Sensitivity summation theorems for stochastic biochemical reaction systems

We investigate how stochastic reaction processes are affected by external perturbations. We describe an extension of the deterministic metabolic control analysis (MCA) to the stochastic regime. We introduce stochastic sensitivities for mean and covariance values of reactant concentrations and reaction fluxes and show that there exist MCA-like summation theorems among these sensitivities. The summation theorems for flux variances is shown to depend on the size of the measurement time window (?) within which reaction events are counted for measuring a single flux. It is found that the degree of the ?-dependency can become significant for processes involving multi-time-scale dynamics and is estimated by introducing a new measure of time-scale separation. This ?-dependency is shown to be closely related to the power-law scaling observed in flux fluctuations in various complex networks.     

An analysis of a stochastic model for bacteriophage systems

In this article, we analyze a system modeling bacteriophage treatments for infections in a noisy context. In the small noise regime, we show that after a reasonable amount of time the system is close to a bacteria free equilibrium (which is a relevant biologic information) with high probability. Mathematically speaking, our study hinges on concentration techniques for delayed stochastic differential equations.     

Deterministic analysis of stochastic bifurcations in multi-stable neurodynamical systems

Many perceptual and cognitive processes, like decision-making and bistable perception, involve multistable phenomena under the influence of noise. The role of noise in a multistable neurodynamical system can be formally treated within the Fokker–Planck framework. Nevertheless, because of the underlying nonlinearities, one usually considers numerical simulations of the stochastic differential equations describing the original system, which are time consuming. An alternative analytical approach involves the derivation of reduced deterministic differential equations for the moments of the distribution of the activity of the neuronal populations. The study of the reduced deterministic system avoids time consuming computations associated with the need to average over many trials. We apply this technique to describe multistable phenomena. We show that increasing the noise amplitude results in a shifting of the bifurcation structure of the system.     

Review of stochastic hybrid systems with applications in biological systems modeling and analysis

Stochastic hybrid systems (SHS) have attracted a lot of research interests in recent years. In this paper, we review some of the recent applications of SHS to biological systems modeling and analysis. Due to the nature of molecular interactions, many biological processes can be conveniently described as a mixture of continuous and discrete phenomena employing SHS models. With the advancement of SHS theory, it is expected that insights can be obtained about biological processes such as drug effects on gene regulation. Furthermore, combining with advanced experimental methods, in silico simulations using SHS modeling techniques can be carried out for massive and rapid verification or falsification of biological hypotheses. The hope is to substitute costly and time-consuming in vitro or in vivo experiments or provide guidance for those experiments and generate better hypotheses.     

The SBML discrete stochastic models test suite

MOTIVATION: Stochastic simulation is a very important tool for mathematical modelling. However, it is difficult to check the correctness of a stochastic simulator, since any two realizations from a single model will typically be different. RESULTS: We have developed a test suite of stochastic models that have been solved either analytically or using numerical methods. This allows the accuracy of stochastic simulators to be tested against known results. The test suite is already being used by a number of stochastic simulator developers. AVAILABILITY: The latest version of the test suite can be obtained from http://www.calibayes.ncl.ac.uk/Resources/dsmts/ and is licensed under GNU Lesser General Public License.     

On linear stochastic compartmental models in discrete time

This note presents a general time-dependent study of linear stochastic compartmental models in discrete time. The transient distribution of the state of the system is obtained by adapting methods used in the continuous time analysis. Covariance functions with and without a time lag are then deduced by a simple probabilistic argument. Results are derived in the Markov case and are partly extended to the semi-Markov case.     

Sustained oscillations in stochastic systems

Many non-linear deterministic models for interacting populations present damped oscillations towards the corresponding equilibrium values. However, simulations produced with related stochastic models usually present sustained oscillations which preserve the natural frequency of the damped oscillations of the deterministic model but showing non-vanishing amplitudes. The relation between the amplitude of the stochastic oscillations and the values of the equilibrium populations is not intuitive in general but scales with the square root of the populations when the ratio between different populations is kept fixed. In this work, we explain such phenomena for the case of a general epidemic model. We estimate the stochastic fluctuations of the populations around the equilibrium point in the epidemiological model showing their (approximated) relation with the mean values.     

Patterns of mesenchymal condensation in a multiscale, discrete stochastic model

Cells of the embryonic vertebrate limb in high-density culture undergo chondrogenic pattern formation, which results in the production of regularly spaced “islands” of cartilage similar to the cartilage primordia of the developing limb skeleton. The first step in this process, in vitro and in vivo, is the generation of “cell condensations,” in which the precartilage cells become more tightly packed at the sites at which cartilage will form. In this paper we describe a discrete, stochastic model for the behavior of limb bud precartilage mesenchymal cells in vitro. The model uses a biologically motivated reaction–diffusion process and cell-matrix adhesion (haptotaxis) as the bases of chondrogenic pattern formation, whereby the biochemically distinct condensing cells, as well as the size, number, and arrangement of the multicellular condensations, are generated in a self-organizing fashion. Improving on an earlier lattice-gas representation of the same process, it is multiscale (i.e., cell and molecular dynamics occur on distinct scales), and the cells are represented as spatially extended objects that can change their shape. The authors calibrate the model using experimental data and study sensitivity to changes in key parameters. The simulations have disclosed two distinct dynamic regimes for pattern self-organization involving transient or stationary inductive patterns of morphogens. The authors discuss these modes of pattern formation in relation to available experimental evidence for the in vitro system, as well as their implications for understanding limb skeletal patterning during embryonic development.     

