249 research outputs found
Visualizing and quantitating the spatiotemporal regulation of Ras/ERK signaling by dual-specificity mitogen-activated protein phosphatases (MKPs)
The spatiotemporal regulation of the Ras/ERK pathway is critical in determining the physiological and pathophysiological outcome of signaling. Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (DUSPs or MKPs) are key regulators of pathway activity and may also localize ERK to distinct subcellular locations. Here we present methods largely based on the use of high content microscopy to both visualize and quantitate the subcellular distribution of activated (p-ERK) and total ERK in populations of mouse embryonic fibroblasts derived from mice lacking DUSP5, a nuclear ERK-specific MKP. Such methods in combination with rescue experiments using adenoviral vectors encoding wild-type and mutant forms of DUSP5 have allowed us to visualize specific defects in ERK regulation in these cells thus confirming the role of this phosphatase as both a nuclear regulator of ERK activity and localization.</p
Accretion-ejection instability in magnetized disks: Feeding the corona with Alfven waves
We present a detailed calculation of the mechanism by which the
Accretion-Ejection Instability can extract accretion energy and angular
momentum from a magnetized disk, and redirect them to its corona. In a disk
threaded by a poloidal magnetic field of the order of equipartition with the
gas pressure, the instability is composed of a spiral wave (analogous to
galactic ones) and a Rossby vortex. The mechanism detailed here describes how
the vortex, twisting the footpoints of field lines threading the disk,
generates Alfven waves propagating to the corona. We find that this is a very
efficient mechanism, providing to the corona (where it could feed a jet or a
wind) a substantial fraction of the accretion energy.Comment: accepted by A&
Local models of stellar convection II: Rotation dependence of the mixing length relations
We study the mixing length concept in comparison to three-dimensional
numerical calculations of convection with rotation. In a limited range, the
velocity and temperature fluctuations are linearly proportional to the
superadiabaticity, as predicted by the mixing length concept and in accordance
with published results. The effects of rotation are investigated by varying the
Coriolis number, Co = 2 Omega tau, from zero to roughly ten, and by calculating
models at different latitudes. We find that \alpha decreases monotonically as a
function of the Coriolis number. This can be explained by the decreased spatial
scale of convection and the diminished efficiency of the convective energy
transport, the latter of which leads to a large increase of the
superadibaticity, \delta = \nabla - \nabla_ad as function of Co. Applying a
decreased mixing length parameter in a solar model yields very small
differences in comparison to the standard model within the convection zone. The
main difference is the reduction of the overshooting depth, and thus the depth
of the convection zone, when a non-local version of the mixing length concept
is used. Reduction of \alpha by a factor of roughly 2.5 is sufficient to
reconcile the difference between the model and helioseismic results. The
numerical results indicate reduction of \alpha by this order of magnitude.Comment: Final published version, 8 pages, 9 figure
A local prescription for the softening length in self-gravitating gaseous discs
In 2D-simulations of self-gravitating gaseous discs, the potential is often
computed in the framework of "softened gravity" initially designed for N-body
codes. In this special context, the role of the softening length LAMBDA is
twofold: i) to avoid numerical singularities in the integral representation of
the potential (i.e., arising when the relative separation vanishes), and ii) to
acount for stratification of matter in the direction perpendicular to the disc
mid-plane. So far, most studies have considered LAMBDA as a free parameter and
various values or formulae have been proposed without much mathematical
justification. In this paper, we demonstrate by means of a rigorous calculus
that it is possible to define LAMBDA such that the gravitational potential of a
flat disc coincides at order zero with that of a geometically thin disc of the
same surface density. Our prescription for LAMBDA, valid in the local,
axisymmetric limit, has the required properties i) and ii). It is mainly an
analytical function of the radius and disc thickness, and is sensitive to the
vertical stratification. For mass density profiles considered (namely, profiles
expandable over even powers of the altitude), we find that LAMBDA : i) is
independant of the numerical mesh, ii) is always a fraction of the local
thickness H, iii) goes through a minimum at the singularity (i.e., at null
separation), and iv) is such that 0.13 < LAMBDA/H < 0.29 typically (depending
on the separation and on density profile). These results should help us to
improve the quality of 2D- and 3D-simulations of gaseous discs in several
respects (physical realism, accuracy, and computing time).Comment: accepted in A&A, 7 pages, 7 figures, web link for the F90 code and
on-line calculations :
http://www.obs.u-bordeaux1.fr/radio/JMHure/intro2single.ph
Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing
The computation model used in the study of GnRH signalling which was used to generate the data appearing in this paper is in ORE at http://hdl.handle.net/10871/27844Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization.This work was supported by a Biochemical and Biophysical Science Research Council award (BBSRC BB/J014699/1; to C. A. M. and K. T.-A.)
