2020-10-22T04:56:57Zhttp://edoc.mpg.de/ac_p_oai.ploai:edoc.mpg.de:137492004-03-1719:94
Calculability analysis in underdetermined metabolic networks illustrated by a model of the central metabolism in purple nonsulfur bacteria
Klamt, S.
Schuster, S.
Gilles, E. D.
expertsonly
metabolic flux analysis; metabolite balancing; calculability; observability; underdetermined systems; stoichiometric analysis; purple nonsulfur bacteria; photosynthetic bacteria
Metabolite balancing has turned out to be a powerful computational tool in metabolic engineering. However, the linear equation systems occurring in this analysis are often underdetermined. If it is difficult or impossible to find the missing constraints, it is nevertheless feasible in some cases to determine the values of a subset of the unknown rates. Here, a procedure for finding out which reaction rates can be uniquely calculated in underdetermined metabolic networks and computing these rates is given. The method is based on the null space to the stoichiometry matrix corresponding to the reactions with unknown rates. It is shown that this method is considerably easier to handle than an algorithm given previously (Van der Heijden et al, 1994a). Furthermore, a useful elementary representation of the null space is presented which is closely related with the elementary flux modes. This unique representation is central to a more general approach to observability/calculability analysis. In particular, it allows one to find, in an easy way, those sets of measurable rates that enable a calculation of a certain unknown rate. Besides, rates which are never calculable by metabolite balancing may be easily detected by this method. The applicability of these methods is illustrated by a model of the central metabolism in purple nonsulfur bacteria. The photoheterotrophic growth of these representatives of anoxygenic photosynthetic bacteria is stoichiometrically analyzed. Interesting metabolic constraints caused by the necessary balancing of NAD(P)H can be detected in a highly underdetermined system. This is, to our knowledge, the first application of stoichiometric analysis to the metabolic network in this bacteria group using metabolite balancing techniques. A new software tool, the FluxAnalyzer, is introduced. It allows quantitative and structural analysis of metabolic networks in a graphical user interface. (C) 2002 John Wiley Sons, Inc.
2002
Article
http://edoc.mpg.de/13749
urn:ISSN:0006-3592
Biotechnology and Bioengineering, v.77, 734-751 (2002)
en
oai:edoc.mpg.de:137512004-02-2719:94
The organization of metabolic reaction networks - II. Signal processing in hierarchical structured functional units
Kremling, A.
Gilles, E. D.
expertsonly
Based on the analysis of molecular interactions of proteins with DNA binding sites, a new approach to developing mathematical models describing gene expression is introduced. Detection of hierarchical structures in metabolic networks can be used to decompose complex reaction schemes. This will be achieved by assigning each regulator protein to one level in the hierarchy. Signals are then transduced from the top level to the lower level, but not vice versa. The method is shown by a simple example with two interacting proteins. A comparison of simulation results shows good agreement between a model taking all interactions into account and a model developed with the new approach. Finally, the method is applied to the crpA modulon in Escherichia coli, which controls uptake and metabolism for a number of carbohydrates. Here, RNA polymerase represents the top level, CrpA the second level, and the lactose-specific repressor LacI the lowest level, respectively. Besides the lactose operon, the method is applied to the adenylate cyclase gene and the gene for the regulator CrpA. (C) 2001 Academic Press.
2001
Article
http://edoc.mpg.de/13751
urn:ISSN:1096-7176
Metabolic Engineering, v.3, 138-150 (2001)
en
oai:edoc.mpg.de:137532004-02-0919:94
The organization of metabolic reaction networks. III. Application for diauxic growth on glucose and lactose
Kremling, A.
Bettenbrock, K.
Laube, B.
Jahreis, K.
Lengeler, J. W.
