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Future improvements in particle accelerator performance is predicated on increasingly accurate online modeling of accelerators. Hysteresis effects in magnetic, mechanical, and material components of accelerators are often neglected in online accelerator models used to inform control algorithms, even though reproducibility errors from systems exhibiting hysteresis are not negligible in high precision accelerators. In this work, we combine the classical Preisach model of hysteresis with machine learning techniques to efficiently create non-parametric, high-fidelity models of arbitrary systems exhibiting hysteresis. We demonstrate that our technique accurately predicts hysteresis effects in physical accelerator magnets. We also experimentally demonstrate how these methods can be used in-situ, where the hysteresis model is combined with a Bayesian statistical model of the beam response, allowing characterization of hysteresis in accelerator magnets solely from measurements of the beam. Furthermore, we explore how using these joint hysteresis-beam models allows us to overcome optimization performance limitations when hysteresis effects are ignored.

International audience; Delays appear in the dynamics of many systems due to non-vanishing reaction times of control systems. In biochemical systems, long sequences of repeated steps, especially in biopolymerization processes, can be modeled by delays. However, modelling systems with delays is often complicated by physical constraints, such as the requirement that solutions representing concentrations of chemical species remain positive. In this work, we consider a model for a detoxifying enzyme whose synthesis is controlled by its substrate. The model includes bindingsite clearance delays, caused by the time required for an RNA polymerase or ribosome to clear its binding site before another such machine can bind. The existence of a positive equilibrium and the positivity and boundedness of solutions of the corresponding delay-differential equations are proven. In addition, the stability of the model is studied using the "small-gain" theorem.

Characterizing the phase space distribution of particle beams in accelerators is a central part of accelerator understanding and performance optimization. However, conventional reconstruction-based techniques either use simplifying assumptions or require specialized diagnostics to infer high-dimensional ($>$ 2D) beam properties. In this Letter, we introduce a general-purpose algorithm that combines neural networks with differentiable particle tracking to efficiently reconstruct high-dimensional phase space distributions without using specialized beam diagnostics or beam manipulations. We demonstrate that our algorithm accurately reconstructs detailed 4D phase space distributions with corresponding confidence intervals in both simulation and experiment using a single focusing quadrupole and diagnostic screen. This technique allows for the measurement of multiple correlated phase spaces simultaneously, which will enable simplified 6D phase space distribution reconstructions in the future.

The evolution of the digital technologies allowed since the early 1990s, to multiply the photogrammetric acquisitions, the digital and mechanical diagnosis and the 3D diagnosis of the sculptural heritage, generating a better knowledge of these objects. The multiplication of these tools therefore allowed to establish multidisciplinary methodologies, generally leading towards less invasive restorations protocol. Here, the diagnosis of a case study is first accomplished, starting with a photogrammetric acquisition, then tested in the two and three dimension annotation platform named aïoli, in order to determine the current possibilities for an innovative use of these tools, benefiting at the diagnosis of the sculptural heritage. On the order hand, along with the multiplication of the multidisciplinary methodologies, a very contemporary problematic arises: the need to improve the communication and discussion between different professionals. The goal was here to offer innovative methods to give all professionals the same vocabulary, a shared knowledge, therefore allowing a better diagnosis of these pieces of art.

In 1977, Michael Mackey and Leon Glass published a short paper thatВ presented and analyzed three delay-differential physiological models, oneВ of which, now known as the Mackey-Glass equation, was shown to generateВ chaotic behavior. This paper also introduced the concept of a dynamicalВ disease. In this perspective article, I attempt to place the Mackey-Glass paperВ andВ a 1979 followup in historical context, and thereby to gain someВ understanding of the very significant influence it has had across theВ sciences. This influence is mapped through a citation analysis, revealingВ both the timelessness of the themes broached in the Glass-Mackey papers, andВ of the broad influence of these papers, far transcending the specificВ scientific problems originally tackled.

