Reducing Boolean Networks with Backward Boolean Equivalence

Boolean Networks (BNs) are established models to qualitatively describe biological systems. The analysis of BNs might be infeasible for medium to large BNs due to the state-space explosion problem. We propose a novel reduction technique called \emph{Backward Boolean Equivalence} (BBE), which preserves some properties of interest of BNs. In particular, reduced BNs provide a compact representation by grouping variables that, if initialized equally, are always updated equally. The resulting reduced state space is a subset of the original one, restricted to identical initialization of grouped variables. The corresponding trajectories of the original BN can be exactly restored. We show the effectiveness of BBE by performing a large-scale validation on the whole GINsim BN repository. In selected cases, we show how our method enables analyses that would be otherwise intractable. Our method complements, and can be combined with, other reduction methods found in the literature

SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools

Background: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. Results: We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. Conclusions: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks

Model Checking to Assess T-Helper Cell Plasticity

Computational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific Th cell polarizing or reprograming events.LabEx MemoLife, Ecole Normale Supérieure, FCT grants: (PEst-OE/EEI/LA0021/2013, IF/01333/2013), Ph.D.program of the Agence National de Recherche sur Le Sida (ANRS), European Research Council consolidator grant

Attractor Equivalence: An Observational Semantics for Reaction Networks

International audienceWe study observational semantics for networks of chemical reactions as used in systems biology. Reaction networks without kinetic information, as we consider, can be identified with Petri nets. We present a new observational semantics for reaction networks that we call the attractor equivalence. The main idea of the attractor equivalence is to observe reachable attractors and reachability of an attractor divergence in all possible contexts. The attractor equivalence can support powerful simplifications for reaction networks as we illustrate at the example of the Tet-On system. Alternative semantics based on bisimulations or traces, in contrast, do not support all needed simplifications