Gilles, E. D.
expertsonly
A mathematical model to describe carbon catabolite repression in Escherichia coli is developed and in part validated. The model is aggregated from two functional units describing glucose and lactose transport and degradation. Both units are members of the erp modulon and are under control of a global signal transduction system which calculates the signals that turn on or off gene expression for the specific enzymes. Using isogenic mutant strains, our model is validated by a set of experiments. In these experiments, substrate composition of the preculture and of the experimental culture are varied in order to stimulate the system in different ways. With the obtained measurements (three states in the liquid phase and one intracellular component) a part of the model parameters could be estimated. Therefore all experiments could be sufficiently described with a single set of parameters. (C) 2001 Academic Press.
2001
Article
http://edoc.mpg.de/13753
urn:ISSN:1096-7176
Metabolic Engineering, v.3, 362-379 (2001)
en
oai:edoc.mpg.de:137592004-03-1819:94
Use of network analysis of metabolic systems in bioengineering
Schuster, S.
Klamt, S.
Weckwerth, W.
Moldenhauer, F.
Pfeiffer, T.
expertsonly
Basic ideas and recent developments in network analysis of metabolic systems and various applications of this analysis in bioengineering are reviewed. Central concepts are the null- space to the stoichiometry matrix and the elementary flux modes. The applicability of elementary-modes analysis in biotechnology is illustrated by the synthesis of the cyclooctadepsipeptides PF1022 in the fungus Mycelia sterilia. Network analysis is also useful in metabolic flux analysis. In particular, a procedure for finding out which reaction rates can be uniquely calculated in underdetermined reaction networks is outlined. The concept of 'enzyme subsets' is explained and its use for analysing genetic regulation is demonstrated. In particular, the correlation between expression data concerning the diauxic shift in yeast and the enzyme subsets in yeast metabolism is discussed.
2002
Article
http://edoc.mpg.de/13759
urn:ISSN:1615-7591
Bioprocess and Biosystems Engineering, v.24, 363-372 (2002)
en
oai:edoc.mpg.de:137662004-03-1719:94
Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors
Schöberl, B.
Eichler-Jonsson, C.
Gilles, E. D.
Müller, G.
expertsonly
We present a computational model that offers an integrated quantitative, dynamic, and topological representation of intracellular signal networks, based on known components of epidermal growth factor (EGF) receptor signal pathways. The model provides insight into signal-response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade. It shows that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration and that the critical parameter in determining signal efficacy is the initial velocity of receptor activation. The predictions of the model agree well with experimental analysis of the effect of EGF on two downstream responses, phosphorylation of ERK-1/2 and expression of the target gene, c-fos.
2002
Article
http://edoc.mpg.de/13766
urn:ISSN:1087-0156
Nature Biotechnology, v.20, 370-375 (2002)
en
oai:edoc.mpg.de:137892004-03-1719:94
Combinatorial complexity of pathway analysis in metabolic networks
Klamt, S.
Stelling, J.
expertsonly
combinatorial complexity in metabolic networks; elementary flux modes; metabolic pathway analysis; structural network analysis
Elementary flux mode analysis is a promising approach for a pathway-oriented perspective of metabolic networks. However, in larger networks it is hampered by the combinatorial explosion of possible routes. In this work we give some estimations on the combinatorial complexity including theoretical upper bounds for the number of elementary flux modes in a network of a given size. In a case study, we computed the elementary modes in the central metabolism of Escherichia coli while utilizing four different substrates. Interestingly, although the number of modes occurring in this complex network can exceed half a million, it is still far below the upper bound. Hence, to a certain extent, pathway analysis of central catabolism is feasible to assess network properties such as flexibility and functionality.
2002
Article
http://edoc.mpg.de/13789
urn:ISSN:0301-4851
Molecular Biology Reports, v.29, 233-236 (2002)
en
oai:edoc.mpg.de:137902004-03-1719:94
Calculating as many fluxes as possible in underdetermined metabolic networks
Klamt, S.