The conditions for the validity of the standard quasi-steady-state approximation in the Michaelis--Menten mechanism in a closed reaction vessel have been well studied, but much less so the conditions for the validity of this approximation for the system with substrate inflow. We analyze quasi-steady-state scenarios for the open system attributable to singular perturbations, as well as less restrictive conditions. For both settings we obtain distinguished invariant slow manifolds and time scale estimates, and we highlight the special role of singular perturbation parameters in higher order approximations of slow manifolds. We close the paper with a discussion of distinguished invariant manifolds in the global phase portrait., 32 pages, 6 figures

Delay-differential equations belong to the class of infinite-dimensional dynamical systems. However, it is often observed that the solutions are rapidly attracted to smooth manifolds embedded in the finite-dimensional state space, called inertial manifolds. The computation of an inertial manifold yields an ordinary differential equation (ODE) model representing the long-term dynamics of the system. Note in particular that any attractors must be embedded in the inertial manifold when one exists, therefore reducing the study of these attractors to the ODE context, for which methods of analysis are well developed. This contribution presents a study of a previously developed method for constructing inertial manifolds based on an expansion of the delayed term in small powers of the delay, and subsequent solution of the invariance equation by the Fraser functional iteration method. The combined perturbative-iterative method is applied to several variations of a model for the expression of an inducible enzyme, where the delay represents the time required to transcribe messenger RNA and to translate that RNA into the protein. It is shown that inertial manifolds of different dimensions can be computed. Qualitatively correct inertial manifolds are obtained. Among other things, the dynamics confined to computed inertial manifolds display Andronov&ndash, Hopf bifurcations at similar parameter values as the original DDE model.

Developments of LiDAR technology are decreasing the unit cost per single point (e.g. single-photo counting). This brings to the possibility of future LiDAR datasets having very dense point clouds. In this work, we process a very dense point cloud (~200 points per square meter), using three different methods for segmenting single trees and extracting tree positions and other metrics of interest in forestry, such as tree height distribution and canopy area distribution. The three algorithms are tested at decreasing densities, up to a lowest density of ~5 point per square meter. Accuracy assessment is done using Kappa, recall, precision and F-Score metrics comparing results with tree positions from groundtruth measurements in six ground plots where tree positions and heights were surveyed manually. Results show that one method provides better Kappa and recall accuracy results for all cases, and that different point densities, in the range used in this study, do not affect accuracy significantly. Processing time is also considered; the method with better accuracy is several times slower than the other two methods and increases exponentially with point density. Best performer gave Kappa = 0.7. The implications of metrics for determining the accuracy of results of point positions’ detection is reported. Motives for the different performances of the three methods is discussed and further research direction is proposed.

Differential equation models of chemical or biochemical systems usually display multiple, widely varying time scales, i.e. they are stiff. After the decay of transients, trajectories of these systems approach low-dimensional invariant manifolds on which the eventual attractor (an equilibrium point in a closed system) is approached, and in which this attractor is embedded. Computing one of these slow invariant manifolds (SIMs) results in a reduced model of dimension equal to the dimension of the SIM. Another approach to model reduction involves lumping, the formulation of a reduced set of variables that combine the original model variables and in terms of which the reduced model is framed. In this study, we combine lumping with a constructive method for SIMs based on the iterative solution of the invariance equation. We illustrate these methods using a simple model of a linear metabolic pathway, and a model for hydrogen oxidation. The former is treated with a linear lumping function, while a nonlinear lumping function based on a Lyapunov function is used in the latter.

The dielectric relaxation mechanism associated with the interfacial polarization in polyaniline/reduced graphene oxide (PANI/RGO) nano-composites is found to shift towards lower frequencies on increasing temperature. Accordingly, the effective activation energy value is negative. Basic concepts of the Sillars dielectric theory of a heterogeneous medium are revisited for a material consisting of conducting platelets dispersed in a semi-insulating matrix in order to explain the negative sign of the relaxation energy. A plausible explanation to this observation involves a thermally activated de-trapping mechanism through the effective potential barrier at the interfaces between RGO and PANI. This results in an enhancement of the density of charge carriers which contributes to dc conductivity at the expense of the density of charge carriers that relax within RGO inclusions. Subsequently, the intensity of the dielectric peak is suppressed on heating which results in a systematic modification of the shapes of the dc conductivity vs temperature curves. © 2016 Author(s).

