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Limitations on length scales for electrostatically induced submicrometer pillars and holes.

Thin leaky and perfect dielectric films can be driven electrically to form well-ordered patterns, typically of pillar arrays. While the technique appears to promise nanometer scale features, this paper begins to examine some of the limitations. The process, sometimes referred to as lithographically induced self-assembly, begins by spin coating a polymer onto a silicon wafer generating an initially featureless film and then overlaying a mask, which may be patterned, leaving a small gap. This configuration is heated above the glass transition temperature of the polymer, upon which flow ensues with a characteristic wavelength set by a combination of electrical forces and surface tension. The authors recently examined the initial stages of this process under pattern-free masks by deriving a generalized linear stability analysis not restricted to the lubrication approximation (J. Chem. Phys. 2003, 118, 3790). Herein comparison of this model with experimental data from the literature finds good agreement over a wide range of conditions including applied voltages and oxide layers on the mask and substrate. A significant discrepancy at the highest fields may be due to dielectric breakdown, suggesting that the minimum feature size may be limited. Viscous effects may also limit the effectiveness of large decreases in surface tension or large increases in electric field, leading to lower limits for the feature size. Long-range ordering seems to decrease as surface tension decreases and the potential increases, indicating that smaller pillars come with decreased quality. In the absence of an electric field, consideration of the viscosity-dependent time scale suggests an explanation for the apparent conflict between observations by Schäffer et al. (Nature 2000, 403, 874) and those of Chou and Zhuang (J. Vac. Sci. Technol., B 1999, 17, 3197).

Journal Article↗

Stress generation by solvent absorption and wrinkling of a cross-linked coating atop a viscous or elastic base.

An in-plane constrained cross-linked gel layer absorbs an equilibrium amount of solvent and experiences in-plane compressive stress. A stability analysis of such an elastic gel layer that is attached to either a viscous or an elastic bottom layer atop a rigid substrate is considered. The effects of the top and bottom layer moduli (E(t) and E(b)), the bottom-to-top layer thickness ratio (H/h), and the polymer solvent interaction parameter (chi) on the critical condition of wrinkling, wrinkle wavelength, and amplitude are examined. When the bottom layer is viscous, the compressed top layer is always unstable, and wrinkling is rate-controlled. The viscous flow of the bottom layer governs the rate and determines the fastest growing wavelength. As E(t) rises, the bending stiffness of the elastic layer does as well, and so the fastest growing wavelength (lambda(m)) rises and the equilibrium amplitude (A(e)) falls. As H/h rises, the constraint of the rigid substrate diminishes, and so lambda(m) and A(e) rise. As chi falls or as the solvent has higher affinity for the polymeric gel, lambda(m) falls and A(e) rises because better solvents create higher compressive strain that promote low-wavelength, high-amplitude wrinkles. When the bottom layer is elastic, a critical compressive stress exists. If the generated compressive stress by solvent absorption is greater than the critical stress, the top layer wrinkles. It was found that wrinkling is most likely at intermediate E(t), low E(b), high H/h, and low chi. Further, lower chi, higher H/h, and lower E(b) were found to promote higher equilibrium amplitude and higher wavelength wrinkles.

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Bootstrap investigation of the stability of disease mapping of Bayesian cancer relative risk estimations.

BACKGROUND: Bayesian approaches to disease mapping of relative risks are useful for rare disease when geographical units have very different population sizes. As Bayesian approaches may induce very different estimations, it is useful to consider the stability of the estimations as a criterion for evaluating the quality of the results. MATERIAL: Cancer incidence data, from the Isere cancer registry (France) over the 1985-1994 period, have been used to check the proposed method: the study is based on 22 cancer sites among males and 24 among females. METHOD: A bootstrap approach has been retained to evaluate the stability of the estimations. The coefficient of variation was chosen as an indicator of stability. Three Bayesian models corresponding to global, local and combined smoothing techniques, have been considered. The stability analysis has taken account of the results of spatial autocorrelation and heterogeneity tests. RESULTS: Bayesian approaches do not necessarily lead to stable estimations. The local smoothing approach induces estimations that are often unstable. The global smoothing approach is the most stable, but is conservative. Combined smoothing appears to be a good compromise if significant spatial variations and heterogeneity of relative risks exist. CONCLUSION: Bayesian estimations of relative risks may be very unstable. However, when results of spatial autocorrelation and heterogeneity tests are taken into account to choose between the different Bayesian approaches, instability becomes negligible.

