Simple Mechanism for the Observed Breakdown of the Nernst-Einstein Relation for Ions in Carbon Nanotubes.

In this Letter, we present a simple mechanism that explains the recent experimental observation of the breakdown of the Nernst-Einstein (NE) relation for an ion moving in a carbon nanotube of subnanometer diameter. We argue that the friction acting on the ion is largely independent of the ion velocity, i.e., dry friction, and demonstrate, based on the Langevin equation for a particle subject to both dry and viscous friction, that the NE relation is violated when dry friction dominates. We predict that the ratio of the diffusion constant to the mobility of the ion is a few orders of magnitude smaller than the value predicted by the NE relation, in quantitative agreement with experiment.

Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft.

At chemical synapses, synaptic vesicles release their acidic contents into the cleft, leading to the expectation that the cleft should acidify. However, fluorescent pH probes targeted to the cleft of conventional glutamatergic synapses in both fruit flies and mice reveal cleft alkalinization rather than acidification. Here, using a reaction-diffusion scheme, we modeled pH dynamics at the Drosophila neuromuscular junction as glutamate, ATP, and protons (H+) were released into the cleft. The model incorporates bicarbonate and phosphate buffering systems as well as plasma membrane calcium-ATPase activity and predicts substantial cleft acidification but only for fractions of a millisecond after neurotransmitter release. Thereafter, the cleft rapidly alkalinizes and remains alkaline for over 100 ms because the plasma membrane calcium-ATPase removes H+ from the cleft in exchange for calcium ions from adjacent pre- and postsynaptic compartments, thus recapitulating the empirical data. The extent of synaptic vesicle loading and time course of exocytosis have little influence on the magnitude of acidification. Phosphate but not bicarbonate buffering is effective at suppressing the magnitude and time course of the acid spike, whereas both buffering systems are effective at suppressing cleft alkalinization. The small volume of the cleft levies a powerful influence on the magnitude of alkalinization and its time course. Structural features that open the cleft to adjacent spaces appear to be essential for alleviating the extent of pH transients accompanying neurotransmission.

Neuronal Glutamatergic Synaptic Clefts Alkalinize Rather Than Acidify during Neurotransmission.

The dogma that the synaptic cleft acidifies during neurotransmission is based on the corelease of neurotransmitters and protons from synaptic vesicles, and is supported by direct data from sensory ribbon-type synapses. However, it is unclear whether acidification occurs at non-ribbon-type synapses. Here we used genetically encoded fluorescent pH indicators to examine cleft pH at conventional neuronal synapses. At the neuromuscular junction of female Drosophila larvae, we observed alkaline spikes of over 1 log unit during fictive locomotion in vivo. Ex vivo, single action potentials evoked alkalinizing pH transients of only ∼0.01 log unit, but these transients summated rapidly during burst firing. A chemical pH indicator targeted to the cleft corroborated these findings. Cleft pH transients were dependent on Ca2+ movement across the postsynaptic membrane, rather than neurotransmitter release per se, a result consistent with cleft alkalinization being driven by the Ca2+/H+ antiporting activity of the plasma membrane Ca2+-ATPase at the postsynaptic membrane. Targeting the pH indicators to the microenvironment of the presynaptic voltage gated Ca2+ channels revealed that alkalinization also occurred within the cleft proper at the active zone and not just within extrasynaptic regions. Application of the pH indicators at the mouse calyx of Held, a mammalian central synapse, similarly revealed cleft alkalinization during burst firing in both males and females. These findings, made at two quite different non-ribbon type synapses, suggest that cleft alkalinization during neurotransmission, rather than acidification, is a generalizable phenomenon across conventional neuronal synapses.SIGNIFICANCE STATEMENT Neurotransmission is highly sensitive to the pH of the extracellular milieu. This is readily evident in the neurological symptoms that accompany systemic acid/base imbalances. Imaging data from sensory ribbon-type synapses show that neurotransmission itself can acidify the synaptic cleft, likely due to the corelease of protons and glutamate. It is not clear whether the same phenomenon occurs at conventional neuronal synapses due to the difficulties in collecting such data. If it does occur, it would provide for an additional layer of activity-dependent modulation of neurotransmission. Our findings of alkalinization, rather than acidification, within the cleft of two different neuronal synapses encourages a reassessment of the scope of activity-dependent pH influences on neurotransmission and short-term synaptic plasticity.