A mathematical model is devised to study the diffusion of mRNA in the nucleus from the site of synthesis to a nuclear pore where it is exported to the cytoplasm. This study examines the role that nuclear structure can play in determining the kinetics of export by considering models in which elements of the nuclear skeleton and confinement by chromatin direct the mRNA movement. As a rule, a dense chromatin layer favours rapid export by reducing the effective volume for diffusion. However, it may also result in a heavy tail in the export time distribution because of the low mobility of molecules that accidentally find their way deep into the dense layer. An anisotropic solid-state transport system can also assist export. There exist both an optimal ratio of the anisotropy and an optimal depth of the solid-state transport layer that favour rapid export. [Includes supplementary material]

When the anisotropy of a harmonic ion trap is increased, the ions eventually collapse into a two-dimensional structure consisting of concentric shells of ions. This collapse generally behaves like a second-order phase transition. A graph of the critical value of the anisotropy parameter vs. the number of ions displays substructure closely related to the inner-shell configurations of the clusters. The critical exponent for the order parameter of this phase transition (maximum extent in the z direction) was found computationally to have the value β = 1/2. A second critical exponent related to displacements perpendicular to the z axis was found to have the value δ = 1. Using these estimates of the critical exponents, we derive an equation that relates the amplitudes of the displacements of the ions parallel to the x–y plane to the amplitudes along the z axis during the flattening process.

We monitored a continuous culture of the yeast Saccharomyces cerevisiae by membrane-inlet mass spectrometry. This technique allows very rapid simultaneous measurements (one point every 12 s) of several dissolved gases. During our experiment, the culture exhibited a multioscillatory mode in which the dissolved oxygen and carbon dioxide records displayed periodicities of 13 h, 36 min and 4 min. The 36- and 4-min modes were not visible at all times, but returned at regular intervals during the 13-h cycle. The 4-min mode, which has not previously been described in continuous culture, can also be seen when the culture displays simpler oscillatory behavior. The data can be used to visualize a metabolic attractor of this system, i.e. the set of dissolved gas concentrations which are consistent with the multioscillatory state. Computation of the leading Lyapunov exponent reveals the dynamics on this attractor to be chaotic.

Phase synchronization of two systems with different dynamical parameters driven by a common external signal is studied using a model of the photosensitive Belousov−Zhabotinsky reaction. Complex dynamics, including chaos, arise when the external light intensity is periodically switched between two levels. Two dynamical conditions are investigated here: (a) the two systems are driven between two limit cycles and (b) both systems are driven between excitable and oscillatory states. Phase synchronization is achieved with both Gaussian-distributed and dichotomous noise when the random variation is added to the duration of the periodic forcing. In the case that noise is added to the intensity of the periodic forcing, perfect phase synchronization is achieved with dichotomous noise, whereas only transient synchronization is observed with Gaussian-distributed random variation. Studies with correlated noise show that the compound system may have two attractors, one corresponding to the phase synchronized state an...

In this paper we studied the behavior of a model of a periodically driven photosensitive Belousov−Zhabotinsky reaction. The computations were carried out with a two-variable Oregonator model modified to account for photosensitivity. The external light intensity was periodically switched between two levels. By keeping the total cycle length fixed while varying the duration of the positive and negative perturbations, a variety of dynamical behaviors can be observed, including phase locking, torus oscillations, periodic transitions, and chaos. The results suggest that not only are the forcing frequency and amplitude important, as was already known, but the detailed waveform of the external forcing is also essential in determining the behavior of a driven dynamical system. Two scenarios have been investigated in this study: (a) the system was driven between two limit cycles; (b) the system was driven between excitable and oscillatory states. Random modulation of the durations of the positive and negative per...

