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- EpiLog: A software for the logical modelling of epithelial dynamicsPublication . Varela, Pedro L.; Ramos, Camila V.; Monteiro, Pedro T.; Chaouiya, ClaudineCellular responses are governed by regulatory networks subject to external signals from surrounding cells and to other micro-environmental cues. The logical (Boolean or multi-valued) framework proved well suited to study such processes at the cellular level, by specifying qualitative models of involved signalling pathways and gene regulatory networks. Here, we describe and illustrate the main features of EpiLog, a computational tool that implements an extension of the logical framework to the tissue level. EpiLog defines a collection of hexagonal cells over a 2D grid, which embodies a mono-layer epithelium. Basically, it defines a cellular automaton in which cell behaviours are driven by associated logical models subject to external signals. EpiLog is freely available on the web at http://epilog-tool.org. It is implemented in Java (version ≥1.7 required) and the source code is provided at https://github.com/epilog-tool/epilog under a GNU General Public License v3.0.
- Impact of changing cell-cell communication network in models of epithelial pattern formationPublication . Varela, Pedro L.; Monteiro, Pedro T.; Chaouiya, ClaudineWhen modelling multi-cellular systems, one has to account for cell-cell signalling in addition to the molecular networks driving cell behaviours. Here, we aim at exploring how the topology of the cell-cell communication network impacts the behaviour of the whole multicellular system. More precisely, we focus on epithelial pattern formation, on which our question can be rephrased in terms of cell sizes and shapes. Relying on a logical modelling framework, and using a simple lateral inhibition model over a population of epithelial cells, we assess the model behaviours considering a variety of communication networks. This study suggests that reasonable deviations from a fixed grid (with regular hexagonal shaped cells) do not change much the resulting patterns. We further explore the impact of cell shapes and show that characteristics such as network regularity and number of shared neighbours of contacting cells are relevant to qualify such deviations.
- Partial Order on the set of Boolean Regulatory FunctionsPublication . José E. R. Cury; Pedro T. Monteiro; Claudine ChaouiyaLogical models have been successfully used to describe regulatory and signaling networks without requiring quantitative data. However, existing data is insufficient to adequately define a unique model, rendering the parametrization of a given model a difficult task. Here, we focus on the characterization of the set of Boolean functions compatible with a given regulatory structure, i.e. the set of all monotone nondegenerate Boolean functions. We then propose an original set of rules to locally explore the direct neighboring functions of any function in this set, without explicitly generating the whole set. Also, we provide relationships between the regulatory functions and their corresponding dynamics. Finally, we illustrate the usefulness of this approach by revisiting Probabilistic Boolean Networks with the model of T helper cell differentiation from Mendoza & Xenarios.
- The Systems Biology Markup Language (SBML): Language Specification for Level 3 Version 2 Core Release 2Publication . Hucka, Michael; Bergmann, Frank T.; Chaouiya, Claudine; Dräger, Andreas; Hoops, Stefan; Keating, Sarah M.; König, Matthias; Novère, Nicolas Le; Myers, Chris J.; Olivier, Brett G.; Sahle, Sven; Schaff, James C.; Sheriff, Rahuman; Smith, Lucian P.; Waltemath, Dagmar; Wilkinson, Darren J.; Zhang, FengkaiComputational models can help researchers to interpret data, understand biological functions, and make quantitative predictions. The Systems Biology Markup Language (SBML) is a file format for representing computational models in a declarative form that different software systems can exchange. SBML is oriented towards describing biological processes of the sort common in research on a number of topics, including metabolic pathways, cell signaling pathways, and many others. By supporting SBML as an input/output format, different tools can all operate on an identical representation of a model, removing opportunities for translation errors and assuring a common starting point for analyses and simulations. This document provides the specification for Release 2 of Version 2 of SBML Level 3 Core. The specification defines the data structures prescribed by SBML as well as their encoding in XML, the eXtensible Markup Language. Release 2 corrects some errors and clarifies some ambiguities discovered in Release 1. This specification also defines validation rules that determine the validity of an SBML document, and provides many examples of models in SBML form. Other materials and software are available from the SBML project website at http://sbml.org/.
- Local Negative Circuits and Cyclic Attractors in Boolean Networks with at most Five ComponentsPublication . Tonello, Elisa; Farcot, Etienne; Chaouiya, ClaudineWe consider the following question on the relationship between the asymptotic behaviors of asynchronous dynamics of Boolean networks and their regulatory structures: Does the presence of a cyclic attractor imply the existence of a local negative circuit in the regulatory graph? When the number of model components n verifies n ≥ 6, the answer is known to be negative. We show that the question can be translated into a Boolean satisfiability problem on n ∙ 2^n variables. A Boolean formula expressing the absence of local negative circuits and a necessary condition for the existence of cyclic attractors is found to be unsatisfiable for n ≤ 5. In other words, for Boolean networks with up to 5 components, the presence of a cyclic attractor requires the existence of a local negative circuit.
