ABSTRACT
Petri nets are a common method for modeling and simulation of systems biology application cases. Usually different Petri net concepts (e.g. discrete, hybrid, functional) are demanded depending on the purpose of the application cases. Modeling complex application cases requires a unification of those concepts, e.g. hybrid functional Petri nets (HFPN) and extended hybrid Petri nets (xHPN). Existing tools have certain limitations which motivated the extension of VANESA, an existing open-source editor for biological networks. The extension can be used to model, simulate, and visualize Petri nets based on the xHPN formalism. Moreover, it comprises additional functionality to support and help the user. Complex (kinetic) functions are syntactically analyzed and mathematically rendered. Based on syntax and given physical unit information, modeling errors are revealed. The numerical simulation is seamlessly integrated and executed in the background by the open-source simulation environment OpenModelica utilizing the Modelica library PNlib. Visualization of simulation results for places, transitions, and arcs are useful to investigate and understand the model and its dynamic behavior. The impact of single parameters can be revealed by comparing multiple simulation results. Simulation results, charts, and entire specification of the Petri net model as Latex file can be exported. All these features are shown in the demonstration case. The utilized Petri net formalism xHPN is fully specified and implemented in PNlib. This assures transparency, reliability, and comprehensible simulation results. Thus, the combination of VANESA and OpenModelica shape a unique open-source Petri net environment focusing on systems biology application cases. VANESA is available at: http://agbi.techfak.uni-bielefeld.de/vanesa.
Subject(s)
Computer Simulation , Models, Biological , Nomograms , Software , Systems Biology/methods , Animals , Computer Simulation/trends , Humans , Metabolic Networks and Pathways/physiology , Software/trends , Systems Biology/trendsABSTRACT
In this work we present new concepts of VANESA, a tool for modeling and simulation in systems biology. We provide a convenient way to handle mathematical expressions and take physical units into account. Simulation and result management has been improved, and syntax and consistency checks, based on physical units, reduce modeling errors. As a proof of concept, essential components of the aerobic carbon metabolism of the green microalga Chlamydomonas reinhardtii are modeled and simulated. The modeling process is based on xHPN Petri net formalism and simulation is performed with OpenModelica, a powerful environment and compiler for Modelica. VANESA, as well as OpenModelica, is open source, free-of-charge for non-commercial use, and is available at: http://agbi.techfak.uni-bielefeld.de/vanesa.
Subject(s)
Carbon/metabolism , Chlamydomonas reinhardtii/metabolism , Computer Simulation , Metabolic Networks and Pathways , Software , Algorithms , Models, Biological , WorkflowABSTRACT
MicroRNAs (miRNAs), approximately 22 nucleotides long, post-transcriptionally active gene expression regulators, play active roles in modulating cellular processes. Gene regulation and miRNA regulation are intertwined and the main aim of this study is to facilitate the analysis of miRNAs within gene regulatory pathways. VANESA enables the reconstruction of biological pathways and supports visualization and simulation. To support integrative miRNA and gene pathway analyses, a custom database of experimentally proven miRNAs, integrating data from miRBase, TarBase and miRTarBase, was added to DAWIS-M.D., which is the main data source for VANESA. Analysis of human KEGG pathways within DAWIS-M.D. showed that 661 miRNAs (~1/3 recorded human miRNAs) lead to 65,474 interactions. hsa-miR-335-5p targets most genes in our system (2,544); while the most targeted gene (with 71 miRNAs) is NUFIP2 (Nuclear Fragile X Mental Retardation Protein Interacting Protein 2). Amyotrophic Lateral Sclerosis (ALS), a complex neurodegenerative disease, was chosen as a proof of concept model. Using our system, it was possible to reduce the initially several hundred genes and miRNAs associated with ALS to eight genes, 19 miRNAs and 31 interactions. This highlights the effectiveness of the implemented system to distill important information from otherwise hard to access, highly convoluted and vast regulatory networks.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Databases, Genetic , Gene Expression Regulation , Gene Regulatory Networks , MicroRNAs , Gene Expression Profiling , Humans , Statistics as TopicABSTRACT
MicroRNAs (miRNAs) are small RNA molecules which are known to take part in post-transcriptional regulation of gene expression. Here, VANESA, an existing platform for reconstructing, visualizing, and analysis of large biological networks, has been further expanded to include all experimentally validated human miRNAs available within miRBase, TarBase and miRTarBase. This is done by integrating a custom hybrid miRNA database to DAWIS-M.D., VANESA's main data source, enabling the visualization and analysis of miRNAs within large biological pathways such as those found within the Kyoto Encyclopedia of Genes and Genomes (KEGG). Interestingly, 99.15 % of human KEGG pathways either contain genes which are targeted by miRNAs or harbor them. This is mainly due to the high number of interaction partners that each miRNA could have (e.g.: hsa-miR-335-5p targets 2544 genes and 71 miRNAs target NUFIP2). We demonstrate the usability of our system by analyzing the measles virus KEGG pathway as a proof-of-principle model and further highlight the importance of integrating miRNAs (both experimentally validated and predicted) into biological networks for the elucidation of novel miRNA-mRNA interactions of biological importance.
Subject(s)
Gene Regulatory Networks/genetics , Genes , Genome/genetics , MicroRNAs/analysis , MicroRNAs/genetics , Databases, Genetic , Gene Expression Regulation/genetics , Humans , Japan , Nuclear Proteins/genetics , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , Reproducibility of ResultsABSTRACT
VANESA is a modeling software for the automatic reconstruction and analysis of biological networks based on life-science database information. Using VANESA, scientists are able to model any kind of biological processes and systems as biological networks. It is now possible for scientists to automatically reconstruct important molecular systems with information from the databases KEGG, MINT, IntAct, HPRD, and BRENDA. Additionally, experimental results can be expanded with database information to better analyze the investigated elements and processes in an overall context. Users also have the possibility to use graph theoretical approaches in VANESA to identify regulatory structures and significant actors within the modeled systems. These structures can then be further investigated in the Petri net environment of VANESA. It is platform-independent, free-of-charge, and available at http://vanesa.sf.net.
