D Noble

..This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems...

..In neuroscience, the systems approach leads naturally to 2 important conclusions: first, that the idea of 'programs' in the brain is confusing, and second, that the self is better interpreted as a process than as an object...

..The principles outlined are illustrated with examples from various aspects of physiology and biochemistry. Applying and developing these principles should form a major part of the future of physiology...

..Despite the enormity of the challenge, which is certainly greater than that facing the pioneers of the human genome project 20 years ago, there is reason for optimism that real and accelerating progress is being made...

..Second, there are major problems of translation and interpretation to be tackled. Exploring the full semantic frame of the oriental concepts will be necessary before mapping to concepts in western medicine can be useful...

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..We will also require mathematical insight, perhaps of a nature we have not yet identified. This article is therefore also a challenge to mathematicians to develop such insights...

..The reverse seems to be true only in pathological conditions. Studies from tissue-level work and on the development of the heart also provide valuable insights into the integrative action of the cardiac pacemaker...

..e. the 'success' in the gene pool that is supposed to be attributable to the 'selfish' property. It is not a physiologically testable hypothesis...

..The new model has been tested against experimental data on action potential clamp, and on force-interval and duration-interval relations; it has been found to reliably reproduce experimental observations...

..While excitation-contraction coupling is rather well characterized, less is known about cellular mechanisms that promote mechanically induced changes in cardiac electrical activity--mechano-electric feedback...

..Because these can be fatal, potential electrophysiological cardiotoxicity is among the most stringent exclusion criteria in the licensing process...

..We discuss the role of models in Systems Biology and conclude with a consideration of their utility in biomedical research and development...

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..Modelling suggests this result may be explained by the effects of changes in [K+]0 on the current-voltage relationship for I(K,ACh)...

..Systems biology of the 21st century is set to become highly quantitative, and therefore one of the most computer-intensive disciplines...

..I use models of the heart to demonstrate that we can now go all the way from individual genetic information (on mutations, for example) to exploring the consequences at a whole organ level...

..With over 40 years of interaction between simulation and experiment, the models are now sufficiently refined to begin to be of use in drug development...

..This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia-related arrhythmias and how to efficiently terminate them...

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..The effects can therefore be expected to be species-specific, and it is not possible to extrapolate the mouse results to those that may occur in the Guinea pig or human...

..Our modelling results support the claim that NCX regulates the local control of Ca2+ and provide a powerful tool for future investigations of the control of sarcoplasmic reticulum (SR) Ca2+ release under pathological conditions...

..The principles outlined are illustrated with examples from cardiac and other aspects of physiology and biochemistry...

..The models have also been incorporated into tissue and organ models that enable arrhythmia to be modelled also at these levels. Work at these levels can reproduce both re-entrant arrhythmia and fibrillation...

..Such profiling suggests new avenues for development of methodologies to predict drug action effects in cardiac cells...

..Cardiac multicellular modeling has traditionally focused on ventricular electromechanics. More recently, models of the atria have started to emerge, and there is much interest in addressing sinoatrial node structure and function...

..The K(d) required for such regulation is consistent with current experimental estimates of this parameter...

..So, why has all this happened so suddenly?..

..The first models of calcium balance were made in the 1980s and have now reached a high degree of physiological detail. During the 1990s, these cell models were incorporated into anatomically detailed tissue and organ models...

..Because it can solve the 'genetic differential effect problem', modelling of biological function has an essential role to play in unravelling genetic causation...

..If such oscillations play a role in acute ischemic arrhythmias, then block of Na/Ca exchange may not be therapeutic...

..The ideal model will be as simple as possible and as complex as necessary for the particular question raised...

..The insights gained are evident in the most recent developments in this field, both experimental and theoretical. The prospects for the future are discussed...

..This review illustrates this development in the case of the heart. Systems physiology of the 21st century is set to become highly quantitative and, therefore, one of the most computer-intensive disciplines...

..The major obstacle to achieving this will be obtaining the relevant experimental data at levels higher than genomics and proteomics...

..1) and cardiac Nav1.5 isoforms are involved in pacemaking, although the cardiac Nav1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle...

..These results indicate that even though the models aim to represent the same physiological system, both the sources of parameter values and the function of equivalent components are significantly different...

..The results account for the large difference between therapeutic levels (approximately 30 microM) in whole tissue and the concentration (approximately 500 microM) required to suppress excitation in isolated cells...

..Complexity in biological systems also arises from tissue and organ geometry. This is illustrated using modelling of the whole heart...

..Small differences occurred in the ramps, but even at fast ramp speeds the effects are very much smaller than in Purkinje tissue. Only part of ib,Na is TTX sensitive and the effect does not occur in all cells...

..I use models of the heart to demonstrate that we can now go all the way from individual genetic information (on mutations, for example) to exploring the consequences at a whole-organ level...

..It is the iterative interaction between experiment and simulation that is important. Examples are given where this process has been instrumental in some of the major advances in the field...

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..Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline...

..The computer simulation shows that the difference in the intrinsic CL could explain the difference in response to If blocking in these two cardiac nodes...

..Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium-calcium overload is a major feature...

..When the exchanger is operating near equilibrium, drug action is found to be equally effective in both directions...

..The predicted changes in speed of conduction and refractory period are very small...

..g., impaired LCCs, local NCXs become an enhancer of sarcoplasmic reticulum release. Under such conditions incorporation of local NCXs is critical to accurately capture mechanisms of excitation-contraction coupling...

..The development of such models of airway myocytes is important for the understanding of the cellular mechanisms of airway reactivity and their possible modulation by pharmacological agents...

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..The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue...

..In conclusion, AS significantly increased AP-induced Ca2+ influx in epicardial but not in endocardial myocytes of the rat left ventricle...

..Modeling the mechanisms responsible for the decoding of calcium signals is developed in a lesser extent; however, the most recent theoretical studies are briefly presented in relation with the known experimental results...

..Our overall goal is to understand the genesis of the T-wave of the human electrocardiogram...

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