MOTIVATION: This article presents libRoadRunner 2.0, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using the systems biology markup language (SBML). RESULTS: libRoadRunner is a self-contained library, able to run either as a component inside other tools via its C++, C and Python APIs, or interactively through its Python or Julia interface. 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 large variety of processors, making it fast enough to simulate extremely large models or repeated runs in reasonable timeframes. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and non-linear algebraic equations) as well as several SBML extensions such as hierarchical composition and probability distributions. It offers multiple deterministic and stochastic integrators, as well as tools for steady-state, sensitivity, stability and structural analyses. AVAILABILITY AND IMPLEMENTATION: libRoadRunner binary distributions for Windows, Mac OS and Linux, Julia and Python bindings, source code and documentation are all available at https://github.com/sys-bio/roadrunner, and Python bindings are also available via pip. The source code can be compiled for the supported systems as well as in principle any system supported by LLVM-13, such as ARM-based computers like the Raspberry Pi. The library is licensed under the Apache License Version 2.0.

SUMMARY: Studying biological systems generally relies on computational modeling and simulation, e.g., model-driven discovery and hypothesis testing. Progress in standardization efforts led to the development of interrelated file formats to exchange and reuse models in systems biology, such as SBML, the Simulation Experiment Description Markup Language (SED-ML) or the Open Modeling EXchange format. Conducting simulation experiments based on these formats requires efficient and reusable implementations to make them accessible to the broader scientific community and to ensure the reproducibility of the results. The Systems Biology Simulation Core Library (SBSCL) provides interpreters and solvers for these standards as a versatile open-source API in JavaTM. The library simulates even complex bio-models and supports deterministic Ordinary Differential Equations; Stochastic Differential Equations; constraint-based analyses; recent SBML and SED-ML versions; exchange of results, and visualization of in silico experiments; open modeling exchange formats (COMBINE archives); hierarchically structured models; and compatibility with standard testing systems, including the Systems Biology Test Suite and published models from the BioModels and BiGG databases. AVAILABILITY AND IMPLEMENTATION: SBSCL is freely available at https://draeger-lab.github.io/SBSCL/ and via Maven Central. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Life science researchers use computational models to articulate and test hypotheses about the behavior of biological systems. Semantic annotation is a critical component for enhancing the interoperability and reusability of such models as well as for the integration of the data needed for model parameterization and validation. Encoded as machine-readable links to knowledge resource terms, semantic annotations describe the computational or biological meaning of what models and data represent. These annotations help researchers find and repurpose models, accelerate model composition and enable knowledge integration across model repositories and experimental data stores. However, realizing the potential benefits of semantic annotation requires the development of model annotation standards that adhere to a community-based annotation protocol. Without such standards, tool developers must account for a variety of annotation formats and approaches, a situation that can become prohibitively cumbersome and which can defeat the purpose of linking model elements to controlled knowledge resource terms. Currently, no consensus protocol for semantic annotation exists among the larger biological modeling community. Here, we report on the landscape of current annotation practices among the COmputational Modeling in BIology NEtwork community and provide a set of recommendations for building a consensus approach to semantic annotation.

The considerable difficulty encountered in reproducing the results of published dynamical models limits validation, exploration and reuse of this increasingly large biomedical research resource. To address this problem, we have developed Tellurium Notebook, a software system for model authoring, simulation, and teaching that facilitates building reproducible dynamical models and reusing models by 1) providing a notebook environment which allows models, Python code, and narrative to be intermixed, 2) supporting the COMBINE archive format during model development for capturing model information in an exchangeable format and 3) enabling users to easily simulate and edit public COMBINE-compliant models from public repositories to facilitate studying model dynamics, variants and test cases. Tellurium Notebook, a Python-based Jupyter-like environment, is designed to seamlessly inter-operate with these community standards by automating conversion between COMBINE standards formulations and corresponding in-line, human-readable representations. Thus, Tellurium brings to systems biology the strategy used by other literate notebook systems such as Mathematica. These capabilities allow users to edit every aspect of the standards-compliant models and simulations, run the simulations in-line, and re-export to standard formats. We provide several use cases illustrating the advantages of our approach and how it allows development and reuse of models without requiring technical knowledge of standards. Adoption of Tellurium should accelerate model development, reproducibility and reuse.

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: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: CySBML is a plugin designed to work with Systems Biology Markup Language (SBML) in Cytoscape having the following features: SBML import, support of the SBML layout and qualitative model packages, navigation in network layouts based on SBML structure, access to MIRIAM and SBO-based annotations and SBML validation. CySBML includes an importer for BioModels to load SBML from standard repositories. AVAILABILITY AND IMPLEMENTATION: Freely available for non-commercial purposes through the Cytoscape plugin manager or for download at http://sourceforge.net/projects/cysbml/. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Tutorial, usage guide, installation instructions and additional figures are available for download at http://www.charite.de/sysbio/people/koenig/software/cysbml/.

Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.