Publications about 'stability' |
Articles in journal or book chapters |
Recent work on data-driven control and reinforcement learning has renewed interest in a relatively old field in control theory: model-free optimal control approaches which work directly with a cost function and do not rely upon perfect knowledge of a system model. Instead, an "oracle" returns an estimate of the cost associated to, for example, a proposed linear feedback law to solve a linear-quadratic regulator problem. This estimate, and an estimate of the gradient of the cost, might be obtained by performing experiments on the physical system being controlled. This motivates in turn the analysis of steepest descent algorithms and their associated gradient differential equations. This paper studies the effect of errors in the estimation of the gradient, framed in the language of input to state stability, where the input represents a perturbation from the true gradient. Since one needs to study systems evolving on proper open subsets of Euclidean space, a self-contained review of input to state stability definitions and theorems for systems that evolve on such sets is included. The results are then applied to the study of noisy gradient systems, as well as the associated steepest descent algorithms. |
The notion of input to state stability (ISS) qualitatively describes stability of the mapping from initial states and inputs to internal states (and more generally outputs). This encyclopedia-style article entry gives a brief introduction to the definition of ISS and a discussion of equivalent characterizations. It is an update of the article in the 2015 edition, including additional citations to recent PDE work. |
This paper deals with the analysis of the dynamics of chemical reaction networks, developing a theoretical framework based only on graphical knowledge and applying regardless of the particular form of kinetics. It paper introduces a class of networks that are "structurally (mono) attractive", by which we mean that they are incapable of exhibiting multiple steady states, oscillation, or chaos by the virtue of their reaction graphs. These networks are characterized by the existence of a universal energy-like function which we call a Robust Lyapunov function (RLF). To find such functions, a finite set of rank-one linear systems is introduced, which form the extremals of a linear convex cone. The problem is then reduced to that of finding a common Lyapunov function for this set of extremals. Based on this characterization, a computational package, Lyapunov-Enabled Analysis of Reaction Networks (LEARN), is provided that constructs such functions or rules out their existence. An extensive study of biochemical networks demonstrates that LEARN offers a new unified framework. We study basic motifs, three-body binding, and transcriptional networks. We focus on cellular signalling networks including various post-translational modification cascades, phosphotransfer and phosphorelay networks, T-cell kinetic proofreading, ERK signaling, and the Ribosome Flow Model. |
Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation, with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ``Basin of Attraction percentage'' is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that methylation plays in enhancing the stability of the silenced gene state. |
A matrix is totally nonnegative (resp., totally positive) if all its minors are nonnegative (resp., positive). This paper draws connections between B. Schwarz's 1970 work on TN and TP matrices to Smillie's 1984 and Smith's 1991 work on stability of nonlinear tridiagonal cooperative systems, simplifying proofs in the later paper and suggesting new research questions. |
This is an expository paper, which compares in detail various alternative weak contraction ideas for nonlinear system stability. |
Contraction theory is a powerful tool for proving asymptotic properties of nonlinear dynamical systems including convergence to an attractor and entrainment to a periodic excitation. We introduce three new forms of generalized contraction (GC) that are motivated by allowing contraction to take place after small transients in time and/or amplitude. These forms of GC are useful for several reasons. First, allowing small transients does not destroy the asymptotic properties provided by standard contraction. Second, in some cases as we change the parameters in a contractive system it becomes a GC just before it looses contractivity. In this respect, GC is the analogue of marginal stability in Lyapunov stability theory. We provide checkable sufficient conditions for GC, and demonstrate their usefulness using several models from systems biology that are not contractive, with respect to any norm, yet are GC. |
Synthetic constructs in biotechnology, bio-computing, and proposed gene therapy interventions are often based on plasmids or transfected circuits which implement some form of on-off (toggle or flip-flop) switch. For example, the expression of a protein used for therapeutic purposes might be triggered by the recognition of a specific combination of inducers (e.g., antigens), and memory of this event should be maintained across a cell population until a specific stimulus commands a coordinated shut-off. The robustness of such a design is hampered by molecular (intrinsic) or environmental (extrinsic) noise, which may lead to spontaneous changes of state in a subset of the population and is reflected in the bimodality of protein expression, as measured for example using flow cytometry. In this context, a majority-vote correction circuit, which brings deviant cells back into the required state, is highly desirable. To address this concrete challenge, we have developed a new theoretical design for quorum-sensing (QS) synthetic toggles. QS provides a way for cells to broadcast their states to the population as a whole so as to facilitate consensus. Our design is endowed with strong theoretical guarantees, based on monotone dynamical systems theory, of global stability and no oscillations, and which leads to robust consensus states. |
We develop and analyze a general model for large-scale simultaneous mRNA translation and competition for ribosomes. Such models are especially important when dealing with highly expressed genes, as these consume more resources. For our model, we prove that the compound system always converges to a steady-state and that it always entrains or phase locks to periodically time-varying transition rates in any of the mRNA molecules. We use this model to explore the interactions between the various mRNA molecules and ribosomes at steady-state. We show that increasing the length of an mRNA molecule decreases the production rate of all the mRNAs. Increasing any of the codon translation rates in a specific mRNA molecule yields a local effect: an increase in the translation rate of this mRNA, and also a global effect: the translation rates in the other mRNA molecules all increase or all decrease. These results suggest that the effect of codon decoding rates of endogenous and heterologous mRNAs on protein production might be more complicated than previously thought. |
The notion of input to state stability (ISS) qualitatively describes stability of the mapping from initial states and inputs to internal states (and more generally outputs). This entry focuses on the definition of ISS and a discussion of equivalent characterizations. |
A formalism for the study of random dynamical systems with inputs and outputs (RDSIO) is introduced. An axiomatic framework and basic properties of RDSIO are developed, and a theorem is shown that guarantees the stability of interconnected systems. |