Algorithms↗

Rapid changes of glacial climate simulated in a coupled climate model.

Abrupt changes in climate, termed Dansgaard-Oeschger and Heinrich events, have punctuated the last glacial period (approximately 100-10 kyr ago) but not the Holocene (the past 10 kyr). Here we use an intermediate-complexity climate model to investigate the stability of glacial climate, and we find that only one mode of Atlantic Ocean circulation is stable: a cold mode with deep water formation in the Atlantic Ocean south of Iceland. However, a 'warm' circulation mode similar to the present-day Atlantic Ocean is only marginally unstable, and temporary transitions to this warm mode can easily be triggered. This leads to abrupt warm events in the model which share many characteristics of the observed Dansgaard-Oeschger events. For a large freshwater input (such as a large release of icebergs), the model's deep water formation is temporarily switched off, causing no strong cooling in Greenland but warming in Antarctica, as is observed for Heinrich events. Our stability analysis provides an explanation why glacial climate is much more variable than Holocene climate.

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Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia.

Carotid body type I cells and the O2 sensitive pheochromocytoma (PC12) cells release dopamine during hypoxia. Reduced O2 tension causes inhibition of an outward rectifying the O2-sensitive potassium (K) channel in the O2-sensitive pheochromocytoma (PC12) cell line, which leads to membrane depolarization and increased intracellular free Ca2+. We found that removal of Ca2+ from the extracellular milieu, inhibition of voltage-dependent Ca2+ channels, and chelation of intracellular Ca2+ prevents full activation of the TH gene expression during hypoxia. These findings suggest that membrane depolarization and regulation of intracellular free Ca2+ are critical signal transduction events that regulate expression of the TH gene in PC12 cells during hypoxia. Gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of dopamine, is stimulated by reduced O2 tension in both type I cells and PC12 cells. The increase in TH gene expression in PC12 cells during hypoxia is due to increases in both the rate of transcription and mRNA stability. Analysis of reporter-gene constructs revealed that increased transcription of the TH gene during hypoxia is regulated by a region of the proximal promoter that extends from -284 to -150 bases, relative to the transcription start site. This region of the gene contains a number of cis-acting regulatory elements including AP1, AP2 and hypoxia-inducible factor (HIF-1). Competition assays revealed that hypoxia-induced binding occurs at both the AP1 and HIF-1 sites. Results from super-shift and shift Western assays showed that a heterodimer consisting of c-Fos and JunB binds to the AP1 site during hypoxia. Mutagenesis experiments revealed that the AP1 site is required for increased transcription of the TH gene during hypoxia. We also found that the genes that encode the c-Fos and JunB transcription factor proteins are regulated by reduced O2 tension.

Animals↗

An economic model of haemophilia in Mexico.

A model was developed to assess the lifetime costs and outcomes associated with haemophilia in Mexico. A retrospective chart review of 182 type A haemophiliacs was conducted for patients aged 0-34 years receiving one of three treatments: (i) cryoprecipitate at clinic; (ii) concentrate at home; or (iii) concentrate at clinic. Patients treated at home experienced 30% less joint damage, used 13-54% less factor VIII, had four times fewer clinic visits, and utilized half as many hospital days than those treated at a clinic. For cryoprecipitate at clinic patients, the annual incidence rates of HCV and HIV were calculated to be 3.6% and 1.4% respectively. The life expectancy for patients receiving cryoprecipitate and those receiving concentrate was estimated to be 49 years and 69 years respectively, with 58% of cryoprecipitate patients predicted to die of AIDS before age 69. Across the lifespan, the average annual cost of care was US$11,677 (MN$110,464) for cryoprecipitate at clinic patients, US$10,104 (M$95,580) for concentrate at home patients and US$18,819 (MN$178,027) for concentrate at clinic patients. Using a 5% discount rate, the incremental lifetime cost per year of life added for treatment with concentrate at home compared with cryoprecipitate at a clinic was US$738 (MN$6981). Rank order stability analysis demonstrated that the model was most sensitive to the cost of fVIII. These results indicate that treatment with concentrate at home compared with cryoprecipitate at a clinic substantially improves clinical outcomes at reduced annual cost levels.

