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Mercadal B.,University Pompeu Fabra | Vernier P.T.,Frank Reidy Research Center for Bioelectrics | Ivorra A.,University Pompeu Fabra
Journal of Membrane Biology | Year: 2016

It is widely accepted that electroporation occurs when the cell transmembrane voltage induced by an external applied electric field reaches a threshold. Under this assumption, in order to trigger electroporation in a spherical cell, Schwan’s equation leads to an inversely proportional relationship between the cell radius and the minimum magnitude of the applied electric field. And, indeed, several publications report experimental evidences of an inverse relationship between the cell size and the field required to achieve electroporation. However, this dependence is not always observed or is not as steep as predicted by Schwan’s equation. The present numerical study attempts to explain these observations that do not fit Schwan’s equation on the basis of the interplay between cell membrane conductivity, permeability, and transmembrane voltage. For that, a single cell in suspension was modeled and the electric field necessary to achieve electroporation with a single pulse was determined according to two effectiveness criteria: a specific permeabilization level, understood as the relative area occupied by the pores during the pulse, and a final intracellular concentration of a molecule due to uptake by diffusion after the pulse, during membrane resealing. The results indicate that plausible model parameters can lead to divergent dependencies of the electric field threshold on the cell radius. These divergent dependencies were obtained through both criteria and using two different permeabilization models. This suggests that the interplay between cell membrane conductivity, permeability, and transmembrane voltage might be the cause of results which are noncompatible with the Schwan’s equation model. © 2016 Springer Science+Business Media New York

Zemlin C.W.,Old Dominion University | Zemlin C.W.,Frank Reidy Research Center for Bioelectrics | Pertsov A.M.,SUNY Upstate Medical University
Physical Review Letters | Year: 2012

Anchoring of spiral and scroll waves in excitable media has attracted considerable interest in the context of cardiac arrhythmias. Here, by bombarding inclusions with drifting spiral and scroll waves, we explore the forces exerted by inclusions onto an approaching spiral and derive the equations of motion governing spiral dynamics in the vicinity of inclusion. We demonstrate that these forces nonmonotonically depend on distance and can lead to complex behavior: (a)anchoring to small but circumnavigating larger inclusions; (b)chirality-dependent anchoring. © 2012 American Physical Society.

Kohler S.,CNRS XLIM Research Institute, Limoges | Ho M.-C.,University of Southern California | Levine Z.A.,University of Southern California | Vernier P.T.,University of Southern California | And 3 more authors.
IEEE MTT-S International Microwave Symposium Digest | Year: 2014

Pulsed electric fields of nanosecond duration and high intensity (in the megavolt-per-meter range) have the ability to trigger functional modifications in biological cells, without irreversible disruption of the cell membranes. Although the biophysical mechanisms underlying the induced biological effects are not yet clear, promising applications have been found in biology, medicine and environment. Applications in medicine include cancer treatment, acceleration of wound healing or pain control. Transient nanometer-sized pores are believed to form on a nanosecond time scale in cell membranes exposed to high-intensity nanosecond pulsed electric fields. Direct observation of pore creation has not yet been achieved due to the involved spatiotemporal scales and the experimental constraints. In this study, we combine molecular dynamics (MD) simulations and a quasi-static approach using a custom implementation of the 3D finite-difference method to investigate the interactions that drive pore formation in cell membranes exposed to an intense nanosecond pulsed electric field. The developed method allows to compute and map at cell membranes the 3D spatiotemporal profiles of the electric potentials, electric fields and electric field gradients with atomistic details and subnanosecond dynamics. © 2014 IEEE.

Barabutis N.,Frank Reidy Research Center for Bioelectrics | Dimitropoulou C.,Frank Reidy Research Center for Bioelectrics | Birmpas C.,Frank Reidy Research Center for Bioelectrics | Joshi A.,Frank Reidy Research Center for Bioelectrics | And 3 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2015

New therapies toward heart and blood vessel disorders may emerge from the development of Hsp90 inhibitors. Several independent studies suggest potent anti-inflammatory activities of those agents in human tissues. The molecular mechanisms responsible for their protective effects in the vasculature remain unclear. The present study demonstrates that the transcription factor p53, an Hsp90 client protein, is crucial for the maintenance of vascular integrity, protects again LPS-induced endothelial barrier dysfunction, and is involved in the mediation of the anti-inflammatory activity of Hsp90 inhibitors in lung tissues. p53 silencing by siRNA decreased transendothelial resistance (a measure of endothelial barrier function). A similar effect was induced by the p53 inhibitor pifithrin, which also potentiated the LPS-induced hyperpermeability in human lung microvascular endothelial cells (HLMVEC). On the other hand, p53 induction by nutlin suppressed the LPS-induced vascular barrier dysfunction. LPS decreased p53 expression in lung tissues and that effect was blocked by pretreatment with Hsp90 inhibitors both in vivo and in vitro. Furthermore, the Hsp90 inhibitor 17-allyl-amino-demethoxy- geldanamycin suppressed the LPS-induced overexpression of the p53 negative regulator MDMX as well as p53 and MDM2 (another p53 negative regulator) phosphorylation in HLMVEC. Both negative p53 regulators were downregulated by LPS in vivo. Chemically induced p53 overexpression resulted in the suppression of LPS-induced RhoA activation and MLC2 phosphorylation, whereas p53 suppression caused the opposite effects. These observations reveal new mechanisms for the anti-inflammatory actions of Hsp90 inhibitors, i.e., the induction of the transcription factor p53, which in turn can orchestrate robust vascular anti-inflammatory responses both in vivo and in vitro. © 2015, American Physiological Society. All rights reserved.

Joshi R.P.,Old Dominion University | Joshi R.P.,Frank Reidy Research Center for Bioelectrics | Song J.,Frank Reidy Research Center for Bioelectrics
IEEE Transactions on Plasma Science | Year: 2010

A cylindrical dielectric model is used to compute transmembrane potential changes and evaluate the axial electric field magnitudes produced within a nerve by a high-intensity relatively short electrical pulse. For concreteness, the pulse was taken to have a duration of about 700 ns and large current magnitudes in keeping with ongoing experimental studies within our group. Interest in this quantitative analysis arises from probing the possibility of triggering bioeffects at intracellular organelles in tissues (or even whole animals) through such electric stimulation. Almost all other studies have focused on simple spherical cells. This paper provides a theoretical framework for computing electric fields (especially the axial components) within such cylindrical geometries (e.g., nerve cells). It is shown that fields can become sufficiently high within microseconds and initiate electroporation, modulate electrochemical processes (e.g., calcium release), or trigger secondary biochemical effects depending on the electrical pulsing parameters. © 2010 IEEE.

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