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 Articles in journal or book chapters
1. M.A. Al-Radhawi, M. Sadeghi, and E.D. Sontag. Long-term regulation of prolonged epidemic outbreaks in large populations via adaptive control: a singular perturbation approach. IEEE Control Systems Letters, 6:578-583, 2022. [PDF] Keyword(s): epidemiology, COVID-19, COVID, systems biology.
Abstract:
 In order to control highly-contagious and prolonged outbreaks, public health authorities intervene to institute social distancing, lock-down policies, and other Non-Pharmaceutical Interventions (NPIs). Given the high social, educational, psychological, and economic costs of NPIs, authorities tune them, alternatively tightening up or relaxing rules, with the result that, in effect, a relatively flat infection rate results. For example, during the summer of 2020 in parts of the United States, daily COVID-19 infection numbers dropped to a plateau. This paper approaches NPI tuning as a control-theoretic problem, starting from a simple dynamic model for social distancing based on the classical SIR epidemics model. Using a singular-perturbation approach, the plateau becomes a Quasi-Steady-State (QSS) of a reduced two-dimensional SIR model regulated by adaptive dynamic feedback. It is shown that the QSS can be assigned and it is globally asymptotically stable. Interestingly, the dynamic model for social distancing can be interpreted as a nonlinear integral controller. Problems of data fitting and parameter identifiability are also studied for this model. This letter also discusses how this simple model allows for a meaningful study of the effect of population size, vaccinations, and the emergence of second waves.

2. Eduardo D. Sontag. Remarks on input to state stability of perturbed gradient flows, motivated by model-free feedback control learning. Systems and Control Letters, 161:105138, 2022. [PDF] Keyword(s): iss, input to state stability, data-driven control, gradient systems, steepest descent, model-free control.
Abstract:
 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 note 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.

3. D.K. Agrawal, R. Marshall, V. Noireaux, and E.D. Sontag. In vitro implementation of robust gene regulation in a synthetic biomolecular integral controller. Nature Communications, 10:1-12, 2019. [PDF] Keyword(s): tracking, synthetic biology, integral feedback, TX/TL, systems biology, dynamical systems, adaptation, internal model principle, identifiability.
Abstract:
 Cells respond to biochemical and physical internal as well as external signals. These signals can be broadly classified into two categories: (a) actionable'' or reference'' inputs that should elicit appropriate biological or physical responses such as gene expression or motility, and (b) disturbances'' or perturbations'' that should be ignored or actively filtered-out. These disturbances might be exogenous, such as binding of nonspecific ligands, or endogenous, such as variations in enzyme concentrations or gene copy numbers. In this context, the term robustness describes the capability to produce appropriate responses to reference inputs while at the same time being insensitive to disturbances. These two objectives often conflict with each other and require delicate design trade-offs. Indeed, natural biological systems use complicated and still poorly understood control strategies in order to finely balance the goals of responsiveness and robustness. A better understanding of such natural strategies remains an important scientific goal in itself and will play a role in the construction of synthetic circuits for therapeutic and biosensing applications. A prototype problem in robustly responding to inputs is that of robust tracking'', defined by the requirement that some designated internal quantity (for example, the level of expression of a reporter protein) should faithfully follow an input signal while being insensitive to an appropriate class of perturbations. Control theory predicts that a certain type of motif, called integral feedback, will help achieve this goal, and this motif is, in fact, a necessary feature of any system that exhibits robust tracking. Indeed, integral feedback has always been a key component of electrical and mechanical control systems, at least since the 18th century when James Watt employed the centrifugal governor to regulate steam engines. Motivated by this knowledge, biological engineers have proposed various designs for biomolecular integral feedback control mechanisms. However, practical and quantitatively predictable implementations have proved challenging, in part due to the difficulty in obtaining accurate models of transcription, translation, and resource competition in living cells, and the stochasticity inherent in cellular reactions. These challenges prevent first-principles rational design and parameter optimization. In this work, we exploit the versatility of an Escherichia coli cell-free transcription-translation (TXTL) to accurately design, model and then build, a synthetic biomolecular integral controller that precisely controls the expression of a target gene. To our knowledge, this is the first design of a functioning gene network that achieves the goal of making gene expression track an externally imposed reference level, achieves this goal even in the presence of disturbances, and whose performance quantitatively agrees with mathematical predictions.

4. E.V. Nikolaev, S.J. Rahi, and E.D. Sontag. Chaos in simple periodically-forced biological models. Biophysical Journal, 114:1232-1240, 2018. [PDF] Keyword(s): chaos, entrainment, systems biology, periodic inputs, subharmonic responses, biochemical systems, forced oscillations.
Abstract:
 What complicated dynamics can arise in the simplest biochemical systems, in response to a periodic input? This paper discusses two models that commonly appear as components of larger sensing and signal transduction pathways in systems biology: a simple two-species negative feedback loop, and a prototype nonlinear integral feedback. These systems have globally attracting steady states when unforced, yet, when subject to a periodic excitation, subharmonic responses and strange attractors can arise via period-doubling cascades. These behaviors are similar to those exhibited by classical forced nonlinear oscillators such as those described by van der Pol or Duffing equations. The lack of entrainment to external oscillations, in even the simplest biochemical networks, represents a level of additional complexity in molecular biology.

5. S. J. Rahi, J. Larsch, K. Pecani, N. Mansouri, A. Y. Katsov, K. Tsaneva-Atanasova, E. D. Sontag, and F. R. Cross. Oscillatory stimuli differentiate adapting circuit topologies. Nature Methods, 14:1010-1016, 2017. [PDF] Keyword(s): biochemical networks, periodic behaviors, monotone systems, entrainment, oscillations, incoherent feedforward loop, feedforward, IFFL, systems biology.
Abstract:
 Elucidating the structure of biological intracellular networks from experimental data remains a major challenge. This paper studies two types of response signatures'' to identify specific circuit motifs, from the observed response to periodic inputs. In particular, the objective is to distinguish negative feedback loops (NFLs) from incoherent feedforward loops (IFFLs), which are two types of circuits capable of producing exact adaptation. The theory of monotone systems with inputs is used to show that period skipping'' (non-harmonic responses) is ruled out in IFFL's, and a notion called refractory period stabilization'' is also analyzed. The approach is then applied to identify a circuit dominating cell cycle timing in yeast, and to uncover a calcium-mediated NFL circuit in \emph{C.elegans} olfactory sensory neurons.

6. E.D. Sontag. A dynamical model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination. Cell Systems, 4:231-241, 2017. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, cancer, internal model principle, incoherent feedforward loop, feedforward, IFFL, systems biology.
Abstract:
 Since the early 1990s, many authors have independently suggested that self/nonself recognition by the immune system might be modulated by the rates of change of antigen challenges. This paper introduces an extremely simple and purely conceptual mathematical model that allows dynamic discrimination of immune challenges. The main component of the model is a motif which is ubiquitous in systems biology, the incoherent feedforward loop, which endows the system with the capability to estimate exponential growth exponents, a prediction which is consistent with experimental work showing that exponentially increasing antigen stimulation is a determinant of immune reactivity. Combined with a bistable system and a simple feedback repression mechanism, an interesting phenomenon emerges as a tumor growth rate increases: elimination, tolerance (tumor growth), again elimination, and finally a second zone of tolerance (tumor escape). This prediction from our model is analogous to the two-zone tumor tolerance'' phenomenon experimentally validated since the mid 1970s. Moreover, we provide a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.

