Short Paper

The general question of what constitutes bio-curation for rule-based modelling of cellular signalling is posed. A general approach to the problem is presented, based on rewriting in hierarchies of graphs, together with a specific instantiation of the methodology that addresses our particular bio-curation problem. The current state of the ongoing development of the KAMI bio-curation tool, based on this approach, is outlined along with our plans for future development.

A generalised framework of site graphs is introduced in order to provide the first fully semantic definition of the side-effect-free core of the rule-based language Kappa. This formalisation allows the use of types either to confirm that a rule respects a certain invariant or to guide a restricted refinement process that allows us to constrain its run-time applicability.

In this paper, we introduce a novel way of constructing concise causal histories (pathways) to represent how specified structures are formed during simulation of systems represented by rule-based models. This is founded on a new, clean, graph-based semantics introduced in the first part of this paper for Kappa, a rule-based modelling language that has emerged as a natural description of protein-protein interactions in molecular biology [Bachman 2011]. The semantics is capable of capturing the whole of Kappa, including subtle side-effects on deletion of structure, and its structured presentation provides the basis for the translation of techniques to other models. In particular, we give a notion of trajectory compression, which restricts a trace culminating in the production of a given structure to the actions necessary for the structure to occur. This is central to the reconstruction of biochemical pathways due to the failure of traditional techniques to provide adequately concise causal histories, and we expect it to be applicable in a range of other modelling situations.

Rule-based approaches (as in our own Kappa, or the BNG language, or many other propositions allowing the consideration of "reaction classes'') offer new and more powerful ways to capture the combinatorial interactions that are typical of molecular biological systems. They afford relatively compact and faithful descriptions of cellular interaction networks despite the combination of two broad types of interaction: the formation of complexes (a biological term for the ubiquitous non-covalent binding of bio-molecules), and the chemical modifications of macromolecules (aka post-translational modifications). However, all is not perfect. This same combinatorial explosion that pervades biological systems also seems to prevent the simulation of molecular networks using systems of differential equations. In all but the simplest cases the generation (and even more the integration) of the explicit system of differential equations which is canonically associated to a rule set is unfeasible. So there seems to be a price to pay for this increase in clarity and precision of the description, namely that one can only execute such rule-based systems using their stochastic semantics as continuous time Markov chains, which means a slower if more accurate simulation. In this paper, we take a fresh look at this question, and, using techniques from the abstract interpretation framework, we construct a reduction method which generates (typically) far smaller systems of differential equations than the concrete/canonical one. We show that the abstract/reduced differential system has solutions which are linear combinations of the canonical ones. Importantly, our method: 1) does not require the concrete system to be explicitly computed, so it is intensional, 2) nor does it rely on the choice of a specific set of rate constants for the system to be reduced, so it is symbolic, and 3) achieves good compression when tested on rule-based models of significant size, so it is also realistic.

We show how to construct the category of games and innocent strategies from a more primitive category of games. On that category we define a comonad and monad with the former distributing over the latter. Innocent strategies are the maps in the induced two-sided Kleisli category. Thus the problematic composition of innocent strategies reflects the use of the distributive law. The composition of simple strategies, and the combinatorics of pointers used to give the comonad and monad are themselves described in categorical terms. The notions of view and of legal play arise naturally in the explanation of the distributivity. The category-theoretic perspective provides a clear discipline for the necessary combinatorics.

A category of HO/N-style games and probabilistic strategies is developed where the possible choices of a strategy are quantified so as to give a measure of the likelihood of seeing a given play. A two-sided die is shown to be universal in this category, in the sense that any strategy breaks down into a composition between some deterministic strategy and that die. The interpretative power of the category is then demonstrated by delineating a Cartesian closed subcategory that provides a fully abstract model of a probabilistic extension of Idealized Algol.

A category of HO/N-style games and probabilistic strategies is developed where the possible choices of a strategy are quantified so as to give a measure of the likelihood of seeing a given play. A 2-sided die is shown to be universal in this category, in the sense that any strategy breaks down into a composition between some deterministic strategy and that die. The interpretative power of the category is then demonstrated by delineating a Cartesian closed subcategory which provides a fully abstract model of a probabilistic extension of Idealized Algol.

A game semantics of finite nondeterminism is proposed. In this model, a strategy may make a choice between different moves in a given situation; moreover, strategies carry extra information about their possible divergent behaviour. A Cartesian closed category is built and a model of a simple, higher-order nondeterministic imperative language is given. This model is shown to be fully abstract, with respect to an equivalence based on both safety and liveness properties, by means of a factorization theorem which states that every nondeterministic strategy is the composite of a deterministic strategy with a nondeterministic oracle.