Adolescent↗

The TolQ-TolR proteins energize TolA and share homologies with the flagellar motor proteins MotA-MotB.

The Tol-Pal system of Escherichia coli is required for the maintenance of outer membrane stability. Recently, proton motive force (pmf) has been found to be necessary for the co-precipitation of the outer membrane lipoprotein Pal with the inner membrane TolA protein, indicating that the Tol-Pal system forms a transmembrane link in which TolA is energized. In this study, we show that both TolQ and TolR proteins are essential for the TolA-Pal interaction. A point mutation within the third transmembrane (TM) segment of TolQ was found to affect the TolA-Pal interaction strongly, whereas suppressor mutations within the TM segment of TolR restored this interaction. Modifying the Asp residue within the TM region of TolR indicated that an acidic residue was important for the pmf-dependent interaction of TolA with Pal and outer membrane stabilization. Analysis of sequence alignments of TolQ and TolR homologues from numerous Gram-negative bacterial genomes, together with analyses of the different tolQ-tolR mutants, revealed that the TM domains of TolQ and TolR present structural and functional homologies not only to ExbB and ExbD of the TonB system but also with MotA and MotB of the flagellar motor. The function of these three systems, as ion potential-driven molecular motors, is discussed

Amino Acid Sequence↗

Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81Ser MIF.

Macrophage migration inhibitory factor (MIF) displays both cytokine and enzyme activities, but its molecular mode of action is still unclear. MIF contains three cysteine residues and we showed recently that the conserved Cys57-Ala-Leu-Cys60 (CALC) motif is critical for the oxidoreductase and macrophage-activating activities of MIF. Here we probed further the role of this catalytic centre by expression, purification, and characterization of the cysteine-->serine mutants Cys60Ser, Cys57Ser/Cys60Ser, and Cys81Ser of human MIF and of mutants Ala58Gly/Leu59Pro and Ala58Gly/Leu59His, containing a thioredoxin (Trx)-like and protein disulphide isomerase (PDI)-like dipeptide, respectively. The catalytic centre mutants formed inclusion bodies and the resultant mutant proteins Cys57Ser/Cys60Ser, Ala58Gly/Leu59Pro, and Als58Gly/Leu59His were only soluble in organic solvent or 6 m GdmHCl when reconstituted at concentrations above 1 microgram.mL-1. This made it necessary to devise new purification methods. By contrast, mutant Cys81Ser was soluble. Effects of pH, solvent, and ionic strength conditions on the conformation of the mutants were analysed by far-UV CD spectropolarimetry and mutant stability was examined by denaturant-induced unfolding. The mutants, except for mutant Cys81Ser, showed a close conformational similarity to wild-type (wt) MIF, and stabilization of the mutants was due mainly to acid pH conditions. Intramolecular disulphide bond formation at the CALC region was confirmed by near-UV CD of mutant Cys60Ser. Mutant Cys81Ser was not involved in disulphide bond formation, yet had decreased stability. Analysis in the oxidoreductase and a MIF-specific cytokine assay revealed that only substitution of the active site residues led to inactivation of MIF. Mutant Cys60Ser had no enzyme and markedly reduced cytokine activity, whereas mutant Cys81Ser was active in both tests. The Trx-like variant showed significant enzyme activity but was less active than wtMIF; PDI-like MIF was enzymatically inactive. However, both variants had full cytokine activity. Together with the low but nonzero cytokine activity of mutant Cys60Ser, this indicated that the cytokine activity of MIF may not be tightly regulated by redox effects or that a distinguishable receptor mechanism exists. This study provides evidence for a role of the CALC motif in the oxidoreductase and cytokine activities of MIF, and suggests that Cys81 could mediate conformational effects. Availability and characterization of the mutants should greatly aid in the further elucidation of the mechanism of action of the unusual cytokine MIF.

Base Sequence↗

Stability and velocity in incomplete spinal cord injured subject gaits.

We have defined 2 indices describing gait kinematic and dynamic stability. We assessed their values in the gaits of 5 different paraparetic subjects. The indices are correlated to the gait velocity to prove the close relationship between overall gate velocity and stability. Based on stability analysis and certain kinematic parameters, some possible ways of increasing the average gait velocity are explained.

Algorithms↗

The effect of reactor geometry on frontal polymerization spin modes.

