IEE Proceedings - Systems Biology
Online ISSN
1741-248X
Print ISSN 1741-2471
Print ISSN 1741-2471
Published from 2005-2006, IEE Proceedings - Systems Biology covered intra- and inter-cellular dynamics, using systems- and signal-oriented approaches.
This journal was previously known as Systems Biology 2004-2005. ISSN 1741-2471. more..
This publication is continued by IET Systems Biology 2007-. ISSN 1751-8849. more..
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p.
409
–411
(3)
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Systems theory of Smad signalling
- Author(s): D.C. Clarke ; M.D. Betterton ; X. Liu
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p.
412
–424
(13)
Transforming growth factor-β (TGFβ) signalling is an important regulator of cellular growth and differentiation. The principal intracellular mediators of TGFβ signalling are the Smad proteins, which upon TGFβ stimulation accumulate in the nucleus and regulate the transcription of target genes. To investigate the mechanisms of Smad nuclear accumulation, we developed a simple mathematical model of canonical Smad signalling. The model was built using both published data and our experimentally determined cellular Smad concentrations (isoforms 2, 3 and 4). We found in mink lung epithelial cells that Smad2 (8.5–12×104 molecules cell−1) was present in similar amounts to Smad4 (9.3–12×104 molecules cell−1), whereas both were in excess of Smad3 (1.1–2.0×104 molecules cell−1). Variation of the model parameters and statistical analysis showed that Smad nuclear accumulation is most sensitive to parameters affecting the rates of R-Smad phosphorylation and dephosphorylation and Smad complex formation/dissociation in the nucleus. Deleting Smad4 from the model revealed that rate-limiting phospho-R-Smad dephosphorylation could be an important mechanism for Smad nuclear accumulation. Furthermore, we observed that binding factors constitutively localised to the nucleus do not efficiently mediate Smad nuclear accumulation, if dephosphorylation is rapid. We therefore conclude that an imbalance in the rates of R-Smad phosphorylation and dephosphorylation is likely an important mechanism of Smad nuclear accumulation during TGFβ signalling.
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Direct Lyapunov exponent analysis enables parametric study of transient signalling governing cell behaviour
- Author(s): B.B. Aldridge ; G. Haller ; P.K. Sorger ; D.A. Lauffenburger
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p.
425
–432
(8)
Computational models aid in the quantitative understanding of cell signalling networks. One important goal is to ascertain how multiple network components work together to govern cellular responses, that is, to determine cell ‘signal-response’ relationships. Several methods exist to study steady-state signals in the context of differential equation-based models. However, many biological networks influence cell behaviour through time-varying signals operating during a transient activated state that ultimately returns to a basal steady-state. A computational approach adapted from dynamical systems analysis to discern how diverse transient signals relate to alternative cell fates is described. Direct finite-time Lyapunov exponents (DLEs) are employed to identify phase-space domains of high sensitivity to initial conditions. These domains delineate regions exhibiting qualitatively different transient activities that would be indistinguishable using steady-state analysis but which correspond to different outcomes. These methods are applied to a physico-chemical model of molecular interactions among caspase-3, caspase-8 and X-linked inhibitor of apoptosis – proteins whose transient activation determines cell death against survival fates. DLE analysis enabled identification of a separatrix that quantitatively characterises network behaviour by defining initial conditions leading to apoptotic cell death. It is anticipated that DLE analysis will facilitate theoretical investigation of phenotypic outcomes in larger models of signalling networks.
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Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways
- Author(s): U. Klingmüller ; A. Bauer ; S. Bohl ; P.J. Nickel ; K. Breitkopf ; S. Dooley ; S. Zellmer ; C. Kern ; I. Merfort ; T. Sparna ; J. Donauer ; G. Walz ; M. Geyer ; C. Kreutz ; M. Hermes ; F. Götschel ; A. Hecht ; D. Walter ; L. Egger ; K. Neubert ; C. Borner ; M. Brulport ; W. Schormann ; C. Sauer ; F. Baumann ; R. Preiss ; S. MacNelly ; P. Godoy ; E. Wiercinska ; L. Ciuclan ; J. Edelmann ; K. Zeilinger ; M. Heinrich ; U.M. Zanger ; R. Gebhardt ; T. Maiwald ; R. Heinrich ; J. Timmer ; F. von Weizsäcker ; J.G. Hengstler
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p.
433
–447
(15)
Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-κB and Wnt/β-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFβ was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent β-catenin was monitored in response to the inhibition of GSK3β. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFβ-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.
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Elimination of the initial value parameters when identifying a system close to a Hopf bifurcation
- Author(s): G. Cedersund
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p.
448
–456
(9)
One of the biggest problems when performing system identification of biological systems is that it is seldom possible to measure more than a small fraction of the total number of variables. If that is the case, the initial state, from where the simulation should start, has to be estimated along with the kinetic parameters appearing in the rate expressions. This is often done by introducing extra parameters, describing the initial state, and one way to eliminate them is by starting in a steady state. We report a generalisation of this approach to all systems starting on the centre manifold, close to a Hopf bifurcation. There exist biochemical systems where such data have already been collected, for example, of glycolysis in yeast. The initial value parameters are solved for in an optimisation sub-problem, for each step in the estimation of the other parameters. For systems starting in stationary oscillations, the sub-problem is solved in a straight-forward manner, without integration of the differential equations, and without the problem of local minima. This is possible because of a combination of a centre manifold and normal form reduction, which reveals the special structure of the Hopf bifurcation. The advantage of the method is demonstrated on the Brusselator.
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