A structured approach for the engineering of biochemical network models, illustrated for signalling pathways

http://dx.doi.org/10.1093/bib/bbn026Quantitative models of biochemical networks (signal transduction cascades, metabolic pathways, gene regulatory circuits) are a central component of modern systems biology. Building and managing these complex models is a major challenge that can benefit from the application of formal methods adopted from theoretical computing science. Here we provide a general introduction to the field of formal modelling, which emphasizes the intuitive biochemical basis of the modelling process, but is also accessible for an audience with a background in computing science and/or model engineering. We show how signal transduction cascades can be modelled in a modular fashion, using both a qualitative approach { Qualitative Petri nets, and quantitative approaches { Continuous Petri Nets and Ordinary Differential Equations. We review the major elementary building blocks of a cellular signalling model, discuss which critical design decisions have to be made during model building, and present ..

An Object-Oriented Framework for Explicit-State Model Checking

This paper presents a conceptual architecture for an object-oriented framework to support the development of formal verification tools (i.e. model checkers). The objective of the architecture is to support the reuse of algorithms and to encourage a modular design of tools. The conceptual framework is accompanied by a C++ implementation which provides reusable algorithms for the simulation and verification of explicit-state models as well as a model representation for simple models based on guard-based process descriptions. The framework has been successfully used to develop a model checker for a subset of PROMELA

A petri net formalization of a publish-subscribe process system.

Publish/subscribe systems are getting more and more integrated into the execution of business processes in process aware information systems. This integration enables the distribution of the process logic and increases the scalability and adaptability of the process enactment infrastructure. A consequence is however that the original specified process model doesn't accurately represent the actual running process anymore, as the publish/subscribe specific operations are not incorporated into the original model. In this paper we propose a formal model of a publish/subscribe system that can be integrated into a business process model, creating in this way an accurate representation of the actual runtime process. The resulting model can be used for model checking the executable process: inspect system properties, discover problems and validate changes.

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

A Nice Labelling for Tree-Like Event Structures of Degree 3 (Extended Version)

We address the problem of finding nice labellings for event structures of degree 3. We develop a minimum theory by which we prove that the labelling number of an event structure of degree 3 is bounded by a linear function of the height. The main theorem we present in this paper states that event structures of degree 3 whose causality order is a tree have a nice labelling with 3 colors. Finally, we exemplify how to use this theorem to construct upper bounds for the labelling number of other event structures of degree 3

A review of modelling and verification approaches for computational biology

This paper reviews most frequently used computational modelling approaches and formal verification techniques in computational biology. The paper also compares a number of model checking tools and software suits used in analysing biological systems and biochemical networks and verifiying a wide range of biological properties

Petri nets for modelling metabolic pathways: a survey

In the last 15 years, several research efforts have been directed towards the representation and the analysis of metabolic pathways by using Petri nets. The goal of this paper is twofold. First, we discuss how the knowledge about metabolic pathways can be represented with Petri nets. We point out the main problems that arise in the construction of a Petri net model of a metabolic pathway and we outline some solutions proposed in the literature. Second, we present a comprehensive review of recent research on this topic, in order to assess the maturity of the field and the availability of a methodology for modelling a metabolic pathway by a corresponding Petri net

Synthesis of Distributed Testers from True-concurrency Models of Reactive Systems

Automatic synthesis of test cases for conformance testing has been principall- y developed with the objective of generating sequential test cases. In the distributed system context, it is worth extending the synthesis techniques to the generation of multiple testers. We base our work on our experience in using model-checking techniques, as successfully implemented in the TGV tool. Continuing the works of A. Ulrich and H. König, we propose to use a true-concurrency model based on graph unfolding. The article presents the principles of a complete chain of synthesis, starting from the definition of test purposes and ending with a projection onto a set of testers

Synthesis of Distributed Testers from True-concurrency Models of Reactive Systems

Automatic synthesis of test cases for conformance testing has been principall- y developed with the objective of generating sequential test cases. In the distributed system context, it is worth extending the synthesis techniques to the generation of multiple testers. We base our work on our experience in using model-checking techniques, as successfully implemented in the TGV tool. Continuing the works of A. Ulrich and H. König, we propose to use a true-concurrency model based on graph unfolding. The article presents the principles of a complete chain of synthesis, starting from the definition of test purposes and ending with a projection onto a set of testers

Modeling and Analyzing Cyber-Physical Systems Using Hybrid Predicate Transition Nets

Cyber-Physical Systems (CPSs) are software controlled physical devices that are being used everywhere from utility features in household devices to safety-critical features in cars, trains, aircraft, robots, smart healthcare devices. CPSs have complex hybrid behaviors combining discrete states and continuous states capturing physical laws. Developing reliable CPSs are extremely difficult. Formal modeling methods are especially useful for abstracting and understanding complex systems and detecting and preventing early system design problems. To ensure the dependability of formal models, various analysis techniques, including simulation and reachability analysis, have been proposed in recent decades. This thesis aims to provide a unified formal modeling and analysis methodology for studying CPSs. Firstly, this thesis contributes to the modeling and analysis of discrete, continuous, and hybrid systems. This work enhances modeling of discrete systems using predicate transition nets (PrTNs) by fully realizing the underlying specification through incorporating the first-order logic with set theory, improving the type system, and providing incremental model composition. This work enhances the technique of analyzing discrete systems using PrTN by improving the simulation algorithm and its efficient implementation. This work also improves the analysis of discrete systems using SPIN by providing a more accurate and complete translation method. Secondly, this work contributes to the modeling and analysis of hybrid systems by proposing an extension of PrTNs, hybrid predicate transition nets (HPrTNs). The proposed method incorporates a novel concept of token evolution, which nicely addresses the continuous state evolution and the conflicts present in other related works. This work presents a powerful simulation capability that can handle linear, non-linear dynamics, transcendental functions through differential equations. This work also provides a complementary technique for reachability analysis through the translation of HPrTN models for analysis using SpaceEx