Modelling metapopulations with stochastic membrane systems

Metapopulations, or multi-patch systems, are models describing the interactions and the behavior of populations living in fragmented habitats. Dispersal, persistence and extinction are some of the characteristics of interest in ecological studies of metapopulations. In this paper, we propose a novel method to analyze metapopulations, which is based on a discrete and stochastic modelling framework in the area of Membrane Computing. New structural features of membrane systems, necessary to appropriately describe a multi-patch system, are introduced, such as the reduction of the maximal parallel consumption of objects, the spatial arrangement of membranes and the stochastic creation of objects. The role of the additional features, their meaning for a metapopulation model and the emergence of relevant behaviors are then investigated by means of stochastic simulations. Conclusive remarks and ideas for future research are finally presented.     

Sensitivity of membranes to their environment. Role of stochastic processes

Ionic flow through biomembranes often exhibits a sensitivity to the environment, which is difficult to explain by classical theory, that usually assumes that the free energy available to change the membrane permeability results from the environmental change acting directly on the permeability control mechanism. This implies, for example, that a change delta V in the trans-membrane potential can produce a maximum free energy change, delta V X q, on a gate (control mechanism) carrying a charge q. The analysis presented here shows that when stochastic fluctuations are considered, under suitable conditions (gate cycle times rapid compared with the field relaxation time within a channel), the change in free energy is limited, not by the magnitude of the stimulus, but by the electrochemical potential difference across the membrane, which may be very much greater. Conformational channel gates probably relax more slowly than the field within the channel; this would preclude appreciable direct amplification of the stimulus. It is shown, however, that the effect of impermeable cations such as Ca++ is to restore the amplification of the stimulus through its interaction with the electric field. The analysis predicts that the effect of Ca++ should be primarily to affect the number of channels that are open, while only slightly affecting the conductivity of an open channel.     

Influence of stochastic perturbation on prey-predator systems

We analyse the influence of various stochastic perturbations on prey-predator systems. The prey-predator model is described by stochastic versions of a deterministic Lotka-Volterra system. We study long-time behaviour of both trajectories and distributions of the solutions. We indicate the differences between the deterministic and stochastic models.     

A class of general stochastic compartmental systems

In this paper a general class of semi-Markov compartmental systems is studied. Two models for different input processes are analysed. Attention has been paid to the recurrence times associated with each compartment and to the distribution of the number of particles in each compartment. As an example, a three-compartment system is discussed to study the movement between three health states of patients with chronic diseases.     

Comparison of deterministic and stochastic SIS and SIR models in discrete time

The dynamics of deterministic and stochastic discrete-time epidemic models are analyzed and compared. The discrete-time stochastic models are Markov chains, approximations to the continuous-time models. Models of SIS and SIR type with constant population size and general force of infection are analyzed, then a more general SIS model with variable population size is analyzed. In the deterministic models, the value of the basic reproductive number R0 determines persistence or extinction of the disease. If R0 < 1, the disease is eliminated, whereas if R0 > 1, the disease persists in the population. Since all stochastic models considered in this paper have finite state spaces with at least one absorbing state, ultimate disease extinction is certain regardless of the value of R0. However, in some cases, the time until disease extinction may be very long. In these cases, if the probability distribution is conditioned on non-extinction, then when R0 > 1, there exists a quasi-stationary probability distribution whose mean agrees with deterministic endemic equilibrium. The expected duration of the epidemic is investigated numerically.     

A discrete model to study reaction-diffusion-mechanics systems

This article introduces a discrete reaction-diffusion-mechanics (dRDM) model to study the effects of deformation on reaction-diffusion (RD) processes. The dRDM framework employs a FitzHugh-Nagumo type RD model coupled to a mass-lattice model, that undergoes finite deformations. The dRDM model describes a material whose elastic properties are described by a generalized Hooke's law for finite deformations (Seth material). Numerically, the dRDM approach combines a finite difference approach for the RD equations with a Verlet integration scheme for the equations of the mass-lattice system. Using this framework results were reproduced on self-organized pacemaking activity that have been previously found with a continuous RD mechanics model. Mechanisms that determine the period of pacemakers and its dependency on the medium size are identified. Finally it is shown how the drift direction of pacemakers in RDM systems is related to the spatial distribution of deformation and curvature effects.     

A nonlinear ergodic theorem for discrete systems

A theorem concerning the asymptotic behavior of a general class of systems of difference equations is proven. This theorem guarantees the existence of a stable normalized distribution vector, and enables the constructing of a scalar limiting equation for an aggregate variable. This theory is illustrated using an example from population dynamics, a nonlinear size-structured model of competition for a dynamically modeled limiting resource.Supported in the Program in Applied Mathematics at the University of Arizona by the Applied Mathematics and Population Biology/Ecology Divisions of the National Science Foundation under grant No. DMS-8902508. Supported at Cornell University by the US Army Research Office through the Mathematical Sciences Institute, Contract DAAL03-91-C-0027, and by the National Science Foundation through the Biometrics Unit, grant No. DEB-9253570; This work comprises part of the author's dissertation at the University of Arizona, directed by J. M. Cushing