Robust model matching design methodology for a stochastic synthetic gene network

Synthetic biology has shown its potential and promising applications in the last decade. However, many synthetic gene networks cannot work properly and maintain their desired behaviors due to intrinsic parameter variations and extrinsic disturbances. In this study, the intrinsic parameter uncertainties and external disturbances are modeled in a non-linear stochastic gene network to mimic the real environment in the host cell. Then a non-linear stochastic robust matching design methodology is introduced to withstand the intrinsic parameter fluctuations and to attenuate the extrinsic disturbances in order to achieve a desired reference matching purpose. To avoid solving the Hamilton-Jacobi inequality (HJI) in the non-linear stochastic robust matching design, global linearization technique is used to simplify the design procedure by solving a set of linear matrix inequalities (LMIs). As a result, the proposed matching design methodology of the robust synthetic gene network can be efficiently designed with the help of LMI toolbox in Matlab. Finally, two in silico design examples of the robust synthetic gene network are given to illustrate the design procedure and to confirm the robust model matching performance to achieve the desired behavior in spite of stochastic parameter fluctuations and environmental disturbances in the host cell.     

Design of state estimator for genetic regulatory networks with time-varying delays and randomly occurring uncertainties

In this paper, the design problem of state estimator for genetic regulatory networks with time delays and randomly occurring uncertainties has been addressed by a delay decomposition approach. The norm-bounded uncertainties enter into the genetic regulatory networks (GRNs) in random ways, and such randomly occurring uncertainties (ROUs) obey certain mutually uncorrelated Bernoulli distributed white noise sequences. Under these circumstances, the state estimator is designed to estimate the true concentration of the mRNA and the protein of the uncertain GRNs. Delay-dependent stability criteria are obtained in terms of linear matrix inequalities by constructing a Lyapunov–Krasovskii functional and using some inequality techniques (LMIs). Then, the desired state estimator, which can ensure the estimation error dynamics to be globally asymptotically robustly stochastically stable, is designed from the solutions of LMIs. Finally, a numerical example is provided to demonstrate the feasibility of the proposed estimation schemes.     

Robust stability of stochastic delayed genetic regulatory networks

Gene regulation is an intrinsically noisy process, which is subject to intracellular and extracellular noise perturbations and environment fluctuations. In this paper, we consider the robust stability analysis problem of genetic regulatory networks with time-varying delays and stochastic perturbation. Different from other papers, the genetic regulate system considers not only stochastic perturbation but also parameter disturbances, it is in close proximity to the real gene regulation process than determinate model. Based on the Lyapunov functional theory, sufficient conditions are given to ensure the stability of the genetic regulatory networks. All the stability conditions are given in terms of LMIs which are easy to be verified. Illustrative examples are presented to show the effectiveness of the obtained results.     

H∞ filtering for discrete-time genetic regulatory networks with random delays

The H(∞) filtering problem is investigated in this paper for a class of discrete-time genetic regulatory networks (GRNs) with random delays. The addressed filtering problem is to estimate the concentrations of mRNA and protein, and the filtering error system is modeled as a Markovian switched system. By using a properly constructed Lyapunov function, a sufficient condition is derived in terms of linear matrix inequalities (LMIs), which can guarantee stochastic stabilization of the filtering error system. Then, an optimization problem with LMIs constraints is established to design an H(∞) filter which ensures an optimal H(∞) disturbance attenuation level. Finally, an illustrative example is given to demonstrate the effectiveness of the proposed results.     

Delay-dependent robust exponential stability for uncertain recurrent neural networks with time-varying delays

This paper considers the problem of robust exponential stability for a class of recurrent neural networks with time-varying delays and parameter uncertainties. The time delays are not necessarily differentiable and the uncertainties are assumed to be time-varying but norm-bounded. Sufficient conditions, which guarantee that the concerned uncertain delayed neural network is robustly, globally, exponentially stable for all admissible parameter uncertainties, are obtained under a weak assumption on the neuron activation functions. These conditions are dependent on the size of the time delay and expressed in terms of linear matrix inequalities. Numerical examples are provided to demonstrate the effectiveness and less conservatism of the proposed stability results.     

Relaxed stability conditions for delayed recurrent neural networks with polytopic uncertainties

This paper investigates the problem of stability analysis for recurrent neural networks with time-varying delays and polytopic uncertainties. Parameter-dependent Lypaunov functionals are employed to obtain sufficient conditions that guarantee the robust global exponential stability of the equilibrium point of the considered neural network. The derived stability criteria are expressed in terms of a set of relaxed linear matrix inequalities, which can be easily tested by using commercially available software. Two numerical examples are provided to demonstrate the effectiveness of the proposed results.     

