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Klamt S.,Max Planck Institute for Dynamics of Complex Technical Systems | Klamt S.,Magdeburg Center for Systems Biology | Flassig R.J.,Max Planck Institute for Dynamics of Complex Technical Systems | Sundmacher K.,Max Planck Institute for Dynamics of Complex Technical Systems | Sundmacher K.,Otto Von Guericke University of Magdeburg
Bioinformatics | Year: 2010

Motivation: Distinguishing direct from indirect influences is a central issue in reverse engineering of biological networks because it facilitates detection and removal of false positive edges. Transitive reduction is one approach for eliminating edges reflecting indirect effects but its use in reconstructing cyclic interaction graphs with true redundant structures is problematic. Results: We present TRANSWESD, an elaborated variant of TRANSitive reduction for WEighted Signed Digraphs that overcomes conceptual problems of existing versions. Major changes and improvements concern: (i) new statistical approaches for generating high-quality perturbation graphs from systematic perturbation experiments; (ii) the use of edge weights (association strengths) for recognizing true redundant structures; (iii) causal interpretation of cycles; (iv) relaxed definition of transitive reduction; and (v) approximation algorithms for large networks. Using standardized benchmark tests, we demonstrate that our method outperforms existing variants of transitive reduction and is, despite its conceptual simplicity, highly competitive with other reverse engineering methods. © The Author(s) 2010. Published by Oxford University Press.

Carius A.B.,Max Planck Institute for Dynamics of Complex Technical Systems | Henkel M.,Magdeburg Center for Systems Biology | Grammel H.,Max Planck Institute for Dynamics of Complex Technical Systems
Journal of Bacteriology | Year: 2011

The formation of intracytoplasmic photosynthetic membranes by facultative anoxygenic photosynthetic bacteria has become a prime example for exploring redox control of gene expression in response to oxygen and light. Although a number of redox-responsive sensor proteins and transcription factors have been characterized in several species during the last several years in some detail, the overall understanding of the metabolic events that determine the cellular redox environment and initiate redox signaling is still poor. In the present study we demonstrate that in Rhodospirillum rubrum, the amount of photosynthetic membranes can be drastically elevated by external supplementation of the growth medium with the low-molecular-weight thiol glutathione. Neither the widely used reductant dithiothreitol nor oxidized glutathione caused the same response, suggesting that the effect was specific for reduced glutathione. By determination of the extracellular and intracellular glutathione levels, we correlate the GSH/GSSG redox potential to the expression level of photosynthetic membranes. Possible regulatory interactions with periplasmic, membrane, and cytosolic proteins are discussed. Furthermore, we found that R. rubrum cultures excrete substantial amounts of glutathione to the environment. © 2011, American Society for Microbiology.

Schwarick M.,TU Brandenburg | Heiner M.,TU Brandenburg | Rohr C.,Magdeburg Center for Systems Biology
Proceedings of the 2011 8th International Conference on Quantitative Evaluation of Systems, QEST 2011 | Year: 2011

MARCIE is a multi-threaded tool for the analysis of Generalized Stochastic Petri Nets. Its capabilities range from standard properties of qualitative Petri nets to CTL and CSL model checking, recently extended by rewards. The core of MARCIE builds upon Interval Decision Diagrams for the symbolic representation of marking sets of bounded Petri nets (finite state space) and on-the-fly matrix computation for numerical analysis. Approximative engines supporting fast adaptive uniformization and Gillespie simulation open the door to quantitative reasoning on unbounded Petri nets (infinite state space). This paper presents MARCIE's architecture and its most important distinguishing features. Extensive computational experiments demonstrate MARCIE''s strength in comparison with related tools. © 2011 IEEE.

Franz A.,Max Planck Institute for Dynamics of Complex Technical Systems | Franz A.,Magdeburg Center for Systems Biology | Song H.-S.,Purdue University | Ramkrishna D.,Purdue University | And 3 more authors.
Biochemical Engineering Journal | Year: 2011

In this paper a mathematical model is presented to describe poly(β-hydroxybutyrate) (PHB) formation and consumption in Ralstonia eutropha. The model is based on the hybrid cybernetic modeling approach, which was introduced by Kim et al. [1] and which allows a systematic derivation of the model equations from elementary mode analysis. An extension of this approach is presented to allow for non quasi-stationary metabolites, i.e. PHB. The model is shown to be in good agreement with experimental data for PHB formation and consumption. The model is used afterwards to discuss the occurrence of multiple steady states in a continuous bio reactor. It is shown that the multiplicity region predicted by the model is rather small and it is argued that multiple steady states are therefore unlikely to occur in practice for this specific system. Due to various desirable features such as accounting for cellular regulation at network level and dynamics of intracellular metabolites with a moderate complexity, it is believed that the constructed model is most suitable for control, optimization and monitoring of industrial PHB production processes. © 2011 Elsevier B.V.

Hadicke O.,Max Planck Institute for Dynamics of Complex Technical Systems | Hadicke O.,Magdeburg Center for Systems Biology | Klamt S.,Max Planck Institute for Dynamics of Complex Technical Systems | Klamt S.,Magdeburg Center for Systems Biology
Metabolic Engineering | Year: 2011

The model-driven search for gene deletion strategies that increase the production performance of microorganisms is an essential part of metabolic engineering. One theoretical approach is based on Minimal Cut Sets (MCSs) which are minimal sets of knockouts disabling the operation of a specified set of target elementary modes. A limitation of the current approach is that MCSs can induce side effects disabling also desired functionalities. We, therefore, generalize MCSs to Constrained MCSs (cMCSs) allowing for the additional definition of a set of desired modes of which a minimum number must be preserved. Exemplarily for ethanol production by Escherichia coli, we demonstrate that this approach offers enormous flexibility in defining and solving knockout problems. Moreover, many existing methods can be reformulated as special cMCS problems. The cMCSs approach allows systematic enumeration of all equivalent gene deletion combinations and also helps to determine robust knockout strategies for coupled product and biomass synthesis. © 2010 Elsevier Inc.

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