Modulation of Elementary Calcium Release Mediates a Transition from Puffs to Waves in an IP3R Cluster Model

The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter- cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell

Maximal conductances ionic parameters estimation in cardiac electrophysiology multiscale modelling

International audienceIn this work, we present an optimal control formulation for the bidomain model in order to estimate maximal conductances parameters in the physiological ionic model. We consider a general Hodgkin-Huxley formalism to describe the ionic exchanges at the microcopic level. We consider the parameters as control variables to minimize the mismatch between the measured and the computed potentials under the constraint of the bidomain system. The solution of the optimization problem is based on a gradient descent method, where the gradient is obtained by solving an adjoint problem. We show through some numerical examples the capability of this approach to estimate the values of sodium, calcium and potassium ion channels conductances in the Luo Rudy phase I model

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis

Altres ajuts: Cancer Prevention and Research Institute of Texas (CPRIT), Core Facility Support Award (CPRIT-RP180672, R1313, 1R01GM138781-01); NIH (CA125123, RR024574); Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (P50HD103555); BCM start-up funds; Albert and Margaret Alkek Foundation; McNair Medical Institute; Robert and Janice McNair Foundation; BCM Seed Funding (1P20CA221731-01A1); National Institute of General Medical Sciences (R01 GM120033); Cynthia and Antony Petrello Endowment; Mark A. Wallace Endowment; McKnight Foundation; Dana Foundation; BCM Computational and Integrative Biomedical Research Center seed grant.Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known. Here, we identify oleic acid (18:1ω9 monounsaturated fatty acid) as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis

Numerical Analysis of a Finite Element Method for an Optimal Control of Bidomain-bath Model

This work is concerned with the study of the convergence analysis for an optimal control of bidomain-bath model by using the finite element scheme. The bidomain-bath model equations describe the cardiac bioelectric activity at the tissue and bath volumes where the control acts at the boundary of the tissue domain. We establish the existence of the finite element scheme, and convergence of the unique weak solution of the direct bidomain-bath model. The convergence proof is based on deriving a series of a priori estimates and using a general L 2-compactness criterion. Moreover, the well-posedness of the adjoint problem and the first order necessary optimality conditions are shown. Comparing to the direct problem, the convergence proof of the adjoint problem is based on using a general L 1-compactness criterion. The numerical tests are demonstrated which achieve the successful cardiac defibrillation by utilizing less total current. Finally, the robustness of the Newton optimization algorithm is presented for different finer mesh geometries. 1. Introduction. The electrical behavior of the cardiac tissue surrounded by a nonconductive bath is described by a coupled partial and ordinary differential equations which are so called bidomain model equations [17, 22, 24]. The bidomain model equations consist of two parabolic partial differential equations (PDEs) which describe the dynamics of the intra and the extracellular potentials. The PDEs coupled with an ordinary differential equations which model the ionic currents associated with the reaction terms. Furthermore , an additional Poisson problem has to be solved when the cardiac tissue is immersed in a conductive fluid, e.g. tissue bath in an experimental context or a surrounding torso to model in vivo scenarios

Boundary control of bidomain equations with state dependent switching source functions in the ionic model

Optimal control for cardiac electrophysiology based on the bidomain equations in conjunction with the FentonKarma ionic model is considered. This generic ventricular model approximates well the restitution properties and spiral wave behavior of more complex ionic models of cardiac action potentials. However, it is challenging due to the appearance of state-dependent discontinuities in the source terms. A computational framework for the numerical realization of optimal control problems is presented. Essential ingredients are a shape calculus based treatment of the sensitivities of the discontinuous source terms and a marching cubes algorithm to track iso-surface of excitation wavefronts. Numerical results exhibit successful defibrillation by applying an optimally controlled extracellular stimulus