Schuster, S.
expertsonly
A frequently occurring problem in Metabolic Flux Analysis is that the linear equation systems are underdetermined. A procedure for determining which reaction velocities can be calculated in underdetermined metabolic systems from measured rates and computing these velocities is given. The method is based on the null-space matrix to the stoichiometry matrix corresponding to the reactions with unknown velocities. Moreover, an elementary representation of the null-space is presented. This representation enables one to find those sets of measurable velocities that allow calculation of a certain non-measurable rate. The approach is illustrated by an example from monosaccharide metabolism.
2002
Article
http://edoc.mpg.de/13790
urn:ISSN:0301-4851
Molecular Biology Reports, v.29, 243-248 (2002)
en
oai:edoc.mpg.de:137912004-03-1719:94
Metabolic network structure determines key aspects of functionality and regulation
Stelling, J.
Klamt, S.
Bettenbrock, K.
Schuster, S.
Gilles, E. D.
expertsonly
The relationship between structure, function and regulation in complex cellular networks is a still largely open question(1- 3). Systems biology aims to explain this relationship by combining experimental and theoretical approaches(4). Current theories have various strengths and shortcomings in providing an integrated, predictive description of cellular networks. Specifically, dynamic mathematical modelling of large-scale networks meets difficulties because the necessary mechanistic detail and kinetic parameters are rarely available. In contrast, structure-oriented analyses only require network topology, which is well known in many cases. Previous approaches of this type focus on network robustness(5) or metabolic phenotype(2,6), but do not give predictions on cellular regulation. Here, we devise a theoretical method for simultaneously predicting key aspects of network functionality, robustness and gene regulation from network structure alone. This is achieved by determining and analysing the non- decomposable pathways able to operate coherently at steady state (elementary flux modes). We use the example of Escherichia coli central metabolism to illustrate the method.
2002
Article
http://edoc.mpg.de/13791
urn:ISSN:0028-0836
Nature, v.420, 190-193 (2002)
en
oai:edoc.mpg.de:137962007-10-2619:94
A network theory for the structured modelling of chemical processes
Mangold, M.
Motz, S.
Gilles, E. D.
expertsonly
systematic modelling; computer aided modelling; mathematical modelling; spatially distributed systems; population balances; dynamic simulation; process control
A structuring methodology for dynamic models of chemical engineering processes is presented. The main ideas of the methodology were outlined in a previous publication for the class of well-mixed systems. In this contribution, the methodology is extended to spatially distributed systems and to particulate processes. Furthermore, the structuring principle is used to make a conceptual link between the macroscopic world of process simulation and the microscopic world of molecular simulation. It is shown that a uniform structuring principle can be applied to the modularisation of most classes of chemical engineering models. The structuring principle can be used as a theoretical framework for the implementation of modular families of chemical engineering models in modem computer aided modelling tools.
2002
Article
http://edoc.mpg.de/13796
urn:ISSN:0009-2509
Chemical Engineering Science, v.57, 4099-4116 (2002)
en
oai:edoc.mpg.de:138062004-06-2219:94
FluxAnalyzer : exploring structure, pathways, and flux distributions in metabolic networks on interactive flux maps
Klamt, S.
Stelling, J.
Ginkel, M.
Gilles, E. D.
expertsonly
Motivation: The analysis of structure, pathways and flux distributions in metabolic networks has become an important approach for understanding the functionality of metabolic systems. The need of a user-friendly platform for stoichiometric modeling of metabolic networks in silico is evident. Results: The FluxAnalyzer is a package for MATLAB(R) and facilitates integrated pathway and flux analysis for metabolic networks within a graphical user interface. Arbitrary metabolic network models can be composed by instances of four types of network elements. The abstract network model is linked with network graphics leading to interactive flux maps which allow for user input and display of calculation results within a network visualization. Therein, a large and powerful collection of tools and algorithms can be applied interactively including metabolic flux analysis, flux optimization, detection of topological features and pathway analysis by elementary flux modes or extreme pathways. The FluxAnalyzer has been applied and tested for complex networks with more than 500 000 elementary modes. Some aspects of the combinatorial complexity of pathway analysis in metabolic networks are discussed. Availability: Upon request from the corresponding author. Free for academic users (license agreement). Special contracts are available for industrial corporations. Supplementary information: http://www.mpi-magdeburg.mpg.de/projects/fluxanalyzer Contact: klamt@mpi-magdeburg.mpg.de.