7. M. Skataric, E.V. Nikolaev, and E.D. Sontag. A fundamental limitation to fold-change detection by biological systems with multiple time scales. IET Systems Biology, 9:1-15, 2015. [PDF] Keyword(s): adaptation, biological adaptation, perfect adaptation, singular perturbations, scale invariance, systems biology, transient behavior, symmetries, fcd, fold-change detection, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 The phenomenon of fold-change detection, or scale invariance, is exhibited by a variety of sensory systems, in both bacterial and eukaryotic signaling pathways. It has been often remarked in the systems biology literature that certain systems whose output variables respond at a faster time scale than internal components give rise to an approximate scale-invariant behavior, allowing approximate fold-change detection in stimuli. This paper establishes a fundamental limitation of such a mechanism, showing that there is a minimal fold-change detection error that cannot be overcome, no matter how large the separation of time scales is. To illustrate this theoretically predicted limitation, we discuss two common biomolecular network motifs, an incoherent feedforward loop and a feedback system, as well as a published model of the chemotaxis signaling pathway of Dictyostelium discoideum.

8. D. Angeli, G.A. Enciso, and E.D. Sontag. A small-gain result for orthant-monotone systems under mixed feedback. Systems and Control Letters, 68:9-19, 2014. [PDF] Keyword(s): small-gain theorem, monotone systems.
Abstract:
 This paper introduces a small-gain result for interconnected orthant-monotone systems for which no matching condition is required between the partial orders in input and output spaces. Previous results assumed that the partial orders adopted would be induced by positivity cones in input and output spaces and that such positivity cones should fulfill a compatibility rule: namely either be coincident or be opposite. Those two configurations correspond to positive feedback or negative feedback cases. We relax those results by allowing arbitrary orthant orders.

9. S. Prabakaran, J. Gunawardena, and E.D. Sontag. Paradoxical results in perturbation-based signaling network reconstruction. Biophysical Journal, 106:2720-2728, 2014. [PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, gene and protein networks, reverse engineering, systems identification, retroactivity.
Abstract:
 This paper describes a potential pitfall of perturbation-based approaches to network inference It is shows experimentally, and then explained mathematically, how even in the simplest signaling systems, perturbation methods may lead to paradoxical conclusions: for any given pair of two components X and Y, and depending upon the specific intervention on Y, either an activation or a repression of X could be inferred. The experiments are performed in an in vitro minimal system, thus isolating the effect and showing that it cannot be explained by feedbacks due to unknown intermediates; this system utilizes proteins from a pathway in mammalian (and other eukaryotic) cells that play a central role in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis and is a perturbation target of contemporary therapies for various types of cancers. The results show that the simplistic view of intracellular signaling networks being made up of activation and repression links is seriously misleading, and call for a fundamental rethinking of signaling network analysis and inference methods.

10. M. Marcondes de Freitas and E.D. Sontag. Random dynamical systems with inputs. In C. Pötzsche and P. Kloeden, editors, Nonautonomous Dynamical Systems in the Life Sciences, Lecture Notes in Mathematics vol. 2102, pages 41-87. Springer-Verlag, 2013. [PDF] Keyword(s): random dynamical systems, monotone systems.
Abstract:
 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.

11. V. Shimoga, J.T. White, Y. Li, E.D. Sontag, and L. Bleris. Synthetic mammalian transgene negative autoregulation. Molecular Systems Biology, 9:670-, 2013. [PDF] Keyword(s): systems biology, synthetic biology, gene expression.
Abstract:
 Using synthetic circuits stably integrated in human kidney cells, we study the effect of negative feedback regulation on cell-wide (extrinsic) and gene-specific (intrinsic) sources of uncertainty. We develop a theoretical approach to extract the two noise components from experiments and show that negative feedback reduces extrinsic noise while marginally increasing intrinsic noise, resulting to significant total noise reduction. We compare the results to simple negative regulation, where a constitutively transcribed transcription factor represses a reporter protein. We observe that the control architecture also reduces the extrinsic noise but results in substantially higher intrinsic fluctuations. We conclude that negative feedback is the most efficient way to mitigate the effects of extrinsic fluctuations by a sole regulatory wiring.

12. E.D. Sontag. Stability and feedback stabilization. In Robert Meyers, editor, Mathematics of Complexity and Dynamical Systems, pages 1639-1652. Springer-Verlag, Berlin, 2011. [PDF] Keyword(s): stability, nonlinear control, feedback stabilization.
Abstract:
 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.

13. O. Shoval, U. Alon, and E.D. Sontag. Symmetry invariance for adapting biological systems. SIAM Journal on Applied Dynamical Systems, 10:857-886, 2011. Note: (See here for a small typo: http://www.sontaglab.org/FTPDIR/shoval.alon.sontag.erratum.pdf). [PDF] Keyword(s): adaptation, biological adaptation, perfect adaptation, adaptation, feedforward loops, integral feedback, scale invariance, systems biology, transient behavior, symmetries, fcd, fold-change detection, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 Often, the ultimate goal of regulation is to maintain a narrow range of concentration levels of vital quantities (homeostasis, adaptation) while at the same time appropriately reacting to changes in the environment (signal detection or sensitivity). Much theoretical, modeling, and analysis effort has been devoted to the understanding of these questions, traditionally in the context of steady-state responses to constant or step-changing stimuli. In this paper, we present a new theorem that provides a necessary and sufficient characterization of invariance of transient responses to symmetries in inputs. A particular example of this property, scale invariance (a.k.a. "fold change detection"), appears to be exhibited by biological sensory systems ranging from bacterial chemotaxis pathways to signal transduction mechanisms in eukaryotes. The new characterization amounts to the solvability of an associated partial differential equation. It is framed in terms of a notion which considerably extends equivariant actions of compact Lie groups. For several simple system motifs that are recurrent in biology, the solvability criterion may be checked explicitly.

14. O. Shoval, L. Goentoro, Y. Hart, A. Mayo, E.D. Sontag, and U. Alon. Fold change detection and scalar symmetry of sensory input fields. Proc Natl Acad Sci USA, 107:15995-16000, 2010. [PDF] Keyword(s): adaptation, biological adaptation, perfect adaptation, adaptation, feedforward loops, integral feedback, scale invariance, systems biology, transient behavior, symmetries, fcd, fold-change detection, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 Certain cellular sensory systems display fold-change detection (FCD): a response whose entire shape, including amplitude and duration, depends only on fold-changes in input, and not on absolute changes. Thus, a step change in input from, say, level 1 to 2, gives precisely the same dynamical output as a step from level 2 to 4, since the steps have the same fold-change. We ask what is the benefit of FCD, and show that FCD is necessary and sufficient for sensory search to be independent of multiplying the input-field by a scalar. Thus the FCD search pattern depends only on the spatial profile of the input, and not on its amplitude. Such scalar symmetry occurs in a wide range of sensory inputs, such as source strength multiplying diffusing/convecting chemical fields sensed in chemotaxis, ambient light multiplying the contrast field in vision, and protein concentrations multiplying the output in cellular signaling-systems.Furthermore, we demonstrate that FCD entails two features found across sensory systems, exact adaptation and Weber's law, but that these two features are not sufficient for FCD. Finally, we present a wide class of mechanisms that have FCD, including certain non-linear feedback and feedforward loops.. We find that bacterial chemotaxis displays feedback within the present class, and hence is expected to show FCD. This can explain experiments in which chemotaxis searches are insensitive to attractant source levels. This study thus suggests a connection between properties of biological sensory systems and scalar symmetry stemming from physical properties of their input-fields.

15. E.D. Sontag. Remarks on Feedforward Circuits, Adaptation, and Pulse Memory. IET Systems Biology, 4:39-51, 2010. [PDF] Keyword(s): adaptation, feedforward loops, integral feedback, systems biology, transient behavior, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 This note studies feedforward circuits as models for perfect adaptation to step signals in biological systems. A global convergence theorem is proved in a general framework, which includes examples from the literature as particular cases. A notable aspect of these circuits is that they do not adapt to pulse signals, because they display a memory phenomenon. Estimates are given of the magnitude of this effect.

