CiteULike: cactus's network

Intrinsic noise, dissipation cost, and robustness of cellular networks: The underlying energy landscape of MAPK signal transduction

Saul Lapidus — 2008-04-18T18:35:19-00:00

Proceedings of the National Academy of Sciences (17 April 2008), 0708708105.

We develop a probabilistic method for analyzing global features of a cellular network under intrinsic statistical fluctuations, which is important when there are finite numbers of molecules. By making a self-consistent mean field approximation of splitting the variables in order to reduce the large number of degrees of freedom, which is reasonable for a not very strongly interacting network, we discovered that the underlying energy landscape of the mitogen-activated protein kinases (MAPKs) signal transduction network (with experimentally measured or inferred parameters such as chemical reaction rate coefficients in the network) is funneled toward a global minimum characterized by the nonequilibrium steady-state fixed point of the system at the end of the signal transduction process. For this system, we also show that the energy landscape is robust against intrinsic fluctuations and random perturbation to the inherent chemical reaction rates. The ratio of the slope versus the roughness of the energy landscape becomes a quantitative measure of robustness and stability of the network. Furthermore, we quantify the dissipation cost of this nonequilibrium system through entropy production, caused by the nonequilibrium flux in the system. We found that a lower dissipation cost corresponds to a more robust network. This least dissipation property might provide a design principle for robust and functional networks. Finally, we find the possibility of bistable and oscillatory-like solutions, which are important for cell fate decisions, upon perturbations. The method described here can be used in a variety of biological networks. 10.1073/pnas.0708708105

Hierarchical structure and the prediction of missing links in networks

Aaron Clauset — 2008-04-30T19:31:59-00:00

Nature, Vol. 453, No. 7191., pp. 98-101.

Evolvability and hierarchy in rewired bacterial gene networks

Mark Isalan — 2008-04-16T19:45:06-00:00

Nature, Vol. 452, No. 7189. (17 April 2008), pp. 840-845.

Maps of random walks on complex networks reveal community structure

Martin Rosvall — 2008-01-24T08:30:08-00:00

Proceedings of the National Academy of Sciences (23 January 2008), 0706851105.

To comprehend the multipartite organization of large-scale biological and social systems, we introduce an information theoretic approach that reveals community structure in weighted and directed networks. We use the probability flow of random walks on a network as a proxy for information flows in the real system and decompose the network into modules by compressing a description of the probability flow. The result is a map that both simplifies and highlights the regularities in the structure and their relationships. We illustrate the method by making a map of scientific communication as captured in the citation patterns of >6,000 journals. We discover a multicentric organization with fields that vary dramatically in size and degree of integration into the network of science. Along the backbone of the networkincluding physics, chemistry, molecular biology, and medicineinformation flows bidirectionally, but the map reveals a directional pattern of citation from the applied fields to the basic sciences. 10.1073/pnas.0706851105

The Frequency Dependence of Osmo-Adaptation in Saccharomyces cerevisiae

Jerome Mettetal — 2008-01-25T07:19:00-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 482-484.

The propagation of information through signaling cascades spans a wide range of time scales, including the rapid ligand-receptor interaction and the much slower response of downstream gene expression. To determine which dynamic range dominates a response, we used periodic stimuli to measure the frequency dependence of signal transduction in the osmo-adaptation pathway of Saccharomyces cerevisiae. We applied system identification methods to infer a concise predictive model. We found that the dynamics of the osmo-adaptation response are dominated by a fast-acting negative feedback through the kinase Hog1 that does not require protein synthesis. After large osmotic shocks, an additional, much slower, negative feedback through gene expression allows cells to respond faster to future stimuli. 10.1126/science.1151582

A mathematical tool for exploring the dynamics of biological networks

Paolo Barbano — 2007-11-22T12:53:12-00:00

Proceedings of the National Academy of Sciences (21 November 2007), 0709955104.

