Principles that govern competition or co-existence in Rho-GTPase driven polarization.

Rho-GTPases are master regulators of polarity establishment and cell morphology. Positive feedback enables concentration of Rho-GTPases into clusters at the cell cortex, from where they regulate the cytoskeleton. Different cell types reproducibly generate either one (e.g. the front of a migrating cell) or several clusters (e.g. the multiple dendrites of a neuron), but the mechanistic basis for unipolar or multipolar outcomes is unclear. The design principles of Rho-GTPase circuits are captured by two-component reaction-diffusion models based on conserved aspects of Rho-GTPase biochemistry. Some such models display rapid winner-takes-all competition between clusters, yielding a unipolar outcome. Other models allow prolonged co-existence of clusters. We investigate the behavior of a simple class of models and show that while the timescale of competition varies enormously depending on model parameters, a single factor explains a large majority of this variation. The dominant factor concerns the degree to which the maximal active GTPase concentration in a cluster approaches a "saturation point" determined by model parameters. We suggest that both saturation and the effect of saturation on competition reflect fundamental properties of the Rho-GTPase polarity machinery, regardless of the specific feedback mechanism, which predict whether the system will generate unipolar or multipolar outcomes.

Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway.

BACKGROUND: The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Δ and pde2Δ) and double (pde1Δpde2Δ) phosphodiesterase mutants. RESULTS: Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model. CONCLUSIONS: Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network.

Chaos for cardiac arrhythmias through a one-dimensional modulation equation for alternans.

Instabilities in cardiac dynamics have been widely investigated in recent years. One facet of this work has studied chaotic behavior, especially possible correlations with fatal arrhythmias. Previously chaotic behavior was observed in various models, specifically in the breakup of spiral and scroll waves. In this paper we study cardiac dynamics and find spatiotemporal chaotic behavior through the Echebarria-Karma modulation equation for alternans in one dimension. Although extreme parameter values are required to produce chaos in this model, it seems significant mathematically that chaos may occur by a different mechanism from previous observations.

Shortening of cardiac action potential duration near an insulating boundary.

It is known, from both experiments and simulations, that cardiac action potentials are shortened near a non-conducting boundary. In the present paper, this effect is studied in a simple, two-current ionic model, with propagation restricted to a 1D fibre. An asymptotic approximation for the dependence of action potential duration on distance to the boundary is derived. This estimate agrees well with simulations.

Asymptotic approximation of an ionic model for cardiac restitution.

Cardiac restitution has been described both in terms of ionic models-systems of ODE's-and in terms of mapping models. While the former provide a more fundamental description, the latter are more flexible in trying to fit experimental data. Recently we proposed a two-dimensional mapping that accurately reproduces restitution behavior of a paced cardiac patch, including rate dependence and accommodation. By contrast, with previous models only a qualitative, not a quantitative, fit had been possible. In this paper, a theoretical foundation for the new mapping is established by deriving it as an asymptotic limit of an idealized ionic model.

Period-doubling bifurcation to alternans in paced cardiac tissue: crossover from smooth to border-collision characteristics.

We investigate, both experimentally and theoretically, the period-doubling bifurcation to alternans in heart tissue. Previously, this phenomenon has been modeled with either smooth or border-collision dynamics. Using a modification of existing experimental techniques, we find a hybrid behavior: Very close to the bifurcation point, the dynamics is smooth, whereas further away it is border-collision-like. The essence of this behavior is captured by a model that exhibits what we call an unfolded border-collision bifurcation. This new model elucidates that, in an experiment, where only a limited number of data points can be measured, the smooth behavior of the bifurcation can easily be missed.

An ionically based mapping model with memory for cardiac restitution.

Many features of the sequence of action potentials produced by repeated stimulation of a patch of cardiac muscle can be modeled by a 1D mapping, but not the full behavior included in the restitution portrait. Specifically, recent experiments have found that (i) the dynamic and S1-S2 restitution curves are different (rate dependence) and (ii) the approach to steady state, which requires many action potentials (accommodation), occurs along a curve distinct from either restitution curve. Neither behavior can be produced by a 1D mapping. To address these shortcomings, ad hoc 2D mappings, where the second variable is a "memory" variable, have been proposed; these models exhibit qualitative features of the relevant behavior, but a quantitative fit is not possible. In this paper we introduce a new 2D mapping and determine a set of parameters for it that gives a quantitatively accurate description of the full restitution portrait measured from a bullfrog ventricle. The mapping can be derived as an asymptotic limit of an idealized ionic model in which a generalized concentration acts as a memory variable. This ionic basis clarifies how the present model differs from previous models. The ionic basis also provides the foundation for more extensive cardiac modeling: e.g., constructing a PDE model that may be used to study the effect of memory on propagation. The fitting procedure for the mapping is straightforward and can easily be applied to obtain a mathematical model for data from other experiments, including experiments on different species.

Small-Signal Amplification of Period-Doubling Bifurcations in Smooth Iterated Maps.

Various authors have shown that, near the onset of a period-doubling bifurcation, small perturbations in the control parameter may result in much larger disturbances in the response of the dynamical system. Such amplification of small signals can be measured by a gain defined as the magnitude of the disturbance in the response divided by the perturbation amplitude. In this paper, the perturbed response is studied using normal forms based on the most general assumptions of iterated maps. Such an analysis provides a theoretical footing for previous experimental and numerical observations, such as the failure of linear analysis and the saturation of the gain. Qualitative as well as quantitative features of the gain are exhibited using selected models of cardiac dynamics.

