Modular modelling of signalling pathways and their crosstalk

Signalling pathways are well-known abstractions that explain the mechanisms whereby cells respond to signals. Collections of pathways form networks, and interactions between pathways in a network, known as cross-talk, enables further complex signalling behaviours. While there are several formal modelling approaches for signalling pathways, none make cross-talk explicit; the aim of this paper is to define and categorise cross-talk in a rigorous way. We define a modular approach to pathway and network modelling, based on the module construct in the PRISM modelling language, and a set of generic signalling modules. Five different types of cross-talk are defined according to various biologically meaningful combinations of variable sharing, synchronisation labels and reaction renaming. The approach is illustrated with a case-study analysis of cross-talk between the TGF-β, WNT and MAPK pathways

A Spatial Calculus of Wrapped Compartments

The Calculus of Wrapped Compartments (CWC) is a recently proposed modelling language for the representation and simulation of biological systems behaviour. Although CWC has no explicit structure modelling a spatial geometry, its compartment labelling feature can be exploited to model various examples of spatial interactions in a natural way. However, specifying large networks of compartments may require a long modelling phase. In this work we present a surface language for CWC that provides basic constructs for modelling spatial interactions. These constructs can be compiled away to obtain a standard CWC model, thus exploiting the existing CWC simulation tool. A case study concerning the modelling of Arbuscular Mychorrizal fungi growth is discussed.Comment: Presented at MeCBIC 201

MarCaSPiS: a Markovian Extension of a Calculus for Services

Service Oriented Computing (SOC) is a design paradigm that has evolved from earlier paradigms including object-orientation and component-based software engineering. Important features of services are compositionality, context-independence, encapsulation and re-usability. To support the formal design and analysis of SOC applications recently a number of Service Oriented Calculi have been proposed. Most of them are based on process algebras enriched with primitives specific of service orientation such as operators for manipulating semi-structured data, mechanisms for describing safe client-service interactions, constructors for composing possibly unreliable services and techniques for services query and discovery. In this paper we show a versatile technique for the definition of Structural Operational Semantics of MarCaSPiS, a Markovian extension of one of such calculi, namely the Calculus of Sessions and Pipelines, CaSPiS. The semantics deals in an elegant way with a stochastic version of two-party synchronisation, typical of a service-oriented approach, and with the problem of transition multiplicity while preserving highly desirable mathematical properties such as associativity and commutativity of parallel composition. We also show how the proposed semantics can be naturally used for defining a bisimulation-based behavioural equivalence for MarCaSPiS terms that induces the same equalities as those obtained via Strong Markovian Equivalence

Verification of Spatial and Temporal Modalities in Biochemical Systems

AbstractBiochemical systems such as metabolic and signaling pathways tend to be arranged in a physical space: the product of one reaction must be in the right place to become the reactant for the subsequent reaction in the pathway. Moreover, in some cases, the behavior of the systems can depend on both, the location of the reactants as well as on the time needed for the reaction to occur. We address the problem of specifying and verifying properties of biochemical systems that exhibit both temporal and spatial modalities at the same time. For that, we use as specification language a fragment of intuitionistic linear logic with subexponentials (SELL). The subexponential signature allows us to capture the spatial relations among the different components of the system and the timed constraints for reactions to occur. We show that our framework is general enough to give a declarative semantics to P-Systems and we show that such logical characterization has a strong level of adequacy. Hence, derivations in SELL follow exactly the behavior of the modeled system

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

Beta-binders with Biological Transactions

In this work we propose an extension of Beta-binders with biological transactions, called TBeta-binders, in order to model a sequence of elementary actions atomically. This extension is useful when we need to specify multi-reactant multi-product reactions or when we use a sequence of actions to represent a single biological interaction. Some properties of these transactions are reported. Finally, some simple but explicative examples are described to validate our extension

Process algebra for epidemiology: evaluating and enhancing the ability of PEPA to describe biological systems

