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

Recent advances in petri nets and concurrency

CEUR Workshop Proceeding

A systems biology approach to multi-scale modelling and analysis of planar cell polarity in drosophila melanogaster wing

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Systems biology aims to describe and understand biology at a global scale where biological systems function as a result of complex mechanisms that happen at several scales. Modelling and simulation are computational tools that are invaluable for description, understanding and prediction these mechanisms in a quantitative and integrative way. Thus multi-scale methods that couple the design, simulation and analysis of models spanning several spatial and temporal scales is becoming a new emerging focus of systems biology. This thesis uses an exemplar – Planar cell polarity (PCP) signalling – to illustrate a generic approach to model biological systems at different spatial scales, using the new concept of Hierarchically Coloured Petri Nets (HCPN). PCP signalling refers to the coordinated polarisation of cells within the plane of various epithelial tissues to generate sub-cellular asymmetry along an axis orthogonal to their apical-basal axes. This polarisation is required for many developmental events in both vertebrates and non-vertebrates. Defects in PCP in vertebrates are responsible for developmental abnormalities in multiple tissues including the neural tube, the kidney and the inner ear. In Drosophila wing, PCP is seen in the parallel orientation of hairs that protrude from each of the approximately 30,000 epithelial cells to robustly point toward the wing tip. This work applies HCPN to model a tissue comprising multiple cells hexagonally packed in a honeycomb formation in order to describe the phenomenon of Planar Cell Polarity (PCP) in Drosophila wing. HCPN facilitate the construction of mathematically tractable, compact and parameterised large-scale models. Different levels of abstraction that can be used in order to simplify such a complex system are first illustrated. The PCP system is first represented at an abstract level without modelling details of the cell. Each cell is then sub-divided into seven virtual compartments with adjacent cells being coupled via the formation of intercellular complexes. A more detailed model is later developed, describing the intra- and inter-cellular signalling mechanisms involved in PCP signalling. The initial model is for a wild-type organism, and then a family of related models, permitting different hypotheses to be explored regarding the mechanisms underlying PCP, are constructed. Among them, the largest model consists of 800 cells which when unfolded yields 164,000 places (each of which is described by an ordinary differential equation). This thesis illustrates the power and validity of the approach by showing how the models can be easily adapted to describe well-documented genetic mutations in the Drosophila wing using the proposed approach including clustering and model checking over time series of primary and secondary data, which can be employed to analyse and check such multi-scale models similar to the case of PCP. The HCPN models support the interpretation of biological observations reported in literature and are able to make sensible predictions. As HCPN model multi-scale systems in a compact, parameterised and scalable way, this modelling approach can be applied to other large-scale or multi-scale systems.This study was funded by Brunel University

ML-Space: hybrid spatial Gillespie and Brownian motion simulation at multiple levels, and a rule-based description language

Computer simulations of biological cells as well-stirred systems are well established but neglect the spatial distribution of key actors. In this thesis, a simulation algorithm "ML-Space" for spatial models with dynamic hierarchies is presented. It combines stochastic spatial algorithms in discretized space with individual particles moving in continuous space that have spatial extensions and can contain other particles. For formal descriptions of the systems to be simulated spatially, ML-Space provides a rule-based specification language.Computersimulationen mikrobiologischer Prozesse, bei denen eine homogene Verteilung der Akteure einer Zelle angenommen wird, sind gut etabliert. In dieser Arbeit wird ein räumlicher Simulationsalgorithmus "ML-Space" für Mehrebenenmodelle vorgestellt, der auch dynamische Hierarchien abdeckt. Er vereint stochastische räumliche Algorithmen in diskretisiertem Raum mit individuellen Partikeln mit kontinuierlichen Koordinaten, die andere Partikel enthalten können. Zur formalen Beschreibung der räumlich zu simulierenden Systeme bietet ML-Space eine regelbasierte Modellierungssprache

Tools and Algorithms for the Construction and Analysis of Systems

This book is Open Access under a CC BY licence. The LNCS 11427 and 11428 proceedings set constitutes the proceedings of the 25th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2019, which took place in Prague, Czech Republic, in April 2019, held as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2019. The total of 42 full and 8 short tool demo papers presented in these volumes was carefully reviewed and selected from 164 submissions. The papers are organized in topical sections as follows: Part I: SAT and SMT, SAT solving and theorem proving; verification and analysis; model checking; tool demo; and machine learning. Part II: concurrent and distributed systems; monitoring and runtime verification; hybrid and stochastic systems; synthesis; symbolic verification; and safety and fault-tolerant systems

