1,112 research outputs found

    Computational reconstitution of spine calcium transients from individual proteins

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    We have built a stochastic model in the program MCell that simulates Ca^(2+) transients in spines from the principal molecular components believed to control Ca^(2+) entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 × 6 × 5 μm^3 cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca^(2+) channels, Na^+/Ca^(2+) exchangers, plasma membrane Ca^(2+) ATPases, smooth endoplasmic reticulum Ca^(2+) ATPases, immobile Ca2+ buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re-adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca^(2+) transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca^(2+) transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca^(2+) influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca^(2+) influx

    Treatment of Fibromyalgia with Formula Acupuncture: Investigation of Needle Placement, Needle Stimulation, and Treatment Frequency

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    Objectives: The objective of this study was to investigate whether typical acupuncture methods such as needle placement, needle stimulation, and treatment frequency were important factors in fibromyalgia symptom improvement. Design/settings/subjects: A single-site, single-blind, randomized trial of 114 participants diagnosed with fibromyalgia for at least 1 year was performed. Intervention: Participants were randomized to one of four treatment groups: (1) T/S needles placed in traditional sites with manual needle stimulation (n = 29): (2) T/0 traditional needle location without stimulation (n = 30); (3) N/S needles inserted in nontraditional locations that were not thought to be acupuncture sites, with stimulation (n = 28); and (4) N/0 nontraditional needle location without stimulation (n = 2 7). All groups received treatment once weekly, followed by twice weekly, and finally three times weekly, for a total of 18 treatments. Each increase in frequency was separated by a 2-week washout period. Outcome measures: Pain was assessed by a numerical rating scale, fatigue by the Multi-dimensional Fatigue Inventory, and physical function by the Short Form–36. Results: Overall pain improvement was noted with 25%–35% of subjects having a clinically significant decrease in pain; however this was not dependent upon "correct" needle stimulation (t = 1.03; p = 0.307) or location (t = 0.76; p = 0.450). An overall dose effect of treatment was observed, with three sessions weekly providing more analgesia than sessions once weekly (t = 2.10; p = 0.039). Among treatment responders, improvements in pain, fatigue, and physical function were highly codependent (all p ≤ 0.002). Conclusions: Although needle insertion led to analgesia and improvement in other somatic symptoms, correct needle location and stimulation were not crucial.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63411/1/acm.2005.11.663.pd

    Transverse Wave Propagation in Relativistic Two-fluid Plasmas in de Sitter Space

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    We investigate transverse electromagnetic waves propagating in a plasma in the de Sitter space. Using the 3+1 formalism we derive the relativistic two-fluid equations to take account of the effects due to the horizon and describe the set of simultaneous linear equations for the perturbations. We use a local approximation to investigate the one-dimensional radial propagation of Alfv\'en and high frequency electromagnetic waves and solve the dispersion relation for these waves numerically.Comment: 19 pages, 12 figure

    Current-voltage characteristics of diluted Josephson-junction arrays: scaling behavior at current and percolation threshold

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    Dynamical simulations and scaling arguments are used to study the current-voltage (IV) characteristics of a two-dimensional model of resistively shunted Josephson-junction arrays in presence of percolative disorder, at zero external field. Two different limits of the Josephson-coupling concentration pp are considered, where pcp_c is the percolation threshold. For pp >> pcp_c and zero temperature, the IV curves show power-law behavior above a disorder dependent critical current. The power-law behavior and critical exponents are consistent with a simple scaling analysis. At pcp_c and finite temperature TT, the results show the scaling behavior of a T=0 superconducting transition. The resistance is linear but vanishes for decreasing TT with an apparent exponential behavior. Crossover to non-linearity appears at currents proportional to % T^{1+\nu_T}, with a thermal-correlation length exponent νT\nu_T consistent with the corresponding value for the diluted XY model at pcp_c.Comment: Revtex, 9 postscript pages, to appear in Phys. Rev.

    Phase-coherence threshold and vortex-glass state in diluted Josephson-junction arrays in a magnetic field

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    We study numerically the interplay of phase coherence and vortex-glass state in two-dimensional Josephson-junction arrays with average rational values of flux quantum per plaquette ff and random dilution of junctions. For f=1/2f=1/2, we find evidence of a phase coherence threshold value xsx_s, below the percolation concentration of diluted junctions xpx_p, where the superconducting transition vanishes. For xs<x<xpx_s < x < x_p the array behaves as a zero-temperature vortex glass with nonzero linear resistance at finite temperatures. The zero-temperature critical currents are insensitive to variations in ff in the vortex glass region while they are strongly ff dependent in the phase coherent region.Comment: 6 pages, 4 figures, to appear in Phys. Rev.

