The Physiome Model Repository 2.

MOTIVATION: The Physiome Model Repository 2 (PMR2) software was created as part of the IUPS Physiome Project (Hunter and Borg, 2003), and today it serves as the foundation for the CellML model repository. Key advantages brought to the end user by PMR2 include: facilities for model exchange, enhanced collaboration and a detailed change history for each model. AVAILABILITY: PMR2 is available under an open source license at http://www.cellml.org/tools/pmr/; a fully functional instance of this software can be accessed at http://models.physiomeproject.org/.

A tool for multi-scale modelling of the renal nephron.

We present the development of a tool, which provides users with the ability to visualize and interact with a comprehensive description of a multi-scale model of the renal nephron. A one-dimensional anatomical model of the nephron has been created and is used for visualization and modelling of tubule transport in various nephron anatomical segments. Mathematical models of nephron segments are embedded in the one-dimensional model. At the cellular level, these segment models use models encoded in CellML to describe cellular and subcellular transport kinetics. A web-based presentation environment has been developed that allows the user to visualize and navigate through the multi-scale nephron model, including simulation results, at the different spatial scales encompassed by the model description. The Zinc extension to Firefox is used to provide an interactive three-dimensional view of the tubule model and the native Firefox rendering of scalable vector graphics is used to present schematic diagrams for cellular and subcellular scale models. The model viewer is embedded in a web page that dynamically presents content based on user input. For example, when viewing the whole nephron model, the user might be presented with information on the various embedded segment models as they select them in the three-dimensional model view. Alternatively, the user chooses to focus the model viewer on a cellular model located in a particular nephron segment in order to view the various membrane transport proteins. Selecting a specific protein may then present the user with a description of the mathematical model governing the behaviour of that protein-including the mathematical model itself and various simulation experiments used to validate the model against the literature.

Using Physiome standards to couple cellular functions for rat cardiac excitation-contraction.

Scientific endeavour is reliant upon the extension and reuse of previous knowledge. The formalization of this process for computational modelling is facilitated by the use of accepted standards with which to describe and simulate models, ensuring consistency between the models and thus reducing the development and propagation of errors. CellML 1.1, an XML-based programming language, has been designed as a modelling standard which, by virtue of its import and grouping functions, facilitates model combination and reuse. Using CellML 1.1, we demonstrate the process of formalized model reuse by combining three separate models of rat cardiomyocyte function (an electrophysiology model, a model of cellular calcium dynamics and a mechanics model) which together make up the Pandit-Hinch-Niederer et al. cell model. Not only is this integrative model of rat electromechanics a useful tool for cardiac modelling but it is also an ideal framework with which to demonstrate both the power of model reuse and the challenges associated with this process. We highlight and classify a number of these issues associated with combining models and provide some suggested solutions.

The balance between inactivation and activation of the Na+-K+ pump underlies the triphasic accumulation of extracellular K+ during myocardial ischemia.

Ischemia-induced hyperkalemia (accumulation of extracellular K(+)) predisposes the heart to the development of lethal reentrant ventricular arrhythmias. This phenomenon exhibits a triphasic time course and is thought to be mediated by a combination of three mechanisms: 1) increased cellular K(+) efflux, 2) decreased cellular K(+) influx, and 3) shrinkage of the extracellular space. These ischemia-induced electrophysiological changes are driven by an impaired cellular metabolism. However, the relative contributions of these mechanisms, as well as the origin of the triphasic profile, have proven to be difficult to determine experimentally. In this study, the changes in metabolite concentrations that arise during 15 min of zero-flow global ischemia were incorporated into a dynamic model of cellular electrophysiology, which was extended to include a metabolically sensitive description of the Na(+)-K(+) pump and ATP-sensitive K(+) channel, in addition to cell volume regulation. The coupling of altered K(+) fluxes and cell volume regulation enables an integrative simulation of ischemic hyperkalemia. These simulations were able to quantitatively reproduce experimental measurements of the accumulation of extracellular K(+) during 15 min of simulated ischemia, both with respect to the degree of K(+) loss as well as the triphasic time course. Analysis of the model indicates that the inhibition of the Na(+)-K(+) pump is the dominant factor underlying this hyperkalemic behavior, accounting for approximately 85% of the observed extracellular K(+) accumulation. It was found that the balance between activation and inhibition of the Na(+)-K(+) pump, affected by the changing metabolite and ion concentrations (in particular, [ADP]), give rise to the triphasic profile associated with ischemic hyperkalemia.