Modelling is a powerful method for understanding complex systems, which works by simplifying them to their most essential components. The choice of the components is driven by the aspects studied. The tool chosen to perform this task will determine what can be modelled, the maximum number of components which can be represented, as well as the analyses which can be performed on the system. Performance Evaluation Process Algebra (PEPA) was initially developed to tackle computer systems issues. Nevertheless, it possesses some interesting properties which could be exploited for the study of epidemiological systems. PEPA's main advantage resides in its capacity to change scale: the assumptions and parameter values describe the behaviour of a single individual, while the resulting model provides information on the population behaviour. Additionally, stochasticity and continuous time have already proven to be useful features in epidemiology. While each of these features is already available in other tools, to find all three combined in a single tool is novel, and PEPA is proposed as a useful addition to the epidemiologist's toolbox. Moreover, an algorithm has been developed which allows converting a PEPA model into a system of Ordinary Differential Equations (ODEs). This provides access to countless additional software and theoretical analysis methods which enable the epidemiologist to gain further insight into the model. Finally, most existing tools require a deep understanding of the logic they are based on and the resulting model can be difficult to read and modify. PEPA's grammar, on the other hand, is easy to understand since it is based on few, yet powerful concepts. This makes it a very accessible formalism for any epidemiologist. The objective of this thesis is to determine precisely PEPA's ability to describe epidemiological systems, as well as extend the formalism when required. This involved modelling two systems: the bubonic plague in prairie dogs, and measles in England and Wales. These models were chosen as they exhibit a good range of typical features, allowing to thoroughly test PEPA. All features required in each of these models have been analysed in detail, and a solution has been provided for representing each of these features. While some of them could be expressed in a straightforward manner, PEPA did not provide the tools to express others. In those cases, we determined methods to approach the desired behaviour, and the limitations of said methods were carefully analysed. In the case of models with a structured population, PEPA was extended to simplify their expression and facilitate the writing process of the PEPA model. The work also required the development of an algorithm to derive ODEs adapted to the type of models encountered. Finally, the PEPAdum software was developed to assist the modeller in the generation and analysis of PEPA models, by simplifying the process of writing a PEPA model with compartments, performing the average of stochastic simulations and deriving and explicitly providing the ODEs using the Stirling Amendment

A diversity-aware computational framework for systems biology

L'abstract è presente nell'allegato / the abstract is in the attachmen

Continuous-time temporal logic specification and verification for nonlinear biological systems in uncertain contexts

In this thesis we introduce a complete framework for modelling and verification of biological systems in uncertain contexts based on the bond-calculus process algebra and the LBUC spatio-temporal logic. The bond-calculus is a biological process algebra which captures complex patterns of interaction based on affinity patterns, a novel communication mechanism using pattern matching to express multiway interaction affinities and general kinetic laws, whilst retaining an agent-centric modelling style for biomolecular species. The bond-calculus is equipped with a novel continuous semantics which maps models to systems of Ordinary Differential Equations (ODEs) in a compositional way. We then extend the bond-calculus to handle uncertain models, featuring interval uncertainties in their species concentrations and reaction rate parameters. Our semantics is also extended to handle uncertainty in every aspect of a model, producing non-deterministic continuous systems whose behaviour depends either on time-independent uncertain parameters and initial conditions, corresponding to our partial knowledge of the system at hand, or time-varying uncertain inputs, corresponding to genuine variability in a system’s behaviour based on environmental factors. This language is then coupled with the LBUC spatio-temporal logic which combines Signal Temporal Logic (STL) temporal operators with an uncertain context operator which quantifies over an uncertain context model describing the range of environments over which a property must hold. We develop model-checking procedures for STL and LBUC properties based on verified signal monitoring over flowpipes produced by the Flow* verified integrator, including the technique of masking which directs monitoring for atomic propositions to time regions relevant to the overall verification problem at hand. This allows us to monitor many interesting nested contextual properties and frequently reduces monitoring costs by an order of magnitude. Finally, we explore the technique of contextual signal monitoring which can use a single Flow* flowpipe representing a functional dependency to complete a whole tree of signals corresponding to different uncertain contexts. This allows us to produce refined monitoring results over the whole space and to explore the variation in system behaviour in different contexts

Beta-binders for biological quantitative experiments

The similarities between biological systems and distributed and mobile systems suggest that the theory of process calculi could be a useful starting point for understanding, if not predicting, the behaviour of complex biological systems. To formally model in vitro or in vivo experiments, appropriate quantitative extensions of process calculi have to be investigated. This paper focuses on Beta-binders, a language of processes with typed interaction sites which has been recently introduced to accurately represent biological entities. Here the syntax and semantics of Beta-binders are enriched to achieve a stochastic version of it, in order to obtain quantitative measures on biological phenomena. The quantitative parameters are derived from typed interaction sites introducing the concept of affinity. The relevance of quantitative reasoning is outlined running a biological example