    Vitamin D and subsequent all-age and premature mortality: a systematic review

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    &lt;br&gt;Background: All-cause mortality in the population &#60; 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.&lt;/br&gt; &lt;br&gt;Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.&lt;/br&gt; &lt;br&gt;Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).&lt;/br&gt; &lt;br&gt;Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.&lt;/br&gt

    Quantum kinetics and thermalization in an exactly solvable model

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    We study the dynamics of relaxation and thermalization in an exactly solvable model with the goal of understanding the effects of off-shell processes. The focus is to compare the exact evolution of the distribution function with different approximations to the relaxational dynamics: Boltzmann, non-Markovian and Markovian quantum kinetics. The time evolution of the distribution function is evaluated exactly using two methods: time evolution of an initially prepared density matrix and by solving the Heisenberg equations of motion. There are two different cases that are studied in detail: i) no stable particle states below threshold of the bath and a quasiparticle resonance above it and ii) a stable discrete exact `particle' state below threshold. For the case of quasiparticles in the continuum (resonances) the exact quasiparticle distribution asymptotically tends to a statistical equilibrium distribution that differs from a simple Bose-Einstein form as a result of off-shell processes. In the case ii), the distribution of particles does not thermalize with the bath. We study the kinetics of thermalization and relaxation by deriving a non-Markovian quantum kinetic equation which resums the perturbative series and includes off-shell effects. A Markovian approximation that includes off-shell contributions and the usual Boltzmann equation are obtained from the quantum kinetic equation in the limit of wide separation of time scales upon different coarse-graining assumptions. The relaxational dynamics predicted by the non-Markovian, Markovian and Boltzmann approximations are compared to the exact result of the model. The Boltzmann approach is seen to fail in the case of wide resonances and when threshold and renormalization effects are important.Comment: 49 pages, LaTex, 17 figures (16 eps figures

    Fluctuations of elastic interfaces in fluids: Theory and simulation

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    We study the dynamics of elastic interfaces-membranes-immersed in thermally excited fluids. The work contains three components: the development of a numerical method, a purely theoretical approach, and numerical simulation. In developing a numerical method, we first discuss the dynamical coupling between the interface and the surrounding fluids. An argument is then presented that generalizes the single-relaxation time lattice-Boltzmann method for the simulation of hydrodynamic interfaces to include the elastic properties of the boundary. The implementation of the new method is outlined and it is tested by simulating the static behavior of spherical bubbles and the dynamics of bending waves. By means of the fluctuation-dissipation theorem we recover analytically the equilibrium frequency power spectrum of thermally fluctuating membranes and the correlation function of the excitations. Also, the non-equilibrium scaling properties of the membrane roughening are deduced, leading us to formulate a scaling law describing the interface growth, W^2(L,T)=L^3 g[t/L^(5/2)], where W, L and T are the width of the interface, the linear size of the system and the temperature respectively, and g is a scaling function. Finally, the phenomenology of thermally fluctuating membranes is simulated and the frequency power spectrum is recovered, confirming the decay of the correlation function of the fluctuations. As a further numerical study of fluctuating elastic interfaces, the non-equilibrium regime is reproduced by initializing the system as an interface immersed in thermally pre-excited fluids.Comment: 15 pages, 11 figure

    Microevolution of Helicobacter pylori during prolonged infection of single hosts and within families

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    Our understanding of basic evolutionary processes in bacteria is still very limited. For example, multiple recent dating estimates are based on a universal inter-species molecular clock rate, but that rate was calibrated using estimates of geological dates that are no longer accepted. We therefore estimated the short-term rates of mutation and recombination in Helicobacter pylori by sequencing an average of 39,300 bp in 78 gene fragments from 97 isolates. These isolates included 34 pairs of sequential samples, which were sampled at intervals of 0.25 to 10.2 years. They also included single isolates from 29 individuals (average age: 45 years) from 10 families. The accumulation of sequence diversity increased with time of separation in a clock-like manner in the sequential isolates. We used Approximate Bayesian Computation to estimate the rates of mutation, recombination, mean length of recombination tracts, and average diversity in those tracts. The estimates indicate that the short-term mutation rate is 1.4×10−6 (serial isolates) to 4.5×10−6 (family isolates) per nucleotide per year and that three times as many substitutions are introduced by recombination as by mutation. The long-term mutation rate over millennia is 5–17-fold lower, partly due to the removal of non-synonymous mutations due to purifying selection. Comparisons with the recent literature show that short-term mutation rates vary dramatically in different bacterial species and can span a range of several orders of magnitude
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