Numerical simulations of the Accretion-Ejection Instability in magnetised accretion disks
The Accretion-Ejection Instability (AEI) described by Tagger & Pellat (1999)
is explored numerically using a global 2d model of the inner region of a
magnetised accretion disk. The disk is initially currentless but threaded by a
vertical magnetic field created by external currents, and frozen in the flow.
In agreement with the theory a spiral instability, similar in many ways to
those observed in self-gravitating disks, develops when the magnetic field is,
within a factor of a few, at equipartition with the disk thermal pressure.
Perturbations in the flow build up currents and create a perturbed magnetic
field within the disk. The present non-linear simulations give good evidence
that such an instability can occur in the inner region of accretion disks, and
generate accretion of gas and vertical magnetic flux toward the central object,
if the equilibrium radial profiles of density and magnetic flux exceed a
critical threshold.Comment: single tar file with GIF figure
Orbital Advection by Interpolation: A Fast and Accurate Numerical Scheme for Super-Fast MHD Flows
In numerical models of thin astrophysical disks that use an Eulerian scheme,
gas orbits supersonically through a fixed grid. As a result the time step is
sharply limited by the Courant condition. Also, because the mean flow speed
with respect to the grid varies with position, the truncation error varies
systematically with position. For hydrodynamic (unmagnetized) disks an
algorithm called FARGO has been developed that advects the gas along its mean
orbit using a separate interpolation substep. This relaxes the constraint
imposed by the Courant condition, which now depends only on the peculiar
velocity of the gas, and results in a truncation error that is more nearly
independent of position. This paper describes a FARGO-like algorithm suitable
for evolving magnetized disks. Our method is second order accurate on a smooth
flow and preserves the divergence-free constraint to machine precision. The
main restriction is that the magnetic field must be discretized on a staggered
mesh. We give a detailed description of an implementation of the code and
demonstrate that it produces the expected results on linear and nonlinear
problems. We also point out how the scheme might be generalized to make the
integration of other supersonic/super-fast flows more efficient. Although our
scheme reduces the variation of truncation error with position, it does not
eliminate it. We show that the residual position dependence leads to
characteristic radial variations in the density over long integrations.Comment: 32 pages, 18 figures, accepted for publication in The Astrophysical
Journal. Contains an additional appendix providing more details for some of
the test problems (to be published as an addendum in the ApJS December 2008,
v179n2 issue
Acoustic wave propagation in the solar sub-photosphere with localised magnetic field concentration: effect of magnetic tension
Aims: We analyse numerically the propagation and dispersion of acoustic waves in the solar-like sub-photosphere with localised non-uniform magnetic field concentrations, mimicking sunspots with various representative magnetic field configurations.
Methods: Numerical simulations of wave propagation through the solar sub-photosphere with a localised magnetic field concentration are carried out using SAC, which solves the MHD equations for gravitationally stratified plasma. The initial equilibrium density and pressure stratifications are derived from a standard solar model. Acoustic waves are generated by a source located at the height corresponding approximately to the visible surface of the Sun. By means of local helioseismology we analyse the response of vertical velocity at the level corresponding to the visible solar surface to changes induced by magnetic field in the interior.
Results: The results of numerical simulations of acoustic wave propagation and dispersion in the solar sub-photosphere with localised magnetic field concentrations of various types are presented. Time-distance diagrams of the vertical velocity perturbation at the level corresponding to the visible solar surface show that the magnetic field perturbs and scatters acoustic waves and absorbs the acoustic power of the wave packet. For the weakly magnetised case, the effect of magnetic field is mainly thermodynamic, since the magnetic field changes the temperature stratification. However, we observe the signature of slow magnetoacoustic mode, propagating downwards, for the strong magnetic field cases
Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling
Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAF(V600E), a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAF(V600E)-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate
Information Transfer in Gonadotropin-Releasing Hormone (GnRH) Signaling:Extracellular Signal-Regulated Kinase (ERK)-Mediated Feedback Loops Control Hormone Sensing
Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization
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