Mean square exponential and robust stability of stochastic discrete-time genetic regulatory networks with uncertainties

This paper aims to analyze global robust exponential stability in the mean square sense of stochastic discrete-time genetic regulatory networks with stochastic delays and parameter uncertainties. Comparing to the previous research works, time-varying delays are assumed to be stochastic whose variation ranges and probability distributions of the time-varying delays are explored. Based on the stochastic analysis approach and some analysis techniques, several sufficient criteria for the global robust exponential stability in the mean square sense of the networks are derived. Moreover, two numerical examples are presented to show the effectiveness of the obtained results.     

Estimating the time to extinction in an island population of song sparrows

We estimated and modelled how uncertainties in stochastic population dynamics and biases in parameter estimates affect the accuracy of the projections of a small island population of song sparrows which was enumerated every spring for 24 years. The estimate of the density regulation in a theta-logistic model (theta = 1.09 suggests that the dynamics are nearly logistic, with specific growth rate r1 = 0.99 and carrying capacity K = 41.54. The song sparrow population was strongly influenced by demographic (ŝigma2(d) = 0.66) and environmental (ŝigma2(d) = 0.41) stochasticity. Bootstrap replicates of the different parameters revealed that the uncertainties in the estimates of the specific growth rate r1 and the density regulation theta were larger than the uncertainties in the environmental variance sigma2(e) and the carrying capacity K. We introduce the concept of the population prediction interval (PPI), which is a stochastic interval which includes the unknown population size with probability (1 - alpha). The width of the PPI increased rapidly with time because of uncertainties in the estimates of density regulation as well as demographic and environmental variance in the stochastic population dynamics. Accepting a 10% probability of extinction within 100 years, neglecting uncertainties in the parameters will lead to a 33% overestimation of the time it takes for the extinction barrier (population size X = 1) to be included into the PPI. This study shows that ignoring uncertainties in population dynamics produces a substantial underestimation of the extinction risk.     

Pattern of variation in avian population growth rates

A central question in population ecology is to understand why population growth rates differ over time. Here, we describe how the long-term growth of populations is not only influenced by parameters affecting the expected dynamics, for example form of density dependence and specific population growth rate, but is also affected by environmental and demographic stochasticity. Using long-term studies of fluctuations of bird populations, we show an interaction between the stochastic and the deterministic components of the population dynamics: high specific growth rates at small densities r(1) are typically positively correlated with the environmental variance sigma(e)(2). Furthermore, theta, a single parameter describing the form of the density regulation in the theta-logistic density-regulation model, is negatively correlated with r(1). These patterns are in turn correlated with interspecific differences in life-history characteristics. Higher specific growth rates, larger stochastic effects on the population dynamics and stronger density regulation at small densities are found in species with large clutch sizes or high adult mortality rates than in long-lived species. Unfortunately, large uncertainties in parameter estimates, as well as strong stochastic effects on the population dynamics, will often make even short-term population projections unreliable. We illustrate that the concept of population prediction interval can be useful in evaluating the consequences of these uncertainties in the population projections for the choice of management actions.     

Stochastic Models of Gene Expression with Delayed Degradation

In many biochemical reactions occurring in living cells, number of various molecules might be low which results in significant stochastic fluctuations. In addition, most reactions are not instantaneous, there exist natural time delays in the evolution of cell states. It is a challenge to develop a systematic and rigorous treatment of stochastic dynamics with time delays and to investigate combined effects of stochasticity and delays in concrete models.We propose a new methodology to deal with time delays in biological systems and apply it to simple models of gene expression with delayed degradation. We show that time delay of protein degradation does not cause oscillations as it was recently argued. It follows from our rigorous analysis that one should look for different mechanisms responsible for oscillations observed in biological experiments.We develop a systematic analytical treatment of stochastic models of time delays. Specifically we take into account that some reactions, for example degradation, are consuming, that is: once molecules start to degrade they cannot be part in other degradation processes.We introduce an auxiliary stochastic process and calculate analytically the variance and the autocorrelation function of the number of protein molecules in stationary states in basic models of delayed protein degradation.     