- Estimating Attractor Reachability in Asynchronous Logical ModelsPublication . Mendes, Nuno D.; Henriques, Rui; Remy, Elisabeth; Carneiro, Jorge; Monteiro, Pedro T.; Chaouiya, ClaudineLogical models are well-suited to capture salient dynamical properties of regulatory networks. For networks controlling cell fate decisions, cell fates are associated with model attractors (stable states or cyclic attractors) whose identification and reachability properties are particularly relevant. While synchronous updates assume unlikely instantaneous or identical rates associated with component changes, the consideration of asynchronous updates is more realistic but, for large models, may hinder the analysis of the resulting non-deterministic concurrent dynamics. This complexity hampers the study of asymptotical behaviors, and most existing approaches suffer from efficiency bottlenecks, being generally unable to handle cyclical attractors and quantify attractor reachability. Here, we propose two algorithms providing probability estimates of attractor reachability in asynchronous dynamics. The first algorithm, named Firefront, exhaustively explores the state space from an initial state, and provides quasi-exact evaluations of the reachability probabilities of model attractors. The algorithm progresses in breadth, propagating the probabilities of each encountered state to its successors. Second, Avatar is an adapted Monte Carlo approach, better suited for models with large and intertwined transient and terminal cycles. Avatar iteratively explores the state space by randomly selecting trajectories and by using these random walks to estimate the likelihood of reaching an attractor. Unlike Monte Carlo simulations, Avatar is equipped to avoid getting trapped in transient cycles and to identify cyclic attractors. Firefront and Avatar are validated and compared to related methods, using as test cases logical models of synthetic and biological networks. Both algorithms are implemented as new functionalities of GINsim 3.0, a well-established software tool for logical modeling, providing executable GUI, Java API, and scripting facilities.
- Logical modelling uncovers developmental constraints for primary sex determination of chicken gonadsPublication . Sánchez, Lucas; Chaouiya, ClaudineIn the chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a modelling approach, which assembles the current knowledge and permits exploration of the regulation of this process in chickens. Relying on published experimental data, we assembled a gene network, which led to a logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when the SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.
- Meeting report from the fourth meeting of the Computational Modeling in Biology Network (COMBINE)Publication . Waltemath, Dagmar; Bergmann, Frank T.; Chaouiya, Claudine; Czauderna, Tobias; Gleeson, Padraig; Goble, Carole; Golebiewski, Martin; Hucka, Michael; Juty, Nick; Krebs, Olga; Le Novère, Nicolas; Mi, Huaiyu; Moraru, Ion I.; Myers, Chris J.; Nickerson, David; Olivier, Brett G.; Rodriguez, Nicolas; Schreiber, Falk; Smith, Lucian; Zhang, Fengkai; Bonnet, EricThe Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of community standards and formats in computational systems biology and related fields. This report summarizes the topics and activities of the fourth edition of the annual COMBINE meeting, held in Paris during September 16-20 2013, and attended by a total of 96 people. This edition pioneered a first day devoted to modeling approaches in biology, which attracted a broad audience of scientists thanks to a panel of renowned speakers. During subsequent days, discussions were held on many subjects including the introduction of new features in the various COMBINE standards, new software tools that use the standards, and outreach efforts. Significant emphasis went into work on extensions of the SBML format, and also into community-building. This year’s edition once again demonstrated that the COMBINE community is thriving, and still manages to help coordinate activities between different standards in computational systems biology.
- Logical Modeling and Dynamical Analysis of Cellular NetworksPublication . Abou-Jaoudé, Wassim; Traynard, Pauline; Monteiro, Pedro T.; Saez-Rodriguez, Julio; Helikar, Tomáš; Thieffry, Denis; Chaouiya, ClaudineThe logical (or logic) formalism is increasingly used to model regulatory and signaling networks. Complementing these applications, several groups contributed various methods and tools to support the definition and analysis of logical models. After an introduction to the logical modeling framework and to several of its variants, we review here a number of recent methodological advances to ease the analysis of large and intricate networks. In particular, we survey approaches to determine model attractors and their reachability properties, to assess the dynamical impact of variations of external signals, and to consistently reduce large models. To illustrate these developments, we further consider several published logical models for two important biological processes, namely the differentiation of T helper cells and the control of mammalian cell cycle.
- Primary sex determination of placental mammals: a modelling study uncovers dynamical developmental constraints in the formation of Sertoli and granulosa cellsPublication . Sánchez, Lucas; Chaouiya, ClaudinePrimary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules.