UNLABELLED: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: Microarrays are commonly used to detect changes in gene expression between different biological samples. For this purpose, many analysis tools have been developed that offer visualization, statistical analysis and more sophisticated analysis methods. Most of these tools are designed specifically for messenger RNA microarrays. However, today, more and more different microarray platforms are available. Changes in DNA methylation, microRNA expression or even protein phosphorylation states can be detected with specialized arrays. For these microarray technologies, the number of available tools is small compared with mRNA analysis tools. Especially, a joint analysis of different microarray platforms that have been used on the same set of biological samples is hardly supported by most microarray analysis tools. Here, we present InCroMAP, a tool for the analysis and visualization of high-level microarray data from individual or multiple different platforms. Currently, InCroMAP supports mRNA, microRNA, DNA methylation and protein modification datasets. Several methods are offered that allow for an integrated analysis of data from those platforms. The available features of InCroMAP range from visualization of DNA methylation data over annotation of microRNA targets and integrated gene set enrichment analysis to a joint visualization of data from all platforms in the context of metabolic or signalling pathways. AVAILABILITY: InCroMAP is freely available as Java™ application at www.cogsys.cs.uni-tuebingen.de/software/InCroMAP, including a comprehensive user's guide and example files.

MOTIVATION: The biological pathway exchange language (BioPAX) and the systems biology markup language (SBML) belong to the most popular modeling and data exchange languages in systems biology. The focus of SBML is quantitative modeling and dynamic simulation of models, whereas the BioPAX specification concentrates mainly on visualization and qualitative analysis of pathway maps. BioPAX describes reactions and relations. In contrast, SBML core exclusively describes quantitative processes such as reactions. With the SBML qualitative models extension (qual), it has recently also become possible to describe relations in SBML. Before the development of SBML qual, relations could not be properly translated into SBML. Until now, there exists no BioPAX to SBML converter that is fully capable of translating both reactions and relations. RESULTS: The entire nature pathway interaction database has been converted from BioPAX (Level 2 and Level 3) into SBML (Level 3 Version 1) including both reactions and relations by using the new qual extension package. Additionally, we present the new webtool BioPAX2SBML for further BioPAX to SBML conversions. Compared with previous conversion tools, BioPAX2SBML is more comprehensive, more robust and more exact. AVAILABILITY: BioPAX2SBML is freely available at http://webservices.cs.uni-tuebingen.de/ and the complete collection of the PID models is available at http://www.cogsys.cs.uni-tuebingen.de/downloads/Qualitative-Models/.

MOTIVATION: Traditionally, microarrays were almost exclusively used for the genome-wide analysis of differential gene expression. But nowadays, their scope of application has been extended to various genomic features, such as microRNAs (miRNAs), proteins and DNA methylation (DNAm). Most available methods for the visualization of these datasets are focused on individual platforms and are not capable of integratively visualizing multiple microarray datasets from cross-platform studies. Above all, there is a demand for methods that can visualize genomic features that are not directly linked to protein-coding genes, such as regulatory RNAs (e.g. miRNAs) and epigenetic alterations (e.g. DNAm), in a pathway-centred manner. RESULTS: We present a novel pathway-based visualization method that is especially suitable for the visualization of high-throughput datasets from multiple different microarray platforms that were used for the analysis of diverse genomic features in the same set of biological samples. The proposed methodology includes concepts for linking DNAm and miRNA expression datasets to canonical signalling and metabolic pathways. We further point out strategies for displaying data from multiple proteins and protein modifications corresponding to the same gene. Ultimately, we show how data from four distinct platform types (messenger RNA, miRNA, protein and DNAm arrays) can be integratively visualized in the context of canonical pathways. AVAILABILITY: The described method is implemented as part of the InCroMAP application that is freely available at www.cogsys.cs.uni-tuebingen.de/software/InCroMAP. CONTACT: [email protected] or [email protected].

