Jonathan Higham
University of Manchester
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Featured researches published by Jonathan Higham.
PLOS Computational Biology | 2015
Erick Andres Perez Alday; Michael A. Colman; Philip Langley; Timothy D. Butters; Jonathan Higham; Antony J. Workman; Jules C. Hancox; Henggui Zhang
Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms.
Frontiers in Physiology | 2012
Henggui Zhang; Timothy D. Butters; Ismail Adeniran; Jonathan Higham; Arun V. Holden; Mark R. Boyett; Jules C. Hancox
Introduction: β-adrenergic stimulation increases the heart rate by accelerating the electrical activity of the pacemaker of the heart, the sinoatrial node (SAN). Ionic mechanisms underlying the actions of β-adrenergic stimulation are not yet fully understood. Isoprenaline (ISO), a β-adrenoceptor agonist, shifts voltage-dependent If activation to more positive potentials resulting in an increase of If, which has been suggested to be the main mechanism underlying the effect of β-adrenergic stimulation. However, ISO has been found to increase the firing rate of rabbit SAN cells when If is blocked. ISO also increases ICaL, Ist, IKr, and IKs; and shifts the activation of IKr to more negative potentials and increases the rate of its deactivation. ISO has also been reported to increase the intracellular Ca2+ transient, which can contribute to chronotropy by modulating the “Ca2+ clock.” The aim of this study was to analyze the ionic mechanisms underlying the positive chronotropy of β-adrenergic stimulation using two distinct and well established computational models of the electrical activity of rabbit SAN cells. Methods and results: We modified the Boyett et al. (2001) and Kurata et al. (2008) models of electrical activity for the central and peripheral rabbit SAN cells by incorporating equations for the known dose-dependent actions of ISO on various ionic channel currents (ICaL, Ist, IKr, and IKs), kinetics of IKr and If, and the intracellular Ca2+ transient. These equations were constructed from experimental data. To investigate the ionic basis of the effects of ISO, we simulated the chronotropic effect of a range of ISO concentrations when ISO exerted all its actions or just a subset of them. Conclusion: In both the Boyett et al. and Kurata et al. SAN models, the chronotropic effect of ISO was found to result from an integrated action of ISO on ICaL, If, Ist, IKr, and IKs, among which an increase in the rate of deactivation of IKr plays a prominent role, though the effect of ISO on If and [Ca2+]i also plays a role.
Journal of Biological Chemistry | 2011
Min Zi; Tomomi Kimura; Wei Liu; Jiawei Jin; Jonathan Higham; Sanjay Kharche; Guoliang Hao; Ying Shi; Weijian Shen; Sukhpal Prehar; Aleksandr Mironov; Ludwig Neyses; Marti F. A. Bierhuizen; Mark R. Boyett; Henggui Zhang; Ming Lei; Elizabeth J. Cartwright; Xin Wang
Abstract Connexin 43 (Cx43) is the predominant isoform of gap junction proteins in the working myocardium. In the heart, mitogen-activated protein (MAP) kinases are implicated in regulating Cx43 remodeling; however, their precise roles remain obscure. Mitogen-activated protein kinase kinase 4 (MKK4) is a critical component of the stress-activated MAP kinase signaling pathway. We have previously demonstrated that MKK4 antagonizes cardiomyocyte hypertrophy. Herein, we investigate the role of MKK4 in regulating Cx43 expression in cardiomyocytes. We found that knockdown of MKK4 expression or inhibition of its kinase activity in neonatal rat cardiomyocytes (NRCMs) significantly reduced phenylephrine-induced Cx43 expression. Furthermore, two activator protein-1 (AP-1) binding elements in the Cx43 promoter region were identified as being responsible for the MKK4-regulated Cx43 expression. Consistently, we also detected heterogeneously reduced Cx43 expression and attenuated zonula occludens-1 (ZO-1) content in the hearts of MKK4 cardiomyocyte-specific knockout mice (MKK4cko) following pressure overload. To test whether heterogeneously reduced Cx43 expression contributes to ventricular arrhythmic vulnerability, MKK4cko and control mice were subjected to pressure overload followed by programmed electrical stimulation (PES). 6 of 13 MKK4cko mice, but none of the controls, developed ventricular tachycardia. Epicardial activation mapping recorded from the MKK4cko hypertrophied heart showed ventricular activation delay. Mathematical models have simulated that the spatially heterogeneous decrease in Cx43 causes slowed ventricular conduction and fragmented wave propagations leading to re-entrant excitations. Collectively, these data reveal a novel role for MKK4 in regulating Cx43 expression and preventing hypertrophy-associated arrhythmogenesis.