In earlier studies, treatment with sodium arsenite was shown to decrease total hepatic CYP in rats. A concomitant increase in heme oxygenase, the rate-limiting step in heme degradation to biliverdin, was considered responsible for the decrease in CYP. Here we investigated the effect of sodium arsenite on induction of CYP2H, CYP1A, and heme oxygenase in primary cultures of chicken embryo hepatocytes. When added simultaneously with inducer, arsenite inhibited phenobarbital-mediated increases in CYP2H and 3-methylcholanthrene-mediated increases in CYP1A, as measured enzymatically and immunochemically. Near maximal decreases were observed in these forms of CYP at a concentration of 2.5 microM sodium arsenite. The concentration-dependent decreases in CYP2H and CYP1A by sodium arsenite were concomitant with increases in heme oxygenase. Sodium arsenite was not toxic at concentrations as high as 10 microM, as indicated by protein synthesis and the reduction of MTT by intact cells. Sodium arsenite had no effect on induction of CYP2H1 mRNA, suggesting that the decreases in this form of CYP occurred post-transcriptionally. Treatment of cells with tin mesoporphyrin (SnMeso), an inhibitor of heme oxygenase, resulted in inhibition of arsenite-induced heme oxygenase. However, SnMeso did not alter the effect of arsenite to prevent phenobarbital-mediated increases in CYP2H protein. SnMeso alone inhibited phenobarbital-mediated increases in CYP2H. Inclusion of 2 or 5 microM exogenous heme with arsenite did not prevent the arsenite-mediated decrease in CYP2H. Combined treatment with heme and phenobarbital induced heme oxygenase to the same extent as treatment with heme, arsenite, and phenobarbital. However, CYP2H activity was decreased only when the treatment included arsenite. These results suggest that elevated levels of heme oxygenase alone are not responsible for arsenite-mediated decreases in CYP2H.

It has been noted that single-enzyme systems can undergo strongly damped transient oscillations. In this paper, we present a nonlinear dynamics analysis of oscillations in undriven chemical systems. This analysis allows us to classify transient oscillations into two groups. In the first group, oscillations arise from rapid oscillatory relaxation to a slower transient relaxation mode. These oscillations are always strongly damped. In the second group, it is the slowest relaxation mode which is implicated in the oscillations so these can be very lightly damped. This second class of oscillations has not previously been studied in enzymology. We show that a remarkably simple single-enzyme system, namely competitive inhibition with substrate flow, generates transient oscillations which belong to the second class. In an attempt to design an experimentally realizable version of this model, we then discovered a system which is capable of sustained oscillations. In this experimentally realizable model, two substrates compete to bind to a macromolecule. The flow of one substrate is controlled by a simple feedback device. Sustained oscillations are observed over a very wide range of parameters. In both models, oscillations are favored by a wide disparity in rates of binding and dissociation of the two substrates to the macromolecule.

A simple epidemiological model whose dynamics are described by a pair of nonlinearly coupled Lotka--Volterra oscillators is shown to have a two-dimensional center manifold. This center manifold turns out to be identical to the center eigenspace and is thus analytically determinable. On the center manifold, the system is reduced to a single Lotka--Volterra oscillator.

