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A fully automated framework for control of linear systems from ltl specifications
 In HSCC, volume 3927 of LNCS
, 2006
"... Abstract. We consider the following problem: given a linear system and an LTL−X formula over a set of linear predicates in its state variables, find a feedback control law with polyhedral bounds and a set of initial states so that all trajectories of the closed loop system satisfy the formula. Our ..."
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Cited by 148 (32 self)
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Abstract. We consider the following problem: given a linear system and an LTL−X formula over a set of linear predicates in its state variables, find a feedback control law with polyhedral bounds and a set of initial states so that all trajectories of the closed loop system satisfy the formula. Our solution to this problem consists of three main steps. First, we partition the state space in accordance with the predicates in the formula and construct a transition system over the partition quotient, which captures our capability of designing controllers. Second, using model checking, we determine runs of the transition system satisfying the formula. Third, we generate the control strategy. Illustrative examples are included. 1
Rules for Modeling SignalTransduction Systems
 Science’s STKE
, 2006
"... Formalized rules for proteinprotein interactions have recently been introduced to represent the binding and enzymatic activities of proteins in cellular signaling. Rules encode an understanding of how a system works in terms of the biomolecules in the system and their possible states and interactio ..."
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Cited by 77 (20 self)
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Formalized rules for proteinprotein interactions have recently been introduced to represent the binding and enzymatic activities of proteins in cellular signaling. Rules encode an understanding of how a system works in terms of the biomolecules in the system and their possible states and interactions. A set of rules can be as easy to read as a diagrammatic interaction map, but unlike most such maps, rules have precise interpretations. Rules can be processed to automatically generate a mathematical or computational model for a system, which enables explanatory and predictive insights into the system’s behavior. Rules are independent units of a model specification that facilitate model revision. Instead of changing a large number of equations or lines of code, as may be required in the case of a conventional mathematical model, a protein interaction can be introduced or modified simply by adding or changing a single rule that represents the interaction of interest. Rules can be defined and visualized by using graphs, so no specialized training in mathematics or computer science is necessary to create models or to take advantage of the representational precision of rules. Rules can be encoded in a machinereadable format to enable electronic storage and exchange of models, as well as basic knowledge about proteinprotein interactions. Here, we review the motivation for rulebased modeling; applications of the approach; and issues that arise in model specification, simulation, and testing. We also discuss rule visualization and exchange and the software available for rulebased modeling.
A Bayesian Approach to Model Checking Biological Systems ⋆
"... Abstract. Recently, there has been considerable interest in the use of Model Checking for Systems Biology. Unfortunately, the state space of stochastic biological models is often too large for classical Model Checking techniques. For these models, a statistical approach to Model Checking has been sh ..."
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Cited by 52 (15 self)
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Abstract. Recently, there has been considerable interest in the use of Model Checking for Systems Biology. Unfortunately, the state space of stochastic biological models is often too large for classical Model Checking techniques. For these models, a statistical approach to Model Checking has been shown to be an effective alternative. Extending our earlier work, we present the first algorithm for performing statistical Model Checking using Bayesian Sequential Hypothesis Testing. We show that our Bayesian approach outperforms current statistical Model Checking techniques, which rely on tests from Classical (aka Frequentist) statistics, by requiring fewer system simulations. Another advantage of our approach is the ability to incorporate prior Biological knowledge about the model being verified. We demonstrate our algorithm on a variety of models from the Systems Biology literature and show that it enables faster verification than stateoftheart techniques, even when no prior knowledge is available. 1
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 45 (6 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
On a Continuous Degree of Satisfaction of Temporal Logic Formulae with Applications to Systems Biology
 In M.Heiner and A.M.Uhrmacher (eds.), CMSB’08: Proc. of the sixth international conference on Computational Methods in Systems Biology
, 2008
"... Abstract. Finding mathematical models satisfying a specification built from the formalization of biological experiments, is a common task of the modeller that techniques like modelchecking help solving, in the qualitative but also in the quantitative case. In this article we propose to go one step ..."
