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 Articles in journal or book chapters
1. M. Sadeghi, M.A. Al-Radhawi, M. Margaliot, and E.D. Sontag. No switching policy is optimal for a positive linear system with a bottleneck entrance. IEEE Control Systems Letters, 3:889-894, 2019. Note: (Also in Proc. 2018 IEEE Conf. Decision and Control.). [PDF] Keyword(s): entrainment, switched systems, ribosome flow model, traffic systems, nonlinear systems, nonlinear control.
Abstract:
 We consider a nonlinear SISO system that is a cascade of a scalar "bottleneck entrance" with a stable positive linear system. In response to any periodic inflow, all solutions converge to a unique periodic solution with the same period. We study the problem of maximizing the averaged throughput via controlled switching. We compare two strategies: 1) switching between a high and low value, and 2 ~using a constant inflow equal to the prescribed mean value. We show that no possible switching policy can outperform a constant inflow rate, though it can approach it asymptotically. We describe several potential applications of this problem in traffic systems, ribosome flow models, and scheduling at security checks.

2. 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.

3. 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.
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.

4. M. Margaliot, E.D. Sontag, and T. Tuller. Contraction after small transients. Automatica, 67:178-184, 2016. [PDF] Keyword(s): entrainment, nonlinear systems, stability, contractions, contractive systems.
Abstract:
 Contraction theory is a powerful tool for proving asymptotic properties of nonlinear dynamical systems including convergence to an attractor and entrainment to a periodic excitation. We introduce three new forms of generalized contraction (GC) that are motivated by allowing contraction to take place after small transients in time and/or amplitude. These forms of GC are useful for several reasons. First, allowing small transients does not destroy the asymptotic properties provided by standard contraction. Second, in some cases as we change the parameters in a contractive system it becomes a GC just before it looses contractivity. In this respect, GC is the analogue of marginal stability in Lyapunov stability theory. We provide checkable sufficient conditions for GC, and demonstrate their usefulness using several models from systems biology that are not contractive, with respect to any norm, yet are GC.

5. A. Raveh, M. Margaliot, E.D. Sontag, and T. Tuller. A model for competition for ribosomes in the cell. Proc. Royal Society Interface, 13:2015.1062, 2016. [PDF] Keyword(s): resource competition, ribosomes, entrainment, nonlinear systems, stability, contractions, contractive systems.
Abstract:
 We develop and analyze a general model for large-scale simultaneous mRNA translation and competition for ribosomes. Such models are especially important when dealing with highly expressed genes, as these consume more resources. For our model, we prove that the compound system always converges to a steady-state and that it always entrains or phase locks to periodically time-varying transition rates in any of the mRNA molecules. We use this model to explore the interactions between the various mRNA molecules and ribosomes at steady-state. We show that increasing the length of an mRNA molecule decreases the production rate of all the mRNAs. Increasing any of the codon translation rates in a specific mRNA molecule yields a local effect: an increase in the translation rate of this mRNA, and also a global effect: the translation rates in the other mRNA molecules all increase or all decrease. These results suggest that the effect of codon decoding rates of endogenous and heterologous mRNAs on protein production might be more complicated than previously thought.

6. M. Margaliot, E.D. Sontag, and T. Tuller. Entrainment to periodic initiation and transition rates in a computational model for gene translation. PLoS ONE, 9(5):e96039, 2014. [WWW] [PDF] [doi:10.1371/journal.pone.0096039] Keyword(s): ribosomes, entrainment, nonlinear systems, stability, contractions, contractive systems.
Abstract:
 A recent biological study has demonstrated that the gene expression pattern entrains to a periodically varying abundance of tRNA molecules. This motivates developing mathematical tools for analyzing entrainment of translation elongation to intra-cellular signals such as tRNAs levels and other factors affecting translation. We consider a recent deterministic mathematical model for translation called the Ribosome Flow Model (RFM). We analyze this model under the assumption that the elongation rate of the tRNA genes and/or the initiation rate are periodic functions with a common period T. We show that the protein synthesis pattern indeed converges to a unique periodic trajectory with period T. The analysis is based on introducing a novel property of dynamical systems, called contraction after a short transient (CAST), that may be of independent interest. We provide a sufficient condition for CAST and use it to prove that the RFM is CAST, and that this implies entrainment. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and suggest a new approach for engineering genes to obtain a desired, periodic, synthesis rate.

7. G. Russo, M. di Bernardo, and E.D. Sontag. Global entrainment of transcriptional systems to periodic inputs. PLoS Computational Biology, 6:e1000739, 2010. [PDF] Keyword(s): contractive systems, contractions, systems biology, biochemical networks, gene and protein networks.
Abstract:
 This paper addresses the problem of giving conditions for transcriptional systems to be globally entrained to external periodic inputs. By using contraction theory, a powerful tool from dynamical systems theory, it is shown that certain systems driven by external periodic signals have the property that all solutions converge to fixed limit cycles. General results are proved, and the properties are verified in the specific case of some models of transcriptional systems.

 Conference articles
1. E.D. Sontag, M. Margaliot, and T. Tuller. On three generalizations of contraction. In Proc. IEEE Conf. Decision and Control, Los Angeles, Dec. 2014, pages 1539-1544, 2014. Keyword(s): contractions, contractive systems, stability.
Abstract:
 We introduce three forms of generalized contraction~(GC). Roughly speaking, these are motivated by allowing contraction to take place after small transients in time and/or amplitude. Indeed, contraction is usually used to prove asymptotic properties, like convergence to an attractor or entrainment to a periodic excitation, and allowing initial transients does not affect this asymptotic behavior. We provide sufficient conditions for GC, and demonstrate their usefulness using examples of systems that are not contractive, with respect to any norm, yet are~GC.

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