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Molecular communication (MC) is a concept in communication engineering, where diffusive molecules are used to transmit information between nano or micro-scale chemical reaction systems. Engineering MC to control the reaction systems in cells is expected for many applications such as targeted drug delivery and biocomputing. Toward control of the reaction systems as desired via MC, it is important to transmit signals without distortion by MC since the reaction systems are often triggered depending on the concentration of signaling molecules arriving at the cells. In this paper, we propose a method to analyze signal distortion caused by diffusion-based MC channels using frequency response of channels. The proposed method provides indices that quantitatively evaluate the magnitude of distortion and shows parameter conditions of MC channels that suppress signal distortion. Using the proposed method, we demonstrate the design procedure of specific MC channels that satisfy given specifications. Finally, the roles of MC channels in nature are discussed from the perspective of signal distortion.

Molecular communication (MC) is recently featured as a novel communication tool to connect individual biological nanorobots. It is expected that a large number of nanorobots can form large multi-agent MC systems through MC to accomplish complex and large-scale tasks that cannot be achieved by a single nanorobot. However, most previous models for MC systems assume a unidirectional diffusion communication channel and cannot capture the feedback between each nanorobot, which is important for multi-agent MC systems. In this paper, we introduce a system theoretic model for large-scale multi-agent MC systems using transfer functions, and then propose a method to analyze the stability for multi-agent MC systems. The proposed method decomposes the multi-agent MC system into multiple single-input and single-output (SISO) systems, which facilitates the application of simple analysis technique for SISO systems to the large-scale multi-agent MC system. Finally, we demonstrate the proposed method by analyzing the stability of a specific large-scale multi-agent MC system and clarify a parameter region to synchronize the states of nanorobots, which is important to make cooperative behaviors at a population level.

In this paper, we introduce the system theoretic model for the multi-agent MC systems represented by multi-input and multi-output (MIMO) systems using the transfer functions, and then propose a method to analyze the stability for the special case of the circulant structured multi-agent MC systems. The proposed method decomposes the MIMO MC system into multiple single-input and single-output (SISO) systems, which facilitates to analyze of the stability of the large-scale multi-agent MC system. Finally, we demonstrate the proposed method to analyze the stability of a specific MC system.

We recapitulate the notion of phase change rate maximization and demonstrate the usefulness of its solution on analyzing the robust instability of a cyclic network of multi-agent systems subject to a homogenous multiplicative perturbation. Subsequently, we apply the phase change rate maximization result to two practical applications. The first is a magnetic levitation system, while the second is a repressilator with time-delay in synthetic biology.

Molecular communication (MC) enables cooperation of spatially dispersed molecular robots through the feedback control mediated by diffusing signal molecules. However, conventional analysis frameworks for the MC channels mostly consider the dynamics of unidirectional communication, lacking the effect of feedback interactions. In this paper, we propose a general control-theoretic modeling framework for bidirectional MC systems capable of capturing the dynamics of feedback control via MC in a systematic manner. The proposed framework considers not only the dynamics of molecular diffusion but also the boundary dynamics at the molecular robots that captures the lag due to the molecular transmission/reception process affecting the performance of the entire feedback system. Thus, methods in control theory can be applied to systematically analyze various dynamical properties of the feedback system. We perform a frequency response analysis based on the proposed framework to show a general design guideline for MC channels to transfer signal with desired control bandwidth. Finally, these results are demonstrated by showing the step-by-step design procedure of a specific MC channel satisfying a given specification.

Recently, molecular communication (MC) has been studied as a micro-scale communication between cells or molecular robots. In previous works, the MC channels in unbounded environment was analyzed. However, many of the experimentally implemented MC channels are surrounded by walls, thus the boundary condition should be explicitly considered to analyze the dynamics of MC channels. In this paper, we propose a framework to analyze the frequency response of one-dimensional MC channels based on a diffusion equation with a boundary. In particular, we decompose the MC channel into the diffusion system and the boundary system, and show the relation between the cut-off frequency of the MC channel and the communication distance based on the transfer function. We then analyze the frequency response of a specific MC channel and reveal that the boundary can restrict the communication bandwidth of the MC channel., Comment: 6 pages, 5 figures