Glucocorticoid therapy is being used in a wide variety of systemic disorders. Reference papers, published more than 20 years ago, showed no correlation between adrenal insufficiency risk and dose or duration of glucocorticoid therapy.Our objective was to evaluate the extent to which long-term glucocorticoid therapy damages the pituitary-adrenal axis in patients with systemic inflammatory disorders.We conducted a retrospective observational study from January 2011 to August 2012.This was a monocentric study at the Department of Internal Medicine, Bichat Hospital, Paris-Diderot University, Paris, France.Sixty consecutive patients who were receiving long-term prednisone therapy for systemic inflammatory disorders and in whom discontinuation of glucocorticoid treatment was planned.A short Synacthen test was performed. A bolus of 0.25 mg 1-24-ACTH was injected in the morning, 24 hours after the most recent dose of prednisone. Cortisol was measured at baseline and 60 minutes after Synacthen injection.We assessed frequency and risk estimate of pituitary-adrenal dysfunction.Twenty-nine patients (48.3%) had adrenal insufficiency defined by a plasmatic cortisol100 nmol/L (n = 13) at baseline (time 0) or550 nmol/L (n = 16) 60 minutes after Synacthen injection. Cumulative dose (area under the receiver operating characteristic curve = 0.77 [95% confidence interval = 0.62-0.91], P = .007) and exposure (area under the receiver operating characteristic curve 0.80 [95% confidence interval = 0.67-0.93], P = .002) to prednisone were predictive for adrenal insufficiency based on a T0100 nmol/L. Prednisone was stopped in 29 of 31 patients (93.5%) showing a normal response to short Synacthen test; none of these patients required hydrocortisone replacement with a mean follow-up of 10 (± 6) months.Adrenal insufficiency is frequent in patients treated with long-term glucocorticoids for systemic inflammatory disorders and is related to duration and cumulative dose of steroids.

The transient and steady-state behaviour of the reversible Michaelis–Menten mechanism [R] and Competitive Inhibition (CI) mechanism is studied by analysis in the phase plane. Usually, the kinetics of both mechanisms is simplified to give a modified Michaelis–Menten velocity expression; this applies to the CI mechanism with excess inhibitor and to mechanism [R] in the product inhibition limit. In this paper, [R] is treated exactly as a plane autonomous system of differential equations and its true (dynamical) steady state is described by a line-like slow manifold M. Initial velocity experiments for [R] no longer strictly correspond to the hyperbolic law (as in the irreversible Michaelis–Menten mechanism) and this leads to corrections to the standard integrated rate law. Using a new analysis, the slow dynamics of the CI mechanism is reduced from a three-dimensional system to a planar system. In this mechanism transient decay collapses the trajectory flow onto a two-dimensional "slow" surface Σ; motion on Σ can be treated exactly as projected dynamics in the plane. This projected flow may differ in important ways from that of two-step mechanisms, e.g., it may lack a proper steady state. The relevance of these more accurate dynamical descriptions is discussed in relation to experimental design and metabolic function.

Les cinetiques d'accumulation de l'azote, du phosphore et du potassium en fonction de la production de biomasse ont ete comparees pour la pousse de printemps de 4 prairies permanentes. Ces parcelles presentent a priori des niveaux differents de fourniture de phosphore et de potassium par le sol. Par ailleurs, elles ont ete soumises ou non a des apports d'engrais. La comparaison entre traitements, des biomasses aeriennes produites et des teneurs de l'herbe en phosphore et en potassium, permet de definir des courbes de dilution de reference au-dela desquelles les prelevements supplementaires (ou les apports d'engrais) n'accroissent plus les quantites de biomasse produite (...)

The location of a radiating source can be determined by time-tagging the arrival of the radiated signal at a network of spatially distributed sensors. The accuracy of this approach depends strongly on the particular time-tagging algorithm employed at each of the sensors. If different techniques are used across the network, then the time tags must be referenced to a common fiducial for maximum location accuracy. In this report we derive the time corrections needed to temporally align leading-edge, time-tagging techniques with peak-picking algorithms. We focus on broadband radio frequency (RF) sources, an ionospheric propagation channel, and narrowband receivers, but the final results can be generalized to apply to any source, propagation environment, and sensor. Our analytic results are checked against numerical simulations for a number of representative cases and agree with the specific leading-edge algorithm studied independently by Kim and Eng (1995) and Pongratz (2005 and 2007).