A recent biological study has demonstrated that the gene expression pattern entrains to a periodically varying abundance of tRNA molecules. This motivates developing mathematical tools for analyzing entrainment of translation elongation to intra-cellular signals such as tRNAs levels and other factors affecting translation. We consider a recent deterministic mathematical model for translation called the Ribosome Flow Model (RFM). We analyze this model under the assumption that the elongation rate of the tRNA genes and/or the initiation rate are periodic functions with a common period T. We show that the protein synthesis pattern indeed converges to a unique periodic trajectory with period T. The analysis is based on introducing a novel property of dynamical systems, called contraction after a short transient (CAST), that may be of independent interest. We provide a sufficient condition for CAST and use it to prove that the RFM is CAST, and that this implies entrainment. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and suggest a new approach for engineering genes to obtain a desired, periodic, synthesis rate. |
This work introduces a notion of random dynamical systems with inputs, providing several basic definitions and results on equilibria and convergence. It also presents a "converging input to converging state" result, a concept that plays a key role in the analysis of stability of feedback interconnections, for monotone systems. |
This paper deals with the stability of interconnections of nonlinear stochastic systems, using concepts of passivity and noise-to-state stability. |
An encyclopedia-type article on foundations of ISS. |
The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
An encyclopedia-type article on foundations of input/output stability. |
Contraction theory provides an elegant way of analyzing the behaviors of systems subject to external inputs. Under sometimes easy to check hypotheses, systems can be shown to have the incremental stability property that all trajectories converge to a unique solution. This property is especially interesting when forcing functions are periodic (globally attracting limit cycles result), as well as in the context of establishing synchronization results. The present paper provides a self-contained introduction to some basic results, with a focus on contractions with respect to non-Euclidean metrics. |
This paper derives new results for certain classes of chemical reaction networks, linking structural to dynamical properties. In particular, it investigates their monotonicity and convergence without making assumptions on the form of the kinetics (e.g., mass-action) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find an alternative representation under which the resulting system is monotone. As a simple example, the paper shows that a phosphorylation/dephosphorylation process, which is involved in many signaling cascades, has a global stability property. |
This paper studies monotone tridiagonal systems with negative feedback. These systems possess the Poincar{\'e}-Bendixson property, which implies that, if orbits are bounded, if there is a unique steady state and this unique equilibrium is asymptotically stable, and if one can rule out periodic orbits, then the steady state is globally asymptotically stable. Different approaches are discussed to rule out period orbits. One is based on direct linearization, while the other uses the theory of second additive compound matrices. Among the examples that will illustrate our main theoretical results is the classical Goldbeter model of circadian rhythms. |
Certain mass-action kinetics models of biochemical reaction networks, although described by nonlinear differential equations, may be partially viewed as state-dependent linear time-varying systems, which in turn may be modeled by convex compact valued positive linear differential inclusions. A result is provided on asymptotic stability of such inclusions, and applied to biochemical reaction networks with inflows and outflows. Included is also a characterization of exponential stability of general homogeneous switched systems |
In this expository paper, we provide a streamlined version of the key lemma on stability of interconnections due to Vidyasagar and Moylan and Hill, and then show how it its hypotheses may be verified for network structures of great interest in biology. |
In this note, we show how certain properties of Goldbeter's 1995 model for circadian oscillations can be proved mathematically, using techniques from the recently developed theory of monotone systems with inputs and outputs. The theory establishes global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, based on the application of a tight small gain condition. This stability persists even under arbitrary delays in the feedback loop. On the other hand, when the condition is violated a Poincare'-Bendixson result allows to conclude existence of oscillations, for sufficiently high delays. |
Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property. |
This paper presents a stability test for a class of interconnected nonlinear systems motivated by biochemical reaction networks. One of the main results determines global asymptotic stability of the network from the diagonal stability of a "dissipativity matrix" which incorporates information about the passivity properties of the subsystems, the interconnection structure of the network, and the signs of the interconnection terms. This stability test encompasses the "secant criterion" for cyclic networks presented in our previous paper, and extends it to a general interconnection structure represented by a graph. A second main result allows one to accommodate state products. This extension makes the new stability criterion applicable to a broader class of models, even in the case of cyclic systems. The new stability test is illustrated on a mitogen activated protein kinase (MAPK) cascade model, and on a branched interconnection structure motivated by metabolic networks. Finally, another result addresses the robustness of stability in the presence of diffusion terms in a compartmental system made out of identical systems. |
A class of distributed systems with a cyclic interconnection structure is considered. These systems arise in several biochemical applications and they can undergo diffusion driven instability which leads to a formation of spatially heterogeneous patterns. In this paper, a class of cyclic systems in which addition of diffusion does not have a destabilizing effect is identified. For these systems global stability results hold if the "secant" criterion is satisfied. In the linear case, it is shown that the secant condition is necessary and sufficient for the existence of a decoupled quadratic Lyapunov function, which extends a recent diagonal stability result to partial differential equations. For reaction-diffusion equations with nondecreasing coupling nonlinearities global asymptotic stability of the origin is established. All of the derived results remain true for both linear and nonlinear positive diffusion terms. Similar results are shown for compartmental systems. |
We find that three intracellular regulatory networks contain far more positive "sign-consistent" feedback and feed-forward loops than negative loops. Negative inconsistent loops can be more easily removed from real regulatory network topologies compared to removing negative loops from shuffled networks. The abundance of positive feed-forward loops and feedback loops in real networks emerges from the presence of hubs that are enriched with either negative or positive links, and from the non-uniform connectivity distribution. Boolean dynamics applied to the signaling network further support the stability of its topology. These observations suggest that the "close-to-monotone" structure of intracellular regulatory networks may contribute to the dynamical stability observed in cellular behavior. |
The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation "futile cycle" motif which plays a central role in eukaryotic cell signaling The workis heavily based on Fenichel-Jones geometric singular perturbation theory. |
