Publications about 'cellular signaling'
Articles in journal or book chapters
  1. T. Kang, J.T. White, Z. Xie, Y. Benenson, E.D. Sontag, and L. Bleris. Reverse engineering validation using a benchmark synthetic gene circuit in human cells. ACS Synthetic Biology, 2:255-262, 2013. [PDF] Keyword(s): reverse engineering, systems biology, synthetic biology.
    This work introduces an experimental platform customized for the development and verification of reverse engineering and pathway characterization algorithms in mammalian cells. Specifically, we stably integrate a synthetic gene network in human kidney cells and use it as a benchmark for validating reverse engineering methodologies. The network, which is orthogonal to endogenous cellular signaling, contains a small set of regulatory interactions that can be used to quantify the reconstruction performance. By performing successive perturbations to each modular component of the network and comparing protein and RNA measurements, we study the conditions under which we can reliably reconstruct the causal relationships of the integrated synthetic network.

  2. R. Albert, B. DasGupta, R. Hegde, G.S. Sivanathan, A. Gitter, G. Gürsoy, P. Paul, and E.D. Sontag. A new computationally efficient measure of topological redundancy of biological and social networks. Physical Review E, 84:036117, 2011. [PDF]
    In this paper, we introduce a topological redundancy measure for labeled directed networks that is formal, computationally efficient and applicable to a variety of directed networks such as cellular signaling, metabolic and social interaction networks. We demonstrate the computational efficiency of our measure by computing its value and statistical significance on a number of biological and social networks with up to several thousands of nodes and edges. Our results suggest a number of interesting observations: (1) social networks are more redundant that their biological counterparts, (2) transcriptional networks are less redundant than signaling networks, (3) the topological redundancy of the C. elegans metabolic network is largely due to its inclusion of currency metabolites, and (4) the redundancy of signaling networks is highly (negatively) correlated with monotonicity of their dynamics.

  3. 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): identifiability, 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.
    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.

  4. M. Chaves and E.D. Sontag. Exact computation of amplification for a class of nonlinear systems arising from cellular signaling pathways. Automatica, 42:1987-1992, 2006. [PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, nonlinear stability, dynamical systems.
    A commonly employed measure of the signal amplification properties of an input/output system is its induced L2 norm, sometimes also known as H-infinity gain. In general, however, it is extremely difficult to compute the numerical value for this norm, or even to check that it is finite, unless the system being studied is linear. This paper describes a class of systems for which it is possible to reduce this computation to that of finding the norm of an associated linear system. In contrast to linearization approaches, a precise value, not an estimate, is obtained for the full nonlinear model. The class of systems that we study arose from the modeling of certain biological intracellular signaling cascades, but the results should be of wider applicability.

  5. E.D. Sontag. Molecular systems biology and control. Eur. J. Control, 11(4-5):396-435, 2005. [PDF] Keyword(s): cell biology, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems, molecular biology, systems biology, cellular signaling.
    This paper, prepared for a tutorial at the 2005 IEEE Conference on Decision and Control, presents an introduction to molecular systems biology and some associated problems in control theory. It provides an introduction to basic biological concepts, describes several questions in dynamics and control that arise in the field, and argues that new theoretical problems arise naturally in this context. A final section focuses on the combined use of graph-theoretic, qualitative knowledge about monotone building-blocks and steady-state step responses for components.

  6. E.D. Sontag. Some new directions in control theory inspired by systems biology. IET Systems Biology, 1:9-18, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems, cellular signaling.
    This paper, addressed primarily to engineers and mathematicians with an interest in control theory, argues that entirely new theoretical problems arise naturally when addressing questions in the field of systems biology. Examples from the author's recent work are used to illustrate this point.

  7. B.N. Kholodenko, A. Kiyatkin, F.J. Bruggeman, E.D. Sontag, H.V. Westerhoff, and J. Hoek. Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks. Proceedings of the National Academy of Sciences USA, 99:12841-12846, 2002. [PDF] Keyword(s): modular response analysis, MAPK cascades, systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification.
    Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. This paper proposes a novel quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level, or applied within a modular framework, which dramatically decreases the number of variables to be assayed. The topology and strength of network connections are retrieved from experimentally measured network responses to successive perturbations of all modules. In addition, the method can reveal functional interactions even when the components of the system are not all known, in which case some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated using computer-generated responses of a modeled MAPK cascade and gene network.

Conference articles
  1. E.D. Sontag and M. Chaves. Computation of amplification for systems arising from cellular signaling pathways. In Proc. 16th IFAC World Congress, Prague, July 2005, 2005. Keyword(s): systems biology, biochemical networks, dynamical systems.



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