1. 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, delay-differential systems. 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.




2. 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.




3. 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.

1. L. Wang and E.D. Sontag. Further results on singularly perturbed monotone systems, with an application to double phosphorylation cycles. In Proc. IEEE Conf. Decision and Control, New Orleans, Dec. 2007, pages 627-632, 2007. Note: Conference version of Singularly perturbed monotone systems and an application to double phosphorylation cycles.Keyword(s): singular perturbations, futile cycles, MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, multistability, monotone systems.



2. 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, delay-differential 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.

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