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Modeling and simulation of genetic regulatory systems: A literature review
 Journal of Computational Biology
, 2002
"... In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between ..."
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Cited by 477 (10 self)
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In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between DNA, RNA, proteins, and small molecules. As most genetic regulatory networks of interest involve many components connected through interlocking positive and negative feedback loops, an intuitive understanding of their dynamics is hard to obtain. As a consequence, formal methods and computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This paper reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, Boolean networks and their generalizations, ordinary and partial differential equations, qualitative differential equations, stochastic equations, and rulebased formalisms. In addition, the paper discusses how these formalisms have been used in the simulation of the behavior of actual regulatory systems. Key words: genetic regulatory networks, mathematical modeling, simulation, computational biology.
The LargeScale Organization of Metabolic Networks
, 2000
"... In a cell or microorganism the processes that generate mass, energy, information transfer, and cell fate specification are seamlessly integrated through a complex network of various cellular constituents and reactions. However, despite the key role these networks play in sustaining various cellular ..."
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Cited by 422 (7 self)
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In a cell or microorganism the processes that generate mass, energy, information transfer, and cell fate specification are seamlessly integrated through a complex network of various cellular constituents and reactions. However, despite the key role these networks play in sustaining various cellular functions, their largescale structure is essentially unknown. Here we present the first systematic comparative mathematical analysis of the metabolic networks of 43 organisms representing all three domains of life. We show that, despite significant variances in their individual constituents and pathways, these metabolic networks display the same topologic scaling properties demonstrating striking similarities to the inherent organization of complex nonbiological systems. This suggests that the metabolic organization is not only identical for all living organisms, but complies with the design principles of robust and errortolerant networks, and may represent a common blueprint for the largescale organization of interactions among all cellular constituents.
Qualitative Simulation of Genetic Regulatory Networks Using PiecewiseLinear Models
, 2001
"... In order to cope with the large amounts of data that have become available in genomics, mathematical tools for the analysis of networks of interactions between genes, proteins, and other molecules are indispensable. We present a method for the qualitative simulation of genetic regulatory networks ..."
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Cited by 143 (23 self)
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In order to cope with the large amounts of data that have become available in genomics, mathematical tools for the analysis of networks of interactions between genes, proteins, and other molecules are indispensable. We present a method for the qualitative simulation of genetic regulatory networks, based on a class of piecewiselinear (PL) differential equations that has been wellstudied in mathematical biology. The simulation method is welladapted to stateoftheart measurement techniques in genomics, which often provide qualitative and coarsegrained descriptions of genetic regulatory networks. Given a qualitative model of a genetic regulatory network, consisting of a system of PL differential equations and inequality constraints on the parameter values, the method produces a graph of qualitative states and transitions between qualitative states, summarizing the qualitative dynamics of the system. The qualitative simulation method has been implemented in Java in the computer tool Genetic Network Analyzer.
Sensitivity and specificity of inferring genetic regulatory interactions from microarray experiments with dynamic Bayesian networks
 Bioinformatics
, 2003
"... Motivation: Bayesian networks have been applied to infer genetic regulatory interactions from microarray gene expression data. This inference problem is particularly hard in that interactions between hundreds of genes have to be learned from very small data sets, typically containing only a few doze ..."
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Cited by 119 (4 self)
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Motivation: Bayesian networks have been applied to infer genetic regulatory interactions from microarray gene expression data. This inference problem is particularly hard in that interactions between hundreds of genes have to be learned from very small data sets, typically containing only a few dozen time points during a cell cycle. Most previous studies have assessed the inference results on real gene expression data by comparing predicted genetic regulatory interactions with those known from the biological literature. This approach is controversial due to the absence of known gold standards, which renders the estimation of the sensitivity and specificity, that is, the true and (complementary) false detection rate, unreliable and difficult. The objective of the present study is to test the viability of the Bayesian network paradigm in a realistic simulation study. First, gene expression data are simulated from a realistic biological network involving DNAs, mRNAs, inactive protein monomers and active protein dimers. Then, interaction networks are inferred from these data in a reverse engineering approach, using Bayesian networks and Bayesian learning with Markov chain Monte Carlo.
Results: The simulation results are presented as receiver operator characteristics curves. This allows estimating the proportion of spurious gene interactions incurred for a specified target proportion of recovered true interactions. The findings demonstrate how the network inference performance varies with the training set size, the degree of inadequacy of prior assumptions, the experimental sampling strategy and the inclusion of further, sequencebased information.
Bayesian inference and optimal design in the sparse linear model
 Workshop on Artificial Intelligence and Statistics
"... The linear model with sparsityfavouring prior on the coefficients has important applications in many different domains. In machine learning, most methods to date search for maximum a posteriori sparse solutions and neglect to represent posterior uncertainties. In this paper, we address problems of ..."