Higher organisms are able to respond to continuously changing external conditions by transducing cellular signals into specific regulatory programs, which control gene expression states of thousands of different genes. One of the central problems in understanding gene regulation is to decipher how combinations of transcription factors control sets of co expressed genes under specific experimental conditions. Existing methods in this field mainly focus on sequence aspects and pattern recognition, e.g., by detecting cis-regulatory modules (CRMs) based on gene expression profiling data. We propose a novel approach by combining experimental data with a priori knowledge of respective experimental conditions. These various sources of evidence are likewise considered using multi-objective evolutionary optimization. In this work, we present three objective functions that are especially designed for stimulus-response experiments and can be used to integrate a priori knowledge into the detection of gene regulatory modules. This method was tested and evaluated on whole-genome microarray measurements of drug-response in human hepatocytes.

SUMMARY: The specifications of the Systems Biology Markup Language (SBML) define standards for storing and exchanging computer models of biological processes in text files. In order to perform model simulations, graphical visualizations and other software manipulations, an in-memory representation of SBML is required. We developed JSBML for this purpose. In contrast to prior implementations of SBML APIs, JSBML has been designed from the ground up for the Java programming language, and can therefore be used on all platforms supported by a Java Runtime Environment. This offers important benefits for Java users, including the ability to distribute software as Java Web Start applications. JSBML supports all SBML Levels and Versions through Level 3 Version 1, and we have strived to maintain the highest possible degree of compatibility with the popular library libSBML. JSBML also supports modules that can facilitate the development of plugins for end user applications, as well as ease migration from a libSBML-based backend. AVAILABILITY: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML.

MOTIVATION: Statins are the most widely used cholesterol-lowering drugs. The primary target of statins is HMG-CoA reductase, a key enzyme in cholesterol synthesis. However, statins elicit pleitropic responses including beneficial as well as adverse effects in the liver or other organs. Today, the regulatory mechanisms that cause these pleiotropic effects are not sufficiently understood. RESULTS: In this work, genome-wide RNA expression changes in primary human hepatocytes of six individuals were measured at up to six time points upon atorvastatin treatment. A computational analysis workflow was applied to reconstruct regulatory mechanisms based on these drug-response data and available knowledge about transcription factor (TF) binding specificities and protein-drug interactions. Several previously unknown TFs were predicted to be involved in atorvastatin-responsive gene expression. The novel relationships of nuclear receptors NR2C2 and PPARA on CYP3A4 were successfully validated in wet-lab experiments. AVAILABILITY: Microarray data are available at the Gene Expression Omnibus (GEO) database at www.ncbi.nlm.nih.gov/geo/, under accession number GSE29868. CONTACT: [email protected]; [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: The KEGG PATHWAY database provides a widely used service for metabolic and nonmetabolic pathways. It contains manually drawn pathway maps with information about the genes, reactions and relations contained therein. To store these pathways, KEGG uses KGML, a proprietary XML-format. Parsers and translators are needed to process the pathway maps for usage in other applications and algorithms. We have developed KEGGtranslator, an easy-to-use stand-alone application that can visualize and convert KGML formatted XML-files into multiple output formats. Unlike other translators, KEGGtranslator supports a plethora of output formats, is able to augment the information in translated documents (e.g. MIRIAM annotations) beyond the scope of the KGML document, and amends missing components to fragmentary reactions within the pathway to allow simulations on those. AVAILABILITY: KEGGtranslator is freely available as a Java(™) Web Start application and for download at http://www.cogsys.cs.uni-tuebingen.de/software/KEGGtranslator/. KGML files can be downloaded from within the application. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Structured peer-to-peer systems are designed for a highly scalable, self organizing, and efficient lookup for data. The key space of the so-called distributed hash tables (DHTs) is partitioned and each partition with its keys and values is assigned to a node in the DHT. For data retrieval however, the very nature of hash tables allows only exact pattern matches. We propose Cerco, a simple solution for the problem of range queries by employing a hierarchically structured P2P approach based on the principles of distributed hash tables. We show that a dynamic hierarchy of DHTs with on-demand classification of items can positively influence the response time of queries while maintaining lookup correctness