2003
Article
http://edoc.mpg.de/13806
urn:ISSN:1367-4803
Bioinformatics, v.19, 261-269 (2003)
en
oai:edoc.mpg.de:138152004-09-1019:94
The systems biology markup language (SBML) : a medium for representation and exchange of biochemical network models
Hucka, M.
Finney, A.
Sauro, H. M.
Bolouri, H.
Doyle, J. C.
Kitano, H.
Arkin, A. P.
Bornstein, B. J.
Bray, D.
Cornish-Bowden, A.
Cuellar, A. A.
Dronov, S.
Gilles, E. D.
Ginkel, M.
Gor, V.
Goryanin, I. I.
Hedley, W. J.
Hodgman, T. C.
Hofmeyr, J. H.
Hunter, P. J.
Juty, N. S.
Kasberger, J. L.
Kremling, A.
Kummer, U.
Le Novere, N.
Loew, L. M.
Lucio, D.
Mendes, P.
Minch, E.
Mjolsness, E. D.
Nakayama, Y.
Nelson, M. R.
Nielsen, P. F.
Sakurada, T.
Schaff, J. C.
Shapiro, B. E.
Shimizu, T. S.
Spence, H. D.
Stelling, J.
Takahashi, K.
Tomita, M.
Wagner, J.
Wang, J.
expertsonly
Motivation: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. Results: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others.
2003
Article
http://edoc.mpg.de/13815
urn:ISSN:1367-4803
Bioinformatics, v.19, 524-531 (2003)
en
oai:edoc.mpg.de:138202004-05-1819:94
Two approaches for metabolic pathway analysis?
Klamt, S.
Stelling, J.
expertsonly
Metabolic pathway analysis is becoming increasingly important for assessing inherent network properties in (reconstructed) biochemical reaction networks. Of the two most promising concepts for pathway analysis, one relies on elementary flux modes and the other on extreme pathways. These concepts are closely related because extreme pathways are a subset of elementary modes. Here, the common features, differences and applicability of these concepts are discussed. Assessing metabolic systems by the set of extreme pathways can, in general, give misleading results owing to the exclusion of possibly important routes. However, in certain network topologies, the sets of elementary modes and extreme pathways coincide. This is quite often the case in realistic applications. In our opinion, the unification of both approaches into one common framework for metabolic pathway analysis is necessary and achievable.
2003
Article
http://edoc.mpg.de/13820
urn:ISSN:0167-7799
Trends in Biotechnology, v.21, 64-69 (2003)
en
oai:edoc.mpg.de:349002004-02-1819:94
Development, analysis and validation of population models for continuous and batch crystallizers
Gerstlauer, A.
Motz, S.
Mitrovic, A.
Gilles, E. D.
expertsonly
This contribution deals with the derivation of mathematical models for continuous and batch crystallizers based on the population balance approach. Detailed kinetic expressions for primary nucleation, crystal growth and attrition are incorporated into the models. The proper mathematical formulation of these phenomena as well as their incorporation into the population balance are discussed. Subsequently, system theoretical properties (e.g. the differential index of the resulting differential-algebraic equation system) of the derived models are analysed. Finally, the models for the continuous and the batch crystallizer are validated by comparison to measurements of temperature, supersaturation and particle size distribution.
2002
Article
http://edoc.mpg.de/34900
Chemical Engineering Science, v.57, 4311-4327 (2002)
oai:edoc.mpg.de:349472004-02-1819:94oai:edoc.mpg.de:349842003-07-3119:94oai:edoc.mpg.de:349882003-07-3019:94oai:edoc.mpg.de:350032003-07-2819:94
Applying metabolic pathway analysis to make good use of methanol
Schuster, S.