Journal of Chemical Physics | 2015
Anupam Chatterjee; Jonathan Higham; Richard H. Henchman
A range of methods are presented to calculate a solutes hydration shell from computer simulations of dilute solutions of monatomic ions and noble gas atoms. The methods are designed to be parameter-free and instantaneous so as to make them more general, accurate, and consequently applicable to disordered systems. One method is a modified nearest-neighbor method, another considers solute-water Lennard-Jones overlap followed by hydrogen-bond rearrangement, while three methods compare various combinations of water-solute and water-water forces. The methods are tested on a series of monatomic ions and solutes and compared with the values from cutoffs in the radial distribution function, the nearest-neighbor distribution functions, and the strongest-acceptor hydrogen bond definition for anions. The Lennard-Jones overlap method and one of the force-comparison methods are found to give a hydration shell for cations which is in reasonable agreement with that using a cutoff in the radial distribution function. Further modifications would be required, though, to make them capture the neighboring water molecules of noble-gas solutes if these weakly interacting molecules are considered to constitute the hydration shell.
Journal of Physical Chemistry B | 2016
Hasti Haghighi; Jonathan Higham; Richard H. Henchman
DSSP is the most commonly used method to assign protein secondary structure. It is based on a hydrogen-bond definition with an energy cutoff. To assess whether hydrogen bonds defined in a parameter-free way may give more generality while preserving accuracy, we examine a series of hydrogen-bond definitions to assign secondary structure for a series of proteins. Assignment by the strongest-acceptor bifurcated definition with provision for unassigned donor hydrogens, termed the SABLE method, is found to match DSSP with 95% agreement. The small disagreement mainly occurs for helices, turns, and bends. While there is no absolute way to assign protein secondary structure, avoiding molecule-specific cutoff parameters should be advantageous in generalizing structure-assignment methods to any hydrogen-bonded system.
Journal of Computational Chemistry | 2018
Jonathan Higham; Richard H. Henchman
A common way to understand structure in multimolecular systems is the coordination shell which comprises all the neighbors of an atom. Coordination, however, is nontrivial to determine because there is no obvious way to determine when atoms are neighbors. A common solution is to take all atoms within a cutoff at the first minimum of the radial distribution function, g(r). We show that such an approach cannot be consistently applied to model multicomponent systems, namely mixtures of atoms differing in size or charge. Coordination shells using the total g(r) are found to be too restrictive for atoms of different size while those using pairwise g(r)s are excessive for charged mixtures. The recently introduced relative angular distance algorithm, however, which defines coordination instantaneously from atomic positions, is consistently able to define coordination shells containing the expected neighboring atoms for all these systems. This more robust way to determine coordination should in turn make coordination a more robust way to understand structure.
Molecular Physics | 2018
Jonathan Higham; Szu-Yu Chou; Frauke Gräter; Richard H. Henchman
ABSTRACT New theory is presented to calculate the entropy of a liquid of flexible molecules from a molecular dynamics simulation. Entropy is expressed in two terms: a vibrational term, representing the average number of configurations and momentum states in an energy well, and a topographical term, representing the effective number of energy wells. The vibrational term is derived in a hierarchical manner from two force–torque covariance matrices, one at the molecular level and one at the united-atom level. The topographical term comprises conformations and orientations, which are derived from the dihedral distributions and coordination numbers, respectively. The method is tested on 14 liquids, ranging from argon to cyclohexane. For most molecules, our results lie within the experimental range, and are slightly higher than those by the 2PT method, the only other method currently capable of directly calculating entropy for such systems. As well as providing an efficient and practical way to calculate entropy, the theory serves to give a comprehensive characterisation and quantification of molecular structure.
Journal of Chemical Physics | 2016
Jonathan Higham; Richard H. Henchman
computing in cardiology conference | 2013
Erick Andres Perez Alday; Michael A. Colman; Tim D. Butters; Jonathan Higham; Daniele Giacopelli; Philip Langley; Henggui Zhang
Computing in Cardiology | 2011
Jonathan Higham; Oleg Aslanidi; Henggui Zhang