16. L. Wang, P. de Leenheer, and E.D. Sontag. Conditions for global stability of monotone tridiagonal systems with negative feedback. Systems and Control Letters, 59:138-130, 2010. [PDF] Keyword(s): systems biology, monotone systems, tridiagonal systems, global stability.
Abstract:
 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.

17. D. Angeli, M.W. Hirsch, and E.D. Sontag. Attractors in coherent systems of differential equations. J. of Differential Equations, 246:3058-3076, 2009. [PDF] Keyword(s): monotone systems, positive feedback systems.
Abstract:
 Attractors of cooperative dynamical systems are particularly simple; for example, a nontrivial periodic orbit cannot be an attractor. This paper provides characterizations of attractors for the wider class of systems defined by the property that all directed feedback loops are positive. Several new results for cooperative systems are obtained in the process.

18. A.M. Weinstein and E.D. Sontag. Modeling proximal tubule cell homeostasis: Tracking changes in luminal flow. Bulletin of Mathematical Biology, 71:1285-1322, 2009. [PDF]
Abstract:
 During normal kidney function, there are are routinely wide swings in proximal tubule fluid flow and proportional changes in Na+ reabsorption across tubule epithelial cells. This "glomerulotubular balance" occurs in the absence of any substantial change in cell volume, and is thus a challenge to coordinate luminal membrane solute entry with peritubular membrane solute exit. In this work, linear optimal control theory is applied to generate a configuration of regulated transporters that could achieve this result. A previously developed model of rat proximal tubule epithelium is linearized about a physiologic reference condition; the approximate linear system is recast as a dynamical system; and a Riccati equation is solved to yield optimal linear feedback that stabilizes Na+ flux, cell volume, and cell pH. This optimal feedback control is largely consigned to three physiologic variables, cell volume, cell electrical potential, and lateral intercellular hydrostatic pressure. Transport modulation by cell volume stabilizes cell volume; transport modulation by electrical potential or interspace pressure act to stabilize Na+ flux and cell pH. This feedback control is utilized in a tracking problem, in which reabsorptive Na+ flux varies over a factor of two. The resulting control parameters consist of two terms, an autonomous term and a feedback term, and both terms include transporters on both luminal and peritubular cell membranes. Overall, the increase in Na+ flux is achieved with upregulation of luminal Na+/H+ exchange and Na+-glucose cotransport, with increased peritubular Na+-3HCO_3- and K+-Cl- cotransport, and with increased Na+,K+-ATPase activity. The configuration of activated transporters emerges as testable hypothesis of the molecular basis for glomerulotubular balance. It is suggested that the autonomous control component at each cell membrane could represent the cytoskeletal effects of luminal flow.

19. D. Angeli and E.D. Sontag. Oscillations in I/O monotone systems. IEEE Transactions on Circuits and Systems, Special Issue on Systems Biology, 55:166-176, 2008. Note: Preprint version in arXiv q-bio.QM/0701018, 14 Jan 2007. [PDF] Keyword(s): monotone systems, hopf bifurcations, circadian rhythms, tridiagonal systems, nonlinear dynamics, systems biology, biochemical networks, oscillations, periodic behavior.
Abstract:
 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.

20. M. Arcak and E.D. Sontag. A passivity-based stability criterion for a class of interconnected systems and applications to biochemical reaction networks. Mathematical Biosciences and Engineering, 5:1-19, 2008. Note: Also, preprint: arxiv0705.3188v1 [q-bio], May 2007. [PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.
Abstract:
 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.

21. D. Del Vecchio, A.J. Ninfa, and E.D. Sontag. Modular Cell Biology: Retroactivity and Insulation. Molecular Systems Biology, 4:161, 2008. [PDF] Keyword(s): retroactivity, systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.
Abstract:
 Modularity plays a fundamental role in the prediction of the behavior of a system from the behavior of its components, guaranteeing that the properties of individual components do not change upon interconnection. Just as electrical, hydraulic, and other physical systems often do not display modularity, nor do many biochemical systems, and specifically, genetic networks. Here, we study the effect of interconnections on the input/output dynamic characteristics of transcriptional components, focusing on a property, which we call "retroactivity," that plays a role analogous to non-zero output impedance in electrical systems. In transcriptional networks, retroactivity is large when the amount of transcription factor is comparable to, or smaller than, the amount of promoter binding sites, or when the affinity of such binding sites is high. In order to attenuate the effect of retroactivity, we propose a feedback mechanism inspired by the design of amplifiers in electronics. We introduce, in particular, a mechanism based on a phosphorylation/dephosphorylation cycle. This mechanism enjoys a remarkable insulation property, due to the fast time scales of the phosphorylation and dephosphorylation reactions. Such a mechanism, when viewed as a signal transduction system, has thus an inherent capacity to provide insulation and hence to increase the modularity of the system in which it is placed.

22. M.R. Jovanovic, M. Arcak, and E.D. Sontag. A passivity-based approach to stability of spatially distributed systems with a cyclic interconnection structure. IEEE Transactions on Circuits and Systems, Special Issue on Systems Biology, 55:75-86, 2008. Note: Preprint: also arXiv math.OC/0701622, 22 January 2007.[PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, diffusion, secant condition, cyclic feedback systems.
Abstract:
 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.

23. A. Maayan, R. Iyengar, and E.D. Sontag. Intracellular Regulatory Networks are close to Monotone Systems. IET Systems Biology, 2:103-112, 2008. [PDF]
Abstract:
 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.

24. E.D. Sontag. Network reconstruction based on steady-state data. Essays in Biochemistry, 45:161-176, 2008. [PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, gene and protein networks, reverse engineering, systems identification.
Abstract:
 The reverse engineering problem'' in systems biology is that of unraveling of the web of interactions among the components of protein and gene regulatory networks, so as to map out the direct or local interactions among components. These direct interactions capture the topology of the functional network. An intrinsic difficulty in capturing these direct interactions, at least in intact cells, is that any perturbation to a particular gene or signaling component may rapidly propagate throughout the network, thus causing global changes which cannot be easily distinguished from direct effects. Thus, a major goal in reverse engineering is to use these observed global responses - such as steady-state changes in concentrations of active proteins, mRNA levels, or transcription rates - in order to infer the local interactions between individual nodes. One approach to solving this global-to-local problem is the Modular Response Analysis'' (MRA) method proposed in work of the author with Kholodenko et. al. (PNAS, 2002) and further elaborated in other papers. The basic method deals only with steady-state data. However, recently, quasi-steady state MRA has been used by Santos et. al. (Nature Cell Biology, 2007) for quantifying positive and negative feedback effects in the Raf/Mek/Erk MAPK network in rat adrenal pheochromocytoma (PC-12) cells. This paper presents an overview of the MRA technique, as well as a generalization of the algorithm to that quasi-steady state case.

25. E.D. Sontag, A. Veliz-Cuba, R. Laubenbacher, and A.S. Jarrah. The effect of negative feedback loops on the dynamics of Boolean networks. Biophysical Journal, 95:518-526, 2008. [PDF] Keyword(s): monotone systems, positive feedback systems, Boolean networks, limit cycles.
Abstract:
 Feedback loops play an important role in determining the dynamics of biological networks. In order to study the role of negative feedback loops, this paper introduces the notion of "distance to positive feedback (PF-distance)" which in essence captures the number of "independent" negative feedback loops in the network, a property inherent in the network topology. Through a computational study using Boolean networks it is shown that PF-distance has a strong influence on network dynamics and correlates very well with the number and length of limit cycles in the phase space of the network. To be precise, it is shown that, as the number of independent negative feedback loops increases, the number (length) of limit cycles tends to decrease (increase). These conclusions are consistent with the fact that certain natural biological networks exhibit generally regular behavior and have fewer negative feedback loops than randomized networks with the same numbers of nodes and connectivity.