This expository presentation, prepared for a summer course, addresses the precise formulation of questions of robustness with respect to disturbances, using the paradigm of input to state stability. It provides an intuitive and informal presentation of the main concepts. |
See abstract and pdf for ``Monotone and near-monotone biochemical networks''. |
The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
Persistency is the property, for differential equations in Rn, that solutions starting in the positive orthant do not approach the boundary. For chemical reactions and population models, this translates into the non-extinction property: provided that every species is present at the start of the reaction, no species will tend to be eliminated in the course of the reaction. This paper provides checkable conditions for persistence of chemical species in reaction networks, using concepts and tools from Petri net theory, and verifies these conditions on various systems which arise in the modeling of cell signaling pathways. |
This paper gives a theorem showing that a slow feedback adaptation, acting entirely analogously to the role of negative feedback for ordinary relaxation oscillations, leads to periodic orbits for bistable monotone systems. The proof is based upon a combination of i/o monotone systems theory and Conley Index theory. |
This paper provides an expository introduction to monotone and near-monotone biochemical network structures. Monotone systems respond in a predictable fashion to perturbations, and have very robust dynamical characteristics. This makes them reliable components of more complex networks, and suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone. In addition, interconnections of monotone systems may be fruitfully analyzed using tools from control theory. |
We analyze certain chemical reaction networks and show that every solution converges to some steady state. The reaction kinetics are assumed to be monotone but otherwise arbitrary. When diffusion effects are taken into account, the conclusions remain unchanged. The main tools used in our analysis come from the theory of monotone dynamical systems. We review some of the features of this theory and provide a self-contained proof of a particular attractivity result which is used in proving our main result. |
This paper considers a class of systems with a cyclic structure that arises, among other examples, in dynamic models for certain biochemical reactions. We first show that a criterion for local stability, derived earlier in the literature, is in fact a necessary and sufficient condition for diagonal stability of the corresponding class of matrices. We then revisit a recent generalization of this criterion to output strictly passive systems, and recover the same stability condition using our diagonal stability result as a tool for constructing a Lyapunov function. Using this procedure for Lyapunov construction we exhibit classes of cyclic systems with sector nonlinearities and characterize their global stability properties. |
A commonly employed measure of the signal amplification properties of an input/output system is its induced L2 norm, sometimes also known as H-infinity gain. In general, however, it is extremely difficult to compute the numerical value for this norm, or even to check that it is finite, unless the system being studied is linear. This paper describes a class of systems for which it is possible to reduce this computation to that of finding the norm of an associated linear system. In contrast to linearization approaches, a precise value, not an estimate, is obtained for the full nonlinear model. The class of systems that we study arose from the modeling of certain biological intracellular signaling cascades, but the results should be of wider applicability. |
Motivated by the theory of monotone i/o systems, this paper shows that certain finite and infinite dimensional semi-dynamical systems with negative feedback can be decomposed into a monotone open loop system with inputs and a decreasing output function. The original system is reconstituted by plugging the output into the input. By embedding the system into a larger symmetric monotone system, this paper obtains finer information on the asymptotic behavior of solutions, including existence of positively invariant sets and global convergence. An important new result is the extension of the "small gain theorem" of monotone i/o theory to reaction-diffusion partial differential equations: adding diffusion preserves the global attraction of the ODE equilibrium. |
This paper further develops a method, originally introduced in a paper by Angeli and Sontag, for proving global attractivity of steady states in certain classes of dynamical systems. In this aproach, one views the given system as a negative feedback loop of a monotone controlled system. An auxiliary discrete system, whose global attractivity implies that of the original system, plays a key role in the theory, which is presented in a general Banach space setting. Applications are given to delay systems, as well as to systems with multiple inputs and outputs, and the question of expressing a given system in the required negative feedback form is addressed. |
This paper shows that any globally asymptotically controllable system on any smooth manifold can be globally stabilized by a state feedback. Since discontinuous feedbacks are allowed, solutions are understood in the ``sample and hold'' sense introduced by Clarke-Ledyaev-Sontag-Subbotin (CLSS). This work generalizes the CLSS Theorem, which is the special case of our result for systems on Euclidean space. We apply our result to the input-to-state stabilization of systems on manifolds relative to actuator errors, under small observation noise. |
Systems for which each constant input gives rise to a unique globally attracting equilibrium are considered. A counterexample is provided to show that inputs which are only asymptotically constant may not result in states converging to equilibria (failure of the converging-input converging state, or ``CICS'' property). |
A generalization of the classical secant condition for the stability of cascades of scalar linear systems is provided for passive systems. The key is the introduction of a quantity that combines gain and phase information for each system in the cascade. For linear one-dimensional systems, the known result is recovered exactly. |
We provide an almost-global stability result for a particular chemostat model, in which crowding effects are taken into consideration. The model can be rewritten as a negative feedback interconnection of two monotone i/o systems with well-defined characteristics, which allows the use of a small-gain theorem for feedback interconnections of monotone systems. This leads to a sufficient condition for almost-global stability, and we show that coexistence occurs in this model if the crowding effects are large enough. |
We study a single species in a chemostat, limited by two nutrients, and separate nutrient uptake from growth. For a broad class of uptake and growth functions it is proved that a nontrivial equilibrium may exist. Moreover, if it exists it is unique and globally stable, generalizing a previous result by Legovic and Cruzado. |
For feedback loops involving single input, single output monotone systems with well-defined I/O characteristics, a previous paper provided an approach to determining the location and stability of steady states. A result on global convergence for multistable systems followed as a consequence of the technique. The present paper extends the approach to multiple inputs and outputs. A key idea is the introduction of a reduced system which preserves local stability properties. New results characterizing strong monotonicity of feedback loops involving cascades are also presented. |
