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Motivation: Probability distributions play a central role in mathematical and statistical modelling. The encoding, annotation and exchange of such models could be greatly simplified by a resource providing a common reference for the definition of probability distributions. Although some resources exist, no suitably detailed and complex ontology exists nor any database allowing programmatic access., Results: ProbOnto, is an ontology-based knowledge base of probability distributions, featuring more than 80 uni- and multivariate distributions with their defining functions, characteristics, relationships and re-parameterization formulas. It can be used for model annotation and facilitates the encoding of distribution-based models, related functions and quantities., Availability and Implementation: http://probonto.org, Contact: mjswat@ebi.ac.uk, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Motivation: This article presents libRoadRunner, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using Systems Biology Markup Language (SBML). SBML is the most widely used standard for representing dynamic networks, especially biochemical networks. libRoadRunner is fast enough to support large-scale problems such as tissue models, studies that require large numbers of repeated runs and interactive simulations., Results: libRoadRunner is a self-contained library, able to run both as a component inside other tools via its C++ and C bindings, and interactively through its Python interface. Its Python Application Programming Interface (API) is similar to the APIs of MATLAB ( WWWMATHWORKSCOM: ) and SciPy ( HTTP//WWWSCIPYORG/: ), making it fast and easy to learn. libRoadRunner uses a custom Just-In-Time (JIT) compiler built on the widely used LLVM JIT compiler framework. It compiles SBML-specified models directly into native machine code for a variety of processors, making it appropriate for solving extremely large models or repeated runs. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and non-linear algebraic equations) including several SBML extensions (composition and distributions). It offers multiple deterministic and stochastic integrators, as well as tools for steady-state analysis, stability analysis and structural analysis of the stoichiometric matrix., Availability and Implementation: libRoadRunner binary distributions are available for Mac OS X, Linux and Windows. The library is licensed under Apache License Version 2.0. libRoadRunner is also available for ARM-based computers such as the Raspberry Pi. http://www.libroadrunner.org provides online documentation, full build instructions, binaries and a git source repository., Contacts: hsauro@u.washington.edu or somogyie@indiana.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (Published by Oxford University Press 2015. This work is written by US Government employees and is in the public domain in the US.)

Motivation: Currently, there are no ontologies capable of describing both the spatial organization of groups of cells and the behaviors of those cells. The lack of a formalized method for describing the spatiality and intrinsic biological behaviors of cells makes it difficult to adequately describe cells, tissues and organs as spatial objects in living tissues, in vitro assays and in computational models of tissues., Results: We have developed an OWL-2 ontology to describe the intrinsic physical and biological characteristics of cells and tissues. The Cell Behavior Ontology (CBO) provides a basis for describing the spatial and observable behaviors of cells and extracellular components suitable for describing in vivo, in vitro and in silico multicell systems. Using the CBO, a modeler can create a meta-model of a simulation of a biological model and link that meta-model to experiment or simulation results. Annotation of a multicell model and its computational representation, using the CBO, makes the statement of the underlying biology explicit. The formal representation of such biological abstraction facilitates the validation, falsification, discovery, sharing and reuse of both models and experimental data., Availability and Implementation: The CBO, developed using Protégé 4, is available at http://cbo.biocomplexity.indiana.edu/cbo/ and at BioPortal (http://bioportal.bioontology.org/ontologies/CBO)., (© The Author 2014. Published by Oxford University Press.)

Motivation: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network., Results: We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.