Motile eukaryotic cells polarize in response to external signals. Numerous mechanisms have been suggested to account for this symmetry breaking and for the ensuing robust polarization. Implicated in this process are various proteins that are recruited to the plasma membrane and segregate at an emergent front or back of the polarizing cell. Among these are PI3K, PTEN, and members of the Rho family GTPases such as Cdc42, Rac, and Rho. Many such proteins, including the Rho GTPases, cycle between active membrane-bound forms and inactive cytosolic forms. In previous work, we have shown that this property, together with appropriate crosstalk, endows a biochemical circuit (Cdc42, Rac, and Rho) with the property of inherent polarizability. Here we show that this property is present in an even simpler system comprised of a single active/inactive protein pair with positive feedback to its own activation. The simplicity of this minimal system also allows us to explain the mechanism using insights from mathematical analysis. The basic idea resides in a well-known property of reaction-diffusion systems with bistable kinetics, namely, propagation of fronts. However, it crucially depends on exchange between active and inactive forms of the chemicals with unequal rates of diffusion, and overall conservation to pin the waves into a stable polar distribution. We refer to these dynamics as wave-pinning and we show that this phenomenon is distinct from Turing-instability-generated pattern formation that occurs in reaction-diffusion systems that appear to be very similar. We explain the mathematical basis of the phenomenon, relate it to spatial segregation of Rho GTPases, and show how it can account for spatial amplification and maintenance of polarity, as well as sensitivity to new stimuli typical in polarization of eukaryotic cells.

We study cardiac action potential propagation under severe reduction in gap junction conductance. We use a mathematical model of cellular electrical activity that takes into account both threedimensional geometry and ionic concentration effects. Certain anatomical and biophysical parameters are varied to see their impact on cardiac action potential conduction velocity. This study uncovers quantitative features of ephaptic propagation that differ from previous studies based on one-dimensional models. We also identify a mode of cardiac action potential propagation in which the ephaptic and gap-junction-mediated mechanisms alternate. Our study demonstrates the usefulness of this modeling approach for electrophysiological systems especially when detailed membrane geometry plays an important role.

We describe and analyze a bistable reaction-diffusion (RD) model for two interconverting chemical species that exhibits a phenomenon of wave-pinning: a wave of activation of one of the species is initiated at one end of the domain, moves into the domain, decelerates, and eventually stops inside the domain, forming a stationary front. The second (“inactive”) species is depleted in this process. This behavior arises in a model for chemical polarization of a cell by Rho GTPases in response to stimulation. The initially spatially homogeneous concentration profile (representative of a resting cell) develops into an asymmetric stationary front profile (typical of a polarized cell). Wave-pinning here is based on three properties: (1) mass conservation in a finite domain, (2) nonlinear reaction kinetics allowing for multiple stable steady states, and (3) a sufficiently large difference in diffusion of the two species. Using matched asymptotic analysis, we explain the mathematical basis of wave-pinning, and predict the speed and pinned position of the wave. An analysis of the bifurcation of the pinned front solution reveals how the wave-pinning regime depends on parameters such as rates of diffusion and total mass of the species. We describe two ways in which the pinned solution can be lost depending on the details of the reaction kinetics: a saddle-node or a pitchfork bifurcation.

Slender body theory facilitates computational simulations of thin fibers immersed in a viscous fluid by approximating each fiber using only the geometry of the fiber centerline curve and the line force density along it. However, it has been unclear how well slender body theory actually approximates Stokes flow about a thin but truly three-dimensional fiber, in part due to the fact that simply prescribing data along a 1D curve does not result in a well-posed boundary value problem for the Stokes equations in R 3 . Here, we introduce a PDE problem to which slender body theory (SBT) provides an approximation, thereby placing SBT on firm theoretical footing. The slender body PDE is a new type of boundary value problem for Stokes flow where partial Dirichlet and partial Neumann conditions are specified everywhere along the fiber surface. Given only a 1D force density along a closed fiber, we show that the flow field exterior to the thin fiber is uniquely determined by imposing a fiber integrity condition: the surface velocity field on the fiber must be constant along cross sections orthogonal to the fiber centerline. Furthermore, a careful estimation of the residual, together with stability estimates provided by the PDE well-posedness framework, allows us to establish error estimates between the slender body approximation and the exact solution to the above problem. The error is bounded by an expression proportional to the fiber radius (up to logarithmic corrections) under mild regularity assumptions on the 1D force density and fiber centerline geometry.

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