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Cited by 36 (4 self)
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Abstract. Finding mathematical models satisfying a specification built from the formalization of biological experiments, is a common task of the modeller that techniques like modelchecking help solving, in the qualitative but also in the quantitative case. In this article we propose to go one step further by defining a continuous degree of satisfaction of a temporal logic formula with constraints. We show how such a satisfaction measure can be used as a fitness function with stateoftheart search methods in order to find biochemical kinetic parameter values satisfying a set of biological properties formalized in temporal logic. We also show how it can be used to define a measure of robustness of a biological model with respect to some specification. These methods are evaluated on models of the cell cycle and of the MAPK signalling cascade. 1
Hybrid modeling and simulation of genetic regulatory networks: a qualitative approach
 ERCIM News
, 2003
"... The functioning and development of living organisms is controlled by large and complex networks of genes, proteins, small molecules, and their interactions, socalled genetic regulatory networks. The concerted efforts of genetics, molecular biology, biochemistry, and physiology have led to the accum ..."
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Cited by 35 (1 self)
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The functioning and development of living organisms is controlled by large and complex networks of genes, proteins, small molecules, and their interactions, socalled genetic regulatory networks. The concerted efforts of genetics, molecular biology, biochemistry, and physiology have led to the accumulation of enormous amounts of data on the molecular components of genetic regulatory networks and their interactions. Notwithstanding the advances in the mapping of the network structure, surprisingly little is understood about how the dynamic behavior of the system emerges from the interactions between the network components. This has incited an increasingly large group of researchers to turn from the structure to the behavior of genetic regulatory networks, against the background of a broader movement nowadays often referred to as systems biology
Statistical Model Checking in BioLab: Applications to the automated analysis of TCell Receptor Signaling Pathway ⋆
"... Abstract. We present an algorithm, called BioLab, for verifying temporal properties of rulebased models of cellular signalling networks. BioLab models are encoded in the BioNetGen language, and properties are expressed as formulae in probabilistic bounded linear temporal logic. Temporal logic is a ..."
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Cited by 25 (7 self)
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Abstract. We present an algorithm, called BioLab, for verifying temporal properties of rulebased models of cellular signalling networks. BioLab models are encoded in the BioNetGen language, and properties are expressed as formulae in probabilistic bounded linear temporal logic. Temporal logic is a formalism for representing and reasoning about propositions qualified in terms of time. Properties are then verified using sequential hypothesis testing on executions generated using stochastic simulation. BioLab is optimal, in the sense that it generates the minimum number of executions necessary to verify the given property. BioLab also provides guarantees on the probability of it generating TypeI (i.e., falsepositive) and TypeII (i.e., falsenegative) errors. Moreover, these error bounds are prespecified by the user. We demonstrate BioLab by verifying stochastic effects and bistability in the dynamics of the Tcell receptor signaling network. 1
A general computational method for robustness analysis with applications to synthetic gene networks
, 2009
"... Motivation: Robustness is the capacity of a system to maintain a function in the face of perturbations. It is essential for the correct functioning of natural and engineered biological systems. Robustness is generally defined in an adhoc, problemdependent manner, thus hampering the fruitful develo ..."
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Cited by 22 (7 self)
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Motivation: Robustness is the capacity of a system to maintain a function in the face of perturbations. It is essential for the correct functioning of natural and engineered biological systems. Robustness is generally defined in an adhoc, problemdependent manner, thus hampering the fruitful development of a theory of biological robustness, advocated by Kitano [Mol Syst Biol, 3:137, 2007]. Results: In this paper, we propose a general definition of robustness that applies to any biological function expressible in temporal logic LTL, and to broad model classes and perturbation types. Moreover, we propose a computational approach and an implementation in BIOCHAM 2.8 for the automated estimation of the robustness of a given behavior with respect to a given set of perturbations. The applicability and biological relevance of our approach is demonstrated by testing and improving the robustness of the timed behavior of a synthetic transcriptional cascade that could be used as a biological timer for synthetic biology applications. Availability: Version 2.8 of BIOCHAM and the transcriptional cascade model are available at