Volume 11, Issue 1, March 2001
 REGULAR ARTICLES


Exact solutions to chaotic and stochastic systems
View Description Hide DescriptionWe investigate functions that are exact solutions to chaotic dynamical systems. A generalization of these functions can produce truly random numbers. For the first time, we present solutions to random maps. This allows us to check, analytically, some recent results about the complexity of random dynamical systems. We confirm the result that a negative Lyapunov exponent does not imply predictability in random systems. We test the effectiveness of forecasting methods in distinguishing between chaotic and random time series. Using the explicit random functions, we can give explicit analytical formulas for the output signal in some systems with stochastic resonance. We study the influence of chaos on the stochastic resonance. We show, theoretically, the existence of a new type of solitonic stochastic resonance, where the shape of the kink is crucial. Using our models we can predict specific patterns in the output signal of stochastic resonancesystems.

Geometrical constraints on finitetime Lyapunov exponents in two and three dimensions
View Description Hide DescriptionConstraints are found on the spatial variation of finitetime Lyapunov exponents of two and threedimensional systems of ordinary differential equations. In a chaotic system, finitetime Lyapunov exponents describe the average rate of separation, along characteristic directions, of neighboring trajectories. The solution of the equations is a coordinate transformation that takes initial conditions (the Lagrangian coordinates) to the state of the system at a later time (the Eulerian coordinates). This coordinate transformation naturally defines a metric tensor, from which the Lyapunov exponents and characteristic directions are obtained. By requiring that the Riemann curvature tensor vanish for the metric tensor (a basic result of differential geometry in a flat space), differential constraints relating the finitetime Lyapunov exponents to the characteristic directions are derived. These constraints are realized with exponential accuracy in time. A consequence of the relations is that the finitetime Lyapunov exponents are locally small in regions where the curvature of the stable manifold is large, which has implications for the efficiency of chaotic mixing in the advection–diffusion equation. The constraints also modify previous estimates of the asymptotic growth rates of quantities in the dynamo problem, such as the magnitude of the induced current.

Chaotic synchronization of coupled ergodic maps
View Description Hide DescriptionWith few exceptions, studies of chaotic synchronization have focused on dissipative chaos. Though less well known, chaotic systems that lack dissipation may also synchronize. Motivated by an application in communication systems, we couple a family of ergodic maps on the Ntorus and study the global stability of the synchronous state. While most trajectories synchronize at some time, there is a measure zero set that never synchronizes. We give explicit examples of these asynchronous orbits in dimensions two and four. On more typical trajectories, the synchronization error reaches arbitrarily small values and, in practice, converges. In dimension two we derive bounds on the average synchronization time for trajectories resulting from randomly chosen initial conditions. Numerical experiments suggest similar bounds exist in higher dimensions as well. Adding noise to the coupling signal destroys the invariance of the synchronous state and causes typical trajectories to desynchronize. We propose a modification of the standard coupling scheme that corrects this problem resulting in robust synchronization in the presence of noise.

Synchronization experiments with an atmospheric global circulation model
View Description Hide DescriptionSynchronization in a chaotic system with many degrees of freedom is investigated by coupling two identical global atmospheric circulationmodels. Starting from different initial conditions, the two submodels show complete synchronization as well as noncomplete synchronization depending on the coupling strength. The relatively low value of the coupling strength threshold for complete synchronization indicates the potential importance of synchronization mechanisms involved in climate variability. In addition, the results suggest synchronizationexperiments as a valuable additional method to analyze complex dynamical models, e.g., to estimate the largest Lyapunov exponent.

