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 ..

Supporting user-oriented analysis for multi-view domain-specific visual languages

This is the post-print version of the final paper published in Information and Software Technology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2008 Elsevier B.V.The integration of usable and flexible analysis support in modelling environments is a key success factor in Model-Driven Development. In this paradigm, models are the core asset from which code is automatically generated, and thus ensuring model correctness is a fundamental quality control activity. For this purpose, a common approach is to transform the system models into formal semantic domains for verification. However, if the analysis results are not shown in a proper way to the end-user (e.g. in terms of the original language) they may become useless. In this paper we present a novel DSVL called BaVeL that facilitates the flexible annotation of verification results obtained in semantic domains to different formats, including the context of the original language. BaVeL is used in combination with a consistency framework, providing support for all steps in a verification process: acquisition of additional input data, transformation of the system models into semantic domains, verification, and flexible annotation of analysis results. The approach has been validated analytically by the cognitive dimensions framework, and empirically by its implementation and application to several DSVLs. Here we present a case study of a notation in the area of Digital Libraries, where the analysis is performed by transformations into Petri nets and a process algebra.Spanish Ministry of Education and Science and MODUWEB

Semantic Embedding of Petri Nets into Event-B

We present an embedding of Petri nets into B abstract systems. The embedding is achieved by translating both the static structure (modelling aspect) and the evolution semantics of Petri nets. The static structure of a Petri-net is captured within a B abstract system through a graph structure. This abstract system is then included in another abstract system which captures the evolution semantics of Petri-nets. The evolution semantics results in some B events depending on the chosen policies: basic nets or high level Petri nets. The current embedding enables one to use conjointly Petri nets and Event-B in the same system development, but at different steps and for various analysis.Comment: 16 pages, 3 figure

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)

A Petri Nets-based Scheduling Methodology forMultipurpose Batch Plants.

This article presents an optimization methodology of batch production processes assembled by shared resources which rely on a mapping of state-events into time-events allowing in this way the straightforward use of a well consolidated scheduling policies developed for manufacturing systems. A technique to generate the timed Petri net representation from a continuous dynamic representation (Differential-Algebraic Equations systems (DAEs)) of the production system is presented together with the main characteristics of a Petri nets-based tool implemented for optimization purposes. This paper describes also how the implemented tool generates the coverability tree and how it can be pruned by a general purpose heuristic. An example of a distillation process with two shared batch resources is used to illustrate the optimization methodology proposed

Object-based Control/Data-flow Analysis

Not only does a clear distinction between control and data flow enhance the readability of models, but it also allows different tools to operate on the two distinct parts of the model. This paper shows how the modelling based on control/data-flow analysis can benefit from an object-based approach. We have developed a translation mechanism that is faithful and gives an extra dimension (hierarchy) to the existing paradigm of control and data flow interacting in a model. Our methodology provides a comprehensible separation of these two parts, which can be used to feed another analysis or synthesis tools, while still being able to reason about both parts through formal methods of verification

Modelling epistasis in genetic disease using Petri nets, evolutionary computation and frequent itemset mining

Petri nets are useful for mathematically modelling disease-causing genetic epistasis. A Petri net model of an interaction has the potential to lead to biological insight into the cause of a genetic disease. However, defining a Petri net by hand for a particular interaction is extremely difficult because of the sheer complexity of the problem and degrees of freedom inherent in a Petri net’s architecture. We propose therefore a novel method, based on evolutionary computation and data mining, for automatically constructing Petri net models of non-linear gene interactions. The method comprises two main steps. Firstly, an initial partial Petri net is set up with several repeated sub-nets that model individual genes and a set of constraints, comprising relevant common sense and biological knowledge, is also defined. These constraints characterise the class of Petri nets that are desired. Secondly, this initial Petri net structure and the constraints are used as the input to a genetic algorithm. The genetic algorithm searches for a Petri net architecture that is both a superset of the initial net, and also conforms to all of the given constraints. The genetic algorithm evaluation function that we employ gives equal weighting to both the accuracy of the net and also its parsimony. We demonstrate our method using an epistatic model related to the presence of digital ulcers in systemic sclerosis patients that was recently reported in the literature. Our results show that although individual “perfect” Petri nets can frequently be discovered for this interaction, the true value of this approach lies in generating many different perfect nets, and applying data mining techniques to them in order to elucidate common and statistically significant patterns of interaction

Subtyping for Hierarchical, Reconfigurable Petri Nets

Hierarchical Petri nets allow a more abstract view and reconfigurable Petri nets model dynamic structural adaptation. In this contribution we present the combination of reconfigurable Petri nets and hierarchical Petri nets yielding hierarchical structure for reconfigurable Petri nets. Hierarchies are established by substituting transitions by subnets. These subnets are themselves reconfigurable, so they are supplied with their own set of rules. Moreover, global rules that can be applied in all of the net, are provided

On Modelling and Analysis of Dynamic Reconfiguration of Dependable Real-Time Systems

This paper motivates the need for a formalism for the modelling and analysis of dynamic reconfiguration of dependable real-time systems. We present requirements that the formalism must meet, and use these to evaluate well established formalisms and two process algebras that we have been developing, namely, Webpi and CCSdp. A simple case study is developed to illustrate the modelling power of these two formalisms. The paper shows how Webpi and CCSdp represent a significant step forward in modelling adaptive and dependable real-time systems.Comment: Presented and published at DEPEND 201