Klamt, S.
expertsonly
Comment article - no abstract available.
2002
Article
http://edoc.mpg.de/35003
Trends in Biotechnology, v.20, 322 (2002)
oai:edoc.mpg.de:350162004-09-0619:94
Control-key to better understanding biological systems
Gilles, E. D.
expertsonly
Biological cells use very effcient and hierarchically structured regulations to control their metabolism and to adapt it to variations in the environmental conditions. Only these regulations prevent the potential chaos of thousands of individual reactions occurring in a cell. To understand the functioning of these regulations and the complexity of their interactions mathematical modelling on the basis of a detailed biomolecular description of cellular functional units is not only helpful but necessary. This modelling process can be supported by a modelling concept interconnecting elementary modelling objects assigned to elementary biomolecular building blocks. This correspondence allows for biological transparency and facilitates interdisciplinary co-operation between biology and system sciences as an important precondition to enable a deeper understanding of regulatory processes. The important role regulation plays in cellular biological systems is demonstrated by means of two typical functional units, the catabolite repression in E. coli and the cell cycle regulation in Saccharomyces cerevisiae. These two examples show both the typical hierarchical structure and the high effciency of regulatory processes in cells.
2002
Article
http://edoc.mpg.de/35016
Automatisierungstechnik, v.50, 7-17 (2002)
oai:edoc.mpg.de:350392004-09-0619:94
Analysis of the dynamics of the Escherichia coli glucose PTS in different time windows
Sauter, T.
Kremling, A.
Bettenbrock, K.
Fischer, S.
Gilles, E. D.
expertsonly
The analysis of metabolic pathways with mathematical models contributes to the better understanding of the behaviour of metabolic processes. In this paper, the analysis of the glucose phosphotransferase system in Escherichia coli is presented. It is shown that dynamic processes cover a broad time span from some milliseconds to several hours. This is shown by simulation as well as by experimental studies.
AKA-Verl.-Ges.
2002
Conference-Paper
http://edoc.mpg.de/35039
urn:ISBN:3-89838-030-0
Polani, D.; Kim, J.; Martinetz, T.: Abstracting and synthesizing the principles of living systems: Proceedings of the Fifth German Workshop on Artificial Life, AKA-Verl.-Ges., 33-42 (2002)
oai:edoc.mpg.de:351392004-09-0619:94
FluxAnalyzer : a graphical user interface for stoichiometric and quantitative analysis of metabolic networks
Klamt, S.
Kremling, A.
Gilles, E. D.
expertsonly
Metabolic Flux Analysis has turned out to be a powerful approach for studying and engineering metabolic networks. Nevertheless, there seems to be a lack of a comprehensive software platform where all computational routines for metabolite balancing and stoichiometric analysis can be used in a convenient way. Therefore, the FluxAnalyzer, a programming package for MATLAB, was developed. The interactive software allows a menu-driven use of various procedures within a graphical user interface, where the metabolic networks under investigation and the results of calculations are visualized in flux maps. Arbitrary networks can be defined symbolically. The FluxAnalyzer is used in current projects at our institute and its application for flux analysis of cell cultures in an industrial process is planned.
Published for the International Federation of Automatic Control by Pergamon
2002
InBook
http://edoc.mpg.de/35139
urn:ISBN:0-08-043681-1
Computer applications in biotechnology 2001 (CAB8): Modelling, monitoring and control of biotechnological processes, 119-124 (2002)
oai:edoc.mpg.de:351462004-07-2619:94
Integrating Workbench for Modeling and Numerical Analysis of Cellular Systems
Kremling, A.
Ginkel, M.
