Two features common to diverse sick excitable cells are "leaky" Nav channels and bleb damage-damaged membranes. The bleb damage, we have argued, causes a channel kinetics based "leakiness." Recombinant (node of Ranvier type) Nav1.6 channels voltage-clamped in mechanically-blebbed cell-attached patches undergo a damage intensity dependent kinetic change. Specifically, they experience a coupled hyperpolarizing (left) shift of the activation and inactivation processes. The biophysical observations on Nav1.6 currents formed the basis of Nav-Coupled Left Shift (Nav-CLS) theory. Node of Ranvier excitability can be modeled with Nav-CLS imposed at varying LS intensities and with varying fractions of total nodal membrane affected. Mild damage from which sick excitable cells might recover is of most interest pathologically. Accordingly, Na/K ATPase (pump) activity was included in the modeling. As we described more fully in our other recent reviews, Nav-CLS in nodes with pumps proves sufficient to predict many of the pathological excitability phenomena reported for sick excitable cells. This review explains how the model came about and outlines how we have used it. Briefly, we direct the reader to studies in which Nav-CLS is being implemented in larger scale models of damaged excitable tissue. For those who might find it useful for teaching or research purposes, we coded the Nav-CLS/node of Ranvier model (with pumps) in NEURON. We include, here, the resulting "Regimes" plot of classes of excitability dysfunction.

Using Coarse-Grained Molecular Dynamics simulations, we study the relaxation of bilayer vesicles, uniaxially compressed by an Atomic Force Microscope (AFM) cantilever. The relaxation time exhibits a strong force-dependence. Force-compression curves are very similar to recent experiments wherein giant unilamellar vesicles were compressed in a nearly identical manner.

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Mild traumatic injury can modify the key sodium (Na+) current underlying the excitability of neurons. It causes the activation and inactivation properties of this current to become shifted to more negative trans-membrane voltages. This so-called coupled left shift (CLS) leads to a chronic influx of Na+ into the cell that eventually causes spontaneous or “ectopic” firing along the axon, even in the absence of stimuli. The bifurcations underlying this enhanced excitability have been worked out in full ionic models of this effect. Here, we present computational evidence that increased temperature T can exacerbate this pathological state. Conversely, and perhaps of clinical relevance, mild cooling is shown to move the naturally quiescent cell further away from the threshold of ectopic behavior. The origin of this stabilization-by-cooling effect is analyzed by knocking in and knocking out, one at a time, various processes thought to be T-dependent. The T-dependence of the Na+ current, quantified by its Q10-Na factor, has the biggest impact on the threshold, followed by Q10-pump of the sodium-potassium exchanger. Below the ectopic boundary, the steady state for the gating variables and the resting potential are not modified by temperature, since our model separately tallies the Na+ and K+ ions including their separate leaks through the pump. When only the gating kinetics are considered, cooling is detrimental, but in the full T-dependent model, it is beneficial because the other processes dominate. Cooling decreases the pump’s activity, and since the pump hyperpolarizes, less hyperpolarization should lead to more excitability and ectopic behavior. But actually the opposite happens in the full model because decreased pump activity leads to smaller gradients of Na+ and K+, which in turn decreases the driving force of the Na+ current.