Charge regulation of a surface immersed in an electrolyte solution.

In this paper, we investigate theoretically a model of charge regulation of a single charged planar surface immersed in an aqueous electrolyte solution. Assuming that the adsorbed ions are mobile in the charged plane, we formulate a field theory of charge regulation where the numbers of adsorbed ions can be determined consistently by equating the chemical potentials of the adsorbed ions to that of the ions in the bulk. We analyze the mean-field treatment of the model for electrolyte of arbitrary valences, and then beyond, where correlation effects are systematically taken into account in a loop expansion. In particular, we compute exactly various one-loop quantities, including electrostatic potentials, ion distributions, and chemical potentials, not only for symmetric (1, 1) electrolyte but also for asymmetric (2, 1) electrolyte, and make use of these quantities to address charge regulation at the one-loop level. We find that correlation effects give rise to various phase transitions in the adsorption of ions, and present phase diagrams for (1, 1) and (2, 1) electrolytes, whose distinct behaviors suggest that charge regulation, at the one-loop level, is no longer universal but depends crucially on the valency of the ions.

Solid friction between soft filaments.

Any macroscopic deformation of a filamentous bundle is necessarily accompanied by local sliding and/or stretching of the constituent filaments. Yet the nature of the sliding friction between two aligned filaments interacting through multiple contacts remains largely unexplored. Here, by directly measuring the sliding forces between two bundled F-actin filaments, we show that these frictional forces are unexpectedly large, scale logarithmically with sliding velocity as in solid-like friction, and exhibit complex dependence on the filaments' overlap length. We also show that a reduction of the frictional force by orders of magnitude, associated with a transition from solid-like friction to Stokes's drag, can be induced by coating F-actin with polymeric brushes. Furthermore, we observe similar transitions in filamentous microtubules and bacterial flagella. Our findings demonstrate how altering a filament's elasticity, structure and interactions can be used to engineer interfilament friction and thus tune the properties of fibrous composite materials.

Theory of the force of friction acting on water chains flowing through carbon nanotubes.

A simple model for the friction experienced by the one-dimensional water chains that flow through subnanometer diameter carbon nanotubes is studied. The model is based on a lowest order perturbation theory treatment of the friction experienced by the water chains due to the excitation of phonon and electron excitations in both the nanotube and the water chain, as a result of the motion of the chain. On the basis of this model, we are able to demonstrate how the observed flow velocities of water chains through carbon nanotubes of the order of several centimeters per second can be accounted for. If the hydrogen bonds between the water molecules are broken (as would occur if there were an electric field oscillating with a frequency equal to the resonant frequency of the hydrogen bonds present), it is shown that the friction experienced by the water flowing in the tube can be much smaller.

Pulling a harmonically bound particle subjected to Coulombic friction: A nonequilibrium analysis.

We address the effects of dry friction, which has emerged only recently to play an important role in some biological systems. In particular, we investigate the nonequilibrium dynamics of a mesoscopic particle, bound to a spring being pulled at a definite speed, moving on a surface with dry friction in a noisy environment. We model the dry friction phenomenologically with a term that is proportional to the sign of the velocity, and by means of numerical simulations of a Langevin equation we show that (a) the frictional force scales with the logarithm of the pulling velocity, (b) the probability distribution function of the spatial displacement away from the potential minimum is non-Gaussian, (c) the fluctuation-dissipation theorem is violated as expected, but (d) the work function obeys the stationary fluctuation theorem, with an effective temperature related to the noise of the system.

