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

Modularization of biochemical networks based on classification of Petri net t-invariants

<p>Abstract</p> <p>Background</p> <p>Structural analysis of biochemical networks is a growing field in bioinformatics and systems biology. The availability of an increasing amount of biological data from molecular biological networks promises a deeper understanding but confronts researchers with the problem of combinatorial explosion. The amount of qualitative network data is growing much faster than the amount of quantitative data, such as enzyme kinetics. In many cases it is even impossible to measure quantitative data because of limitations of experimental methods, or for ethical reasons. Thus, a huge amount of qualitative data, such as interaction data, is available, but it was not sufficiently used for modeling purposes, until now. New approaches have been developed, but the complexity of data often limits the application of many of the methods. Biochemical Petri nets make it possible to explore static and dynamic qualitative system properties. One Petri net approach is model validation based on the computation of the system's invariant properties, focusing on t-invariants. T-invariants correspond to subnetworks, which describe the basic system behavior.</p> <p>With increasing system complexity, the basic behavior can only be expressed by a huge number of t-invariants. According to our validation criteria for biochemical Petri nets, the necessary verification of the biological meaning, by interpreting each subnetwork (t-invariant) manually, is not possible anymore. Thus, an automated, biologically meaningful classification would be helpful in analyzing t-invariants, and supporting the understanding of the basic behavior of the considered biological system.</p> <p>Methods</p> <p>Here, we introduce a new approach to automatically classify t-invariants to cope with network complexity. We apply clustering techniques such as UPGMA, Complete Linkage, Single Linkage, and Neighbor Joining in combination with different distance measures to get biologically meaningful clusters (t-clusters), which can be interpreted as modules. To find the optimal number of t-clusters to consider for interpretation, the cluster validity measure, Silhouette Width, is applied.</p> <p>Results</p> <p>We considered two different case studies as examples: a small signal transduction pathway (pheromone response pathway in <it>Saccharomyces cerevisiae</it>) and a medium-sized gene regulatory network (gene regulation of Duchenne muscular dystrophy). We automatically classified the t-invariants into functionally distinct t-clusters, which could be interpreted biologically as functional modules in the network. We found differences in the suitability of the various distance measures as well as the clustering methods. In terms of a biologically meaningful classification of t-invariants, the best results are obtained using the Tanimoto distance measure. Considering clustering methods, the obtained results suggest that UPGMA and Complete Linkage are suitable for clustering t-invariants with respect to the biological interpretability.</p> <p>Conclusion</p> <p>We propose a new approach for the biological classification of Petri net t-invariants based on cluster analysis. Due to the biologically meaningful data reduction and structuring of network processes, large sets of t-invariants can be evaluated, allowing for model validation of qualitative biochemical Petri nets. This approach can also be applied to elementary mode analysis.</p

Structural characterization of decomposition in rate-insensitive stochastic Petri nets

This paper focuses on stochastic Petri nets that have an equilibrium distribution that is a product form over the number of tokens at the places. We formulate a decomposition result for the class of nets that have a product form solution irrespective of the values of the transition rates. These nets where algebraically characterized by Haddad et al.~as $S\Pi^2$ nets. By providing an intuitive interpretation of this algebraical characterization, and associating state machines to sets of $T$-invariants, we obtain a one-to-one correspondence between the marking of the original places and the places of the added state machines. This enables us to show that the subclass of stochastic Petri nets under study can be decomposed into subnets that are identified by sets of its $T$-invariants

Automating the transformation-based analysis of visual languages

The final publication is available at Springer via http://dx.doi.org/10.1007/s00165-009-0114-yWe present a novel approach for the automatic generation of model-to-model transformations given a description of the operational semantics of the source language in the form of graph transformation rules. The approach is geared to the generation of transformations from Domain-Specific Visual Languages (DSVLs) into semantic domains with an explicit notion of transition, like for example Petri nets. The generated transformation is expressed in the form of operational triple graph grammar rules that transform the static information (initial model) and the dynamics (source rules and their execution control structure). We illustrate these techniques with a DSVL in the domain of production systems, for which we generate a transformation into Petri nets. We also tackle the description of timing aspects in graph transformation rules, and its analysis through their automatic translation into Time Petri netsWork sponsored by the Spanish Ministry of Science and Innovation, project METEORIC (TIN2008-02081/TIN) and by the Canadian Natural Sciences and Engineering Research Council (NSERC)

Independence and concurrent separation logic

A compositional Petri net-based semantics is given to a simple language allowing pointer manipulation and parallelism. The model is then applied to give a notion of validity to the judgements made by concurrent separation logic that emphasizes the process-environment duality inherent in such rely-guarantee reasoning. Soundness of the rules of concurrent separation logic with respect to this definition of validity is shown. The independence information retained by the Petri net model is then exploited to characterize the independence of parallel processes enforced by the logic. This is shown to permit a refinement operation capable of changing the granularity of atomic actions

On the Enforcement of a Class of Nonlinear Constraints on Petri Nets

International audienceThis paper focuses on the enforcement of nonlinear constraints in Petri nets. First, a supervisory structure is proposed for a nonlinear constraint. The proposed structure consists of added places and transitions. It controls the transitions in the net to be controlled only but does not change its states since there is no arc between the added transitions and the places in the original net. Second, an integer linear programming model is proposed to transform a nonlinear constraint to a minimal number of conjunc-tive linear constraints that have the same control performance as the nonlinear one. By using a place invariant based method, the obtained linear constraints can be easily enforced by a set of control places. The control places consist to a supervisor that can enforce the given nonlinear constraint. On condition that the admissible markings space of a nonlinear constraint is non-convex, another integer linear programming model is developed to obtain a minimal number of constraints whose disjunctions are equivalent to the nonlinear constraint. Finally, a number of examples are provided to demonstrate the proposed approach