26. L. Wang and E.D. Sontag. Singularly perturbed monotone systems and an application to double phosphorylation cycles. J. Nonlinear Science, 18:527-550, 2008. [PDF] Keyword(s): singular perturbations, futile cycles, MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, multistability, monotone systems.
Abstract:
 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.

27. E.D. Sontag. Stability and Feedback Stabilization. In Robert Meyers, editor, Encyclopedia of Complexity and Systems Science. Springer-Verlag, Berlin, 2007. Keyword(s): stability, nonlinear control, feedback stabilization.
Abstract:
 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.

28. T. Gedeon and E.D. Sontag. Oscillations in multi-stable monotone systems with slowly varying feedback. J. of Differential Equations, 239:273-295, 2007. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

29. W. Maass, P. Joshi, and E.D. Sontag. Computational aspects of feedback in neural circuits. PLoS Computational Biology, 3:e165 1-20, 2007. [PDF] Keyword(s): machine learning, neural networks, feedback linearization, computation by cortical microcircuits, fading memory.
Abstract:
 It had previously been shown that generic cortical microcircuit models can perform complex real-time computations on continuous input streams, provided that these computations can be carried out with a rapidly fading memory. We investigate in this article the computational capability of such circuits in the more realistic case where not only readout neurons, but in addition a few neurons within the circuit have been trained for specific tasks. This is essentially equivalent to the case where the output of trained readout neurons is fed back into the circuit. We show that this new model overcomes the limitation of a rapidly fading memory. In fact, we prove that in the idealized case without noise it can carry out any conceivable digital or analog computation on time-varying inputs. But even with noise the resulting computational model can perform a large class of biologically relevant real-time computations that require a non-fading memory.

30. W. Maass, P. Joshi, and E.D. Sontag. Principles of real-time computing with feedback applied to cortical microcircuit models. In Advances in Neural Information Processing Systems 18. MIT Press, Cambridge, 2006. [PDF] Keyword(s): neural networks.
Abstract:
 The network topology of neurons in the brain exhibits an abundance of feedback connections, but the computational function of these feedback connections is largely unknown. We present a computational theory that characterizes the gain in computational power achieved through feedback in dynamical systems with fading memory. It implies that many such systems acquire through feedback universal computational capabilities for analog computing with a non-fading memory. In particular, we show that feedback enables such systems to process time-varying input streams in diverse ways according to rules that are implemented through internal states of the dynamical system. In contrast to previous attractor-based computational models for neural networks, these flexible internal states are high-dimensional attractors of the circuit dynamics, that still allow the circuit state to absorb new information from online input streams. In this way one arrives at novel models for working memory, integration of evidence, and reward expectation in cortical circuits. We show that they are applicable to circuits of conductance-based Hodgkin-Huxley (HH) neurons with high levels of noise that reflect experimental data on invivo conditions.

31. M. Arcak and E.D. Sontag. Diagonal stability of a class of cyclic systems and its connection with the secant criterion. Automatica, 42:1531-1537, 2006. [PDF] Keyword(s): passive systems, systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.
Abstract:
 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.

32. G.A. Enciso, H.L. Smith, and E.D. Sontag. Non-monotone systems decomposable into monotone systems with negative feedback. J. of Differential Equations, 224:205-227, 2006. [PDF] Keyword(s): nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

33. G.A. Enciso and E.D. Sontag. Global attractivity, I/O monotone small-gain theorems, and biological delay systems. Discrete Contin. Dyn. Syst., 14(3):549-578, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

34. M. Malisoff, M. Krichman, and E.D. Sontag. Global stabilization for systems evolving on manifolds. Journal of Dynamical and Control Systems, 12:161-184, 2006. [PDF] Keyword(s): nonlinear stability, nonlinear control, feedback stabilization.
Abstract:
 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.

35. E.D. Sontag. Passivity gains and the secant condition'' for stability. Systems Control Lett., 55(3):177-183, 2006. [PDF] Keyword(s): cyclic feedback systems, systems biology, biochemical networks, nonlinear stability, dynamical systems, passive systems, secant condition, biochemical networks.
Abstract:
 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.

36. P. de Leenheer, D. Angeli, and E.D. Sontag. Crowding effects promote coexistence in the chemostat. Journal of Mathematical Analysis and Applications, 319:48-60, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

37. G.A. Enciso and E.D. Sontag. Monotone systems under positive feedback: multistability and a reduction theorem. Systems Control Lett., 54(2):159-168, 2005. [PDF] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

38. J.P. Hespanha, D. Liberzon, D. Angeli, and E.D. Sontag. Nonlinear norm-observability notions and stability of switched systems. IEEE Trans. Automat. Control, 50(2):154-168, 2005. [PDF] Keyword(s): observability, input to state stability, observability, invariance principle.
Abstract:
 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.

39. P. de Leenheer, D. Angeli, and E.D. Sontag. On predator-prey systems and small-gain theorems. Math. Biosci. Eng., 2(1):25-42, 2005. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

40. 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.

41. 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, ISS.
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.

42. 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://sontaglab.org/FTPDIR/nullclines-f-g-REV.jpg; and typos can be found here: http://sontaglab.org/FTPDIR/angeli-ferrell-sontag-pnas04-errata.txt. [WWW] [PDF] [doi:10.1073/pnas.0308265100] Keyword(s): MAPK cascades, 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.

43. 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.

44. 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.

45. 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.

46. 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.

47. P. de Leenheer, D. Angeli, and E.D. Sontag. A feedback perspective for chemostat models with crowding effects. In Positive systems (Rome, 2003), volume 294 of Lecture Notes in Control and Inform. Sci., pages 167-174. Springer, Berlin, 2003. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.

48. D. Angeli and E.D. Sontag. Monotone control systems. IEEE Trans. Automat. Control, 48(10):1684-1698, 2003. Note: Errata are here: http://sontaglab.org/FTPDIR/angeli-sontag-monotone-TAC03-typos.txt. [PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

49. L. Moreau and E.D. Sontag. Balancing at the border of instability. Phys. Rev. E (3), 68(2):020901, 4, 2003. [PDF] Keyword(s): bifurcations, adaptive control.
Abstract:
 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.

50. L. Moreau, E.D. Sontag, and M. Arcak. Feedback tuning of bifurcations. Systems Control Lett., 50(3):229-239, 2003. [PDF] Keyword(s): bifurcations, adaptive control.
Abstract:
 This paper studies a feedback regulation problem that arises in at least two different biological applications. The feedback regulation problem under consideration may be interpreted as an adaptive control problem for tuning bifurcation parameters, and it has not been studied in the control literature. The goal of the paper is to formulate this problem and to present some preliminary results.

51. J. R. Pomerening, E.D. Sontag, and J. E. Ferrell. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biology, 5(4):346-351, 2003. Note: Supplementary materials 2-4 are here: http://sontaglab.org/FTPDIR/pomerening-sontag-ferrell-additional.pdf. [WWW] [PDF] [doi:10.1038/ncb954] Keyword(s): systems biology, biochemical networks, oscillations, nonlinear stability, dynamical systems, monotone systems.
Abstract:
 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.

52. D. Liberzon, E.D. Sontag, and Y. Wang. Universal construction of feedback laws achieving ISS and integral-ISS disturbance attenuation. Systems Control Lett., 46(2):111-127, 2002. Note: Errata here: http://sontaglab.org/FTPDIR/iiss-clf-errata.pdf. [PDF] Keyword(s): input to state stability, integral input to state stability, ISS, iISS, nonlinear control, feedback stabilization.
Abstract:
 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.

53. E.D. Sontag. Asymptotic amplitudes and Cauchy gains: A small-gain principle and an application to inhibitory biological feedback. Systems Control Lett., 47(2):167-179, 2002. [PDF] Keyword(s): MAPK cascades, cyclic feedback systems, small-gain.
Abstract:
 The notions of asymptotic amplitude for signals, and Cauchy gain for input/output systems, and an associated small-gain principle, are introduced. These concepts allow the consideration of systems with multiple, and possibly feedback-dependent, steady states. A Lyapunov-like characterization allows the computation of gains for state-space systems, and the formulation of sufficient conditions insuring the lack of oscillations and chaotic behaviors in a wide variety of cascades and feedback loops. An application in biology (MAPK signaling) is worked out in detail.

