Drug-mediated shortening of action potentials in LQTS2 hiPSC-cardiomyocytes

Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs. β-blockers are the mainstay treatment for patients with LQTS, functioning by reducing heart rate and arrhythmogenesis. However, they are not effective in around a quarter of LQTS2 patients, in part, because they do not correct the defining feature of the condition, which is excessively prolonged QT interval. Since new therapeutics are needed, in this report, we biopsied skin fibroblasts from a patient who was both genetically and clinically diagnosed with LQTS2. By producing LQTS-hiPSC-CMs, we assessed the impact of different drugs on action potential duration (APD), which is used as an in vitro surrogate for QT interval. Not surprisingly, the patient's own β-blocker medication, propranolol, had a marginal effect on APD in the LQTS-hiPSC-CMs. However, APD could be significantly reduced by up to 19% with compounds that enhanced the IKr current by direct channel binding or by indirect mediation through the PPARδ/protein 14-3-3 epsilon/HERG pathway. Drug-induced enhancement of an alternative potassium current, IKATP, also reduced APD by up to 21%. This study demonstrates the utility of LQTS-hiPSC-CMs in evaluating whether drugs can shorten APD and, importantly, shows that PPARδ agonists may form a new class of therapeutics for this condition

Quantum field dynamics of the slow rollover in the linear delta expansion

We show how the linear delta expansion, as applied to the slow-roll transition in quantum mechanics, can be recast in the closed time-path formalism. This results in simpler, explicit expressions than were obtained in the Schr\"odinger formulation and allows for a straightforward generalization to higher dimensions. Motivated by the success of the method in the quantum-mechanical problem, where it has been shown to give more accurate results for longer than existing alternatives, we apply the linear delta expansion to four-dimensional field theory. At small times all methods agree. At later times, the first-order linear delta expansion is consistently higher that Hartree-Fock, but does not show any sign of a turnover. A turnover emerges in second-order of the method, but the value of $$at the turnover is larger that that given by the Hartree-Fock approximation. Based on this calculation, and our experience in the corresponding quantum-mechanical problem, we believe that the Hartree-Fock approximation does indeed underestimate the value of$$ at the turnover. In subsequent applications of the method we hope to implement the calculation in the context of an expanding universe, following the line of earlier calculations by Boyanovsky {\sl et al.}, who used the Hartree-Fock and large-N methods. It seems clear, however, that the method will become unreliable as the system enters the reheating stage.Comment: 17 pages, 9 figures, revised version with extra section 4.2 including second order calculatio

Nonlinear Modulation of Multi-Dimensional Lattice Waves

The equations governing weakly nonlinear modulations of $N$-dimensional lattices are considered using a quasi-discrete multiple-scale approach. It is found that the evolution of a short wave packet for a lattice system with cubic and quartic interatomic potentials is governed by generalized Davey-Stewartson (GDS) equations, which include mean motion induced by the oscillatory wave packet through cubic interatomic interaction. The GDS equations derived here are more general than those known in the theory of water waves because of the anisotropy inherent in lattices. Generalized Kadomtsev-Petviashvili equations describing the evolution of long wavelength acoustic modes in two and three dimensional lattices are also presented. Then the modulational instability of a $N$-dimensional Stokes lattice wave is discussed based on the $N$-dimensional GDS equations obtained. Finally, the one- and two-soliton solutions of two-dimensional GDS equations are provided by means of Hirota's bilinear transformation method.Comment: Submitted to PR

Integrated crop-livestock systems - A key to sustainable intensification in Africa

Mixed crop-livestock systems provide livelihoods for a billion people and produce half the world’s cereal and around a third of its beef and milk. Market orientation and strong and growing demand for food provide powerful incentives for sustainable intensification of both crop and livestock enterprises in smallholders’ mixed systems in Africa. Better exploitation of the mutually reinforcing nature of crop and livestock systems can contribute to a positive, inclusive growth trajectory that is both ecologically and economically sustainable. In mixed systems, livestock intensification is often neglected relative to crops, yet livestock can make a positive contribution to raising productivity of the entire farming system. Similarly, intensification of crop production can pay dividends for livestock and enhance natural resource management, especially through increased biomass availability. Intensification and improved efficiency of livestock production mean less greenhouse gases per unit of milk and more milk per unit of water. This paper argues that the opportunities and challenges justify greater investment in research for development to identify exactly where and how ‘win-win’ outcomes can be achieved and what incentives, policies, technologies and other features of the enabling environment are needed to enable sustainable, integrated and productive mixed crop-livestock system

The Relativistic Factor in the Orbital Dynamics of Point Masses

There is a growing population of relativistically relevant minor bodies in the Solar System and a growing population of massive extrasolar planets with orbits very close to the central star where relativistic effects should have some signature. Our purpose is to review how general relativity affects the orbital dynamics of the planetary systems and to define a suitable relativistic correction for Solar System orbital studies when only point masses are considered. Using relativistic formulae for the N body problem suited for a planetary system given in the literature we present a series of numerical orbital integrations designed to test the relevance of the effects due to the general theory of relativity in the case of our Solar System. Comparison between different algorithms for accounting for the relativistic corrections are performed. Relativistic effects generated by the Sun or by the central star are the most relevant ones and produce evident modifications in the secular dynamics of the inner Solar System. The Kozai mechanism, for example, is modified due to the relativistic effects on the argument of the perihelion. Relativistic effects generated by planets instead are of very low relevance but detectable in numerical simulations

More efficient periodic traversal in anonymous undirected graphs

We consider the problem of periodic graph exploration in which a mobile entity with constant memory, an agent, has to visit all n nodes of an arbitrary undirected graph G in a periodic manner. Graphs are supposed to be anonymous, that is, nodes are unlabeled. However, while visiting a node, the robot has to distinguish between edges incident to it. For each node v the endpoints of the edges incident to v are uniquely identified by different integer labels called port numbers. We are interested in minimisation of the length of the exploration period. This problem is unsolvable if the local port numbers are set arbitrarily. However, surprisingly small periods can be achieved when assigning carefully the local port numbers. Dobrev et al. described an algorithm for assigning port numbers, and an oblivious agent (i.e. agent with no memory) using it, such that the agent explores all graphs of size n within period 10n. Providing the agent with a constant number of memory bits, the optimal length of the period was previously proved to be no more than 3.75n (using a different assignment of the port numbers). In this paper, we improve both these bounds. More precisely, we show a period of length at most 4 1/3 n for oblivious agents, and a period of length at most 3.5n for agents with constant memory. Moreover, we give the first non-trivial lower bound, 2.8n, on the period length for the oblivious case

Coulomb Gauge QCD, Confinement, and the Constituent Representation

Quark confinement and the genesis of the constituent quark model are examined in nonperturbative QCD in Coulomb gauge. We employ a self-consistent method to construct a quasiparticle basis and to determine the quasiparticle interaction. The results agree remarkably well with lattice computations. They also illustrate the mechanism by which confinement and constituent quarks emerge, provide support for the Gribov-Zwanziger confinement scenario, clarify several perplexing issues in the constituent quark model, and permit the construction of an improved model of low energy QCD.Comment: 43 pages, 14 figures, revtex, uses psfig.st