Enhancement of the ion concentration in a salt solution near a wall due to electrical image potentials and enhancement of surface tension due to the presence of salt.

Effects of electrical image potentials on the salt ion concentration near a solid wall are studied using a one-loop approximation treatment of the grand canonical partition function, which is the Debye-Hückel approximation. Electrical image potentials resulting from both metallic and dielectric walls of dielectric constant larger than that of water near the wall are considered. Our treatment of this problem supports the conclusions of an earlier publication by one of the authors which shows that near a solid wall there should be a high concentration of ions, resulting from image potentials. We have also applied our treatment to the increase of the surface tension of a liquid that occurs when salt is dissolved in the liquid. Our treatment gives the -c_{s}log(c_{s}) dependence of the surface tension found by Onsager and Samarasa in the small c_{s} limit, where c_{s} is the salt concentration.

Fluctuating hydrodynamics and microrheology of a dilute suspension of swimming bacteria.

A bacterial bath is a model active system consisting of a population of rodlike motile or self-propelled bacteria suspended in a fluid environment. This system can be viewed as an active, nonequilibrium version of a lyotropic liquid crystal or as a generalization of a driven diffusive system. We derive a set of phenomenological equations, which include the effects of internal force generators in the bacteria, describing the hydrodynamic flow, orientational dynamics of the bacteria, and fluctuations induced by both thermal and nonthermal noises. These equations violate the fluctuation dissipation theorem and the Onsager reciprocity relations. We use them to provide a quantitative account of results from recent microrheological experiments on bacterial baths.

Fluctuation and correlation effects in a charged surface immersed in an electrolyte solution.

We explore correlation and fluctuation effects in an overall neutral system consisting of a single homogeneously charged planar surface with both the counterions and coions distributed on both sides of the surface. Using a field-theoretic formulation, we compute the one-loop correction to the electrostatic potential, to the ion densities, to the surface tension, and to the surface free energy. From the asymptotic behavior of the electrostatic potential, we obtain an exact expression for the effective surface charge density, which can become negative, indicating charge inversion. Furthermore, we find that the ion distributions can be substantially different from the mean-field ion densities. In particular, the counterion density, at high couplings, develops a minimum at some intermediate distances, larger than the Gouy-Chapman length, away from the charged surface, whereas the coion density develops a maximum, whose values can be greater than the counterion density. Therefore, the coions develop a second layer. Moreover, the one-loop correction always lowers the electrostatic contributions to the surface tension and at high couplings, the surface tension may become negative.

Fluctuation theorem and large deviation function for a solvable model of a molecular motor.

We study a discrete stochastic model of a molecular motor. This discrete model can be viewed as a minimal ratchet model. We extend our previous work on this model, by further investigating the constraints imposed by the fluctuation theorem on the operation of a molecular motor far from equilibrium. In this work, we show the connections between different formulations of the fluctuation theorem. One formulation concerns the generating function of the currents while another one concerns the corresponding large deviation function, which we have calculated exactly for this model. A third formulation concerns the ratio of the probability of observing a velocity v to the same probability of observing a velocity -v . Finally, we show that all the formulations of the fluctuation theorem can be understood from the notion of entropy production.

MDM2 and MDMX bind and stabilize the p53-related protein p73.

The p53 gene encodes one of the most important tumor suppressors in human cells and undergoes frequent mutational inactivation in cancers. MDM2, a transcriptional target of p53, binds p53 and can both inhibit p53-mediated transcription [1] [2] and target p53 for proteasome-mediated proteolysis [3] [4]. A close relative of p53, p73, has recently been identified [5] [6]. Here, we report that, like p53, p73alpha and the alternative transcription product p73beta also bind MDM2. Interaction between MDM2 and p53 represents a key step in the regulation of p53, as MDM2 promotes the degradation of p53. In striking contrast to p53, the half-life of p73 was found to be increased by binding to MDM2. Like MDM2, the MDM2-related protein MDMX also bound p73 and stabilized the level of p73. Moreover, the growth suppression functions of p73 and the induction of endogenous p21, a major mediator of the p53-dependent growth arrest pathway, were enhanced in the presence of MDM2. These differences between the regulation of p53 and p73 by MDM2/MDMX may highlight a physiological difference in their action.

Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2.

Cyclin A-Cdk2 complexes bind to Skp1 and Skp2 during S phase, but the function of Skp1 and Skp2 is unclear. Skp1, together with F-box proteins like Skp2, are part of ubiquitin-ligase E3 complexes that target many cell cycle regulators for ubiquitination-mediated proteolysis. In this study, we investigated the potential regulation of cyclin A-Cdk2 activity by Skp1 and Skp2. We found that Skp2 can inhibit the kinase activity of cyclin A-Cdk2 in vitro, both by direct inhibition of cyclin A-Cdk2 and by inhibition of the activation of Cdk2 by cyclin-dependent kinase (CDK)-activating kinase phosphorylation. Only the kinase activity of Cdk2, not of that of Cdc2 or Cdk5, is reduced by Skp2. Skp2 is phosphorylated by cyclin A-Cdk2 on residue Ser76, but nonphosphorylatable mutants of Skp2 can still inhibit the kinase activity of cyclin A-Cdk2 toward histone H1. The F box of Skp2 is required for binding to Skp1, and both the N-terminal and C-terminal regions of Skp2 are involved in binding to cyclin A-Cdk2. Furthermore, Skp2 and the CDK inhibitor p21(Cip1/WAF1) bind to cyclin A-Cdk2 in a mutually exclusive manner. Overexpression of Skp2, but not Skp1, in mammalian cells causes a G1/S cell cycle arrest.

State-dependent diffusion: Thermodynamic consistency and its path integral formulation.

The friction coefficient of a particle can depend on its position, as it does when the particle is near a wall. We formulate the dynamics of particles with such state-dependent friction coefficients in terms of a general Langevin equation with multiplicative noise, whose evaluation requires the introduction of specific rules. Two common conventions, the Ito and the Stratonovich, provide alternative rules for evaluation of the noise, but other conventions are possible. We show that the requirement that a particle's distribution function approach the Boltzmann distribution at long times dictates that a drift term must be added to the Langevin equation. This drift term is proportional to the derivative of the diffusion coefficient times a factor that depends on the convention used to define the multiplicative noise. We explore the consequences of this result in a number of examples with spatially varying diffusion coefficients. We also derive a path integral representation for arbitrary interpretation of the noise, and use it in a perturbative study of correlations in a simple system.

A possible role of p73 on the modulation of p53 level through MDM2.

MDM2, one of the transcriptional targets of p53, can target p53 for degradation in a negative feedback loop. The p53-related protein p73, however, can bind to MDM2 but is not consequently down-regulated. Here we demonstrate that p73 could transactivate the MDM2 promoter in p53-null cell lines. In p53-null cell lines, the level of MDM2 was increased by p73 due to increases in transcription and protein stability of MDM2. In transient transfection assays, inhibition of the transcriptional activity of p73 required a higher amount of MDM2 than that of p53. This is probably due to the fact that MDM2 can target p53, but not p73, for degradation. We demonstrated further that the level of p53 could be altered by a cooperation between MDM2 and p73, but not by transcriptional inactive mutants of p73. Expression of p73 resulted in a reduction of the ectopically expressed p53 in transient transfections or of the endogenous p53 induced by Adriamycin- or UV-mediated damage. These reductions of p53 were likely to be due to an increase in MDM2-mediated proteolysis. These results suggest the possibility that different levels of p73 in the cell may act as a mechanism to modulate p53 responses after DNA damage and other stresses and that an increase rather than a decrease in p73 may play a role in tumorigenesis.