54. X. Bao, Z. Lin, and E.D. Sontag. Finite gain stabilization of discrete-time linear systems subject to actuator saturation. Automatica, 36(2):269-277, 2000. [PDF] Keyword(s): discrete-time, saturation, input-to-state stability, stabilization, ISS, bounded inputs.
Abstract:
 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.

55. M. Malisoff and E.D. Sontag. Universal formulas for feedback stabilization with respect to Minkowski balls. Systems Control Lett., 40(4):247-260, 2000. [PDF] Keyword(s): nonlinear control, feedback stabilization, saturation, control-Lyapunov functions, bounded inputs.
Abstract:
 This note provides explicit algebraic stabilizing formulas for clf's when controls are restricted to certain Minkowski balls in Euclidean space. Feedbacks of this kind are known to exist by a theorem of Artstein, but the proof of Artstein's theorem is nonconstructive. The formulas are obtained from a general feedback stabilization technique and are used to construct approximation solutions to some stabilization problems.

56. E.D. Sontag. Nonlinear feedback stabilization revisited. In Dynamical systems, control, coding, computer vision (Padova, 1998), volume 25 of Progr. Systems Control Theory, pages 223-262. Birkhäuser, Basel, 1999. Note: This is a short conference proceedings paper. Please consult the full version Stability and stabilization: discontinuities and the effect of disturbances.

57. E.D. Sontag. Stability and stabilization: discontinuities and the effect of disturbances. In Nonlinear analysis, differential equations and control (Montreal, QC, 1998), volume 528 of NATO Sci. Ser. C Math. Phys. Sci., pages 551-598. Kluwer Acad. Publ., Dordrecht, 1999. [PDF] Keyword(s): feedback stabilization, nonlinear control, input to state stability.
Abstract:
 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.

58. Y.S. Ledyaev and E.D. Sontag. A Lyapunov characterization of robust stabilization. Nonlinear Anal., 37(7, Ser. A: Theory Methods):813-840, 1999. [PDF] Keyword(s): nonlinear control, feedback stabilization.
Abstract:
 One of the fundamental facts in control theory (Artstein's theorem) is the equivalence, for systems affine in controls, between continuous feedback stabilizability to an equilibrium and the existence of smooth control Lyapunov functions. This equivalence breaks down for general nonlinear systems, not affine in controls. One of the main results in this paper establishes that the existence of smooth Lyapunov functions implies the existence of (in general, discontinuous) feedback stabilizers which are insensitive to small errors in state measurements. Conversely, it is shown that the existence of such stabilizers in turn implies the existence of smooth control Lyapunov functions. Moreover, it is established that, for general nonlinear control systems under persistently acting disturbances, the existence of smooth Lyapunov functions is equivalent to the existence of (possibly) discontinuous) feedback stabilizers which are robust with respect to small measurement errors and small additive external disturbances.

59. E.D. Sontag. Clocks and insensitivity to small measurement errors. ESAIM Control Optim. Calc. Var., 4:537-557, 1999. [PDF] Keyword(s): nonlinear control, feedback stabilization, hybrid systems, discontinuous feedback, measurement noise.
Abstract:
 This paper provides a precise result which shows that insensitivity to small measurement errors in closed-loop stabilization can be attained provided that the feedback controller ignores observations during small time intervals.

60. Y.S. Ledyaev and E.D. Sontag. A notion of discontinuous feedback. In Control using logic-based switching (Block Island, RI, 1995), volume 222 of Lecture Notes in Control and Inform. Sci., pages 97-103. Springer, London, 1997.

61. F. H. Clarke, Y.S. Ledyaev, E.D. Sontag, and A.I. Subbotin. Asymptotic controllability implies feedback stabilization. IEEE Trans. Automat. Control, 42(10):1394-1407, 1997. [PDF]
Abstract:
 It is shown that every asymptotically controllable system can be stabilized by means of some (discontinuous) feedback law. One of the contributions of the paper is in defining precisely the meaning of stabilization when the feedback rule is not continuous. The main ingredients in our construction are: (a) the notion of control-Lyapunov function, (b) methods of nonsmooth analysis, and (c) techniques from positional differential games.

62. Y. Yang, E.D. Sontag, and H.J. Sussmann. Global stabilization of linear discrete-time systems with bounded feedback. Systems Control Lett., 30(5):273-281, 1997. [PDF] [doi:http://dx.doi.org/10.1016/S0167-6911(97)00021-2] Keyword(s): discrete-time, saturation, bounded inputs.
Abstract:
 This paper deals with the problem of global stabilization of linear discrete time systems by means of bounded feedback laws. The main result proved is an analog of one proved for the continuous time case by the authors, and shows that such stabilization is possible if and only if the system is stabilizable with arbitrary controls and the transition matrix has spectral radius less or equal to one. The proof provides in principle an algorithm for the construction of such feedback laws, which can be implemented either as cascades or as parallel connections (single hidden layer neural networks'') of simple saturation functions.

63. W. Liu, Y. Chitour, and E.D. Sontag. On finite-gain stabilizability of linear systems subject to input saturation. SIAM J. Control Optim., 34(4):1190-1219, 1996. [PDF] [doi:http://dx.doi.org/10.1137/S0363012994263469] Keyword(s): saturation, bounded inputs.
Abstract:
 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.

64. Y. Chitour, W. Liu, and E.D. Sontag. On the continuity and incremental-gain properties of certain saturated linear feedback loops. Internat. J. Robust Nonlinear Control, 5(5):413-440, 1995. [PDF] Keyword(s): saturation, bounded inputs, incremental gains.
Abstract:
 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.

65. Y. Lin and E.D. Sontag. Control-Lyapunov universal formulas for restricted inputs. Control Theory Adv. Tech., 10(4, part 5):1981-2004, 1995. [PDF] Keyword(s): control-Lyapunov functions, saturation, bounded inputs.
Abstract:
 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.

66. F. Albertini and E.D. Sontag. For neural networks, function determines form. Neural Networks, 6(7):975-990, 1993. [PDF] Keyword(s): machine learning, neural networks, identifiability, recurrent neural networks, realization theory, observability, neural networks.
Abstract:
 This paper shows that the weights of continuous-time feedback neural networks x'=s(Ax+Bu), y=Cx (where s is a sigmoid) are uniquely identifiable from input/output measurements. Under very weak genericity assumptions, the following is true: Assume given two nets, whose neurons all have the same nonlinear activation function s; if the two nets have equal behaviors as "black boxes" then necessarily they must have the same number of neurons and -except at most for sign reversals at each node- the same weights. Moreover, even if the activations are not a priori known to coincide, they are shown to be also essentially determined from the external measurements.

67. E.D. Sontag. Feedback stabilization using two-hidden-layer nets. IEEE Trans. Neural Networks, 3:981-990, 1992. [PDF] Keyword(s): machine learning, neural networks, feedback stabilization.
Abstract:
 This paper compares the representational capabilities of one hidden layer and two hidden layer nets consisting of feedforward interconnections of linear threshold units. It is remarked that for certain problems two hidden layers are required, contrary to what might be in principle expected from the known approximation theorems. The differences are not based on numerical accuracy or number of units needed, nor on capabilities for feature extraction, but rather on a much more basic classification into "direct" and "inverse" problems. The former correspond to the approximation of continuous functions, while the latter are concerned with approximating one-sided inverses of continuous functions - and are often encountered in the context of inverse kinematics determination or in control questions. A general result is given showing that nonlinear control systems can be stabilized using two hidden layers, but not in general using just one.