Substance use disorders constitute a serious and persistent threat to military readiness and to the health and safety of military personnel and their families. Methamphetamine is among the most addictive and damaging of commonly abused drugs; this is of great concern for military health providers in Hawaii due to the unusually high prevalence in the local community. The effect of regional drug use on active duty subpopulations has not been previously studied. This study includes a 6-year retrospective sample of laboratory-confirmed methamphetamine-, cocaine-, and marijuana-positive drug tests among Army soldiers stationed in Hawaii and western and eastern continental U.S. installations. The findings suggest that active duty members are significantly affected by the local drug climate. However, current military drug policies also deter use as evidenced by low absolute drug-positive rates even in regions of high civilian prevalence.

Temporal organization of biological processes requires massively parallel processing on a synchronized time-base. We analyzed time-series data obtained from the bioenergetic oscillatory outputs of Saccharomyces cerevisiae and isolated cardiomyocytes utilizing Relative Dispersional (RDA) and Power Spectral (PSA) analyses. These analyses revealed broad frequency distributions and evidence for long-term memory in the observed dynamics. Moreover RDA and PSA showed that the bioenergetic dynamics in both systems show fractal scaling over at least 3 orders of magnitude, and that this scaling obeys an inverse power law. Therefore we conclude that in S. cerevisiae and cardiomyocytes the dynamics are scale-free in vivo. Applying RDA and PSA to data generated from an in silico model of mitochondrial function indicated that in yeast and cardiomyocytes the underlying mechanisms regulating the scale-free behavior are similar. We validated this finding in vivo using single cells, and attenuating the activity of the mitochondrial inner membrane anion channel with 4-chlorodiazepam to show that the oscillation of NAD(P)H and reactive oxygen species (ROS) can be abated in these two evolutionarily distant species. Taken together these data strongly support our hypothesis that the generation of ROS, coupled to redox cycling, driven by cytoplasmic and mitochondrial processes, are at the core of the observed rhythmicity and scale-free dynamics. We argue that the operation of scale-free bioenergetic dynamics plays a fundamental role to integrate cellular function, while providing a framework for robust, yet flexible, responses to the environment.

We monitored a continuous culture of the yeast Saccharomyces cerevisiae by membrane-inlet mass spectrometry. This technique allows very rapid simultaneous measurements (one point every 12 s) of several dissolved gases. During our experiment, the culture exhibited a multioscillatory mode in which the dissolved oxygen and carbon dioxide records displayed periodicities of 13 h, 36 min and 4 min. The 36- and 4-min modes were not visible at all times, but returned at regular intervals during the 13-h cycle. The 4-min mode, which has not previously been described in continuous culture, can also be seen when the culture displays simpler oscillatory behavior. The data can be used to visualize a metabolic attractor of this system, i.e. the set of dissolved gas concentrations which are consistent with the multioscillatory state. Computation of the leading Lyapunov exponent reveals the dynamics on this attractor to be chaotic.

The conditions for diffusion-driven (Turing) instabilities in systems with two reactive species are well known. General methods for detecting potential Turing bifurcations in larger reaction schemes are, on the other hand, not well developed. We prove a theorem for a graph-theoretic condition originally given by Volpert and Ivanova [Mathematical Modeling (Nauka, Moscow, 1987) (in Russian), p. 57] for Turing instabilities in a mass-action reaction-diffusion system involving n substances. The method is based on the representation of a reaction mechanism as a bipartite graph with two types of nodes representing chemical species and reactions, respectively. The condition for diffusion-driven instability is related to the existence of a structure in the graph known as a critical fragment. The technique is illustrated using a substrate-inhibited bifunctional enzyme mechanism which involves seven chemical species.