On the estimation of robustness and filtering ability of dynamic biochemical networks under process delays, internal parametric perturbations and external disturbances

Inherently, biochemical regulatory networks suffer from process delays, internal parametrical perturbations as well as external disturbances. Robustness is the property to maintain the functions of intracellular biochemical regulatory networks despite these perturbations. In this study, system and signal processing theories are employed for measurement of robust stability and filtering ability of linear and nonlinear time-delay biochemical regulatory networks. First, based on Lyapunov stability theory, the robust stability of biochemical network is measured for the tolerance of additional process delays and additive internal parameter fluctuations. Then the filtering ability of attenuating additive external disturbances is estimated for time-delay biochemical regulatory networks. In order to overcome the difficulty of solving the Hamilton Jacobi inequality (HJI), the global linearization technique is employed to simplify the measurement procedure by a simple linear matrix inequality (LMI) method. Finally, an example is given in silico to illustrate how to measure the robust stability and filtering ability of a nonlinear time-delay perturbative biochemical network. This robust stability and filtering ability measurement for biochemical network has potential application to synthetic biology, gene therapy and drug design.     

Synchronization of generalized reaction-diffusion neural networks with time-varying delays based on general integral inequalities and sampled-data control approach

This paper explores the problem of synchronization of a class of generalized reaction-diffusion neural networks with mixed time-varying delays. The mixed time-varying delays under consideration comprise of both discrete and distributed delays. Due to the development and merits of digital controllers, sampled-data control is a natural choice to establish synchronization in continuous-time systems. Using a newly introduced integral inequality, less conservative synchronization criteria that assure the global asymptotic synchronization of the considered generalized reaction-diffusion neural network and mixed delays are established in terms of linear matrix inequalities (LMIs). The obtained easy-to-test LMI-based synchronization criteria depends on the delay bounds in addition to the reaction-diffusion terms, which is more practicable. Upon solving these LMIs by using Matlab LMI control toolbox, a desired sampled-data controller gain can be acuqired without any difficulty. Finally, numerical examples are exploited to express the validity of the derived LMI-based synchronization criteria.     

Mean square stability of uncertain stochastic BAM neural networks with interval time-varying delays

The robust asymptotic stability analysis for uncertain BAM neural networks with both interval time-varying delays and stochastic disturbances is considered. By using the stochastic analysis approach, employing some free-weighting matrices and introducing an appropriate type of Lyapunov functional which takes into account the ranges for delays, some new stability criteria are established to guarantee the delayed BAM neural networks to be robustly asymptotically stable in the mean square. Unlike the most existing mean square stability conditions for BAM neural networks, the supplementary requirements that the time derivatives of time-varying delays must be smaller than 1 are released and the lower bounds of time varying delays are not restricted to be 0. Furthermore, in the proposed scheme, the stability conditions are delay-range-dependent and rate-dependent/independent. As a result, the new criteria are applicable to both fast and slow time-varying delays. Three numerical examples are given to illustrate the effectiveness of the proposed criteria.     

New stability criteria for uncertain neural networks with interval time-varying delays

This paper is concerned with the stability analysis for neural networks with interval time-varying delays and parameter uncertainties. An approach combining the Lyapunov-Krasovskii functional with the differential inequality and linear matrix inequality techniques is taken to investigate this problem. By constructing a new Lyapunov-Krasovskii functional and introducing some free weighting matrices, some less conservative delay-derivative-dependent and delay-derivative-independent stability criteria are established in term of linear matrix inequality. And the new criteria are applicable to both fast and slow time-varying delays. Three numerical examples show that the proposed criterion are effective and is an improvement over some existing results in the literature.     

Adaptive Control Based Harvesting Strategy for a Predator–Prey Dynamical System

This paper deals with designing a harvesting control strategy for a predator–prey dynamical system, with parametric uncertainties and exogenous disturbances. A feedback control law for the harvesting rate of the predator is formulated such that the population dynamics is asymptotically stabilized at a positive operating point, while maintaining a positive, steady state harvesting rate. The hierarchical block strict feedback structure of the dynamics is exploited in designing a backstepping control law, based on Lyapunov theory. In order to account for unknown parameters, an adaptive control strategy has been proposed in which the control law depends on an adaptive variable which tracks the unknown parameter. Further, a switching component has been incorporated to robustify the control performance against bounded disturbances. Proofs have been provided to show that the proposed adaptive control strategy ensures asymptotic stability of the dynamics at a desired operating point, as well as exact parameter learning in the disturbance-free case and learning with bounded error in the disturbance prone case. The dynamics, with uncertainty in the death rate of the predator, subjected to a bounded disturbance has been simulated with the proposed control strategy.     

