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Publications by Eduardo D. Sontag in year 2004
Articles in journal or book chapters
  1. D. Angeli and E.D. Sontag. Interconnections of monotone systems with steady-state characteristics. In Optimal control, stabilization and nonsmooth analysis, volume 301 of Lecture Notes in Control and Inform. Sci., pages 135-154. Springer, Berlin, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  2. M. Malisoff and E.D. Sontag. Asymptotic controllability and input-to-state stabilization: the effect of actuator errors. In Optimal control, stabilization and nonsmooth analysis, volume 301 of Lecture Notes in Control and Inform. Sci., pages 155-171. Springer, Berlin, 2004. [PDF] Keyword(s): input to state stability, control-Lyapunov functions, nonlinear control, feedback stabilization.
    Abstract:
    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.


  3. D. Angeli, J. E. Ferrell, and E.D. Sontag. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems.. Proc Natl Acad Sci USA, 101(7):1822-1827, 2004. Note: A revision of Suppl. Fig. 7(b) is here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/nullclines-f-g-REV.jpg; and typos can be found here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/angeli-ferrell-sontag-pnas04-errata.txt. [WWW] [PDF] [doi:10.1073/pnas.0308265100] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  4. D. Angeli, B.P. Ingalls, E.D. Sontag, and Y. Wang. Separation principles for input-output and integral-input-to-state stability. SIAM J. Control Optim., 43(1):256-276, 2004. [PDF] [doi:http://dx.doi.org/10.1137/S0363012902419047] Keyword(s): input to state stability.
    Abstract:
    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.


  5. D. Angeli, B.P. Ingalls, E.D. Sontag, and Y. Wang. Uniform global asymptotic stability of differential inclusions. J. Dynam. Control Systems, 10(3):391-412, 2004. [PDF] [doi:http://dx.doi.org/10.1023/B:JODS.0000034437.54937.7f] Keyword(s): differential inclusions.
    Abstract:
    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.


  6. D. Angeli and E.D. Sontag. Multi-stability in monotone input/output systems. Systems Control Lett., 51(3-4):185-202, 2004. [PDF] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  7. D. Angeli, P. de Leenheer, and E.D. Sontag. A small-gain theorem for almost global convergence of monotone systems. Systems Control Lett., 52(5):407-414, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  8. M. Chaves, R.J. Dinerstein, and E.D. Sontag. Optimal length and signal amplification in weakly activated signal transduction cascades. J. Physical Chemistry, 108:15311-15320, 2004. [PDF] Keyword(s): systems biology, biochemical networks, dynamical systems.
    Abstract:
    Weakly activated signaling cascades can be modeled as linear systems. The input-to-output transfer function and the internal gain of a linear system, provide natural measures for the propagation of the input signal down the cascade and for the characterization of the final outcome. The most efficient design of a cascade for generating sharp signals, is obtained by choosing all the off rates equal, and a "universal" finite optimal length.


  9. M. Chaves, E.D. Sontag, and R. J. Dinerstein. Steady-states of receptor-ligand dynamics: A theoretical framework. J. Theoret. Biol., 227(3):413-428, 2004. [PDF] Keyword(s): zero-deficiency networks, systems biology, biochemical networks, receptor-ligand models, dynamical systems.
    Abstract:
    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.


  10. G.A. Enciso and E.D. Sontag. On the stability of a model of testosterone dynamics. J. Math. Biol., 49(6):627-634, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  11. P. Kuusela, D. Ocone, and E.D. Sontag. Learning Complexity Dimensions for a Continuous-Time Control System. SIAM J. Control Optim., 43(3):872-898, 2004. [PDF] [doi:http://dx.doi.org/10.1137/S0363012901384302] Keyword(s): theory of computing and complexity, VC dimension.
    Abstract:
    This paper takes a computational learning theory approach to a problem of linear systems identification. It is assumed that input signals have only a finite number k of frequency components, and systems to be identified have dimension no greater than n. The main result establishes that the sample complexity needed for identification scales polynomially with n and logarithmically with k.


