The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions.

Neurodegenerative diseases are a heterogeneous group of disorders that are characterized by the progressive dysfunction and loss of neurons. Here, we distil and discuss the current state of modeling in the area of neurodegeneration, and objectively compare the gaps between existing clinical knowledge and the mechanistic understanding of the major pathological processes implicated in neurodegenerative disorders. We also discuss new directions in the field of neurodegeneration that hold potential for furthering therapeutic interventions and strategies.

BioModels: Content, Features, Functionality, and Use.

BioModels is a reference repository hosting mathematical models that describe the dynamic interactions of biological components at various scales. The resource provides access to over 1,200 models described in literature and over 140,000 models automatically generated from pathway resources. Most model components are cross-linked with external resources to facilitate interoperability. A large proportion of models are manually curated to ensure reproducibility of simulation results. This tutorial presents BioModels' content, features, functionality, and usage.

The Input Signal Step Function (ISSF), a standard method to encode input signals in SBML models with software support, applied to circadian clock models.

Time-dependent light input is an important feature of computational models of the circadian clock. However, publicly available models encoded in standard representations such as the Systems Biology Markup Language (SBML) either do not encode this input or use different mechanisms to do so, which hinders reproducibility of published results as well as model reuse. The authors describe here a numerically continuous function suitable for use in SBML for models of circadian rhythms forced by periodic light-dark cycles. The Input Signal Step Function (ISSF) is broadly applicable to encoding experimental manipulations, such as drug treatments, temperature changes, or inducible transgene expression, which may be transient, periodic, or mixed. It is highly configurable and is able to reproduce a wide range of waveforms. The authors have implemented this function in SBML and demonstrated its ability to modify the behavior of publicly available models to accurately reproduce published results. The implementation of ISSF allows standard simulation software to reproduce specialized circadian protocols, such as the phase-response curve. To facilitate the reuse of this function in public models, the authors have developed software to configure its behavior without any specialist knowledge of SBML. A community-standard approach to represent the inputs that entrain circadian clock models could particularly facilitate research in chronobiology.

Simultaneous modelling of metabolic, genetic and product-interaction networks.

The creation of cell models from annotated genome information, as well as additional data from other databases, requires both a format and medium for its distribution. Standards are described for the representation of the data in the form of Document Type Definitions (DTDs) for XML files. Separate DTDs are detailed for genetic, metabolic and gene product-interaction networks, which can be used to hold information on individual subsystems, or which may be combined to create a whole cell DTD. In the execution of this work, a fifth DTD was also created for a metabolite thesaurus, which allows incorporation of metabolite synonyms and generic nomenclature data into the models. A gene-regulation classification scheme was also created, to facilitate incorporation of gene regulatory information in an efficient manner. The work is described with particular reference to the metabolic network of Escherichia coli, which contains 808 individual enzymes. The assignment of confidence levels to these data, through the use of Gene Ontology evidence codes, is highlighted. In silico investigations may now be performed using the mathematical simulation workbench, DBsolve, which incorporates the facility to introduce data directly from XML.

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/