This paper proposes several definitions of observability for nonlinear systems and explores relationships among them. These observability properties involve the existence of a bound on the norm of the state in terms of the norms of the output and the input on some time interval. A Lyapunov-like sufficient condition for observability is also obtained. As an application, we prove several variants of LaSalle's stability theorem for switched nonlinear systems. These results are demonstrated to be useful for control design in the presence of switching as well as for developing stability results of Popov type for switched feedback systems. |
This paper provides representations of switched systems described by controlled differential inclusions, in terms of perturbed control systems. The control systems have dynamics given by differential equations, and their inputs consist of the original controls together with disturbances that evolve in compact sets; their sets of maximal trajectories contain, as a dense subset, the set of maximal trajectories of the original system. Several applications to control theory, dealing with properties of stability with respect to inputs and of detectability, are derived as a consequence of the representation theorem. |
This paper develops characterizations of various uniform stability properties of switched systems described by differential inclusions, and whose switchings are governed by a digraph. These characterizations are given in terms of stability properties of the system with restricted switchings and also in terms of Lyapunov functions. |
This paper, prepared for a tutorial at the 2005 IEEE Conference on Decision and Control, presents an introduction to molecular systems biology and some associated problems in control theory. It provides an introduction to basic biological concepts, describes several questions in dynamics and control that arise in the field, and argues that new theoretical problems arise naturally in this context. A final section focuses on the combined use of graph-theoretic, qualitative knowledge about monotone building-blocks and steady-state step responses for components. |
This paper deals with an almost global attractivity result for Lotka-Volterra systems with predator-prey interactions. These systems can be written as (negative) feedback systems. The subsystems of the feedback loop are monotone control systems, possessing particular input-output properties. We use a small-gain theorem, adapted to a context of systems with multiple equilibrium points to obtain the desired almost global attractivity result. It provides sufficient conditions to rule out oscillatory or more complicated behavior which is often observed in predator-prey systems. |
One of the key ideas in control theory is that of viewing a complex dynamical system as an interconnection of simpler subsystems, thus deriving conclusions regarding the complete system from properties of its building blocks. Following this paradigm, and motivated by questions in molecular biology modeling, the authors have recently developed an approach based on components which are monotone systems with respect to partial orders in state and signal spaces. This paper presents a brief exposition of recent results, with an emphasis on small gain theorems for negative feedback, and the emergence of multi-stability and associated hysteresis effects under positive feedback. |
We discuss several issues related to the stabilizability of nonlinear systems. First, for continuously stabilizable systems, we review constructions of feedbacks that render the system input-to-state stable with respect to actuator errors. Then, we discuss a recent paper which provides a new feedback design that makes globally asymptotically controllable systems input-to-state stable to actuator errors and small observation noise. We illustrate our constructions using the nonholonomic integrator, and discuss a related feedback design for systems with disturbances. |
Multistability is an important recurring theme in cell signaling, of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex than this. Here we show that for a class of feedback systems of arbitrary order, the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this "open loop," feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems, and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable MAPK cascade. |
We present new characterizations of input-output-to-state stability. This is a notion of detectability formulated in the ISS framework. Equivalent properties are presented in terms of asymptotic estimates of the state trajectories based on the magnitudes of the external input and output signals. These results provide a set of "separation principles" for input-output-to-state stability , characterizations of the property in terms of weaker stability notions. When applied to the closely related notion of integral ISS, these characterizations yield analogous results. |
The stability of differential inclusions defined by locally Lipschitz compact valued maps is addressed. It is shown that if such a differential inclusion is globally asymptotically stable, then in fact it is uniformly globally asymptotically stable (with respect to initial states in compacts). This statement is trivial for differential equations, but here we provide the extension to compact (not necessarily convex) valued differential inclusions. The main result is presented in a context which is useful for control-theoretic applications: a differential inclusion with two outputs is considered, and the result applies to the property of global error detectability. |
This paper studies the emergence of multi-stability and hysteresis in those systems that arise, under positive feedback, from monotone systems with well-defined steady-state responses. Such feedback configurations appear routinely in several fields of application, and especially in biology. The results are stated in terms of directly checkable conditions which do not involve explicit knowledge of basins of attractions of each equilibria. |
A small-gain theorem is presented for almost global stability of monotone control systems which are open-loop almost globally stable, when constant inputs are applied. The theorem assumes "negative feedback" interconnections. This typically destroys the monotonicity of the original flow and potentially destabilizes the resulting closed-loop system. |
This paper studies aspects of the dynamics of a conventional mechanism of ligand-receptor interactions, with a focus on the stability and location of steady-states. A theoretical framework is developed, and, as an application, a minimal parametrization is provided for models for two- or multi-state receptor interaction with ligand. In addition, an "affinity quotient" is introduced, which allows an elegant classification of ligands into agonists, neutral agonists, and inverse agonists. |
We prove the global asymptotic stability of a well-known delayed negative-feedback model of testosterone dynamics, which has been proposed as a model of oscillatory behavior. We establish stability (and hence the impossibility of oscillations) even in the presence of delays of arbitrary length. |
The main problem addressed in this paper is the design of feedbacks for globally asymptotically controllable (GAC) control affine systems that render the closed loop systems input to state stable with respect to actuator errors. Extensions for fully nonlinear GAC systems with actuator errors are also discussed. Our controllers have the property that they tolerate small observation noise as well. |
This paper, addressed primarily to engineers and mathematicians with an interest in control theory, argues that entirely new theoretical problems arise naturally when addressing questions in the field of systems biology. Examples from the author's recent work are used to illustrate this point. |