Stochastic Simulation of Delay-Induced Circadian Rhythms in Drosophila

Circadian rhythms are ubiquitous in all eukaryotes and some prokaryotes. Several computational models with or without time delays have been developed for circadian rhythms. Exact stochastic simulations have been carried out for several models without time delays, but no exact stochastic simulation has been done for models with delays. In this paper, we proposed a detailed and a reduced stochastic model with delays for circadian rhythms in Drosophila based on two deterministic models of Smolen et al. and employed exact stochastic simulation to simulate circadian oscillations. Our simulations showed that both models can produce sustained oscillations and that the oscillation is robust to noise in the sense that there is very little variability in oscillation period although there are significant random fluctuations in oscillation peeks. Moreover, although average time delays are essential to simulation of oscillation, random changes in time delays within certain range around fixed average time delay cause little variability in the oscillation period. Our simulation results also showed that both models are robust to parameter variations and that oscillation can be entrained by light/dark circles. Our simulations further demonstrated that within a reasonable range around the experimental result, the rates that dclock and per promoters switch back and forth between activated and repressed sites have little impact on oscillation period.     

Robust synchronization analysis in nonlinear stochastic cellular networks with time-varying delays, intracellular perturbations and intercellular noise

Naturally, a cellular network consisted of a large amount of interacting cells is complex. These cells have to be synchronized in order to emerge their phenomena for some biological purposes. However, the inherently stochastic intra and intercellular interactions are noisy and delayed from biochemical processes. In this study, a robust synchronization scheme is proposed for a nonlinear stochastic time-delay coupled cellular network (TdCCN) in spite of the time-varying process delay and intracellular parameter perturbations. Furthermore, a nonlinear stochastic noise filtering ability is also investigated for this synchronized TdCCN against stochastic intercellular and environmental disturbances. Since it is very difficult to solve a robust synchronization problem with the Hamilton-Jacobi inequality (HJI) matrix, a linear matrix inequality (LMI) is employed to solve this problem via the help of a global linearization method. Through this robust synchronization analysis, we can gain a more systemic insight into not only the robust synchronizability but also the noise filtering ability of TdCCN under time-varying process delays, intracellular perturbations and intercellular disturbances. The measures of robustness and noise filtering ability of a synchronized TdCCN have potential application to the designs of neuron transmitters, on-time mass production of biochemical molecules, and synthetic biology. Finally, a benchmark of robust synchronization design in Escherichia coli repressilators is given to confirm the effectiveness of the proposed methods.     

Robust compensator control of continuous fermentation processes

The paper deals with the robust compensator control of continuous fermentation processes described by a set of three non-linear differential equations. For the design purposes the non-linear model is transformed into linear one with interval parameters. Robust state space compensator is designed by the internal model principle, which ensures robust step-wise set points asymptotic tracking and external disturbances rejection in the wide working range. The effectiveness of the algorithm designed is performed by computer simulation experiments. An important feature of the proposed algorithms is their robustness over parameter uncertainties in the process models.     

Perspectives for ecosystem management based on ecosystem resilience and ecological thresholds against multiple and stochastic disturbances

Ecosystem resilience is the inherent ability to absorb various disturbances and reorganize while undergoing state changes to maintain critical functions. When ecosystem resilience is sufficiently degraded by disturbances, ecosystem is exposed at high risk of shifting from a desirable state to an undesirable state. Ecological thresholds represent the points where even small changes in environmental conditions associated with disturbances lead to switch between ecosystem states. There is a growing body of empirical evidence for such state transitions caused by anthropogenic disturbances in a variety of ecosystems. However, fewer studies addressed the interaction of anthropogenic and natural disturbances that often force an ecosystem to cross a threshold which an anthropogenic disturbance or a natural disturbance alone would not have achieved. This fact highlights how little is known about ecosystem dynamics under uncertainties around multiple and stochastic disturbances. Here, we present two perspectives for providing a predictive scientific basis to the management and conservation of ecosystems against multiple and stochastic disturbances. The first is management of predictable anthropogenic disturbances to maintain a sufficient level of biodiversity for ensuring ecosystem resilience (i.e., resilience-based management). Several biological diversity elements appear to confer ecosystem resilience, such as functional redundancy, response diversity, a dominant species, a foundation species, or a keystone species. The greatest research challenge is to identify key elements of biodiversity conferring ecosystem resilience for each context and to examine how we can manage and conserve them. The second is the identification of ecological thresholds along existing or experimental disturbance gradients. This will facilitate the development of indicators of proximity to thresholds as well as the understanding of threshold mechanisms. The implementation of forewarning indicators will be critical particularly when resilience-based management fails. The ability to detect an ecological threshold along disturbance gradients should therefore be essential to establish a backstop for preventing the threshold from being crossed. These perspectives can take us beyond simply invoking the precautionary principle of conserving biodiversity to a predictive science that informs practical solutions to cope with uncertainties and ecological surprises in a changing world.