Parametrically forced pattern formation
View Description Hide DescriptionPattern formation in a nonlinear damped Mathieutype partial differential equation defined on one space variable is analyzed. A bifurcationanalysis of an averaged equation is performed and compared to full numerical simulations. Parametric resonance leads to periodically varying patterns whose spatial structure is determined by amplitude and detuning of the periodic forcing. At onset, patterns appear subcritically and attractor crowding is observed for large detuning. The evolution of patterns under the increase of the forcing amplitude is studied. It is found that spatially homogeneous and temporally periodic solutions occur for all detuning at a certain amplitude of the forcing. Although the system is dissipative, spatial solitons are found representing domain walls creating a phase jump of the solutions. Qualitative comparisons with experiments in vertically vibrating granular media are made.

Dynamics of spatially nonuniform patterning in the model of blood coagulation
View Description Hide DescriptionWe propose a reactiondiffusion model that describes in detail the cascade of molecular events during blood coagulation. In a reduced form, this model contains three equations in three variables, two of which are selfaccelerated. One of these variables, an activator, behaves in a threshold manner. An inhibitor is also produced autocatalytically, but there is no inhibitor threshold, because it is generated only in the presence of the activator. All model variables are set to have equal diffusion coefficients. The model has a stable stationary trivial state, which is spatially uniform and an excitation threshold. A pulse of excitation runs from the point where the excitation threshold has been exceeded. The regime of its propagation depends on the model parameters. In a onedimensional problem, the pulse either stops running at a certain distance from the excitation point, or it reaches the boundaries as an autowave. However, there is a parameter range where the pulse does not disappear after stopping and exists stationarily. The resulting steadystate profiles of the model variables are symmetrical relative to the center of the structure formed.

Filament instability and rotational tissue anisotropy: A numerical study using detailed cardiac models
View Description Hide DescriptionThe role of cardiac tissue anisotropy in the breakup of vortex filaments is studied using two detailed cardiac models. In the Beeler–Reuter model, modified to produce stable spiral waves in two dimensions, we find that anisotropy can destabilize a vortex filament in a parallelepipedal slab of tissue. The mechanisms of the instability are similar to the ones reported in previous work on a simplified cardiac model by Fenton and Karma [Chaos8, 20 (1998)]. In the Luo–Rudy model, also modified to produce stable spiral waves in two dimensions, we find that anisotropy does not destabilize filaments. A possible explanation for this modeldependent behavior based on spiral tip trajectories is offered.
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 FOCUS ISSUE: MOLECULAR, METABOLIC, AND GENETIC CONTROL


Molecular, metabolic, and genetic control: An introduction
View Description Hide DescriptionThe living cell is a miniature, selfreproducing, biochemical machine. Like all machines, it has a power supply, a set of working components that carry out its necessary tasks, and control systems that ensure the proper coordination of these tasks. In this Special Issue, we focus on the molecular regulatory systems that control cell metabolism, gene expression, environmental responses, development, and reproduction. As for the control systems in humanengineered machines, these regulatory networks can be described by nonlinear dynamical equations, for example, ordinary differential equations, reactiondiffusion equations, stochastic differential equations, or cellular automata. The articles collected here illustrate (i) a range of theoretical problems presented by modern concepts of cellular regulation, (ii) some strategies for converting molecular mechanisms into dynamical systems, (iii) some useful mathematical tools for analyzing and simulating these systems, and (iv) the sort of results that derive from serious interplay between theory and experiment.

Molecular interaction maps as information organizers and simulation guides
View Description Hide DescriptionA graphical method for mapping bioregulatory networks is presented that is suited for the representation of multimolecular complexes, protein modifications, as well as actions at cell membranes and between protein domains. The symbol conventions defined for these molecular interaction maps are designed to accommodate multiprotein assemblies and protein modifications that can generate combinatorially large numbers of molecular species. Diagrams can either be “heuristic,” meaning that detailed knowledge of all possible reaction paths is not required, or “explicit,” meaning that the diagrams are totally unambiguous and suitable for simulation. Interaction maps are linked to annotation lists and indexes that provide ready access to pertinent data and references, and that allow any molecular species to be easily located. Illustrative interaction maps are included on the domain interactions of Src, transcription control of E2Fregulated genes, and signaling from receptor tyrosine kinase through phosphoinositides to Akt/PKB. A simple method of going from an explicit interaction diagram to an input file for a simulation program is outlined, in which the differential equations need not be written out. The role of interaction maps in selecting and defining systems for modeling is discussed.