Monotone systems constitute one of the most important classes of dynamical systems used in mathematical biology modeling. The objective of this paper is to extend the notion of monotonicity to systems with inputs and outputs, a necessary first step in trying to understand interconnections, especially including feedback loops, built up out of monotone components. Basic definitions and theorems are provided, as well as an application to the study of a model of one of the cell's most important subsystems. |
A new notion of input-to-state stability involving infinity norms of input derivatives up to a finite order k is introduced and characterized. An example shows that this notion of stability is indeed weaker than the usual ISS. Applications to the study of global asymptotic stability of cascaded nonlinear systems are discussed. |
Some biological systems operate at the critical point between stability and instability and this requires a fine-tuning of parameters. We bring together two examples from the literature that illustrate this: neural integration in the nervous system and hair cell oscillations in the auditory system. In both examples the question arises as to how the required fine-tuning may be achieved and maintained in a robust and reliable way. We study this question using tools from nonlinear and adaptive control theory. We illustrate our approach on a simple model which captures some of the essential features of neural integration. As a result, we propose a large class of feedback adaptation rules that may be responsible for the experimentally observed robustness of neural integration. We mention extensions of our approach to the case of hair cell oscillations in the ear. |
In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, at whose core is a negative feedback loop: cyclins accumulate and produce active mitotic Cdc2-cyclin B Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback4, with active Cdc2-cyclin B stimulating its activator Cdc25 and inactivating its inhibitors Wee1 and Myt1. Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. This paper examined whether Cdc2 activation is bistable, confirming that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switchlike, as would be expected if Cdc2 activation were bistable. It is also shown that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator. |
A construction is given of a globally asymptotically stable time-invariant system which can be destabilized by some integrable perturbation. Besides its intrinsic interest, this serves to provide counterexamples to an open question regarding Lyapunov functions. |
We analyze nonlinear cascades in which the driven subsystem is integral ISS, and characterize the admissible integral ISS gains for stability. This characterization makes use of the convergence speed of the driving subsystem, and allows a larger class of gain functions when the convergence is faster. We show that our integral ISS gain characterization unifies different approaches in the literature which restrict the nonlinear growth of the driven subsystem and the convergence speed of the driving subsystem. |
This paper provides a necessary and sufficient condition for detectability, and an explicit construction of observers when this condition is satisfied, for chemical reaction networks of the Feinberg-Horn-Jackson zero deficiency type. |
We consider a new Lyapunov-type characterization of detectability for nonlinear systems without controls, in terms of lower-semicontinuous (not necessarily smooth, or even continuous) dissipation functions, and prove its equivalence to the GASMO (global asymptotic stability modulo outputs) and UOSS (uniform output-to-state stability) properties studied in previous work. The result is then extended to provide a construction of a discontinuous dissipation function characterization of the IOSS (input-to-state stability) property for systems with controls. This paper complements a recent result on smooth Lyapunov characterizations of IOSS. The utility of non-smooth Lyapunov characterizations is illustrated by application to a well-known transistor network example. |
This paper introduces and studies a new definition of the minimum-phase property for general smooth nonlinear control systems. The definition does not rely on a particular choice of coordinates in which the system takes a normal form or on the computation of zero dynamics. In the spirit of the ``input-to-state stability'' philosophy, it requires the state and the input of the system to be bounded by a suitable function of the output and derivatives of the output, modulo a decaying term depending on initial conditions. The class of minimum-phase systems thus defined includes all affine systems in global normal form whose internal dynamics are input-to-state stable and also all left-invertible linear systems whose transmission zeros have negative real parts. As an application, we explain how the new concept enables one to develop a natural extension to nonlinear systems of a basic result from linear adaptive control. |
We study nonlinear systems with both control and disturbance inputs. The main problem addressed in the paper is design of state feedback control laws that render the closed-loop system integral-input-to-state stable (iISS) with respect to the disturbances. We introduce an appropriate concept of control Lyapunov function (iISS-CLF), whose existence leads to an explicit construction of such a control law. The same method applies to the problem of input-to-state stabilization. Converse results and techniques for generating iISS-CLFs are also discussed. |
errata for Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction |
A general ISS-type small-gain result is presented. It specializes to a small-gain theorem for ISS operators, and it also recovers the classical statement for ISS systems in state-space form. In addition, we highlight applications to incrementally stable systems, detectable systems, and to interconnections of stable systems. |
(This is an expository paper prepared for a plenary talk given at the Second Nonlinear Control Network Workshop, Paris, June 9, 2000.) The input to state stability (ISS) paradigm is motivated as a generalization of classical linear systems concepts under coordinate changes. A summary is provided of the main theoretical results concerning ISS and related notions of input/output stability and detectability. A bibliography is also included, listing extensions, applications, and other current work. |
This work explores Lyapunov characterizations of the input-output-to-state stability (IOSS) property for nonlinear systems. The notion of IOSS is a natural generalization of the standard zero-detectability property used in the linear case. The main contribution of this work is to establish a complete equivalence between the input-output-to-state stability property and the existence of a certain type of smooth Lyapunov function. As corollaries, one shows the existence of "norm-estimators", and obtains characterizations of nonlinear detectability in terms of relative stability and of finite-energy estimates. |
This paper deals with the theory of structure, stability, robustness, and stabilization for an appealing class of nonlinear systems which arises in the analysis of chemical networks. The results given here extend, but are also heavily based upon, certain previous work by Feinberg, Horn, and Jackson, of which a self-contained and streamlined exposition is included. The theoretical conclusions are illustrated through an application to the kinetic proofreading model proposed by McKeithan for T-cell receptor signal transduction. |
Just as input to state stability (ISS) generalizes the idea of finite gains with respect to supremum norms, the new notion of integral input to state stability (IISS) generalizes the concept of finite gain when using an integral norm on inputs. In this paper, we obtain a necessary and sufficient characterization of the IISS property, expressed in terms of dissipation inequalities. |
