Formal executable descriptions of biological systems

The similarities between systems of living entities and systems of concurrent processes may support biological experiments in silico. Process calculi offer a formal framework to describe biological systems, as well as to analyse their behaviour, both from a qualitative and a quantitative point of view. A couple of little examples help us in showing how this can be done. We mainly focus our attention on the qualitative and quantitative aspects of the considered biological systems, and briefly illustrate which kinds of analysis are possible. We use a known stochastic calculus for the first example. We then present some statistics collected by repeatedly running the specification, that turn out to agree with those obtained by experiments in vivo. Our second example motivates a richer calculus. Its stochastic extension requires a non trivial machinery to faithfully reflect the real dynamic behaviour of biological systems

BlenX-based compositional modeling of complex reaction mechanisms

Molecular interactions are wired in a fascinating way resulting in complex behavior of biological systems. Theoretical modeling provides a useful framework for understanding the dynamics and the function of such networks. The complexity of the biological networks calls for conceptual tools that manage the combinatorial explosion of the set of possible interactions. A suitable conceptual tool to attack complexity is compositionality, already successfully used in the process algebra field to model computer systems. We rely on the BlenX programming language, originated by the beta-binders process calculus, to specify and simulate high-level descriptions of biological circuits. The Gillespie's stochastic framework of BlenX requires the decomposition of phenomenological functions into basic elementary reactions. Systematic unpacking of complex reaction mechanisms into BlenX templates is shown in this study. The estimation/derivation of missing parameters and the challenges emerging from compositional model building in stochastic process algebras are discussed. A biological example on circadian clock is presented as a case study of BlenX compositionality

On proving the equivalence of concurrency primitives

Various concurrency primitives have been added to sequential programming languages, in order to turn them concurrent. Prominent examples are concurrent buffers for Haskell, channels in Concurrent ML, joins in JoCaml, and handled futures in Alice ML. Even though one might conjecture that all these primitives provide the same expressiveness, proving this equivalence is an open challenge in the area of program semantics. In this paper, we establish a first instance of this conjecture. We show that concurrent buffers can be encoded in the lambda calculus with futures underlying Alice ML. Our correctness proof results from a systematic method, based on observational semantics with respect to may and must convergence

Nominal Logic Programming

Nominal logic is an extension of first-order logic which provides a simple foundation for formalizing and reasoning about abstract syntax modulo consistent renaming of bound names (that is, alpha-equivalence). This article investigates logic programming based on nominal logic. We describe some typical nominal logic programs, and develop the model-theoretic, proof-theoretic, and operational semantics of such programs. Besides being of interest for ensuring the correct behavior of implementations, these results provide a rigorous foundation for techniques for analysis and reasoning about nominal logic programs, as we illustrate via examples.Comment: 46 pages; 19 page appendix; 13 figures. Revised journal submission as of July 23, 200

On the decidability and complexity of the structural congruence for beta-binders

AbstractBeta-binders is a recent process calculus developed for modelling and simulating biological systems. As usual for process calculi, the semantic definition heavily relies on a structural congruence. The treatment of the structural congruence is essential for implementation. We present a subset of the calculus for which the structural congruence is decidable and a subset for which it is also efficiently solvable. The obtained results are a first step towards implementations

Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself

A Stochastic Pi Calculus for Concurrent Objects

International audienceWe present SpiCO, a new modeling and simulation language for system biology, based on the stochastic pi-calculus. SpiCO supports higher level modeling via multi-profile concurrent objects with static inheritance. We present a semantics for SpiCO in terms of continuous time Markov chains, and show how to compile SpiCO back into the biochemical stochastic pi-calculus while preserving semantics