68. Y. Lin and E.D. Sontag. A universal formula for stabilization with bounded controls. Systems Control Lett., 16(6):393-397, 1991. [PDF] [doi:http://dx.doi.org/10.1016/0167-6911(91)90111-Q] Keyword(s): saturation, bounded inputs.
Abstract:
 We provide a formula for a stabilizing feedback law using a bounded control, under the assumption that an appropriate control-Lyapunov function is known. Such a feedback, smooth away from the origin and continuous everywhere, is known to exist via Artstein's Theorem. As in the unbounded-control case treated in a previous note, we provide an explicit and universal'' formula given by an algebraic function of Lie derivatives. In particular, we extend to the bounded case the result that the feedback can be chosen analytic if the Lyapunov function and the vector fields defining the system are analytic.

69. E.D. Sontag. Feedback stabilization of nonlinear systems. In Robust control of linear systems and nonlinear control (Amsterdam, 1989), volume 4 of Progr. Systems Control Theory, pages 61-81. Birkhäuser Boston, Boston, MA, 1990. [PDF]
Abstract:
 This paper surveys some well-known facts as well as some recent developments on the topic of stabilization of nonlinear systems. (NOTE: figures are not included in file; they were pasted-in.)

70. E.D. Sontag. Further facts about input to state stabilization. IEEE Trans. Automat. Control, 35(4):473-476, 1990. [PDF] Keyword(s): input to state stability, ISS, stabilization.
Abstract:
 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.

71. A. Arapostathis, B. Jakubczyk, H.-G. Lee, S. I. Marcus, and E.D. Sontag. The effect of sampling on linear equivalence and feedback linearization. Systems Control Lett., 13(5):373-381, 1989. [PDF] [doi:http://dx.doi.org/10.1016/0167-6911(89)90103-5] Keyword(s): discrete-time, sampled-data systems, discrete-time systems, sampling.
Abstract:
 We investigate the effect of sampling on linearization for continuous time systems. It is shown that the discretized system is linearizable by state coordinate change for an open set of sampling times if and only if the continuous time system is linearizable by state coordinate change. Also, it is shown that linearizability via digital feedback imposes highly nongeneric constraints on the structure of the plant, even if this is known to be linearizable with continuous-time feedback.

72. E.D. Sontag. Smooth stabilization implies coprime factorization. IEEE Trans. Automat. Control, 34(4):435-443, 1989. [PDF] Keyword(s): input to state stability, ISS, input to state stability.
Abstract:
 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.)

73. E.D. Sontag and H.J. Sussmann. Further comments on the stabilizability of the angular velocity of a rigid body. Systems Control Lett., 12(3):213-217, 1989. [PDF] [doi:http://dx.doi.org/10.1016/0167-6911(89)90052-2] Keyword(s): satellite control, feedback stabilization.
Abstract:
 We prove that the angular velocity equations can be smoothly stabilized with a single torque controller for bodies having an axis of symmetry. This complements a recent result of Aeyels and Szafranski.

74. E.D. Sontag. Comments on: Some results on pole-placement and reachability'' [Systems Control Lett. 6 (1986), no. 5, 325--328; MR0821927 (87c:93032)] by P. K. Sharma. Systems Control Lett., 8(1):79-83, 1986. [PDF] [doi:http://dx.doi.org/10.1016/0167-6911(86)90034-4]
Abstract:
 We present various comments on a question about systems over rings posed in a recent note by Sharma, proving that a ring R is pole-assignable if and only if, for every reachable system (F,G), G contains a rank-one summand of the state space. We also provide a generalization to deal with dynamic feedback.

75. E.D. Sontag. Continuous stabilizers and high-gain feedback. IMA Journal of Mathematical Control and Information, 3:237-253, 1986. [PDF] Keyword(s): adaptive control, systems over rings.
Abstract:
 A controller is shown to exist, universal for the family of all systems of fixed dimension n, and m controls, which stabilizes those systems that are stabilizable, if certain gains are large enough. The controller parameters are continuous, in fact polynomial, functions of the entries of the plant. As a consequence, a result is proved on polynomial stabilization of families of systems.

76. E.D. Sontag. Parametric stabilization is easy. Systems Control Lett., 4(4):181-188, 1984. [PDF] Keyword(s): systems over rings.
Abstract:
 A polynomially parametrized family of continuous-time controllable linear systems is always stabilizable by polynomially parametrized feedback. (Note: appendix had a MACSYMA computation. I cannot find the source file for that. Please look at journal if interested, but this is not very important. Also, two figures involving root loci are not in the web version.)

77. R.T. Bumby, E.D. Sontag, H.J. Sussmann, and W. Vasconcelos. Remarks on the pole-shifting problem over rings. J. Pure Appl. Algebra, 20(2):113-127, 1981. [PDF] Keyword(s): systems over rings, systems over rings.
Abstract:
 Problems that appear in trying to extend linear control results to systems over rings R have attracted considerable attention lately. This interest has been due mainly to applications-oriented motivations (in particular, dealing with delay-differential equations), and partly to a purely algebraic interest. Given a square n-matrix F and an n-row matrix G. pole-shifting problems consist in obtaining more or less arbitrary characteristic polynomials for F+GK, for suitable ("feedback") matrices K. A review of known facts is given, various partial results are proved, and the case n=2 is studied in some detail.

78. E.D. Sontag. Conditions for abstract nonlinear regulation. Inform. and Control, 51(2):105-127, 1981. [PDF] Keyword(s): feedback stabilization.
Abstract:
 A paper that introduces a separation principle for general finite dimensional analytic continuous-time systems, proving the equivalence between existence of an output regulator (which is an abstract dynamical system) and certain "0-detectability" and asymptotic controllability assumptions.

79. M. L. J. Hautus and E.D. Sontag. An approach to detectability and observers. In Algebraic and geometric methods in linear systems theory (AMS-NASA-NATO Summer Sem., Harvard Univ., Cambridge, Mass., 1979), volume 18 of Lectures in Appl. Math., pages 99-135. Amer. Math. Soc., Providence, R.I., 1980. [PDF] Keyword(s): observability.
Abstract:
 This paper proposes an approach to the problem of establishing the existence of observers for deterministic dynamical systems. This approach differs from the standard one based on Luenberger observers in that the observation error is not required to be Markovian given the past input and output data. A general abstract result is given, which special- izes to new results for parametrized families of linear systems, delay systems and other classes of systems. Related problems of feedback control and regulation are also studied.

 Conference articles
1. D. K. Agrawal, R. Marshall, M. Ali Al-Radhawi, V. Noireaux, and E. D. Sontag. Some remarks on robust gene regulation in a biomolecular integral controller. In Proc. 2019 IEEE Conf. Decision and Control, pages 2820-2825, 2019. [PDF] Keyword(s): adaptation, biological adaptation, perfect adaptation, tracking, synthetic biology, integral feedback, TX/TL, systems biology, dynamical systems, adaptation, internal model principle, systems biology.
Abstract:
 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.

2. S. Bruno, M.A. Al-Radhawi, E.D. Sontag, and D. Del Vecchio. Stochastic analysis of genetic feedback controllers to reprogram a pluripotency gene regulatory network. In Proc. 2019 Automatic Control Conference, pages 5089-5096, 2019. [PDF] Keyword(s): multistability, biochemical networks, systems biology, stochastic systems, cell differentiation, multistationarity, chemical master equations.
Abstract:
 Cellular reprogramming is traditionally accomplished through an open loop control approach, wherein key transcription factors are injected in cells to steer a gene regulatory network toward a pluripotent state. Recently, a closed loop feedback control strategy was proposed in order to achieve more accurate control. Previous analyses of the controller were based on deterministic models, ignoring the substantial stochasticity in these networks, Here we analyze the Chemical Master Equation for reaction models with and without the feedback controller. We computationally and analytically investigate the performance of the controller in biologically relevant parameter regimes where stochastic effects dictate system dynamics. Our results indicate that the feedback control approach still ensures reprogramming even when analyzed using a stochastic model.