This paper continues the study of the integral input-to-state stability (IISS) property. It is shown that the IISS property is equivalent to one which arises from the consideration of mixed norms on states and inputs, as well as to the superposition of a ``bounded energy bounded state'' requirement and the global asymptotic stability of the unforced system. A semiglobal version of IISS is shown to imply the global version, though a counterexample shows that the analogous fact fails for input to state stability (ISS). The results in this note complete the basic theoretical picture regarding IISS and ISS. |
It is shown that, for neutrally stable discrete-time linear systems subject to actuator saturation, finite gain lp stabilization can be achieved by linear output feedback, for all p>1. An explicit construction of the corresponding feedback laws is given. The feedback laws constructed also result in a closed-loop system that is globally asymptotically stable, and in an input-to-state estimate. |
This paper presents necessary and sufficient characterizations of several notions of input to output stability. Similar Lyapunov characterizations have been found to play a key role in the analysis of the input to state stability property, and the results given here extend their validity to the case when the output, but not necessarily the entire internal state, is being regulated. |
In this expository paper, we deal with several questions related to stability and stabilization of nonlinear finite-dimensional continuous-time systems. We review the basic problem of feedback stabilization, placing an emphasis upon relatively new areas of research which concern stability with respect to "noise" (such as errors introduced by actuators or sensors). The table of contents is as follows: Review of Stability and Asymptotic Controllability, The Problem of Stabilization, Obstructions to Continuous Stabilization, Control-Lyapunov Functions and Artstein's Theorem, Discontinuous Feedback, Nonsmooth CLF's, Insensitivity to Small Measurement and Actuator Errors, Effect of Large Disturbances: Input-to-State Stability, Comments on Notions Related to ISS. |
A finite-dimensional continuous-time system is forward complete if solutions exist globally, for positive time. This paper shows that forward completeness can be characterized in a necessary and sufficient manner by means of smooth scalar growth inequalities. Moreover, a version of this fact is also proved for systems with inputs, and a generalization is also provided for systems with outputs and a notion (unboundedness observability) of relative completeness. We apply these results to obtain a bound on reachable states in terms of energy-like estimates of inputs. |
This paper shows that uniformly global asymptotic stability for a family of ordinary differential equations is equivalent to uniformly global exponential stability under a suitable nonlinear change of variables. The same is shown respectively for input-to-state stability, input-to-state exponential stability, and the property of finite square-norm gain ("nonlinear H-infty"). The results are shown for systems of any dimension not equal to 4 or 5. |
We provide an explicit KL stability or input-to-state stability (ISS) estimate for a sampled-data nonlinear system in terms of the KL estimate for the corresponding discrete-time system and a K function describing inter-sample growth. It is quite obvious that a uniform inter-sample growth condition, plus an ISS property for the exact discrete-time model of a closed-loop system, implies uniform ISS of the sampled-data nonlinear system; our results serve to quantify these facts by means of comparison functions. Our results can be used as an alternative to prove and extend results of Aeyels et al and extend some results by Chen et al to a class of nonlinear systems. Finally, the formulas we establish can be used as a tool for some other problems which we indicate. |
This paper deals with several related notions of output stability with respect to inputs (which may be thought of as disturbances). The main such notion is called input to output stability (IOS), and it reduces to input to state stability (ISS) when the output equals the complete state. For systems with no inputs, IOS provides a generalization of the classical concept of partial stability. Several variants, which formalize in different manners the transient behavior, are introduced. The main results provide a comparison among these notions |
This paper considers the problem of stabilization of linear systems for which only the magnitudes of outputs are measured. It is shown that, if a system is controllable and observable, then one can find a stabilizing controller, which is robust with respect to observation noise (in the ISS sense). |
This note discusses two integral variants of the input-to-state stability (ISS) property, which represent nonlinear generalizations of L2 stability, in much the same way that ISS generalizes L-infinity stability. Both variants are equivalent to ISS for linear systems. For general nonlinear systems, it is shown that one of the new properties is strictly weaker than ISS, while the other one is equivalent to it. For bilinear systems, a complete characterization is provided of the weaker property. An interesting fact about functions of type KL is proved as well. |
The notion of input-to-state stability (ISS) has proved to be useful in nonlinear systems analysis. This paper discusses a dual notion, output-to-state stability (OSS). A characterization is provided in terms of a dissipation inequality involving storage (Lyapunov) functions. Combining ISS and OSS there results the notion of input/output-to-state stability (IOSS), which is also studied and related to the notion of detectability, the existence of observers, and output injection. |
This paper presents a Converse Lyapunov Function Theorem motivated by robust control analysis and design. Our result is based upon, but generalizes, various aspects of well-known classical theorems. In a unified and natural manner, it (1) allows arbitrary bounded time-varying parameters in the system description, (2) deals with global asymptotic stability, (3) results in smooth (infinitely differentiable) Lyapunov functions, and (4) applies to stability with respect to not necessarily compact invariant sets. |
This paper deals with (global) finite-gain input/output stabilization of linear systems with saturated controls. For neutrally stable systems, it is shown that the linear feedback law suggested by the passivity approach indeed provides stability, with respect to every Lp-norm. Explicit bounds on closed-loop gains are obtained, and they are related to the norms for the respective systems without saturation. These results do not extend to the class of systems for which the state matrix has eigenvalues on the imaginary axis with nonsimple (size >1) Jordan blocks, contradicting what may be expected from the fact that such systems are globally asymptotically stabilizable in the state-space sense; this is shown in particular for the double integrator. |
We present new characterizations of the Input to State Stability property. As a consequence of these results, we show the equivalence between the ISS property and several (apparent) variations proposed in the literature. |
An encyclopedia-type article on foundations of input/output stability. |
This paper discusses various continuity and incremental-gain properties for neutrally stable linear systems under linear feedback subject to actuator saturation. The results complement our previous ones, which applied to the same class of problems and provided finite-gain stability. |
We consider the problem of characterizing possible supply functions for a given dissipative nonlinear system, and provide a result that allows some freedom in the modification of such functions. |