Alternate Pacing of Border-Collision Period-Doubling Bifurcations.

Unlike classical bifurcations, border-collision bifurcations occur when, for example, a fixed point of a continuous, piecewise C1 map crosses a boundary in state space. Although classical bifurcations have been much studied, border-collision bifurcations are not well understood. This paper considers a particular class of border-collision bifurcations, i.e., border-collision period-doubling bifurcations. We apply a subharmonic perturbation to the bifurcation parameter, which is also known as alternate pacing, and we investigate the response under such pacing near the original bifurcation point. The resulting behavior is characterized quantitatively by a gain, which is the ratio of the response amplitude to the applied perturbation amplitude. The gain in a border-collision period-doubling bifurcation has a qualitatively different dependence on parameters from that of a classical period-doubling bifurcation. Perhaps surprisingly, the differences are more readily apparent if the gain is plotted vs. the perturbation amplitude (with the bifurcation parameter fixed) than if plotted vs. the bifurcation parameter (with the perturbation amplitude fixed). When this observation is exploited, the gain under alternate pacing provides a useful experimental tool to identify a border-collision period-doubling bifurcation.

Two-Term Asymptotic Approximation of a Cardiac Restitution Curve.

If spatial extent is neglected, ionic models of cardiac cells consist of systems of ordinary differential equations (ODEs) which have the property of excitability, i.e., a brief stimulus produces a prolonged evolution (called an action potential in the cardiac context) before the eventual return to equilibrium. Under repeated stimulation, or pacing, cardiac tissue exhibits electrical restitution: the steady-state action potential duration (APD) at a given pacing period B shortens as B is decreased. Independent of ionic models, restitution is often modeled phenomenologically by a one-dimensional mapping of the form APD(next) = f(B - APD(previous)). Under some circumstances, a restitution function f can be derived as an asymptotic approximation to the behavior of an ionic model.In this paper, extending previous work, we derive the next term in such an asymptotic approximation for a particular ionic model consisting of two ODEs. The two-term approximation exhibits excellent quantitative agreement with the actual restitution curve, whereas the leading-order approximation significantly underestimates actual APD values.

Force distributions in a triangular lattice of rigid bars.

We study the uniformly weighted ensemble of force balanced configurations on a triangular network of nontensile contact forces. For periodic boundary conditions corresponding to isotropic compressive stress, we find that the probability distribution for single-contact forces decays faster than exponentially. This superexponential decay persists in lattices diluted to the rigidity percolation threshold. On the other hand, for anisotropic imposed stresses, a broader tail emerges in the force distribution, becoming a pure exponential in the limit of infinite lattice size and infinitely strong anisotropy.

Restitution in mapping models with an arbitrary amount of memory.

Restitution, the characteristic shortening of action potential duration (APD) with increased heart rate, has been studied extensively because of its purported link to the onset of fibrillation. Restitution is often represented in the form of mapping models where APD is a function of previous diastolic intervals (DIs) and/or APDs, A(n+1)=F(D(n),A(n),D(n-1),A(n-1),...), where A(n+1) is the APD following a DI given by D(n). The number of variables previous to D(n) determines the degree of memory in the mapping model. Recent experiments have shown that mapping models should contain at least three variables (D(n),A(n),D(n-1)) to reproduce a restitution portrait (RP) that is qualitatively similar to that seen experimentally, where the RP shows three different types of restitution curves (RCs) [dynamic, S1-S2, and constant-basic cycle length (BCL)] simultaneously. However, an interpretation of the different RCs has only been presented in detail for mapping models of one and two variables. Here we present an analysis of the different RCs in the RP for mapping models with an arbitrary amount of memory. We determine the number of variables necessary to represent the different RCs in the RP. We also present a graphical visualization of these RCs. Our analysis reveals that the dynamic and S1-S2 RCs reside on two-dimensional surfaces, and therefore provide limited information for mapping models with more than two variables. However, constant-BCL restitution is a feature of the RP that depends on higher dimensions and can possibly be used to determine a lower bound on the dimensionality of cardiac dynamics.

Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber.

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, the wave-back velocity exhibits pronounced rate dependence and the wave-front velocity does not. Moreover, the discrepancy between wave-back velocity RCs is most significant for a small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wave-front and wave-back velocities. Our calculations show that rate-dependent wave-back velocity can be present even if neither APD nor wave-front velocity exhibits rate dependence.

A two-current model for the dynamics of cardiac membrane.

In this paper we introduce and study a model for electrical activity of cardiac membrane which incorporates only an inward and an outward current. This model is useful for three reasons: (1) Its simplicity, comparable to the FitzHugh-Nagumo model, makes it useful in numerical simulations, especially in two or three spatial dimensions where numerical efficiency is so important. (2) It can be understood analytically without recourse to numerical simulations. This allows us to determine rather completely how the parameters in the model affect its behavior which in turn provides insight into the effects of the many parameters in more realistic models. (3) It naturally gives rise to a one-dimensional map which specifies the action potential duration as a function of the previous diastolic interval. For certain parameter values, this map exhibits a new phenomenon--subcritical alternans--that does not occur for the commonly used exponential map.