3. M.A. Al-Radhawi, N.S. Kumar, E.D. Sontag, and D. Del Vecchio. Stochastic multistationarity in a model of the hematopoietic stem cell differentiation network. In Proc. 2018 IEEE Conf. Decision and Control, pages 1886-1892, 2018. [PDF] Keyword(s): multistability, biochemical networks, systems biology, stochastic systems, cell differentiation, multistationarity, chemical master equations.
Abstract:
 In the mathematical modeling of cell differentiation, it is common to think of internal states of cells (quanfitied by activation levels of certain genes) as determining different cell types. We study here the "PU.1/GATA-1 circuit" that controls the development of mature blood cells from hematopoietic stem cells (HSCs). We introduce a rigorous chemical reaction network model of the PU.1/GATA-1 circuit, which incorporates current biological knowledge and find that the resulting ODE model of these biomolecular reactions is incapable of exhibiting multistability, contradicting the fact that differentiation networks have, by definition, alternative stable steady states. When considering instead the stochastic version of this chemical network, we analytically construct the stationary distribution, and are able to show that this distribution is indeed capable of admitting a multiplicity of modes. Finally, we study how a judicious choice of system parameters serves to bias the probabilities towards different stationary states. We remark that certain changes in system parameters can be physically implemented by a biological feedback mechanism; tuning this feedback gives extra degrees of freedom that allow one to assign higher likelihood to some cell types over others.

4. F. Blanchini, H. El-Samad, G. Giordano, and E. D. Sontag. Control-theoretic methods for biological networks. In Proc. 2018 IEEE Conf. Decision and Control, pages 466-483, 2018. [PDF] Keyword(s): systems biology, dynamic response phenotypes, multi-stability, oscillations, feedback, nonlinear systems, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 This is a tutorial paper on control-theoretic methods for the analysis of biological systems.

5. E.D. Sontag. Some remarks on a model for immune signal detection and feedback. In Proc. IEEE Conf. Decision and Control, Dec. 2016, pages 2475-2480, 2016. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, cancer.
Abstract:
 This is a conference paper related to the journal paper "A dynamical model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination". The conference paper includes several theorems for a simplified model which were not included in the journal paper.

6. A. O. Hamadeh, E.D. Sontag, and D. Del Vecchio. A contraction approach to output tracking via high-gain feedback. In Proc. IEEE Conf. Decision and Control, Dec. 2015, pages 7689-7694, 2015. [PDF]
Abstract:
 This paper adopts a contraction approach to the analysis of the tracking properties of dynamical systems under high gain feedback when subject to inputs with bounded derivatives. It is shown that if the tracking error dynamics are contracting, then the system is input to output stable with respect to the input signal derivatives and the output tracking error. As an application, it iss hown that the negative feedback connection of plants composed of two strictly positive real LTI subsystems in cascade can follow external inputs with tracking errors that can be made arbitrarily small by applying a sufficiently large feedback gain. We utilize this result to design a biomolecular feedback for a synthetic genetic sensor to make it robust to variations in the availability of a cellular resource required for protein production.

7. D. Angeli and E.D. Sontag. A small-gain result for orthant-monotone systems in feedback: the non sign-definite case. In Proc. IEEE Conf. Decision and Control, Orlando, Dec. 2011, pages WeC09.1, 2011. Keyword(s): small-gain theorem, monotone systems.
Abstract:
 This note introduces a small-gain result for interconnected MIMO orthant-monotone systems for which no matching condition is required between the partial orders in input and output spaces of the considered subsystems. Previous results assumed that the partial orders adopted would be induced by positivity cones in input and output spaces and that such positivity cones should fulfill a compatibility rule: namely either be coincident or be opposite. Those two configurations corresponded to positive-feedback or negative feedback cases. We relax those results by allowing arbitrary orthant orders.

8. O. Shoval, U. Alon, and E.D. Sontag. Input symmetry invariance, and applications to biological systems. In Proc. IEEE Conf. Decision and Control, Orlando, Dec. 2011, pages TuA02.5, 2011. Keyword(s): adaptation, biological adaptation, perfect adaptation, adaptation, feedforward loops, integral feedback, scale invariance, systems biology, transient behavior, symmetries, fcd, fold-change detection, jump Markov processes.
Abstract:
 This paper studies invariance with respect to symmetries in sensory fields, a particular case of which, scale invariance, has recently been found in certain eukaryotic as well as bacterial cell signaling systems. We describe a necessary and sufficient characterization of symmetry invariance in terms of equivariant transformations, show how this characterization helps find all possible symmetries in standard models of biological adaptation, and discuss symmetry-invariant searches.

9. B. Andrews, E.D. Sontag, and P. Iglesias. An approximate internal model principle: Applications to nonlinear models of biological systems. In Proc. 17th IFAC World Congress, Seoul, pages Paper FrB25.3, 6 pages, 2008. [PDF] Keyword(s): biological adaptation, internal model principle.
Abstract:
 The proper function of many biological systems requires that external perturbations be detected, allowing the system to adapt to these environmental changes. It is now well established that this dual detection and adaptation requires that the system have an internal model in the feedback loop. In this paper we relax the requirement that the response of the system adapt perfectly, but instead allow regulation to within a neighborhood of zero. We show, in a nonlinear setting, that systems with the ability to detect input signals and approximately adapt require an approximate model of the input. We illustrate our results by analyzing a well-studied biological system. These results generalize previous work which treats the perfectly adapting case.

10. L. Wang, P. de Leenheer, and E.D. Sontag. Global stability for monotone tridiagonal systems with negative feedback. In Proc. IEEE Conf. Decision and Control, Cancun, Dec. 2008, pages 4091-4096, 2008. Keyword(s): systems biology, monotone systems, tridiagonal systems, global stability.
Abstract:
 Conference version of paper "Conditions for global stability of monotone tridiagonal systems with negative feedback"

11. M. Arcak and E.D. Sontag. A passivity-based stability criterion for a class of interconnected systems and applications to biochemical reaction networks. In Proc. IEEE Conf. Decision and Control, New Orleans, Dec. 2007, pages 4477-4482, 2007. Note: Conference version of journal paper with same title. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.

12. M.R. Jovanovic, M. Arcak, and E.D. Sontag. Remarks on the stability of spatially distributed systems with a cyclic interconnection structure. In Proceedings American Control Conf., New York, July 2007, pages 2696-2701, 2007. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, spatially distributed systems, secant condition.
Abstract:
 For distributed systems with a cyclic interconnection structure, a global stability result is shown to hold if the secant criterion is satisfied.

13. M. Arcak and E.D. Sontag. Connections between diagonal stability and the secant condition for cyclic systems. In Proc. American Control Conference, Minneapolis, June 2006, pages 1493-1498, 2006. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.

14. 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.

15. M. Malisoff, L. Rifford, and E.D. Sontag. Remarks on input to state stabilization. In Proc. IEEE Conf. Decision and Control, Maui, Dec. 2003, IEEE Publications, 2003, pages 1053-1058, 2003. [PDF] Keyword(s): nonlinear control, feedback stabilization.

16. L. Moreau, E.D. Sontag, and M. Arcak. How feedback can tune a bifurcation parameter towards its unknown critical bifurcation value. In Proc. IEEE Conf. Decision and Control, Maui, Dec. 2003, IEEE Publications, 2003, pages 2401-2406, 2003.

17. E.D. Sontag. Asymptotic amplitudes, Cauchy gains, an associated small-gain principle, and an application to inhibitory biological feedback. In Proc. IEEE Conf. Decision and Control, Las Vegas, Dec. 2002, IEEE Publications, pages 4318-4323, 2002. Keyword(s): cyclic feedback systems, small-gain.