Using reactors of different sizes and geometries the dynamics of the frontal polymerization of 1,6-hexanediol diacrylate (HDDA) and pentaerythritol tetraacrylate (PETAC), with ammonium persulfate as the initiator were studied. For this system, the frontal polymerization exhibits complex behavior that depends on the ratio of the monomers. For a particular range of monomers concentration, the polymerization front becomes nonplanar, and spin modes appear. By varying the reactor diameter, we experimentally confirmed the expected shift of the system to a greater number of "hot spots" for larger diameters. For square test tubes a "zig-zag" mode was observed for the first time in frontal polymerization. We confirmed the viscosity-dependence of the spin mode instabilities. We also observed novel modes in cylinder-inside-cylinder reactors. Lastly, using a conical reactor with a continuously varying diameter, we observed what may be evidence for bistability depending on the direction of propagation. We discuss these finding in terms of the standard linear stability analysis for propagating fronts. (c) 2002 American Institute of Physics.

Journal Article↗

Lagrangian averages, averaged Lagrangians, and the mean effects of fluctuations in fluid dynamics.

We begin by placing the generalized Lagrangian mean (GLM) equations for a compressible adiabatic fluid into the Euler-Poincare (EP) variational framework of fluid dynamics, for an averaged Lagrangian. This is the Lagrangian averaged Euler-Poincare (LAEP) theorem. Next, we derive a set of approximate small amplitude GLM equations (glm equations) at second order in the fluctuating displacement of a Lagrangian trajectory from its mean position. These equations express the linear and nonlinear back-reaction effects on the Eulerian mean fluid quantities by the fluctuating displacements of the Lagrangian trajectories in terms of their Eulerian second moments. The derivation of the glm equations uses the linearized relations between Eulerian and Lagrangian fluctuations, in the tradition of Lagrangian stability analysis for fluids. The glm derivation also uses the method of averaged Lagrangians, in the tradition of wave, mean flow interaction. Next, the new glm EP motion equations for incompressible ideal fluids are compared with the Euler-alpha turbulence closure equations. An alpha model is a GLM (or glm) fluid theory with a Taylor hypothesis closure. Such closures are based on the linearized fluctuation relations that determine the dynamics of the Lagrangian statistical quantities in the Euler-alpha equations. Thus, by using the LAEP theorem, we bridge between the GLM equations and the Euler-alpha closure equations, through the small-amplitude glm approximation in the EP variational framework. We conclude by highlighting a new application of the GLM, glm, and alpha-model results for Lagrangian averaged ideal magnetohydrodynamics. (c) 2002 American Institute of Physics.

Journal Article↗

Spatiotemporal control of cardiac alternans.

Electrical alternans are believed to be linked to the onset of life-threatening ventricular arrhythmias and sudden cardiac death. Recent studies have shown that alternans can be suppressed temporally by dynamic feedback control of the pacing interval. Here we investigate theoretically whether control can suppress alternans both temporally and spatially in homogeneous tissue paced at a single site. We first carry out ionic model simulations in a one-dimensional cable geometry which show that control is only effective up to a maximum cable length that decreases sharply away from the alternans bifurcation point. We then explain this finding by a linear stability analysis of an amplitude equation that describes the spatiotemporal evolution of alternans. This analysis reveals that control failure above a critical cable length is caused by the formation of standing wave patterns of alternans that are eigenfunctions of a forced Helmholtz equation, and therefore remarkably analogous to sound harmonics in an open pipe. We discuss the implications of these results for using control to suppress alternans in the human ventricles as well as to probe fundamental aspects of alternans morphogenesis. (c) 2002 American Institute of Physics.

Journal Article↗

Discrete breathers in classical ferromagnetic lattices with easy-plane anisotropy.

Discrete breathers (nonlinear localized modes) have been shown to exist in various nonlinear Hamiltonian lattice systems. This paper is devoted to the investigation of a classical d-dimensional ferromagnetic lattice with easy plane anisotropy. Its dynamics is described via the Heisenberg model. Discrete breathers exist in such a model and represent excitations with locally tilted magnetization. They possess energy thresholds and have no analogs in the continuum limit. We are going to review the previous results on such solutions and also to report new results. Among the new results we show the existence of a big variety of these breather solutions, depending on the respective orientation of the tilted spins. Floquet stability analysis has been used to classify the stable solutions depending on their spatial structure, their frequency, and other system parameters, such as exchange interaction and local (single-ion) anisotropy.

