuing support, and dedication! Vielen herzlichen Dank!

Editorial: phys. stat. sol. (a) 201/5

NASA Astrophysics Data System (ADS)

Stutzmann, Martin

2004-04-01

Physica status solidi was founded in 1961 by a number of eminent solid state physicists as an attempt to overcome the iron curtain, which then separated East and West, at least in the field of science. Since that time our world has changed quite a bit, and so have the boundary conditions of science publishing. However, one thing has not changed: then as now, the general policy and development of a respectable scientific journal should be determined by a board of independent scientists, who volunteer to assume responsibility for the scientific content of the journal, to assure a fair and critical peer review process for all submitted manuscripts, and, in cases of conflict, to finally decide which papers will be published and which will not.As a matter of fact, an international Board of Editors which consists of scientists coming from different countries and continents, with a good reputation in their respective community, and without any conflict of interest with the Publisher of the journal is, in my opinion, these days more important than ever. As our daily scientific work becomes increasingly specialized, but at the same time also increasingly interdisciplinary, we are more and more forced to trust the quality and reliability of published scientific results in the literature, without really having a chance to come to an independent opinion on our own. This is one of the reasons why the many recent cases of plagiarism, scientific misconduct, or outright fraud have caused such a high level of public awareness. It is quite clear that without a serious peer review there would be an even larger number of such cases in the literature, and that without the responsible action taken by concerned Journal Editors, many of the revealed cases probably would have remained under the carpet.It is, therefore, a particular pleasure for me to introduce to you on the following pages the current Editorial Board of physica status solidi (a) in the form of a brief curriculum vitae, a photograph, and an e-mail address (in case you want to contact our Editors directly!). Of course, since 1961 the Editorial Board of our journal has undergone many changes and will continue to do so, but we always have attempted to maintain a good balance between the different areas of solid state physics, between theory and experiment, and between different countries. And although nothing is perfect, I hope that you will find at least one or two board members, who are known to you through their contributions to the literature in solid state physics.For me, this is the perfect occasion to thank all Members of the Editorial Board, past and present, for their advice, continuing support, and dedication! Vielen herzlichen Dank!

Preface: phys. stat. sol. (a) 203/12

NASA Astrophysics Data System (ADS)

Jackman, Richard B.; Nesládek, Milo; Haenen, Ken

2006-09-01

The 30 papers gathered in this issue of physica status solidi (a) give a thorough overview over different topics that were presented during the 11th edition of the International Workshop on Surface and Bulk Defects in CVD Diamond Films (SBDD), which took place from 22 to 24 February 2006, at the Hasselt University in Diepenbeek-Hasselt, Belgium. Since its start more than 10 years ago, the SBDD Workshop has grown into a well-established, yearly early bird meeting place, addressing new emerging science related to the progress in the CVD diamond field. The 10 invited lectures, 29 contributed oral presentations and 26 posters were presented in several sessions during an intense two and a half day long meeting.The number of participants reached 115 this year with participants coming from fifteen countries: Austria, Belgium, Czech Republic, France, Germany, Israel, Italy, Japan, Mexico, Poland, Russia, Singapore, Slovak Republic, Sweden, UK, and USA. The mixture of young and established scientists, including a great proportion of students, made this meeting a hot spot of lively discussions on a wide range of scientific subjects, not only during the meeting itself, but also at several occasions throughout many social events offered by the hospitality of the city of Hasselt.It stands for itself that the workshop would not have been possible without the support of many people and institutions. For financial aid we are especially indebted to the Scientific Research Community Surface Modification of Materials of the F.W.O.-Vlaanderen (Belgium), whose incessant support plays an important role in keeping this meeting going. We also thank the Hasselt University for offering the lecture hall and infrastructure facilities and Seki Technotron Corp. for sponsoring the poster reception and their presence with a table top exhibit. Finally we highly appreciate the active approach of the editorial staff of physica status solidi in this conference and would like to thank most notably Stefan Hildebrandt, Ron Schulz-Rheinländer, Christoph Lellig, and Julia Hübner, for their excellent and patient work, bringing the number of successfully published proceedings of SBDD in pss (a) up to 8 already!To finish, we would all like to invite you to the 12th edition of the SBDD series, newly renamed as Hasselt Diamond Workshop, to be held at its established location of Diepenbeek-Hasselt. We look forward meeting you again at SBDD XII in 2007:Hasselt Diamond Workshop - SBDD XII28 February-2 March 2007Hasselt University, Diepenbeek-Hasselt, Belgiumhttp://www.imo.uhasselt.be/SBDD2007London, Paris, Hasselt, August 2006