This paper is concerned with a new optimization problem named "phase change rate maximization" for single-input-single-output linear time-invariant systems. The problem relates to two control problems, namely robust instability analysis against stable perturbations and minimum-norm strong stabilization. We define an index of the instability margin called "robust instability radius (RIR)" as the smallest $H_\infty$-norm of a stable perturbation that stabilizes a given unstable system. This paper has two main contributions. It is first shown that the problem of finding the exact RIR via the small-gain condition can be transformed into the problem of maximizing the phase change rate at the peak frequency with a phase constraint. Then, we show that the maximum is attained by a constant or a first-order all-pass function and derive conditions, under which the RIR can be exactly characterized, in terms of the phase change rate. Two practical applications are provided to illustrate the utility of our results.

In many practical control applications, the performance level of a closed-loop system degrades over time due to the change of plant characteristics. Thus, there is a strong need for redesigning a controller without going through the system modeling process, which is often difficult for closed-loop systems. Reinforcement learning (RL) is one of the promising approaches that enable model-free redesign of optimal controllers for nonlinear dynamical systems based only on the measurement of the closed-loop system. However, the learning process of RL usually requires a considerable number of trial-and-error experiments using the poorly controlled system that may accumulate wear on the plant. To overcome this limitation, we propose a model-free two-step design approach that improves the transient learning performance of RL in an optimal regulator redesign problem for unknown nonlinear systems. Specifically, we first design a linear control law that attains some degree of control performance in a model-free manner, and then, train the nonlinear optimal control law with online RL by using the designed linear control law in parallel. We introduce an offline RL algorithm for the design of the linear control law and theoretically guarantee its convergence to the LQR controller under mild assumptions. Numerical simulations show that the proposed approach improves the transient learning performance and efficiency in hyperparameter tuning of RL.

The dynamics of cellular chemical reactions are variable due to stochastic noise from intrinsic and extrinsic sources. The intrinsic noise is the intracellular fluctuations of molecular copy numbers caused by the probabilistic encounter of molecules and is modeled by the chemical master equation. The extrinsic noise, on the other hand, represents the intercellular variation of the kinetic parameters due to the variation of global factors affecting gene expression. The objective of this paper is to propose a theoretical framework to analyze the combined effect of the intrinsic and the extrinsic noise modeled by the chemical master equation with uncertain parameters. More specifically, we formulate a semidefinite program to compute the intervals of the stationary solution of uncertain moment equations whose parameters are given only partially in the form of the statistics of their distributions. The semidefinite program is derived without approximating the governing equation in contrast with many existing approaches. Thus, we can obtain guaranteed intervals of the worst possible values of the moments for all parameter distributions satisfying the given statistics, which are prohibitively hard to estimate from sample-path simulations since sampling from all possible uncertain distributions is difficult. We demonstrate the proposed optimization approach using two examples of stochastic chemical reactions and show that the solution of the optimization problem gives informative upper and lower bounds of the statistics of the stationary copy number distributions.

This paper is concerned with robust instability analysis for linear multi-agent dynamical systems with cyclic structure. This relates to interesting and important periodic oscillation phenomena in biology and neuronal science, since the nonlinear phenomena often occur when the linearized model around an equilibrium point is unstable. We first make a problem setting on the analysis and define the notion of robust instability radius (RIR) as a quantitative measure for maximum allowable stable dynamic perturbation in terms of the H-infinity norm. After showing lower bounds of the RIR, we derive the exact RIR, which is analytic and scalable, for first order time-lag agents. Finally, we make a remark on the potential applicability to some classes of higher order systems.

This paper is concerned with a robust instability analysis for the single-input-single-output unstable linear time-invariant (LTI) system under dynamic perturbations. The nominal system itself is possibly perturbed by the static gain of the uncertainty, which would be the case when a nonlinear uncertain system is linearized around an equilibrium point. We define the robust instability radius as the smallest $H_\infty$ norm of the stable linear perturbation that stabilizes the nominal system. There are two main theoretical results: one is on a partial characterization of unperturbed nominal systems for which the robust instability radius can be calculated exactly, and the other is a numerically tractable procedure for calculating the exact robust instability radius for nominal systems parametrized by a perturbation parameter. The results are applied to the repressilator in synthetic biology, where hyperbolic instability of a unique equilibrium guarantees the persistence of oscillation phenomena in the global sense, and the effectiveness of our linear robust instability analysis is confirmed by numerical simulations.