When molecules are present in small numbers, such as is frequently the case in cells, the usual assumptions leading to differential rate equations are invalid and it is necessary to use a stochastic description which takes into account the randomness of reactive encounters in solution. We display a very simple biochemical model, ordinary competitive inhibition with substrate inflow, which is only capable of damped oscillations in the deterministic mass-action rate equation limit, but which displays sustained oscillations in stochastic simulations. We define an observability parameter, which is essentially just the ratio of the amplitude of the oscillations to the mean value of the concentration. A maximum in the observability is seen as the volume is varied, a phenomenon we name system-size observability resonance by analogy with other types of stochastic resonance. For the parameters of this study, the maximum in the observability occurs at volumes similar to those of bacterial cells or of eukaryotic organelles.

A theoretical analysis of the distinguishability problem of two rival models of the single enzyme-single substrate reaction, the Michaelis-Menten and Henri mechanisms, is presented. We also outline a general approach for analysing the structural indistinguishability between two mechanisms. The approach involves constructing, if possible, a smooth mapping between the two candidate models. Evans et al. [N.D. Evans, M.J. Chappell, M.J. Chapman, K.R. Godfrey, Structural indistinguishability between uncontrolled (autonomous) nonlinear analytic systems, Automatica 40 (2004) 1947-1953] have shown that if, in addition, either of the mechanisms satisfies a particular criterion then such a transformation always exists when the models are indistinguishable from their experimentally observable outputs. The approach is applied to the single enzyme-single substrate reaction mechanism. In principle, mechanisms can be distinguished using this analysis, but we show that our ability to distinguish mechanistic models depends both on the precise measurements made, and on our knowledge of the system prior to performing the kinetics experiments.

Reaction-diffusion models are widely used to model developmental processes. The great majority of current models invoke constant diffusion coefficients. However, the diffusion of metabolites or signals through tissues is frequently such that this assumption may reasonably be questioned. We consider several different physical mechanisms leading to effective diffusion coefficients in biological tissues which vary with the local conditions, including models in which juxtacrine signaling results in the diffusion of a signal in the absence of material transport. We develop a mathematical formalism for transforming local transport laws into diffusive terms. This procedure is appropriate when the typical length scale over which the concentrations change significantly is much greater than the dimensions of a cell. We review previous developmental models which considered the possibility of state-dependent diffusion coefficients. We also provide a few new motivating examples.

Chronic human exposure to low levels of inorganic arsenic increases the incidence of vascular diseases and specific cancers. Exposure of endothelial cells to environmentally relevant concentrations of arsenic trioxide (arsenite) induces oxidant formation, activates the transcription factor NF-kappaB, and increases DNA synthesis (Barchowsky et al., Free Radic. Biol. Med. 21, 783-790, 1996). We show, in the current study, that arsenite induces concentration-dependent cell proliferation or death in primary porcine aortic endothelial cells. Low concentrations caused cell proliferation and were associated with increased superoxide and H(2)O(2) accumulation, cSrc activity, H(2)O(2)-dependent tyrosine phosphorylation, and NF-kappaB-dependent transcription. These concentrations were insufficient to activate MAP kinases. However, the MAP kinases, extracellular signal-regulated kinase and p38, were activated in response to levels of arsenite that caused cell death. These data suggest that arsenite-induced oxidant accumulation and subsequent activation of tyrosine phosphorylation represent a MAPK-independent pathway for phenotypic change and proliferation in vascular cells.

An elongated endothelial cell phenotype, which demonstrated increased ICAM-1-dependent neutrophil adherence, was induced when these cells were exposed to noncytotoxic concentrations of asbestos (Treadwell et al., Toxicol. Appl. Pharmacol. 139, 62-70, 1996). The present study examined mechanisms underlying this phenotypic change by investigating the effects of asbestos on transcription factor activation and expression of urokinase-type plasminogen activator (uPA) and its receptor uPAR. In situ zymography was used to compare the effects of these fibers on the activity of uPA. Cultures incubated with chrysotile or crocidolite asbestos, but not refractory ceramic fiber 1 (RCF-1), demonstrate localized cleavage of plasminogen, which was inhibited by amiloride. Immunocytochemistry showed that chrysotile-stimulated uPA activity was associated with a time-dependent augmentation of uPAR protein levels. RT-PCR analysis was used to investigate molecular mechanisms for these increases. Chrysotile asbestos, but not RCF-1, increased endothelial cell uPA message, relative to changes in beta-actin mRNA. This response to asbestos was not limited to endothelial cells, since both uPA and uPAR mRNA levels increase in human bronchial epithelial BEAS-2B cells exposed to chrysotile fibers. Finally, both types of asbestos, but not RCF-1, increased nuclear levels of nuclear factor-kappaB (NF-kappa B), a transcription factor common to increased expression of ICAM-1 and uPA. These data demonstrate that asbestos caused fiber-specific activation of endothelial and pulmonary epithelial cells, resulting in phenotypes capable of facilitating tissue remodeling.