Gilles, E. D.
expertsonly
With increasing knowledge in biology and improved measurement methods it becomes possible to build detailed models of the cells interior. In this contribution a computer framework is described which allows to build modular structured metabolic models using a abstract and general modeling methodology. With this methodology reusable modeling entities are introduced which lead to the development of modeling knowledge-bases. Therefore the modeling tool ProMot is introduced. For the numerical analysis and identification of the resulting models the simulation environment DIVA is described. For the management of the resulting data from measurements and simulations on different models management and visualization facilities are necessary which are available in the MATLAB tool CellView. The described tools are the first steps towards an integrated computer-based modeling, simulation and visualization environment.
2002
Conference-Paper
http://edoc.mpg.de/35146
Dochain, D.; Perrier, M.: Proc. 8th International Conference on Computer Applications in Biotechnology, 85-90 (2002)
oai:edoc.mpg.de:622452004-09-0619:94
Towards a Virtual Biological Laboratory
Stelling, J.
Kremling, A.
Ginkel, M.
Bettenbrock, K.
Gilles, E. D.
expertsonly
For a system-level understanding of living cells, a quantitative representation of these systems involving mathematical models and corresponding computer tools is required. Our approach focuses on a modeling concept which relies upon modular structuring of cellular systems focusing strongly on the biomolecular structure of these systems. Mathematical submodels for functional units comprising metabolism and regulation can be aggregated in a hierarchical way to obtain more complex modules. In the Virtual Biological Laboratory, the process modeling tool ProMoT contains an object-oriented knowledge base with reusable modeling entities and enables a purely symbolical model development process via a graphical user interface. The simulation environment Diva then uses the model library for dynamic simulation, parameter estimation and model analysis. Two examples of models of complex regulatory networks in Escherichia coli and in Saccharomyces cerevisiae are given to demonstrate the usefulness of this approach. It can provide a framework for straightforward development of virtual representations for cellular systems.
MIT Press
2001
InBook
http://edoc.mpg.de/62245
urn:ISBN:0-262-11266-3
Foundations of systems biology, 189-212 (2001)
oai:edoc.mpg.de:624102004-09-0619:94
Inland-ECDIS chart validation and correction using radar image processing technics
Driescher, A.
Saez, L.
Gilles, E. D.
expertsonly
One of the most promising developments in inland navigation are electronic chart based navigation systems. Emerging from the ECDIS standard used in see navigation the Inland-ECDIS standard provides a well-accepted foundation for electronic navigation systems. Meanwhile, industrial vendors start equipping vessels with the first navigation systems and authorities are releasing first river chart series based on the provisional Inland-ECDIS standard. Until now, the process of validating Inland-ECDIS charts is mainly done by feedback from skippers using this charts in there navigation system. While minor problems like missing or misplaced navigation marks can easily be handled by standard chart editing software, more elaborated issues concerning malfunctions in radar overlays due to errors in radar conspicuous objects are not addressed in standard tools. However, correct handling of radar overlays is a corner stone for save and reliable navigation and therefor a need for easy verification arise, leading to a powerful radar image post processing system. The paper will present the standard features implemented in a commercial navigation system that are relevant to chart verification and correction. Based on the mechanisms provided in this system, a radar image post processing algorithm is discussed that can produce overlay pictures for use in ECDIS-chart editors. Although the algorithm is primarily tuned for chart verification it turned out to be even as powerful for automated chart production in areas where traditional charts are not available. The paper will handle the following topics in more detail:- The radar overlay mechanism required by the Inland-ECDIS standard. - Sensor requirements for data acquisition and processing in navigation systems.- Typical features found in commercial systems and there application to chart validation. - Chart production errors and there consequences for navigation systems. - Radar image post-processing by merging image sequences by Bays estimation. - Integration and image handling in commercial ECDIS chart editors. - Examples for data verification and chart production.
Secretariat of National Organising Comittee of EIWN 2001
2001
Conference-Paper
http://edoc.mpg.de/62410
urn:ISBN:963-420-693-X
Hadhazi, D.; Simongati, G.: Proceedings of the European Inland Waterway Navigation Conference, Secretariat of National Organising Comittee of EIWN 2001, keine Paginierung (2001)
oai:edoc.mpg.de:629762004-09-0619:94
Biosystems Engineering: Applying methods from systems theory to biological systems
Kremling, A.