This paper is concerned with robust instability analysis of linear feedback systems subject to a dynamic uncertainty. The work is motivated by, and provides a basic foundation for, a more challenging problem of analyzing persistence of oscillations in nonlinear dynamical systems. We first formalize the problem for SISO LTI systems by introducing a notion of the robust instability radius (RIR). We provide a method for calculating the RIR exactly for a certain class of systems and show that it works well for a class of second order systems. This result is applied to the FitzHugh-Nagumo model for neuronal dynamics, and the effectiveness is confirmed by numerical simulations, where we properly care for the change of the equilibrium point.

Diffusion and flow-driven instability, or transport-driven instability, is one of the central mechanisms to generate inhomogeneous gradient of concentrations in spatially distributed chemical systems. However, verifying the transport-driven instability of reaction-diffusion-advection systems requires checking the Jacobian eigenvalues of infinitely many Fourier modes, which is computationally intractable. To overcome this limitation, this paper proposes mathematical optimization algorithms that determine the stability/instability of reaction-diffusion-advection systems by finite steps of algebraic calculations. Specifically, the stability/instability analysis of Fourier modes is formulated as a sum-of-squares (SOS) optimization program, which is a class of convex optimization whose solvers are widely available as software packages. The optimization program is further extended for facile computation of the destabilizing spatial modes. This extension allows for predicting and designing the shape of concentration gradient without simulating the governing equations. The streamlined analysis process of self-organized pattern formation is demonstrated with a simple illustrative reaction model with diffusion and advection.

The predictive ability of stochastic chemical reactions is currently limited by the lack of closed form solutions to the governing chemical master equation. To overcome this limitation, this paper proposes a computational method capable of predicting mathematically rigorous upper and lower bounds of transient moments for reactions governed by the law of mass action. We first derive an equation that transient moments must satisfy based on the moment equation. Although this equation is underdetermined, we introduce a set of semidefinite constraints known as moment condition to narrow the feasible set of the variables in the equation. Using these conditions, we formulate a semidefinite program that efficiently and rigorously computes the bounds of transient moment dynamics. The proposed method is demonstrated with illustrative numerical examples and is compared with related works to discuss advantages and limitations.

Model-based prediction of stochastic noise in biomolecular reactions often resorts to approximation with unknown precision. As a result, unexpected stochastic fluctuation causes a headache for the designers of biomolecular circuits. This paper proposes a convex optimization approach to quantifying the steady state moments of molecular copy counts with theoretical rigor. We show that the stochastic moments lie in a convex semi-algebraic set specified by linear matrix inequalities. Thus, the upper and the lower bounds of some moments can be computed by a semidefinite program. Using a protein dimerization process as an example, we demonstrate that the proposed method can precisely predict the mean and the variance of the copy number of the monomer protein.

This paper proposes a control theoretic framework to model and analyze the self-organized pattern formation of molecular concentrations in biomolecular communication networks, emerging applications in synthetic biology. In biomolecular communication networks, bionanomachines, or biological cells, communicate with each other using a cell-to-cell communication mechanism mediated by a diffusible signaling molecule, thereby the dynamics of molecular concentrations are approximately modeled as a reaction-diffusion system with a single diffuser. We first introduce a feedback model representation of the reaction-diffusion system and provide a systematic local stability/instability analysis tool using the root locus of the feedback system. The instability analysis then allows us to analytically derive the conditions for the self-organized spatial pattern formation, or Turing pattern formation, of the bionanomachines. We propose a novel synthetic biocircuit motif called activator-repressor-diffuser system and show that it is one of the minimum biomolecular circuits that admit self-organized patterns over cell population.