We have developed a mathematical approach to the study of dynamical biological networks, based on combining large-scale numerical simulation with nonlinear "dimensionality reduction" methods. Our work was motivated by an interest in the complex organization of the signaling cascade centered on the neuronal phosphoprotein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of molecular weight 32,000). Our approach has allowed us to detect robust features of the system in the presence of noise. In particular, the global network topology serves to stabilize the net state of DARPP-32 phosphorylation in response to variation of the input levels of the neurotransmitters dopamine and glutamate, despite significant perturbation to the concentrations and levels of activity of a number of intermediate chemical species. Further, our results suggest that the entire topology of the network is needed to impart this stability to one portion of the network at the expense of the rest. This could have significant implications for systems biology, in that large, complex pathways may have properties that are not easily replicated with simple modules. 10.1073/pnas.0709955104

Engineering Entropy-Driven Reactions and Networks Catalyzed by DNA

David Zhang — 2007-11-20T11:06:25-00:00

Science, Vol. 318, No. 5853. (16 November 2007), pp. 1121-1125.

Artificial biochemical circuits are likely to play as large a role in biological engineering as electrical circuits have played in the engineering of electromechanical devices. Toward that end, nucleic acids provide a designable substrate for the regulation of biochemical reactions. However, it has been difficult to incorporate signal amplification components. We introduce a design strategy that allows a specified input oligonucleotide to catalyze the release of a specified output oligonucleotide, which in turn can serve as a catalyst for other reactions. This reaction, which is driven forward by the configurational entropy of the released molecule, provides an amplifying circuit element that is simple, fast, modular, composable, and robust. We have constructed and characterized several circuits that amplify nucleic acid signals, including a feedforward cascade with quadratic kinetics and a positive feedback circuit with exponential growth kinetics. 10.1126/science.1148532

Reconciling complexity with stability in naturally assembling food webs

Anje-Margriet Neutel — 2007-10-04T14:11:48-00:00

Nature, Vol. 449, No. 7162. (4 October 2007), pp. 599-602.

Integrating molecular and network biology to decode endocytosis

Eva Schmid — 2007-08-23T14:27:13-00:00

Nature, Vol. 448, No. 7156. (2007), pp. 883-888.

Flexible nets. The roles of intrinsic disorder in protein interaction networks.

AK Dunker — 2006-11-11T17:06:48-00:00

FEBS J, Vol. 272, No. 20. (October 2005), pp. 5129-5148.

Proteins participate in complex sets of interactions that represent the mechanistic foundation for much of the physiology and function of the cell. These protein-protein interactions are organized into exquisitely complex networks. The architecture of protein-protein interaction networks was recently proposed to be scale-free, with most of the proteins having only one or two connections but with relatively fewer 'hubs' possessing tens, hundreds or more links. The high level of hub connectivity must somehow be reflected in protein structure. What structural quality of hub proteins enables them to interact with large numbers of diverse targets? One possibility would be to employ binding regions that have the ability to bind multiple, structurally diverse partners. This trait can be imparted by the incorporation of intrinsic disorder in one or both partners. To illustrate the value of such contributions, this review examines the roles of intrinsic disorder in protein network architecture. We show that there are three general ways that intrinsic disorder can contribute: First, intrinsic disorder can serve as the structural basis for hub protein promiscuity; secondly, intrinsically disordered proteins can bind to structured hub proteins; and thirdly, intrinsic disorder can provide flexible linkers between functional domains with the linkers enabling mechanisms that facilitate binding diversity. An important research direction will be to determine what fraction of protein-protein interaction in regulatory networks relies on intrinsic disorder.

Stochastic innovation as a mechanism by which catalysts might self-assemble into chemical reaction networks

Justin Bradford — 2007-06-18T09:26:44-00:00

PNAS, Vol. 104, No. 24. (12 June 2007), pp. 10098-10103.

We develop a computer model for how two different chemical catalysts in solution, A and B, could be driven to form AB complexes, based on the concentration gradients of a substrate or product that they share in common. If A's product is B's substrate, B will be attracted to A, mediated by a common resource that is not otherwise plentiful in the environment. By this simple physicochemical mechanism, chemical reactions could spontaneously associate to become chained together in solution. According to the model, such catalyst self-association processes may resemble other processes of "stochastic innovation," such as Darwinian evolution in biology, that involve a search among options, a selection among those options, and then a lock-in of that selection. Like Darwinian processes, this simple chemical process exhibits cooperation, competition, innovation, and a preference for consistency. This model may be useful for understanding organizational processes in prebiotic chemistry and for developing new kinds of self-organization in chemically reacting systems. 10.1073/pnas.0703522104

ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage

Shuhei Matsuoka — 2007-05-31T20:27:24-00:00

Science, Vol. 316, No. 5828. (25 May 2007), pp. 1160-1166.

Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals. 10.1126/science.1140321