18. M. Arcak, D. Angeli, and E.D. Sontag. Stabilization of cascades using integral input-to-state stability. In Proc. IEEE Conf. Decision and Control, Orlando, Dec. 2001, IEEE Publications, 2001, pages 3814-3819, 2001. Keyword(s): nonlinear control, feedback stabilization, input to state stability.

19. B.P. Ingalls, D. Angeli, E.D. Sontag, and Y. Wang. Asymptotic characterizations of IOSS. In Proc. IEEE Conf. Decision and Control, Orlando, Dec. 2001, IEEE Publications, 2001, pages 881-886, 2001. Keyword(s): nonlinear control, feedback stabilization, input to state stability.

20. E.D. Sontag. Feedback insensitive to small measurement errors. In Proc. IEEE Conf. Decision and Control, Phoenix, Dec. 1999, IEEE Publications, 1999, pages 2661-2666, 1999.

21. Y.S. Ledyaev and E.D. Sontag. A remark on robust stabilization of general asymptotically controllable systems. In Proc. Conf. on Information Sciences and Systems (CISS 97), Johns Hopkins, Baltimore, MD, March 1997, pages 246-251, 1997. [PDF]
Abstract:
 We showned in another recent paper that any asymptotically controllable system can be stabilized by means of a certain type of discontinuous feedback. The feedback laws constructed in that work are robust with respect to actuator errors as well as to perturbations of the system dynamics. A drawback, however, is that they may be highly sensitive to errors in the measurement of the state vector. This paper addresses this shortcoming, and shows how to design a dynamic hybrid stabilizing controller which, while preserving robustness to external perturbations and actuator error, is also robust with respect to measurement error. This new design relies upon a controller which incorporates an internal model of the system driven by the previously constructed feedback.

22. F.H. Clarke, Y.S. Ledyaev, E.D. Sontag, and A.I. Subbotin. Asymptotic controllability and feedback stabilization. In Proc. Conf. on Information Sciences and Systems (CISS 96)Princeton, NJ, pages 1232-1237, 1996. Keyword(s): control-Lyapunov functions, feedback stabilization.

23. E.D. Sontag and H.J. Sussmann. Nonsmooth control-Lyapunov functions. In Proc. IEEE Conf. Decision and Control, New Orleans, Dec. 1995, IEEE Publications, 1995, pages 2799-2805, 1995. [PDF] Keyword(s): control-Lyapunov functions.
Abstract:
 It is shown that the existence of a continuous control-Lyapunov function (CLF) is necessary and sufficient for null asymptotic controllability of nonlinear finite-dimensional control systems. The CLF condition is expressed in terms of a concept of generalized derivative (upper contingent derivative). This result generalizes to the non-smooth case the theorem of Artstein relating closed-loop feedback stabilization to smooth CLF's. It relies on viability theory as well as optimal control techniques. A "non-strict" version of the results, analogous to the LaSalle Invariance Principle, is also provided.

24. Y. Chitour, W. Liu, and E.D. Sontag. On the continuity and incremental gain properties of certain saturated linear feedback loops. In Proc. IEEE Conf. Decision and Control, Orlando, Dec. 1994, IEEE Publications, 1994, pages 127-132, 1994. [PDF] Keyword(s): saturation, bounded inputs.

25. G.A. Lafferriere and E.D. Sontag. Remarks on control Lyapunov functions for discontinuous stabilizing feedback. In Proc. IEEE Conf. Decision and Control, San Antonio, Dec. 1993, IEEE Publications, 1993, pages 306-308, 1993. [PDF] Keyword(s): feedback stabilization.
Abstract:
 We present a formula for a stabilizing feedback law under the assumption that a piecewise smooth control-Lyapunov function exists. The resulting feedback is continuous at the origin and smooth everywhere except on a hypersurface of codimension 1, assuming that certain transversality conditions are imposed there.

26. E.D. Sontag. Feedback Stabilization Using Two-Hidden-Layer Nets. In Proc. Amer. Automatic Control Conf. , Boston, June 1991, pages 815-820, 1991.

27. E.D. Sontag and H.J. Sussmann. Nonlinear output feedback design for linear systems with saturating controls. In Proc. IEEE Conf. Decision and Control, Honolulu, Dec. 1990, IEEE Publications, 1990, pages 3414-3416, 1990. [PDF] Keyword(s): saturation, bounded inputs.
Abstract:
 This paper shows the existence of (nonlinear) smooth dynamic feedback stabilizers for linear time invariant systems under input constraints, assuming only that open-loop asymptotic controllability and detectability hold.

28. E.D. Sontag. Some recent results on nonlinear feedback. In Proc. Conf. Info. Sciences and Systems, Johns Hopkins University Press, 1989, pages 151-156, 1989.

29. B. Jakubczyk and E.D. Sontag. The effect of sampling on feedback linearization. In Proc. IEEE Conf. Decision and Control, Los Angeles, Dec.1987, pages 1374-1379, 1987.

30. E.D. Sontag. Remarks on input/output linearization. In Proc. IEEE Conf. Dec. and Control, Las Vegas, Dec. 1984, pages 409-412, 1984. [PDF]
Abstract:
 In the context of realization theory, conditions are given for the possibility of simulating a given discrete time system, using immersion and/or feedback, by linear or state-affine systems.

31. E.D. Sontag. Abstract regulation of nonlinear systems: Stabilization, Part II. In Proc.Princeton Conf.on Information Sciences and Systems, Princeton, March 1982, pages 431-435, 1982. Keyword(s): feedback stabilization.

32. E.D. Sontag and H.J. Sussmann. Remarks on continuous feedback. In Proc. IEEE Conf. Decision and Control, Albuquerque, Dec.1980, pages 916-921, 1980. [PDF] Keyword(s): feedback stabilization.
Abstract:
 We show that, in general, it is impossible to stabilize a controllable system by means of a continuous feedback, even if memory is allowed. No optimality considerations are involved. All state spaces are Euclidean spaces, so no obstructions arising from the state space topology are involved either. For one dimensional state and input, we prove that continuous stabilization with memory is always possible. (This is an old conference paper, never published in journal form but widely cited nonetheless. Warning: file is very large, since it was scanned.)

 Internal reports
1. M. Margaliot and E.D. Sontag. Compact attractors of an antithetic integral feedback system have a simple structure. Technical report, bioRxiv 2019/868000v1, 2019. [PDF] Keyword(s): Poincare-Bendixson, k-cooperative dynamical systems, sign-regular matrices, synthetic biology, antithetic feedback.
Abstract:
 Since its introduction by Briat, Gupta and Khammash, the antithetic feedback controller design has attracted considerable attention in both theoretical and experimental systems biology. The case in which the plant is a two-dimensional linear system (making the closed-loop system a nonlinear four-dimensional system) has been analyzed in much detail. This system has a unique equilibrium but, depending on parameters, it may exhibit periodic orbits. This note shows that, for any parameter choices, every bounded trajectory satisfies a Poincare'-Bendixson property: the dynamics in the omega-limit set of any precompact solution is conjugate to the dynamics in a compact invariant subset of a two-dimensional Lipschitz dynamical system, thus precluding chaotic and other strange attractors.

2. E.D. Sontag. A remark on incoherent feedforward circuits as change detectors and feedback controllers. Technical report, arXiv:1602.00162, 2016. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, incoherent feedforward loop, feedforward, IFFL.
Abstract:
 This note analyzes incoherent feedforward loops in signal processing and control. It studies the response properties of IFFL's to exponentially growing inputs, both for a standard version of the IFFL and for a variation in which the output variable has a positive self-feedback term. It also considers a negative feedback configuration, using such a device as a controller. It uncovers a somewhat surprising phenomenon in which stabilization is only possible in disconnected regions of parameter space, as the controlled system's growth rate is varied.

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