Sauter, T.
Bullinger, E.
Ederer, M.
Allgöwer, F.
Gilles, E. D.
expertsonly
Using methods and tools from systems theory will offer new possibilities to analyze and design biological systems. The intention of this contribution is two fold: giving an overview on different areas where such methods can be applied. The main focus in the first part will be the set up of mathematical models. Here two complementing ways to come to a suitable model will be discussed. The second part will describe possibilities to validate mathematical models and to design experiments while the third part will discuss methods to analyze complex systems. Besides the overview the second intension is to present also some new ideas for the application of methods from systems theory.
2001
Conference-Paper
http://edoc.mpg.de/62976
Yi,T.-M.; Hucka, M.; Morohashi, M.; Kitano, H.: Proceedings of the Second International Conference on Systems Biology, 282-290 (2001)
oai:edoc.mpg.de:629852004-02-1319:94
Control of Moving Bed Chromatographic Processes
Schramm, H.
Grüner, S.
Kienle, A.
Gilles, E. D.
expertsonly
A new concept for the control of moving bed chromatographic processesis developed. In a first step focus is on the true moving bed process. A fairly simple method is developed for the control of this process with standard PI controllers. This method makes direct use of the underlying spatio-temporal pattern formation phenomena also termed as nonlinear wave propagation. According to the well known ‘Triangle Theory’ the chromatographic unit is working under optimal operating conditions, i.e. with minimal solvent consumption and maximal feed throughput. Finally the application of this method to the simulated moving bed process is discussed.
2001
Conference-Paper
http://edoc.mpg.de/62985
Proceedings of the European Control Conference, ECC'01, 2528-2533 (2001)
oai:edoc.mpg.de:629862004-03-1219:94
Experimentally Coupled Thermokinetic Oscillators: Phase Death and Rhythmogenesis
Zeyer, K.-P.
Mangold, M.
Gilles, E. D.
expertsonly
We present an experimental investigation of two coupled thermokinetic oscillators. The system is the exothermic iron-(III)-nitrate catalyzed oxidation of ethanol with hydrogen peroxide to ethanal and acetic acid. The coupling of two continuous flow stirred tank reactors (CSTRs) is performed in four different ways: via coupling of the cooling circuits, via exchange of reaction mass, and via combinations of both in equal and opposite directions. The experiments are modeled by a set of ordinary differential equations,which we have used in previous studies of the uncoupled free running system in a single CSTR. The model calculations predict three different kinds of qualitative behavior before and after the coupling. First, the qualitative behavior can remain unchanged, i.e. one gets steady states when steady states are coupled or one gets periodic oscillations when periodic oscillations are coupled. Second, oscillations can emerge when stationary states are coupled (rhythmogenesis) and third, oscillations are suppressed and change into steady states (phase death) when the coupling is activated. All these types of behavior can be verified in the experiments. Generating thermal oscillations by coupling can also lead to significant safety implications. We demonstrate experimentally a safe and an unsafe way of performing the rhythmogenesis experiment guided by our model calculations.
2001
Article
http://edoc.mpg.de/62986
Journal of Physical Chemistry A, v.105, 7216-7224 (2001)
oai:edoc.mpg.de:629872004-02-1319:94
Linear mimo controller design for an industrial reactive distillation column
Fernholz, G.
Friedrich, M.
Grüner, S.
Mohl, K. D.
Kienle, A.
Gilles, E. D.
expertsonly
The aim of this paper is to demonstrate the use of advanced linear controller design methods for an industrial scale reactive distillation column. The open-loop analysis of the process behavior indicates that linear control of the process is promising. Therefore, a control structure selection is made by ananalysis of the physical behavior of the system and an RGA-analysis. Afterwards a frequency response approximation technique is used for the design of linear MIMO controllers. Robustness of the closed loop is observed during controller design. Finally, the controller is tested on the nonlinear process model.