  12. M. Malisoff, L. Rifford, and E.D. Sontag. Global Asymptotic Controllability Implies Input-to-State Stabilization. SIAM J. Control Optim., 42(6):2221-2238, 2004. [PDF] [doi:http://dx.doi.org/10.1137/S0363012903422333] Keyword(s): input to state stability, control-Lyapunov functions, nonlinear control, feedback stabilization.
    Abstract:
    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.


  13. E.D. Sontag. Some new directions in control theory inspired by systems biology. IET Systems Biology, 1:9-18, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems, cellular signaling.
    Abstract:
    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.


  14. E.D. Sontag, A. Kiyatkin, and B.N. Kholodenko. Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics, 20(12):1877-1886, 2004. Note: Supplementary materials are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/sontag-kiyatkin-kholodenko-informatics04-supplement.pdf. [PDF] [doi:http://dx.doi.org/10.1093/bioinformatics/bth173] Keyword(s): systems biology, biochemical networks, systems identification, gene and protein networks, reverse engineering.
    Abstract:
    High-throughput technologies have facilitated the acquisition of large genomics and proteomics data sets. However, these data provide snapshots of cellular behavior, rather than help us reveal causal relations. Here, we propose how these technologies can be utilized to infer the topology and strengths of connections among genes, proteins, and metabolites by monitoring time-dependent responses of cellular networks to experimental interventions. We show that all connections leading to a given network node, e.g., to a particular gene, can be deduced from responses to perturbations none of which directly influences that node, e.g., using strains with knock-outs to other genes. To infer all interactions from stationary data, each node should be perturbed separately or in combination with other nodes. Monitoring time series provides richer information and does not require perturbations to all nodes.


Conference articles
  1. D. Angeli and E.D. Sontag. An analysis of a circadian model using the small-gain approach to monotone systems. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 575-578, 2004. [PDF] Keyword(s): circadian rhythms, tridiagonal systems, nonlinear dynamics, systems biology, biochemical networks, oscillations, periodic behavior, monotone systems.
    Abstract:
    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.


  2. D. Angeli, P. de Leenheer, and E.D. Sontag. A tutorial on monotone systems- with an application to chemical reaction networks. In Proc. 16th Int. Symp. Mathematical Theory of Networks and Systems (MTNS 2004), CD-ROM, WP9.1, Katholieke Universiteit Leuven, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    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.


  3. D. Angeli, P. de Leenheer, and E.D. Sontag. Remarks on monotonicity and convergence in chemical reaction networks. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 243-248, 2004. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  4. M. Chaves, E.D. Sontag, and R.J. Dinerstein. Gains and optimal design in signaling pathways. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 596-601, 2004. Keyword(s): systems biology, biochemical networks, dynamical systems.


  5. B. DasGupta, J.P. Hespanha, and E.D. Sontag. Aggregation-based approaches to honey-pot searching with local sensory information. In Proceedings American Control Conf., Boston, June 2004, 2004. Note: (CD-ROM WeM17.4, IEEE Publications, Piscataway). [PDF]
    Abstract:
    We investigate the problem of searching for a hidden target in a bounded region by an autonomous agent that is only able to use limited local sensory information. We propose an aggregation-based approach to solve this problem, in which the continuous search space is partitioned into a finite collection of regions on which we define a discrete search problem. A solution to the original problem is then obtained through a refinement procedure that lifts the discrete path into a continuous one. The resulting solution is in general not optimal but one can construct bounds to gauge the cost penalty incurred.


  6. B. DasGupta, J.P. Hespanha, and E.D. Sontag. Computational complexities of honey-pot searching with local sensory information. In Proceedings American Control Conf., Boston, June 2004, CD-ROM, ThA06.1, IEEE Publications, Piscataway, 2004. [PDF]
    Abstract:
    In this paper we investigate the problem of searching for a hidden target in a bounded region of the plane, by an autonomous robot which is only able to use limited local sensory information. We formalize a discrete version of the problem as a "reward-collecting" path problem and provide efficient approximation algorithms for various cases.


  7. G.A. Enciso and E.D. Sontag. A remark on multistability for monotone systems. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 249-254, 2004. Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  8. J.L. Mancilla-Aguilar, R. Garcža, E.D. Sontag, and Y. Wang. Representation of switched systems by perturbed control systems. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 3259-3264, 2004.



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