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Cited by 65 (13 self)
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The linear model with sparsityfavouring prior on the coefficients has important applications in many different domains. In machine learning, most methods to date search for maximum a posteriori sparse solutions and neglect to represent posterior uncertainties. In this paper, we address problems of Bayesian optimal design (or experiment planning), for which accurate estimates of uncertainty are essential. To this end, we employ expectation propagation approximate inference for the linear model with Laplace prior, giving new insight into numerical stability properties and proposing a robust algorithm. We also show how to estimate model hyperparameters by empirical Bayesian maximisation of the marginal likelihood, and propose ideas in order to scale up the method to very large underdetermined problems. We demonstrate the versatility of our framework on the application of gene regulatory network identification from microarray expression data, where both the Laplace prior and the active experimental design approach are shown to result in significant improvements. We also address the problem of sparse coding of natural images, and show how our framework can be used for compressive sensing tasks. Part of this work appeared in Seeger et al. (2007b). The gene network identification application appears in Steinke et al. (2007).
Multiple equilibria in complex chemical reaction networks: I. the injectivity property
 SIAM Journal on Applied Mathematics
, 2005
"... Abstract. For mass action kinetics, the capacity for multiple equilibria in an isothermal homogeneous continuous flow stirred tank reactor is determined by the structure of the underlying network of chemical reactions. We suggest a new graphtheoretical method for discriminating between complex reac ..."
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Cited by 55 (11 self)
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Abstract. For mass action kinetics, the capacity for multiple equilibria in an isothermal homogeneous continuous flow stirred tank reactor is determined by the structure of the underlying network of chemical reactions. We suggest a new graphtheoretical method for discriminating between complex reaction networks that can admit multiple equilibria and those that cannot. In particular, we associate with each network a speciesreaction graph, which is similar to reaction network representations drawn by biochemists, and we show that, if the graph satisfies certain weak conditions, the differential equations corresponding to the network cannot admit multiple equilibria no matter what values the rate constants take. Because these conditions are very mild, they amount to powerful (and quite delicate) necessary conditions that a network must satisfy if it is to have the capacity to engender multiple equilibria. Broad qualitative results of this kind are especially apt, for individual reaction rate constants are rarely known fully for complex reaction networks (if they are known at all). Some concluding remarks address connections to biology.
Negative autoregulation speeds the response times of transcription networks
 J. Mol. Biol
, 2002
"... A major current challenge is to understand the design principles of gene regulation networks. It is therefore of interest to study the properties of regulatory structures, or “motifs”, that occur frequently ..."
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Cited by 50 (3 self)
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A major current challenge is to understand the design principles of gene regulation networks. It is therefore of interest to study the properties of regulatory structures, or “motifs”, that occur frequently
Model Checking Genetic Regulatory Networks using GNA and CADP
 In: Proceedings of the 11th International SPIN Workshop on Model Checking of Software SPIN’2004
, 2004
"... who are interested in the interdisciplinary methods and applications relevant to the analysis, design and management of complex systems. 15 St. Mary’s St. Brookline MA 02446 l 617.358.1295 l www.bu.edu/systems ..."
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Cited by 42 (7 self)
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who are interested in the interdisciplinary methods and applications relevant to the analysis, design and management of complex systems. 15 St. Mary’s St. Brookline MA 02446 l 617.358.1295 l www.bu.edu/systems
Positive and Negative Feedback: Striking a balance between necessary antagonists
 J. Theor. Biol
, 2002
"... Most biological regulation systems comprise feedback circuits as crucial components. Negative iedback circuits have been well understood for a very long time; indeed, their understanding has been the basis for the engineering of cybernetic machines exhibiting stable behaviour. The importance of posi ..."
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Cited by 41 (6 self)
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Most biological regulation systems comprise feedback circuits as crucial components. Negative iedback circuits have been well understood for a very long time; indeed, their understanding has been the basis for the engineering of cybernetic machines exhibiting stable behaviour. The importance of positive feedback circuits, considered as "vicious circles", has however been underestimated. In this article we give a demonstration based on degree theory for vector fields of the conjecture, made by R.ex Thomas, that the presence of positive feedback circuits is a necessary condition fox' autonomous differential systems, covering a wide class of biologically relevant systems, to possess multiple steady states. We also show ways to derive constraints on the weights of positive and negative feedback circuits. These qualitative and quantitative restilts provide respectively structural constraints (i.e. related to the interaction graph) and numerical constraints (i.e. related to the magnitudes of the interactions) on systems exhibiting complex be haviours, and should make. it easier to reverseengineer the interaction networks animating those systems on the basis of partial, sometimes unreliable, experimental data. X illustrate these concepts on a model multistable switch, in the context of cellular differentiation, showing a requirement ibr sufficient cooperativity. Furtler developments are expected i' tle discovery and modellbg of regulatory networks iu gemral, and in the interpretation of bioarray hybridisation and proteomics experiments in particular.