We deal with the question of obtaining explicit feedback control laws that stabilize a nonlinear system, under the assumption that a "control Lyapunov function" is known. In previous work, the case of unbounded controls was considered. Here we obtain results for bounded and/or positive controls. We also provide some simple preliminary remarks regarding a set stability version of the problem and a version for systems subject to disturbances. |
This paper studies various stability issues for parameterized families of systems, including problems of stabilization with respect to sets. The study of such families is motivated by robust control applications. A Lyapunov-theoretic necessary and sufficient characterization is obtained for a natural notion of robust uniform set stability; this characterization allows replacing ad hoc conditions found in the literature by more conceptual stability notions. We then use these techniques to establish a result linking state space stability to ``input to state'' (bounded-input bounded-state) stability. In addition, the preservation of stabilizability under certain types of cascade interconnections is analyzed. |
The "input to state stability" (ISS) property provides a natural framework in which to formulate notions of stability with respect to input perturbations. In this expository paper, we review various equivalent definitions expressed in stability, Lyapunov-theoretic, and dissipation terms. We sketch some applications to the stabilization of cascades of systems and of linear systems subject to control saturation. |
We consider the problem of characterizing possible supply functions for a given dissipative nonlinear system, and provide a result that allows some freedom in the modification of such functions. |
We show that the well-known Lyapunov sufficient condition for input-to-state stability is also necessary, settling positively an open question raised by several authors during the past few years. Additional characterizations of the ISS property, including one in terms of nonlinear stability margins, are also provided. |
Controllability questions for discrete-time nonlinear systems are addressed in this paper. In particular, we continue the search for conditions under which the group-like notion of transitivity implies the stronger and semigroup-like property of forward accessibility. We show that this implication holds, pointwise, for states which have a weak Poisson stability property, and globally, if there exists a global "attractor" for the system. |
We present two constructions of controllers that globally stabilize linear systems subject to control saturation. We allow essentially arbitrary saturation functions. The only conditions imposed on the system are the obvious necessary ones, namely that no eigenvalues of the uncontrolled system have positive real part and that the standard stabilizability rank condition hold. One of the constructions is in terms of a "neural-network type" one-hidden layer architecture, while the other one is in terms of cascades of linear maps and saturations. |
A basic open question for discrete-time nonlinear systems is that of determining when, in analogy with the classical continuous-time "positive form of Chow's Lemma", accessibility follows from transitivity of a natural group action. This paper studies the problem, and establishes the desired implication for analytic systems in several cases: (i) compact state space, (ii) under a Poisson stability condition, and (iii) in a generic sense. In addition, the paper studies accessibility properties of the "control sets" recently introduced in the context of dynamical systems studies. Finally, various examples and counterexamples are provided relating the various Lie algebras introduced in past work. |
This conference paper reviews various results relating state-space (Lyapunov) stabilization and exponential stabilization to several notions of input/output or bounded-input bounded-output stabilization. It also provides generalizations of some of these results to systems with saturating controls. Some of these latter results were not included in journal papers. |
Previous results about input to state stabilizability are shown to hold even for systems which are not linear in controls, provided that a more general type of feedback be allowed. Applications to certain stabilization problems and coprime factorizations, as well as comparisons to other results on input to state stability, are also briefly discussed.d local minima may occur, if the data are not separable and sigmoids are used. |
This paper shows that coprime right factorizations exist for the input to state mapping of a continuous time nonlinear system provided that the smooth feedback stabilization problem be solvable for this system. In particular, it follows that feedback linearizable systems admit such factorizations. In order to establish the result a Lyapunov-theoretic definition is proposed for bounded input bounded output stability. The main technical fact proved relates the notion of stabilizability studied in the state space nonlinear control literature to a notion of stability under bounded control perturbations analogous to those studied in operator theoretic approaches to systems; it states that smooth stabilization implies smooth input-to-state stabilization. (Note: This is the original ISS paper, but the ISS results have been much improved in later papers. The material on coprime factorizations is still of interest, but the 89 CDC paper has some improvements and should be read too.) |
A book review which also provides a quick introduction to questions of stability and positivity of multivariable polynomials for 2D and spatially-distributed systems. |
Conference articles |
Integral feedback can help achieve robust tracking independently of external disturbances. Motivated by this knowledge, biological engineers have proposed various designs of biomolecular integral feedback controllers to regulate biological processes. In this paper, we theoretically analyze the operation of a particular synthetic biomolecular integral controller, which we have recently proposed and implemented experimentally. Using a combination of methods, ranging from linearized analysis to sum-of-squares (SOS) Lyapunov functions, we demonstrate that, when the controller is operated in closed-loop, it is capable of providing integral corrections to the concentration of an output species in such a manner that the output tracks a reference signal linearly over a large dynamic range. We investigate the output dependency on the reaction parameters through sensitivity analysis, and quantify performance using control theory metrics to characterize response properties, thus providing clear selection guidelines for practical applications. We then demonstrate the stable operation of the closed-loop control system by constructing quartic Lyapunov functions using SOS optimization techniques, and establish global stability for a unique equilibrium. Our analysis suggests that by incorporating effective molecular sequestration, a biomolecular closed-loop integral controller that is capable of robustly regulating gene expression is feasible. |
This is a tutorial paper on control-theoretic methods for the analysis of biological systems. |
Contraction theory provides an elegant way to analyze the behaviors of certain nonlinear dynamical systems. Under sometimes easy to check hypotheses, systems can be shown to have the incremental stability property that trajectories converge to each other. The present paper provides a self-contained introduction to some of the basic concepts and results in contraction theory, discusses applications to synchronization and to reaction-diffusion partial differential equations, and poses several open questions. |
In this paper, we sketch recent results for synchronization in a network of identical ODE models which are diffusively interconnected. In particular, we provide estimates of convergence of the difference in states between components, in the cases of line, complete, and star graphs, and Cartesian products of such graphs. |
