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Publications by Eduardo D. Sontag in year 2009
Articles in journal or book chapters
  1. D. Angeli and E.D. Sontag. Graphs and the Dynamics of Biochemical Networks. In B.P. Ingalls and P. Iglesias, editors, Control Theory in Systems Biology, pages 125-142. MIT Press, 2009.
    Abstract:
    This is an expository paper about graph-theoretical properties of biochemical networks, discussing two approaches, one based on bipartite graphs and Petri net concepts, and another based on decompositions into order-preserving subsystems. Other papers on this website contain basically the same material.


  2. D. Del Vecchio and E.D. Sontag. Synthetic Biology: A Systems Engineering Perspective. In B.P. Ingalls and P. Iglesias, editors, Control Theory in Systems Biology, pages 101-123. MIT Press, 2009.
    Abstract:
    This is an expository paper about certain aspects of Synthetic Biology, including a discussion of the issue of modularity (load effects from downstream components).


  3. 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.


  4. D. Angeli, P. de Leenheer, and E.D. Sontag. Chemical networks with inflows and outflows: A positive linear differential inclusions approach. Biotechnology Progress, 25:632-642, 2009. [PDF] Keyword(s): biochemical networks, fluxes, differential inclusions, positive systems, Petri nets, persistence, switched systems.
    Abstract:
    Certain mass-action kinetics models of biochemical reaction networks, although described by nonlinear differential equations, may be partially viewed as state-dependent linear time-varying systems, which in turn may be modeled by convex compact valued positive linear differential inclusions. A result is provided on asymptotic stability of such inclusions, and applied to biochemical reaction networks with inflows and outflows. Included is also a characterization of exponential stability of general homogeneous switched systems


  5. M. Chaves, A. M. Sengupta, and E.D. Sontag. Geometry and topology of parameter space: investigating measures of robustness in regulatory networks. J. of Mathematical Biology, 59:315-358, 2009. [PDF]
    Abstract:
    The concept of robustness of regulatory networks has been closely related to the nature of the interactions among genes, and the capability of pattern maintenance or reproducibility. Defining this robustness property is a challenging task, but mathematical models have often associated it to the volume of the space of admissible parameters. Not only the volume of the space but also its topology and geometry contain information on essential aspects of the network, including feasible pathways, switching between two parallel pathways or distinct/disconnected active regions of parameters. A method is presented here to characterize the space of admissible parameters, by writing it as a semi-algebraic set, and then theoretically analyzing its topology and geometry, as well as volume. This method provides a more objective and complete measure of the robustness of a developmental module. As a detailed case study, the segment polarity gene network is analyzed.


  6. A. Dayarian, M. Chaves, E.D. Sontag, and A. M. Sengupta. Shape, Size and Robustness: Feasible Regions in the Parameter Space of Biochemical Networks. PLoS Computational Biology, 5:e10000256, 2009. [PDF]
    Abstract:
    The concept of robustness of regulatory networks has received much attention in the last decade. One measure of robustness has been associated with the volume of the feasible region, namely, the region in the parameter space in which the system is functional. In recent work, we emphasized that topology and geometry matter, as well as volume. In this paper, and using the segment polarity gene network to illustrate our approach, we show that random walks in parameter space and how they exit the feasible region provide a rich perspective on the different modes of failure of a model. In particular, for the segment polarity network, we found that, between two alternative ways of activating Wingless, one is more robust. Our method provides a more complete measure of robustness to parameter variation. As a general modeling strategy, our approach is an interesting alternative to Boolean representation of biochemical networks.


  7. D. Del Vecchio and E.D. Sontag. Engineering Principles in Bio-Molecular Systems: From Retroactivity to Modularity. European Journal of Control, 15:389-397, 2009. Note: Preliminary version appeared as paper MoB2.2 in Proceedings of the European Control Conference 2009, August 23-26, 2009, Budapest. [PDF] Keyword(s): systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.


  8. T. Riley, X. Yu, E.D. Sontag, and A. Levine. The P53HMM algorithm: using novel profile Hidden Markov Models to detect p53-responsive genes. BMC Bioinformatics, 10:111, 2009. [PDF] [doi:10.1186/1471-2105-10-111] Keyword(s): Hidden Markov Models, p53, transcription factors.
    Abstract:
    A novel computational method (called p53HMM) is presented that utilizes Profile Hidden Markov Models (PHMM's) to estimate the relative binding affinities of putative p53 response elements (RE's), both p53 single-sites and cluster-sites. These models incorporate a novel ``Correlated Baum Welch'' training algorithm that provides increased predictive power by exploiting the redundancy of information found in the repeated, palindromic p53-binding motif. The predictive accuracy of these new models are compared against other predictive models, including position specic score matrices (PSSM's, or weight matrices). Finally, we provide experimental evidence that verifies a predicted p53-target site that regu- lates the CHMP4C gene. The P53HMM algorithm is available on-line from http://tools.csb.ias.edu.


  9. E.D. Sontag, Y. Wang, and A. Megretski. Input classes for identification of bilinear systems. IEEE Transactions Autom. Control, 54:195-207, 2009. Note: Also arXiv math.OC/0610633, 20 Oct 2006, and short version in ACC'07.[PDF] Keyword(s): realization theory, observability, identifiability, bilinear systems.
    Abstract:
    This paper asks what classes of input signals are sufficient in order to completely identify the input/output behavior of generic bilinear systems. The main results are that step inputs are not sufficient, nor are single pulses, but the family of all pulses (of a fixed amplitude but varying widths) do suffice for identification.


  10. 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.


Conference articles
  1. D. Angeli, P. de Leenheer, and E.D. Sontag. On persistence of chemical reaction networks with time-dependent kinetics and no global conservation laws. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 4559-4564, 2009. [PDF] Keyword(s): biochemical networks, fluxes, Petri nets, persistence, biochemical networks with inputs.
    Abstract:
    This is a very summarized version ofthe first part of the paper "Persistence results for chemical reaction networks with time-dependent kinetics and no global conservation laws".


  2. L. Scardovi, M. Arcak, and E.D. Sontag. Synchronization of interconnected systems with an input-output approach. Part I: Main results. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 609-614, 2009. Note: First part of conference version of journal paper.Keyword(s): passive systems, secant condition, biochemical networks, systems biology.
    Abstract:
    See abstract and link to pdf in entry for Journal paper.


  3. L. Scardovi, M. Arcak, and E.D. Sontag. Synchronization of interconnected systems with an input-output approach. Part II: State-Space result and application to biochemical networks. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 615-620, 2009. Note: Second part of conference version of journal paper.Keyword(s): passive systems, secant condition, biochemical networks, systems biology.
    Abstract:
    See abstract and link to pdf in entry for Journal paper.


Internal reports
  1. E.D. Sontag. An observation regarding systems which converge to steady states for all constant inputs, yet become chaotic with periodic inputs. Technical report, arxiv 0906.2166, 2009. [PDF]



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