Hybrid modeling and optimization of biological processes

Proß S. Hybrid modeling and optimization of biological processes. Bielefeld: Bielefeld University; 2013

Contribution à la Spécification et à la Vérification des Exigences Temporelles (Proposition d'une extension des SRS d'ERTMS niveau 2)

Les travaux développés dans cette thèse visent à assister le processus d ingénierie des exigences temporelles pour les systèmes complexes à contraintes de temps. Nos contributions portent sur trois volets : la spécification des exigences, la modélisation du comportement et la vérification. Pour le volet spécification, une nouvelle classification des exigences temporelles les plus communément utilisées a été proposée. Ensuite, afin de cadrer l utilisateur durant l expression des exigences, une grammaire de spécification à base de motifs prédéfinis en langage naturel est développée. Les exigences générées sont syntaxiquement précises et correctes quand elles sont prises individuellement, néanmoins cela ne garantie pas la cohérence de l ensemble des exigences exprimées. Ainsi, nous avons développé des mécanismes capables de détecter certains types d incohérences entre les exigences temporelles. Pour le volet modélisation du comportement, nous avons proposé un algorithme de transformation des state-machine avec des annotations temporelles en des automates temporisés. L idée étant de manipuler une notation assez intuitive et de générer automatiquement des modèles formels qui se prêtent à la vérification. Finalement, pour le volet vérification, nous avons adopté une technique de vérification à base d observateurs et qui repose sur le model-checking. Concrètement, nous avons élaboré une base de patterns d observation (ou observateurs) ; chacun des patterns développés est relatif à un type d exigence temporelle dans la nouvelle classification. Ainsi, la vérification est réduite à une analyse d accessibilité des états correspondants à la violation de l exigence associéeThe work developed in this thesis aims to assist the engineering process of temporal requirements for time-constrained complex systems. Our contributions concern three phases: the specification, the behaviour modelling and the verification. For the specification of temporal requirements, a new temporal properties typology taking into account all the common requirements one may meet when dealing with requirements specification, is introduced. Then, to facilitate the expression, we have proposed a structured English grammar. Nevertheless, even if each requirement taken individually is correct, we have no guarantee that a set of temporal properties one may express is consistent. Here we have proposed an algorithm based on graph theory techniques to check the consistency of temporal requirements sets. For the behaviour modelling, we have proposed an algorithm for transforming UML State Machine with time annotations into Timed Automata (TA). The idea is to allow the user manipulating a quite intuitive notation (UML SM diagramsduring the modelling phase and thereby, automatically generate formal models (TA) that could be used directly by the verification process. Finally, for the verification phase, we have adopted an observer-based technique. Actually, we have developed a repository of observation patterns where each pattern is relative to a particular temporal requirement class in our classification. Thereby, the verification process is reduced to a reachability analysis of the observers KO states relatives to the requirements violationVILLENEUVE D'ASCQ-ECLI (590092307) / SudocSudocFranceF

Computational modelling of mycobacterium infection and innate immune response in zebrafish

In this thesis we provided a comprehensive overview on the steps that are involved in the modeling process and simulation of biological phenomena; from the choice of the method to the validation of the results. We gradually implemented a model with which we would be able to study the complex interplay of the components involved in the Mycobacterium marinum infection process and innate immune response in zebrafish embryos. In itself this process is a model for deeper understanding of tuberculosis infection in humans using zebrafish as model organism. Each chapter is a building block in the modeling process, which gradually forms a model that can represent cause-and-effect among these components involved in the biological behavior.Computer Systems, Imagery and Medi

Tools and Algorithms for the Construction and Analysis of Systems

This open access book constitutes the proceedings of the 28th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2022, which was held during April 2-7, 2022, in Munich, Germany, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2022. The 46 full papers and 4 short papers presented in this volume were carefully reviewed and selected from 159 submissions. The proceedings also contain 16 tool papers of the affiliated competition SV-Comp and 1 paper consisting of the competition report. TACAS is a forum for researchers, developers, and users interested in rigorously based tools and algorithms for the construction and analysis of systems. The conference aims to bridge the gaps between different communities with this common interest and to support them in their quest to improve the utility, reliability, exibility, and efficiency of tools and algorithms for building computer-controlled systems