Journal Article↗

Energy conversion by autonomous regulation of chaos: dynamical mechanism of loose coupling.

Inspired by recent experiments of molecular motors, a dynamical systems model for a flexible machine is proposed which converts injected energy to output directional motion. The output amount is distributed broadly, and thus the coupling between input energy and output motion is loose, as in the experiments. This energy conversion is shown to be robust against the change of surrounding environment. Stability analysis on the fixed point solutions of the model is presented, which suggests that transient chaotic motion, induced by temporal three-body motion, is relevant to the energy conversion.

Journal Article↗

Asymmetric evolution of eddies in rotating shallow water.

It is demonstrated that cyclones evolve in a way different from that of anticyclones in rotating shallow water. The anticyclones merge and eventually take circular coherent forms, but cyclones are elongated with active enstrophy cascading. This asymmetric evolution is strengthened with increasing surface displacements. When the initial surface displacement exceeds a certain critical value, the initial elongation of a cyclonic ellipse ends up with splitting in two cyclones. This splitting of the cyclonic ellipse is always associated with the first appearance of a saddle point inside the core, due to irrotational, ageostrophic motion. The appearance of the saddle point inside the core seems to be a necessary condition for splitting of the core of the cyclonic ellipse with surface displacements. The linear stability analysis of the elliptical vortex is consistent qualitatively with both of the simulation results and the kinematic axisymmetrization/elongation principle.

Journal Article↗

Pattern formation and competition in photorefractive oscillators.

We introduce a general model of pattern formation in optical systems made of a cavity with an active medium as a photorefractive crystal fed by a pump. The model is based on the interplay of a diffractive equation for the optical field and a diffusive equation for the medium refractivity. The aim of the model is to describe a series of experiments which have shown mode competition (periodic or chaotic alternation) for low Fresnel numbers (F) and mode coexistence, leading to short range space correlations, for high F. For low F, a linear stability analysis provides the set of modes above threshold as a function of the transverse wave number. Due to the interplay of the optical and the diffusive interactions, different behaviors result depending on the thickness of the medium as compared to the optical absorption length and diffusion length. Including the leading nonlinearities compatible with the symmetry constraints, we introduce normal form equations which describe the time-dependent mode competition. In the case of a large number of modes (high F), nonlinear mode-mode interaction is equivalent to a self-induced noise. In this limit, the relevant feature to be compared with the experiment is the power spectrum.

Journal Article↗

A two-parameter study of the extent of chaos in a billiard system.

The billiard system of Benettin and Strelcyn [Phys. Rev. A 17, 773-785 (1978)] is generalized to a two-parameter family of different shapes. Its boundaries are composed of circular segments. The family includes the integrable limit of a circular boundary, convex boundaries of various shapes with mixed dynamics, stadiums, and a variety of nonconvex boundaries, partially with ergodic behavior. The extent of chaos has been measured in two ways: (i) in terms of phase space volume occupied by the main chaotic band; and (ii) in terms of the Lyapunov exponent of that same region. The results are represented as a kind of phase diagram of chaos. We observe complex regularities, related to the bifurcation scheme of the most prominent resonances. A detailed stability analysis of these resonances up to period six explains most of these features. The phenomenon of breathing chaos [Nonlinearity 3, 45-67 (1990)]-that is, the nonmonotonicity of the amount of chaos as a function of the parameters-observed earlier in a one-parameter study of the gravitational wedge billiard, is part of the picture, giving support to the conjecture that this is a fairly common global scenario. (c) 1996 American Institute of Physics.

Journal Article↗

Single-head spin modes in frontal polymerization.

The single-head spin mode is the first two-dimensional pattern of self-propagating thermal reaction fronts observed after the planar front loses stability. A "hot spot" is observed to propagate around the periphery of the front. The dynamics of the single-head frontal polymerization regime were studied experimentally, and two novel results were found. The "hot spot" was measured and found to be superadiabatic. The relationship between the rotational velocity and the propagating velocity was found. Experimental data were also compared with the theoretical results based on the linear stability analysis and found to be in a reasonable agreement. (c) 1998 American Institute of Physics.

Journal Article↗