Phosphorylation of the carboxyl terminus of pp60c-src, the product of the c-src protooncogene, at Tyr-527 suppresses its tyrosine kinase activity and transforming potential. It has been proposed that the phosphorylated carboxyl terminus of pp60c-src inhibits kinase activity by binding to the SH2 (src homology 2) domain. We have synthesized peptides corresponding to the carboxyl-terminal 13 residues of pp60c-src phosphorylated and nonphosphorylated at Tyr-527. A highly transforming mutant, pp60c-src(F527), in which Tyr-527 is mutated to Phe, bound to the phosphorylated peptide immobilized to Affi-Gel 10. Binding of the phosphorylated peptide was abolished by deletion of residues 144-175 in the SH2 domain but not by deletion of residues 93-143, which removes most of the SH3 domain. The phosphorylated peptide also bound to pp60v-src, the transforming protein of Rous sarcoma virus. Only traces of pp60v-src and pp60c-src(F527) bound to the corresponding nonphosphorylated c-src peptide. Normal pp60c-src bound much less efficiently to the phosphorylated peptide than did pp60c-src(F527). A phosphorylated peptide corresponding to the carboxyl terminus of the c-fgr protein also bound to pp60c-src(F527), but with weaker affinity. Furthermore, the phosphorylated synthetic carboxyl-terminal pp60c-src peptide markedly inhibited phosphorylation of pp60c-src(F527) during cytoskeletal kinase assays. These results provide direct evidence for models in which the phosphorylated carboxyl terminus of pp60c-src binds intramolecularly or intermolecularly to the SH2 domain of the c-src protein.

HRTS II has been used to observe the EUV emission of a small bipolar magnetic feature or ephemeral region, where strong EUV line enhancement exhibits contrasts (measured relative to the quiet sun) which range from 10 to 70. The substantiality of the Lyman-alpha and C II-O V emission, and the absence of any measurable emission in coronal forbidden lines, sets a temperature range for the loop's active part of the order of 16,000-300,000 K. The use of the ratios of allowed lines as temperature diagnostics yields temperatures that are very near ionization equilibrium temperatures, and the use of chromospheric lines to form a wavelength standard yields absolute velocities ranging in magnitude from zero to 12 km/sec for C IV, N IV, and O V. This flow is interpreted as a siphon flow.

The Boltzmann-Fokker-Planck equation is solved with the Chapman-Enskog method of analysis for the velocity distribution functions of helium, carbon, nitrogen, and oxygen. The analysis is a perturbation scheme based on the assumption of a collision-dominated gas, and the calculations are carried out to first order. The elements considered are treated as trace constituents in an electron-proton gas. From the resulting distribution functions, diffusion coefficients are computed which are found to be 20-30% less than those obtained by Chapman and Burgers. In addition, it is shown that the return current of cold electrons needed to maintain quasi-neutrality in a plasma with a temperature gradient contributes a term in the thermal diffusion coefficient omitted erroneously in previous works. This added term resolves the longstanding controversy over the discrepancy between the coefficients of Chapman and Burgers, which are seen to be completely equivalent in the light of this analysis. The viscosity coefficient for an electron-proton gas is also computed and found to be 7% less than that obtained by Braginskii.