Characterization of the cullin and F-box protein partner Skp1.

Skp1 interacts with cullins, F-box containing proteins, and forms a complex with cyclin A-Cdk2 in mammalian cells. Skp1 is also involved in diverse biological processes like degradation of key cell cycle regulators, glucose sensing, and kinetochore function. However, little is known about the structure and exact function of Skp1. Here we characterized the interaction between Skp1 and the F-box protein Skp2. We show that Skp1 can bind to Skp2 in vitro using recombinant proteins, and in vivo using the yeast two-hybrid system. Deletion analysis of Skp1 indicated that most of the Skp1 protein is required for binding to Skp2. In mammalian cell extracts, a large portion of Skp1 appears to associate with proteins other than Skp2. Biochemical analysis indicated that Skp1 is likely to be a flexible, non-spherical protein, and is capable of forming dimers.

Psychophysiological arousal in older adults: a critical review.

In spite of the relatively high prevalence rates of anxiety disorders (AD) and related symptoms, very little is known about the experience, presentation, and assessment of anxiety in later life. Because the physiology of the autonomic nervous system changes with age, an enhanced understanding of how these developmental changes affect the somatic-physiological response patterns to anxiety-evoking stimuli among older adults may help explain whether we can generalize current assessment and treatment practices and procedures for AD from younger to older adults. In this paper, we describe and critically evaluate studies that have employed psychophysiological recording of autonomic arousal to anxiety-arousing or stressful stimuli among samples of younger and older adults. The conclusions one can draw from the review are quite limited by both the paucity of relevant literature and the methodological limitations of the published studies.

Counterion condensation and fluctuation-induced attraction.

We consider an overall neutral system consisting of two similarly charged plates and their oppositely charged counterions and analyze the electrostatic interaction between the two surfaces beyond the mean-field Poisson-Boltzmann approximation. Our physical picture is based on the fluctuation-driven counterion condensation model, in which a fraction of the counterions is allowed to "condense" onto the charged plates. In addition, an expression for the pressure is derived, which includes fluctuation contributions of the whole system. We find that for sufficiently high surface charges, the distance at which the attraction, arising from charge fluctuations, starts to dominate can be large compared to the Gouy-Chapmann length. We also demonstrate that depending on the valency, the system may exhibit a first-order binding transition at short distances.

Entropic interactions in suspensions of semiflexible rods: short-range effects of flexibility.

We compute the entropic interactions between two colloidal spheres immersed in a dilute suspension of semiflexible rods. Our model treats the semiflexible rod as a bent rod at fixed angle, set by the rod contour and persistence lengths. The entropic forces arising from this additional rotational degree of freedom are captured quantitatively by the model, and account for observations at short range in a recent experiment. Global fits to the interaction potential data suggest the persistence length of the fd virus is about two to three times smaller than the commonly used value of 2.2 microm.

Electrostatic attraction of coupled Wigner crystals: finite temperature effects.

In this paper we present a unified physical picture for the electrostatic attraction between two coupled planar Wigner crystals at finite temperature. This model may facilitate our conceptual understanding of counterion-mediated attractions between (highly) similarly charged planes. By adopting an elastic theory, we show that the total attractive force between them can be (approximately) decomposed into a short-ranged and a long-ranged component. They are evaluated below the melting temperature of the Wigner crystals. In particular, we analyze the temperature dependence of the short-ranged attraction, arising from ground-state configuration, and we argue that thermal fluctuations may drastically reduce its strength. Also, the long-range force agrees exactly with that based on the charge-fluctuation approach. Furthermore, we take quantum contributions to the long-ranged (fluctuation-induced) attraction into account and show how the fractional power law, which scales as d(-7/2) for large interplanar distance d at zero temperature, crosses over to the classical regime d(-3) via an intermediate regime of d(-2).