Systems Biology
Online ISSN
1741-248X
Print ISSN 1741-2471
Print ISSN 1741-2471
Published from 2004-2005, Systems Biology covered intra- and inter-cellular dynamics, using systems- and signal-oriented approaches.
This publication is continued by IEE Proceedings - Systems Biology 2005-2006. ISSN 1741-2471. more..
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Model identification of signal transduction networks from data using a state regulator problem
- Author(s): K.G. Gadkar ; J. Varner ; F.J. Doyle III
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Advances in molecular biology provide an opportunity to develop detailed models of biological processes that can be used to obtain an integrated understanding of the system. However, development of useful models from the available knowledge of the system and experimental observations still remains a daunting task. In this work, a model identification strategy for complex biological networks is proposed. The approach includes a state regulator problem (SRP) that provides estimates of all the component concentrations and the reaction rates of the network using the available measurements. The full set of the estimates is utilised for model parameter identification for the network of known topology. An a priori model complexity test that indicates the feasibility of performance of the proposed algorithm is developed. Fisher information matrix (FIM) theory is used to address model identifiability issues. Two signalling pathway case studies, the caspase function in apoptosis and the MAP kinase cascade system, are considered. The MAP kinase cascade, with measurements restricted to protein complex concentrations, fails the a priori test and the SRP estimates are poor as expected. The apoptosis network structure used in this work has moderate complexity and is suitable for application of the proposed tools. Using a measurement set of seven protein concentrations, accurate estimates for all unknowns are obtained. Furthermore, the effects of measurement sampling frequency and quality of information in the measurement set on the performance of the identified model are described.
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Precision of intracellular calcium spike timing in primary rat hepatocytes
- Author(s): K. Prank ; M. Waring ; U. Ahlvers ; A. Bader ; E. Penner ; M. Möller ; G. Brabant ; C. Schöfl
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Extracellular stimuli are often encoded in the frequency, amplitude and duration of spikes in the intracellular concentration of calcium ([Ca2+]i). However, the timing of individual [Ca2+]i-spikes in relation to the dynamics of an extracellular stimulus is still an open question. To address this question, we use a systems biology approach combining experimental and theoretical methods. Using computer simulations, we predict that more naturalistic pulsed stimuli generate precisely-timed [Ca2+]i-spikes in contrast to the application of constant stimuli of the same dose. These computational results are confirmed experimentally in single primary rat hepatocytes upon α1-adrenergic stimulation. Hormonal signalling in analogy to neuronal signalling thus has the potential to make use of temporal coding on the level of single cells. The [Ca2+]i-signalling cascade provides a first example for increasing the information capacity of an intracellular regulatory signal beyond the known coding mechanisms of amplitude (AM) and frequency modulation (FM).
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Analysing the robustness of cellular rhythms
- Author(s): J. Wolf ; S. Becker-Weimann ; R. Heinrich
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Autonomous oscillations at the cellular level are important for various timing and signalling functions. The rhythms depend on environmental influences in a specific manner. In particular, the period of some rhythms has been shown to be very robust to certain environmental factors whereas other rhythms show a high sensitivity towards these factors. It is discussed that the robustness of the systems towards environmental changes results from underlying design principles. However, a comparison of robustness properties of different rhythms is lacking. Here we analyse the sensitivity of the oscillatory period with respect to parameter variations in models describing oscillations in calcium signalling, glycolysis and the circadian system. By comparing models for the same and different rhythms it is shown that the sensitivity depends on the oscillatory mechanism rather than the details of the model description. In particular, we find models of calcium oscillations to be very sensitive, those for glycolytic oscillations intermediately sensitive and models for circadian rhythms very robust. The results are discussed with respect to the temperature dependency of the rhythms. The question of what impact design principles have on the robustness of an oscillator, is addressed more explicitly by a direct comparison of systems with positive and negative feedback regulation for various reaction chain lengths. We find that the systems with negative feedback are more robust than corresponding systems with positive feedback. An increase in the length of the reaction chain under regulation leads to a decrease in sensitivity.
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STAT module can function as a biphasic amplitude filter
- Author(s): V. Mayya and L.M. Loew
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Signal transducer and actuator of transcription (STATs) are a family of transcription factors activated by various cytokines, growth factors and hormones. They are important mediators of immune responses and growth and differentiation of various cell types. The STAT signalling system represents a defined functional module with a pattern of signalling that is conserved from flies to mammals. In order to probe and gain insights into the signalling properties of the STAT module by computational means, we developed a simple non-linear ordinary differential equations model within the ‘Virtual Cell’ framework. Our results demonstrate that the STAT module can operate as a ‘biphasic amplitude filter’ with an ability to amplify input signals within a specific intermediate range. We show that dimerisation of phosphorylated STAT is crucial for signal amplification and the amplitude filtering function. We also demonstrate that maximal amplification at intermediate levels of STAT activation is a moderately robust property of STAT module. We propose that these observations can be extrapolated to the analogous SMAD signalling module.
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