A number of biological rhythms originate from networks comprised of multiple cellular oscillators. But analytical results are still lacking on the collective oscillation period of inter-coupled gene regulatory oscillators, which, as has been reported, may be different from that of an autonomous oscillator. Based on cyclic feedback oscillators, we analyze the collective oscillation pattern of coupled cellular oscillators. First we give a condition under which the oscillator network exhibits oscillatory and synchronized behavior. Then we estimate the collective oscillation period based on a novel multivariable harmonic balance technique. Analytical results are derived in terms of biochemical parameters, thus giving insight into the basic mechanism of biological oscillation and providing guidance in synthetic biology design., Comment: arXiv admin note: substantial text overlap with arXiv:1203.1251

Cooperative behaviors arising from bacterial cell-to-cell communication can be modeled by reaction-diffusion equations having only a single diffusible component. This paper presents the following three contributions for the systematic analysis of Turing instability in such reaction-diffusion systems. (i) We first introduce a unified framework to formulate the reaction-diffusion system as an interconnected multi-agent dynamical system. (ii) Then, we mathematically classify biologically plausible and implausible Turing instabilities and characterize them by the root locus of each agent's dynamics, or the local reaction dynamics. (iii) Using this characterization, we derive analytic conditions for biologically plausible Turing instability, which provide useful guidance for the design and the analysis of biological networks. These results are demonstrated on an extended Gray-Scott model with a single diffuser.

This paper is concerned with stochastic reaction-diffusion kinetics governed by the reaction-diffusion master equation. Specifically, the primary goal of this paper is to provide a mechanistic basis of Turing pattern formation that is induced by intrinsic noise. To this end, we first derive an approximate reaction-diffusion system by using linear noise approximation. We show that the approximated system has a certain structure that is associated with a coupled dynamic multi-agent system. This observation then helps us derive an efficient computation tool to examine the spatial power spectrum of the intrinsic noise. We numerically demonstrate that the result is quite effective to analyze noise-induced Turing pattern. Finally, we illustrate the theoretical mechanism behind the noise-induced pattern formation with a H2 norm interpretation of the multi-agent system.

This paper is concerned with conditions for the existence of oscillations in gene regulatory networks with negative cyclic feedback, where time delays in transcription, translation and translocation process are explicitly considered. The primary goal of this paper is to propose systematic analysis tools that are useful for a broad class of cyclic gene regulatory networks, and to provide novel biological insights. To this end, we adopt a simplified model that is suitable for capturing the essence of a large class of gene regulatory networks. It is first shown that local instability of the unique equilibrium state results in oscillations based on a Poincare-Bendixson type theorem. Then, a graphical existence condition, which is equivalent to the local instability of a unique equilibrium, is derived. Based on the graphical condition, the existence condition is analytically presented in terms of biochemical parameters. This allows us to find the dimensionless parameters that primarily affect the existence of oscillations, and to provide biological insights. The analytic conditions and biological insights are illustrated with two existing biochemical networks, Repressilator and the Hes7 gene regulatory networks.

Oscillatory chemical reactions often serve as a timing clock of cellular processes in living cells. The temporal dynamics of protein concentration levels is thus of great interest in biology. Here we propose a theoretical framework to analyze the frequency, phase and amplitude of oscillatory protein concentrations in gene regulatory networks with negative cyclic feedback. We first formulate the analysis framework of oscillation profiles based on multivariable harmonic balance. With this framework, the frequency, phase and amplitude are obtained analytically in terms of kinetic constants of the reactions despite the nonlinearity of the dynamics. These results are demonstrated with the Pentilator and Hes7 self-repression network, and it is shown that the developed analysis method indeed predicts the profiles of the oscillations. A distinctive feature of the presented result is that the waveform of oscillations is analytically obtained for a broad class of biochemical systems. Thus, it is easy to see how the waveform is determined from the system's parameters and structures. We present general biological insights that are applicable for any gene regulatory networks with negative cyclic feedback., Comment: Appendix A and some references have been added

Many biological oscillators are arranged in networks composed of many inter-coupled cellular oscillators. However, results are still lacking on the collective oscillation period of inter-coupled gene regulatory oscillators, which, as has been reported, may be different from the oscillation period of an autonomous cellular oscillator. Based on the Goodwin oscillator, we analyze the collective oscillation pattern of coupled cellular oscillator networks. First we give a condition under which the oscillator network exhibits oscillatory and synchronized behavior, then we estimate the collective oscillation period based on a multivariable harmonic balance technique. Analytical results are derived in terms of biochemical parameters, thus giving insight into the basic mechanism of biological oscillation and providing guidance in synthetic biology design. Simulation results are given to confirm the theoretical predictions., Comment: Technical Report accompanying CDC 2012 submission