AORSA full wave calculations of helicon waves in DIII-D and ITER

NASA Astrophysics Data System (ADS)

Lau, C.; Jaeger, E. F.; Bertelli, N.; Berry, L. A.; Green, D. L.; Murakami, M.; Park, J. M.; Pinsker, R. I.; Prater, R.

2018-06-01

Helicon waves have been recently proposed as an off-axis current drive actuator for DIII-D, FNSF, and DEMO tokamaks. Previous ray tracing modeling using GENRAY predicts strong single pass absorption and current drive in the mid-radius region on DIII-D in high beta tokamak discharges. The full wave code AORSA, which is valid to all order of Larmor radius and can resolve arbitrary ion cyclotron harmonics, has been used to validate the ray tracing technique. If the scrape-off-layer (SOL) is ignored in the modeling, AORSA agrees with GENRAY in both the amplitude and location of driven current for DIII-D and ITER cases. These models also show that helicon current drive can possibly be an efficient current drive actuator for ITER. Previous GENRAY analysis did not include the SOL. AORSA has also been used to extend the simulations to include the SOL and to estimate possible power losses of helicon waves in the SOL. AORSA calculations show that another mode can propagate in the SOL and lead to significant (~10%–20%) SOL losses at high SOL densities. Optimizing the SOL density profile can reduce these SOL losses to a few percent.

AORSA full wave calculations of helicon waves in DIII-D and ITER

DOE PAGES

Lau, Cornwall; Jaeger, E.F.; Bertelli, Nicola; ...

2018-04-11

Helicon waves have been recently proposed as an off-axis current drive actuator for DIII-D, FNSF, and DEMO tokamaks. Previous ray tracing modeling using GENRAY predicts strong single pass absorption and current drive in the mid-radius region on DIII-D in high beta tokamak discharges. The full wave code AORSA, which is valid to all order of Larmor radius and can resolve arbitrary ion cyclotron harmonics, has been used to validate the ray tracing technique. If the scrape-off-layer (SOL) is ignored in the modeling, AORSA agrees with GENRAY in both the amplitude and location of driven current for DIII-D and ITER cases.more » These models also show that helicon current drive can possibly be an efficient current drive actuator for ITER. Previous GENRAY analysis did not include the SOL. AORSA has also been used to extend the simulations to include the SOL and to estimate possible power losses of helicon waves in the SOL. AORSA calculations show that another mode can propagate in the SOL and lead to significant (~10-20%) SOL losses at high SOL densities. Optimizing the SOL density profile can reduce these SOL losses to a few percent.« less

AORSA full wave calculations of helicon waves in DIII-D and ITER

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lau, Cornwall; Jaeger, E.F.; Bertelli, Nicola

Helicon waves have been recently proposed as an off-axis current drive actuator for DIII-D, FNSF, and DEMO tokamaks. Previous ray tracing modeling using GENRAY predicts strong single pass absorption and current drive in the mid-radius region on DIII-D in high beta tokamak discharges. The full wave code AORSA, which is valid to all order of Larmor radius and can resolve arbitrary ion cyclotron harmonics, has been used to validate the ray tracing technique. If the scrape-off-layer (SOL) is ignored in the modeling, AORSA agrees with GENRAY in both the amplitude and location of driven current for DIII-D and ITER cases.more » These models also show that helicon current drive can possibly be an efficient current drive actuator for ITER. Previous GENRAY analysis did not include the SOL. AORSA has also been used to extend the simulations to include the SOL and to estimate possible power losses of helicon waves in the SOL. AORSA calculations show that another mode can propagate in the SOL and lead to significant (~10-20%) SOL losses at high SOL densities. Optimizing the SOL density profile can reduce these SOL losses to a few percent.« less