Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

Characterization of Acylated Anthocyanins in Callus Induced From Storage Root of Purple-Fleshed Sweet Potato, Ipomoea batatas L

Four anthocyanins were isolated from a highly pigmented callus induced from the storage root of purple-fleshed sweet potato (Ipomoea batatas L) cultivar Ayamurasaki. The anthocyanins were respectively identified as cyanidin 3-O-(2-O-(6-O-(E)-caffeoyl-β-D-glucopyranosyl)-β-D-glucopyranoside) -5-O-β-D-glucopyranoside, cyanidin 3-O-(2-O-(6-O-(E)-p -coumaroyl-β-D-glucopyranosyl)-6-O-(E)-caffeoyl-β-D-glucopyranoside)-5-O-β-D-glucopyranoside, cyanidin 3-O-(2-O-(6-O-(E)-p -coumaroyl-β-D-glucopyranosyl)-6-O-(E)-p-coumaroyl-β-D-glucopyranoside)- 5-O-β-D-glucopyranoside, and peonidin 3-O-(2-O-(6-O-(E)-p -coumaroyl-β-D-glucopyranosyl)-6-O-(E)-p-coumaroyl-β-D-glucopyranoside)-5-O-β-D-glucopyranoside by chemical and spectroscopic analyses. These anthocyanins were examined with respect to the stability in neutral aqueous solution as well as the radical scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. These acylated anthocyanins exhibited both higher stability and higher DPPH radical scavenging activity than corresponding nonacylated cyanidin and peonidin 3-O-sophoroside-5-O-glucosides

Diffusion-limited loop formation of semiflexible polymers: Kramers theory and the intertwined time scales of chain relaxation and closing

We show that Kramers rate theory gives a straightforward, accurate estimate of the closing time $\tau_c$ of a semiflexible polymer that is valid in cases of physical interest. The calculation also reveals how the time scales of chain relaxation and closing are intertwined, illuminating an apparent conflict between two ways of calculating $\tau_c$ in the flexible limit.Comment: Europhys. Lett., 2003 (in press). 8 pages, 3 figures. See also, physics/0101087 for physicist's approach to and the importance of semiflexible polymer looping, in DNA replicatio

Static Scaling Behavior of High-Molecular-Weight Polymers in Dilute Solution: A Reexamination

Previous theories of dilute polymer solutions have failed to distinguish clearly between two very different ways of taking the long-chain limit: (I) $N \to\infty$ at fixed temperature $T$, and (II) $N \to\infty$, $T \to T_\theta$ with $x \equiv N^\phi (T-T_\theta)$ fixed. I argue that the modern two-parameter theory (continuum Edwards model) applies to case II --- not case I --- and in fact gives exactly the crossover scaling functions for $x \ge 0$ modulo two nonuniversal scale factors. A Wilson-type renormalization group clarifies the connection between crossover scaling functions and continuum field theories. [Also contains a general discussion of the connection between the Wilson and field-theoretic renormalization groups. Comments solicited.]Comment: 10 pages including 1 figure, 181159 bytes Postscript (NYU-TH-93/05/01

On the Limits of Analogy Between Self-Avoidance and Topology-Driven Swelling of Polymer Loops

The work addresses the analogy between trivial knotting and excluded volume in looped polymer chains of moderate length, $N<N_0$, where the effects of knotting are small. A simple expression for the swelling seen in trivially knotted loops is described and shown to agree with simulation data. Contrast between this expression and the well known expression for excluded volume polymers leads to a graphical mapping of excluded volume to trivial knots, which may be useful for understanding where the analogy between the two physical forms is valid. The work also includes description of a new method for the computational generation of polymer loops via conditional probability. Although computationally intensive, this method generates loops without statistical bias, and thus is preferable to other loop generation routines in the region $N<N_0$.Comment: 10 pages, 5 figures, supplementary tex file and datafil

Projectile Fragmentation of the Extremely Neutron-Rich Nucleus ^<11>Li at o.79 GeV/nucleon

Projectile fragmentations of ^Li, ^He, and ^He have been measured at 0.79 GeV/nucleon. Production cross sections and momentum distributions of the produced isotopes (Z≥2) are measured inclusively. Transverse-momentum distributions of ^Li from the fragmentation of ^Li show two Gaussian components of different widths. The width of the wide component is consistent with the values observed in the fragmentation of stable nuclei, whereas the other component shows an extremely narrow width reflecting the weak binding of the two outer neutrons in the ^Li nucleus

Critical Indices as Limits of Control Functions

A variant of self-similar approximation theory is suggested, permitting an easy and accurate summation of divergent series consisting of only a few terms. The method is based on a power-law algebraic transformation, whose powers play the role of control functions governing the fastest convergence of the renormalized series. A striking relation between the theory of critical phenomena and optimal control theory is discovered: The critical indices are found to be directly related to limits of control functions at critical points. The method is applied to calculating the critical indices for several difficult problems. The results are in very good agreement with accurate numerical data.Comment: 1 file, 5 pages, RevTe

A First Principle Approach to Rescale the Dynamics of Simulated Coarse-Grained Macromolecular Liquids

We present a detailed derivation and testing of our approach to rescale the dynamics of mesoscale simulations of coarse-grained polymer melts (I. Y. Lyubimov et al. J. Chem. Phys. \textbf{132}, 11876, 2010). Starting from the first-principle Liouville equation and applying the Mori-Zwanzig projection operator technique, we derive the Generalized Langevin Equations (GLE) for the coarse-grained representations of the liquid. The chosen slow variables in the projection operators define the length scale of coarse graining. Each polymer is represented at two levels of coarse-graining: monomeric as a bead-and-spring model and molecular as a soft-colloid. In the long-time regime where the center-of-mass follows Brownian motion and the internal dynamics is completely relaxed, the two descriptions must be equivalent. By enforcing this formal relation we derive from the GLEs the analytical rescaling factors to be applied to dynamical data in the coarse-grained representation to recover the monomeric description. Change in entropy and change in friction are the two corrections to be accounted for to compensate the effects of coarse-graining on the polymer dynamics. The solution of the memory functions in the coarse-grained representations provides the dynamical rescaling of the friction coefficient. The calculation of the internal degrees of freedom provides the correction of the change in entropy due to coarse-graining. The resulting rescaling formalism is a function of the coarse-grained model and thermodynamic parameters of the system simulated. The rescaled dynamics obtained from mesoscale simulations of polyethylene, represented as soft colloidal particles, by applying our rescaling approach shows a good agreement with data of translational diffusion measured experimentally and from simulations. The proposed method is used to predict self-diffusion coefficients of new polyethylene samples.Comment: 21 pages, 6 figures, 6 tables. Submitted to Phys. Rev.

Tension dynamics in semiflexible polymers. Part I: Coarse-grained equations of motion

Based on the wormlike chain model, a coarse-grained description of the nonlinear dynamics of a weakly bending semiflexible polymer is developed. By means of a multiple scale perturbation analysis, a length-scale separation inherent to the weakly-bending limit is exploited to reveal the deterministic nature of the spatio-temporal relaxation of the backbone tension and to deduce the corresponding coarse-grained equation of motion. From this partial integro-differential equation, some detailed analytical predictions for the non-linear response of a weakly bending polymer are derived in an accompanying paper (Part II, cond-mat/0609638).Comment: 14 pages, 4 figyres. The second part of this article has the preprint no.: cond-mat/060963