We introduce three forms of generalized contraction~(GC). Roughly speaking, these are motivated by allowing contraction to take place after small transients in time and/or amplitude. Indeed, contraction is usually used to prove asymptotic properties, like convergence to an attractor or entrainment to a periodic excitation, and allowing initial transients does not affect this asymptotic behavior. We provide sufficient conditions for GC, and demonstrate their usefulness using examples of systems that are not contractive, with respect to any norm, yet are~GC. |
Conference version of ``Stability certification of large scale stochastic systems using dissipativity of subsystems''. |
Preliminary conference version of ''A contraction approach to the hierarchical analysis and design of networked systems''. |
Conference version of paper "Conditions for global stability of monotone tridiagonal systems with negative feedback" |
For distributed systems with a cyclic interconnection structure, a global stability result is shown to hold if the secant criterion is satisfied. |
Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property. |
This paper derives new results for certain classes of chemical reaction networks, linking structural to dynamical properties. In particular, it investigates their monotonicity and convergence without making assumptions on the structure (e.g., mass-action kinetics) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find a suitable set of coordinates under which the resulting system is cooperative. As a simple example, the paper shows that a phosphorylation/dephosphorylation process, which is involved in many signaling cascades, has a global stability property. |
This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems. |
This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems. |
We show how certain properties of Goldbeter's original 1995 model for circadian oscillations can be proved mathematically. We establish global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, but, on the other hand, this stability persists even under arbitrary delays in the feedback loop. We are mainly interested in illustrating certain mathematical techniques, including the use of theorems concerning tridiagonal cooperative systems and the recently developed theory of monotone systems with inputs and outputs. |
Monotone systems are dynamical systems for which the flow preserves a partial order. Some applications will be briefly reviewed in this paper. Much of the appeal of the class of monotone systems stems from the fact that roughly, most solutions converge to the set of equilibria. However, this usually requires a stronger monotonicity property which is not always satisfied or easy to check in applications. Following work of J.F. Jiang, we show that monotonicity is enough to conclude global attractivity if there is a unique equilibrium and if the state space satisfies a particular condition. The proof given here is self-contained and does not require the use of any of the results from the theory of monotone systems. We will illustrate it on a class of chemical reaction networks with monotone, but otherwise arbitrary, reaction kinetics. |
The fundamental Filippov--Wazwski Relaxation Theorem states that the solution set of an initial value problem for a locally Lipschitz inclusion is dense in the solution set of the same initial value problem for the corresponding relaxation inclusion on compact intervals. In a recent paper of ours, a complementary result was provided for inclusions with finite dimensional state spaces which says that the approximation can be carried out over non-compact or infinite intervals provided one does not insist on the same initial values. This note extends the infinite-time relaxation theorem to the inclusions whose state spaces are Banach spaces. To illustrate the motivations for studying such approximation results, we briefly discuss a quick application of the result to output stability and uniform output stability properties. |
For systems whose output is to be kept small (thought of as an error output), the notion of input to output stability (IOS) arises. Alternatively, when considering a system whose output is meant to provide information about the state (i.e. a measurement output), one arrives at the detectability notion of output to state stability (OSS). Combining these concepts, one may consider a system with two types of outputs, an error and a measurement. This leads naturally to a notion of partial detectability which we call measurement to error stability (MES). This property characterizes systems in which the error signal is detectable through the measurement signal. This paper provides a partial Lyapunov characterization of the MES property. A closely related property of stability in three measures (SIT) is introduced, which characterizes systems for which the error decays whenever it dominates the measurement. The SIT property is shown to imply MES, and the two are shown to be equivalent under an additional boundedness assumption. A nonsmooth Lyapunov characterization of the SIT property is provided, which yields the partial characterization of MES. The analysis is carried out on systems described by differential inclusions -- implicitly incorporating a disturbance input with compact value-set. |
This paper studies the input-to-state stability (ISS) property for discrete-time nonlinear systems. We show that many standard ISS results may be extended to the discrete-time case. More precisely, we provide a Lyapunov-like sufficient condition for ISS, and we show the equivalence between the ISS property and various other properties, as well as provide a small gain theorem. |
This paper continues the investigation of the recently introduced integral version of input-to-state stability (iISS). We study the problem of designing control laws that achieve iISS disturbance attenuation. The main contribution is an appropriate concept of control Lyapunov function (iISS-CLF), whose existence leads to an explicit construction of such a control law. The results are compared and contrasted with the ones available for the ISS case. |
This paper deals with a notion of "input to output stability (IOS)", which formalizes the idea that outputs depend in an "aymptotically stable" manner on inputs, while internal signals remain bounded. When the output equals the complete state, one recovers the property of input to state stability (ISS). When there are no inputs, one has a generalization of the classical concept of partial stability. The main results provide Lyapunov-function characterizations of IOS. |
Contains a proof of a technical step, which was omitted from the journal paper due to space constraints |
Previous characterizations of ISS-stability are shown to generalize without change to the case of stability with respect to sets. Some results on ISS-stabilizability are mentioned as well. |
Preliminary version of paper published in Automatica in 1995. |
This paper describes how notions of input-to-state stabilization are useful when stabilizing cascades of systems. The simplest result along these lines is local, and it states that a cascade of two locally asymptotically stable systems is again asystable. A global result is obtained if both systems have the origin as a globally asymptotically stable state and the "converging input bounded state" property holds for the second system. Relations to input to state stability and the "bounded input bounded state" property as mentioned as well. |
Internal reports |
Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation, with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ``Basin of Attraction percentage'' is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that methylation plays in enhancing the stability of the silenced gene state. |
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