Systems biology of monovalent cation homeostasis in yeast: the translucent contribution.

Maintenance of monovalent cation homeostasis (mainly K(+) and Na(+)) is vital for cell survival, and cation toxicity is at the basis of a myriad of relevant phenomena, such as salt stress in crops and diverse human diseases. Full understanding of the importance of monovalent cations in the biology of the cell can only be achieved from a systemic perspective. Translucent is a multinational project developed within the context of the SysMO (System Biology of Microorganisms) initiative and focussed in the study of cation homeostasis using the well-known yeast Saccharomyces cerevisiae as a model. The present review summarize how the combination of biochemical, genetic, genomic and computational approaches has boosted our knowledge in this field, providing the basis for a more comprehensive and coherent vision of the role of monovalent cations in the biology of the cell.

Reaction-contingency based bipartite Boolean modelling.

BACKGROUND: Intracellular signalling systems are highly complex, rendering mathematical modelling of large signalling networks infeasible or impractical. Boolean modelling provides one feasible approach to whole-network modelling, but at the cost of dequantification and decontextualisation of activation. That is, these models cannot distinguish between different downstream roles played by the same component activated in different contexts. RESULTS: Here, we address this with a bipartite Boolean modelling approach. Briefly, we use a state oriented approach with separate update rules based on reactions and contingencies. This approach retains contextual activation information and distinguishes distinct signals passing through a single component. Furthermore, we integrate this approach in the rxncon framework to support automatic model generation and iterative model definition and validation. We benchmark this method with the previously mapped MAP kinase network in yeast, showing that minor adjustments suffice to produce a functional network description. CONCLUSIONS: Taken together, we (i) present a bipartite Boolean modelling approach that retains contextual activation information, (ii) provide software support for automatic model generation, visualisation and simulation, and (iii) demonstrate its use for iterative model generation and validation.

Biographer: web-based editing and rendering of SBGN compliant biochemical networks.

MOTIVATION: The rapid accumulation of knowledge in the field of Systems Biology during the past years requires advanced, but simple-to-use, methods for the visualization of information in a structured and easily comprehensible manner. RESULTS: We have developed biographer, a web-based renderer and editor for reaction networks, which can be integrated as a library into tools dealing with network-related information. Our software enables visualizations based on the emerging standard Systems Biology Graphical Notation. It is able to import networks encoded in various formats such as SBML, SBGN-ML and jSBGN, a custom lightweight exchange format. The core package is implemented in HTML5, CSS and JavaScript and can be used within any kind of web-based project. It features interactive graph-editing tools and automatic graph layout algorithms. In addition, we provide a standalone graph editor and a web server, which contains enhanced features like web services for the import and export of models and visualizations in different formats. AVAILABILITY: The biographer tool can be used at and downloaded from the web page http://biographer.biologie.hu-berlin.de/. The different software packages, including a server-independent version as well as a web server for Windows and Linux based systems, are available at http://code.google.com/p/biographer/ under the open-source license LGPL

A framework for mapping, visualisation and automatic model creation of signal-transduction networks.

Intracellular signalling systems are highly complex. This complexity makes handling, analysis and visualisation of available knowledge a major challenge in current signalling research. Here, we present a novel framework for mapping signal-transduction networks that avoids the combinatorial explosion by breaking down the network in reaction and contingency information. It provides two new visualisation methods and automatic export to mathematical models. We use this framework to compile the presently most comprehensive map of the yeast MAP kinase network. Our method improves previous strategies by combining (I) more concise mapping adapted to empirical data, (II) individual referencing for each piece of information, (III) visualisation without simplifications or added uncertainty, (IV) automatic visualisation in multiple formats, (V) automatic export to mathematical models and (VI) compatibility with established formats. The framework is supported by an open source software tool that facilitates integration of the three levels of network analysis: definition, visualisation and mathematical modelling. The framework is species independent and we expect that it will have wider impact in signalling research on any system.

Sustainable model building the role of standards and biological semantics.

Systems biology models can be reused within new simulation scenarios, as parts of more complex models or as sources of biochemical knowledge. Reusability does not come by itself but has to be ensured while creating a model. Most important, models should be designed to remain valid in different contexts-for example, for different experimental conditions-and be published in a standardized and well-documented form. Creating reusable models is worthwhile, but it requires some efforts when a model is developed, implemented, documented, and published. Minimum requirements for published systems biology models have been formulated by the MIRIAM initiative. Main criteria are completeness of information and documentation, availability of machine-readable models in standard formats, and semantic annotations connecting the model elements with entries in biological Web resources. In this chapter, we discuss the assumptions behind bottom-up modeling; present important standards like MIRIAM, the Systems Biology Markup Language (SBML), and the Systems Biology Graphical Notation (SBGN); and describe software tools and services for handling semantic annotations. Finally, we show how standards can facilitate the construction of large metabolic network models.

Retrieval, alignment, and clustering of computational models based on semantic annotations.

The exploding number of computational models produced by Systems Biologists over the last years is an invitation to structure and exploit this new wealth of information. Researchers would like to trace models relevant to specific scientific questions, to explore their biological content, to align and combine them, and to match them with experimental data. To automate these processes, it is essential to consider semantic annotations, which describe their biological meaning. As a prerequisite for a wide range of computational methods, we propose general and flexible similarity measures for Systems Biology models computed from semantic annotations. By using these measures and a large extensible ontology, we implement a platform that can retrieve, cluster, and align Systems Biology models and experimental data sets. At present, its major application is the search for relevant models in the BioModels Database, starting from initial models, data sets, or lists of biological concepts. Beyond similarity searches, the representation of models by semantic feature vectors may pave the way for visualisation, exploration, and statistical analysis of large collections of models and corresponding data.

Annotation and merging of SBML models with semanticSBML.

SUMMARY: Systems Biology Markup Language (SBML) is the leading exchange format for mathematical models in Systems Biology. Semantic annotations link model elements with external knowledge via unique database identifiers and ontology terms, enabling software to check and process models by their biochemical meaning. Such information is essential for model merging, one of the key steps towards the construction of large kinetic models. SemanticSBML is a tool that helps users to check and edit MIRIAM annotations and SBO terms in SBML models. Using a large collection of biochemical names and database identifiers, it supports modellers in finding the right annotations and in merging existing models. Initially, an element matching is derived from the MIRIAM annotations and conflicting element attributes are categorized and highlighted. Conflicts can then be resolved automatically or manually, allowing the user to control the merging process in detail. AVAILABILITY: SemanticSBML comes as a free software written in Python and released under the GPL 3. A Debian package, a source package for other Linux distributions, a Windows installer and an online version of semanticSBML with limited functionality are available at http://www.semanticsbml.org. A preinstalled version can be found on the Linux live DVD SB.OS, available at http://www.sbos.eu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.