Extracting information from cDNA arrays
View Description Hide DescriptionHighdensity DNA arrays allow measurements of gene expression levels (messenger RNA abundance) for thousands of genes simultaneously. We analyze arrays with spotted cDNA used in monitoring of expression profiles. A dilution series of a mouse liver probe is deployed to quantify the reproducibility of expression measurements. Saturation effects limit the accessible signal range at high intensities. Additive noise and outshining from neighboring spots dominate at low intensities. For repeated measurements on the same filter and filtertofilter comparisons correlation coefficients of 0.98 are found. Next we consider the clustering of gene expression time series from stimulated human fibroblasts which aims at finding coregulated genes. We analyze how preprocessing, the distance measure, and the clustering algorithm affect the resulting clusters. Finally we discuss algorithms for the identification of transcription factor binding sites from clusters of coregulated genes.

On the deduction of chemical reaction pathways from measurements of time series of concentrations
View Description Hide DescriptionWe discuss the deduction of reaction pathways in complex chemical systems from measurements of time series of chemical concentrations of reacting species. First we review a technique called correlation metric construction (CMC) and show the construction of a reaction pathway from measurements on a part of glycolysis. Then we present two new improved methods for the analysis of time series of concentrations, entropy metric construction (EMC), and entropy reduction method (ERM), and illustrate (EMC) with calculations on a model reaction system.

Analysis of nonlinear dynamics on arbitrary geometries with the Virtual Cell
View Description Hide DescriptionThe Virtual Cell is a modeling tool that allows biologists and theorists alike to specify and simulate cellbiophysical models on arbitrarily complex geometries. The framework combines an intuitive, frontend graphical user interface that runs in a web browser, sophisticated serverside numerical algorithms, a database for storage of models and simulation results, and flexible visualization capabilities. In this paper, we present an overview of the capabilities of the Virtual Cell, and, for the first time, the detailed mathematical formulation used as the basis for spatial computations. We also present summaries of two rather typical modeling projects, in order to illustrate the principal capabilities of the Virtual Cell.

How gap genes make their domains: An analytical study based on data driven approximations
View Description Hide DescriptionWe consider a mathematical formulation of the problem of protein production during segment determination in the Drosophila blastoderm, together with some preliminary results of its analytical study. We reformulate the spatial difference equations as a set of nonlinear partial differential equations and obtain their dimensionless form in the continuum limit. Using previous results obtained by the gene circuit method, we find an asymptotic statement of the problem with a small parameter. Some results of the comparison method applied to the model are obtained, and exact stationary upper solutions are derived. They exhibit distinctive features of localized bellshaped structures.

Design principles for elementary gene circuits: Elements, methods, and examples
View Description Hide DescriptionThe control of gene expression involves complex circuits that exhibit enormous variation in design. For years the most convenient explanation for these variations was historical accident. According to this view, evolution is a haphazard process in which many different designs are generated by chance; there are many ways to accomplish the same thing, and so no further meaning can be attached to such different but equivalent designs. In recent years a more satisfying explanation based on design principles has been found for at least certain aspects of gene circuitry. By design principle we mean a rule that characterizes some biological feature exhibited by a class of systems such that discovery of the rule allows one not only to understand known instances but also to predict new instances within the class. The central importance of gene regulation in modern molecular biology provides strong motivation to search for more of these underlying design principles. The search is in its infancy and there are undoubtedly many design principles that remain to be discovered. The focus of this threepart review will be the class of elementary gene circuits in bacteria. The first part reviews several elements of design that enter into the characterization of elementary gene circuits in prokaryotic organisms. Each of these elements exhibits a variety of realizations whose meaning is generally unclear. The second part reviews mathematical methods used to represent, analyze, and compare alternative designs. Emphasis is placed on particular methods that have been used successfully to identify design principles for elementary gene circuits. The third part reviews four design principles that make specific predictions regarding (1) two alternative modes of gene control, (2) three patterns of coupling gene expression in elementary circuits, (3) two types of switches in inducible gene circuits, and (4) the realizability of alternative gene circuits and their response to phased environmental cues. In each case, the predictions are supported by experimental evidence. These results are important for understanding the function, design, and evolution of elementary gene circuits.

Symbolic dynamics and computation in model gene networks
View Description Hide DescriptionWe analyze a class of ordinary differential equations representing a simplified model of a genetic network. In this network, the model genes control the production rates of other genes by a logical function. The dynamics in these equations are represented by a directed graph on an ndimensional hypercube (ncube) in which each edge is directed in a unique orientation. The vertices of the ncube correspond to orthants of state space, and the edges correspond to boundaries between adjacent orthants. The dynamics in these equations can be represented symbolically. Starting from a point on the boundary between neighboring orthants, the equation is integrated until the boundary is crossed for a second time. Each different cycle, corresponding to a different sequence of orthants that are traversed during the integration of the equation always starting on a boundary and ending the first time that same boundary is reached, generates a different letter of the alphabet. A word consists of a sequence of letters corresponding to a possible sequence of orthants that arise from integration of the equation starting and ending on the same boundary. The union of the words defines the language. Letters and words correspond to analytically computable Poincaré maps of the equation. This formalism allows us to define bifurcations of chaotic dynamics of the differential equation that correspond to changes in the associated language. Qualitative knowledge about the dynamics found by integrating the equation can be used to help solve the inverse problem of determining the underlying network generating the dynamics. This work places the study of dynamics in genetic networks in a context comprising both nonlinear dynamics and the theory of computation.

Multistationarity, the basis of cell differentiation and memory. I. Structural conditions of multistationarity and other nontrivial behavior
View Description Hide DescriptionA biological introduction serves to remind us that differentiation is an epigenetic process, that multistationarity can account for epigenetic differences, including those involved in cell differentiation, and that positive feedback circuits are a necessary condition for multistationarity and, by inference, for differentiation. The core of the paper is comprised of a formal description of feedback circuits and unions of disjoint circuits. We introduce the concepts of fullcircuit (a circuit or union of disjoint circuits which involves all the variables of the system), and of ambiguous circuit (a circuit whose sign depends on the location in phase space). We describe the partition of phase space (a) according to the signs of the ambiguous circuits, and (b) according to the signs of the eigenvalues or their real part. We introduce a normalization of the system versus one of the circuits; in two variables, this permits an entirely general description in terms of a common diagram in the “circuit space.” The paper ends with general statements concerning the requirements for multistationarity, stable periodicity, and deterministic chaos.

Multistationarity, the basis of cell differentiation and memory. II. Logical analysis of regulatory networks in terms of feedback circuits
View Description Hide DescriptionCircuits and their involvement in complex dynamics are described in differential terms in Part I of this work. Here, we first explain why it may be appropriate to use a logical description, either by itself or in symbiosis with the differential description. The major problem of a logical description is to find an adequate way to involve time. The procedure we adopted differs radically from the classical one by its fully asynchronous character. In Sec. II we describe our “naive” logical approach, and use it to illustrate the major laws of circuitry (namely, the involvement of positive circuits in multistationarity and of negative circuits in periodicity) and in a biological example. Already in the naive description, the major steps of the logical description are to: (i) describe a model as a set of logical equations, (ii) derive the state table from the equations, (iii) derive the graph of the sequences of states from the state table, and (iv) determine which of the possible pathways will be actually followed in terms of time delays. In the following sections we consider multivalued variables where required, the introduction of logical parameters and of logical values ascribed to the thresholds, and the concept of characteristic state of a circuit. This generalized logical description provides an image whose qualitative fit with the differential description is quite remarkable. A major interest of the generalized logical description is that it implies a limited and often quite small number of possible combinations of values of the logical parameters. The space of the logical parameters is thus cut into a limited number of boxes, each of which is characterized by a defined qualitative behavior of the system. Our analysis tells which constraints on the logical parameters must be fulfilled in order for any circuit (or combination of circuits) to be functional. Functionality of a circuit will result in multistationarity (in the case of a positive circuit) or in a cycle (in the case of a negative circuit). The last sections deal with “more about time delays” and “reverse logic,” an approach that aims to proceed rationally from facts to models.

Invariant manifold methods for metabolic model reduction
View Description Hide DescriptionAfter the decay of transients, the behavior of a set of differential equations modeling a chemical or biochemical system generally rests on a lowdimensional surface which is an invariant manifold of the flow. If an equation for such a manifold can be obtained, the model has effectively been reduced to a smaller system of differential equations. Using perturbation methods, we show that the distinction between rapidly decaying and longlived (slow) modes has a rigorous basis. We show how equations for attracting invariant (slow) manifolds can be constructed by a geometric approach based on functional equations derived directly from the differential equations. We apply these methods to two simple metabolic models.

Designer gene networks: Towards fundamental cellular control
View Description Hide DescriptionThe engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics. We first review the relevant work on synthetic gene networks, highlighting the important experimental findings with regard to genetic switches and oscillators. We then present the derivation of a deterministic model describing the temporal evolution of the concentration of protein in a singlegene network. Bistability in the steadystate protein concentration arises naturally as a consequence of autoregulatory feedback, and we focus on the hysteretic properties of the protein concentration as a function of the degradation rate. We then formulate the effect of an external noise source which interacts with the protein degradation rate. We demonstrate the utility of such a formulation by constructing a protein switch, whereby external noise pulses are used to switch the protein concentration between two values. Following the lead of earlier work, we show how the addition of a second network component can be used to construct a relaxation oscillator, whereby the system is driven around the hysteresis loop. We highlight the frequency dependence on the tunable parameter values, and discuss design plausibility. We emphasize how the model equations can be used to develop design criteria for robust oscillations, and illustrate this point with parameter plots illuminating the oscillatory regions for given parameter values. We then turn to the utilization of an intrinsic cellular process as a means of controlling the oscillations. We consider a network design which exhibits selfsustained oscillations, and discuss the driving of the oscillator in the context of synchronization. Then, as a second design, we consider a synthetic network with parameter values near, but outside, the oscillatory boundary. In this case, we show how resonance can lead to the induction of oscillations and amplification of a cellular signal. Finally, we construct a toggle switch from positive regulatory elements, and compare the switching properties for this network with those of a network constructed using negative regulation. Our results demonstrate the utility of model analysis in the construction of synthetic gene regulatory networks.

Robustness of the bistable behavior of a biological signaling feedback loop
View Description Hide DescriptionBiological signaling networks comprised of cellular components including signaling proteins and small molecule messengers control the many cell function in responses to various extracellular and intracellular signals including hormone and neurotransmitter inputs, and genetic events. Many signaling pathways have motifs familiar to electronics and control theory design. Feedback loops are among the most common of these. Using experimentally derived parameters, we modeled a positive feedback loop in signaling pathways used by growth factors to trigger cell proliferation. This feedback loop is bistable under physiological conditions, although the system can move to a monostable state as well. We find that bistability persists under a wide range of regulatory conditions, even when core enzymes in the feedback loop deviate from physiological values. We did not observe any other phenomena in the core feedback loop, but the addition of a delayed inhibitory feedback was able to generate oscillations under rather extreme parameter conditions. Such oscillations may not be of physiological relevance. We propose that the kinetic properties of this feedback loop have evolved to support bistability and flexibility in going between bistable and monostable modes, while simultaneously being very refractory to oscillatory states.