Pergamon Pr.
2001
Conference-Paper
http://edoc.mpg.de/62987
urn:ISBN:0-08-043679-X
Lee, J. H.; Joon, E. S.; Stephanopoulos; G.: Dynamics and Control of Process Systems 2001: a proceedings volume from the 6th IFAC Symposium, Pergamon Pr., 137-142 (2001)
oai:edoc.mpg.de:629882004-10-1319:94
Nonlinear control of an industrial reactive distillation column
Grüner, S.
Mohl, K. D.
Kienle, A.
Gilles, E. D.
Fernholz, G.
expertsonly
Control of reactive distillation columns is a challenging task due to the complex dynamics arising from the coupling of reaction and separation. In this paper asymptotically exact input/output-lineariztion is applied to an industrial reactive distillation column. The control scheme requires knowledge of the complete state of the process and therefore an observer is designed. To compensate for steady state observer offsets an outer control loop with simple PI-controllers is implemented. In comparison to a well tuned linear controller the nonlinear controller shows superior performance with respect to setpoint-changes and disturbances, even in the presence of unknown inputs.
Pergamon Pr.
2001
Conference-Paper
http://edoc.mpg.de/62988
urn:ISBN:0-08-043679-X
Stephanopoulos, G.; Lee, J.H.; Joon, E.S.: Dynamics and Control of Process System 2001 (DYCOPS-6), Pergamon Pr., 125-130 (2001)
oai:edoc.mpg.de:632962004-02-2519:94
Robustness vs. identifiability of regulatory modules? The case of mitotic control in budding yeast cell cycle regulation
Stelling, J.
Gilles, E. D.
expertsonly
Invariant input-output behavior and pathway redundancy provide a competitive advantage for cellular survival. Therefore robustness of cellular control circuits seems to be a general, essential feature. The same property however provides a challenge to the investigator because it hinders the estimation of kinetic parameters and thus the quantitative understanding of cellular regulation. The current study investigated the value of mathematical modeling in the elucidation of cellular control circuits under these constraints. A subsystem responsible for mitotic control in budding yeast cell cycle regulation was chosen as example.On the basis of scare quantitative experimental data we were able to develop a detailed mechanistic model. The model showed desirable descriptive and predictive character. For instance, model predictions agreed well with experimental observations without additional parameter adaptation. Furthermore, the model allowed for specifying barely characterized regulatory interactions. Determination of parameter estimation accuracy subsequently showed that the information content of the data available was much higher than generally expected. Combined data for wild type and for variants with only five measured variables lead to acceptable estimates for about half of the 114 kinetic parameters in this complex model. Analysis also proved, that the combination of data from the unperturbed and the disturbed control circuit was essential for this outcome. Parameter estimation accuracy additionally gives a quantitative measure for robustness, which in our case strongly supports the concept of highly optimized tolerance, i.e. of the co-existence of robustness and fragility in cellular control. A differentiated view on robustness and identifiability is thus required, but based on our experience, realistic models of cellular control are possible despite limited quantitative data.
2001
Conference-Paper
http://edoc.mpg.de/63296
T.M. Yi et al.: Proc. 2nd International Conference on Systems Biology, 181-190 (2001)
oai:edoc.mpg.de:651442004-09-0619:94
PROMOT: A modeling tool for chemical processes
Tränkle, F.
Zeitz, M.
Ginkel, M.
Gilles, E. D.
expertsonly
The novel process modeling tool PROMOT supports the object-oriented modeling of chemical processes for the simulation environment DIVA. In PROMOT, differential-algebraic process models can be built by aggregating structural and behavioral modeling entities that represent the topological structure or the dynamic and steady-state behavior, respectively, of the investigated chemical processes. Process models and their modeling entities may be defined either in an object-oriented modeling language or with a graphical user interface. This paper discusses the modeling concept, the modeling language, the knowledge representation aspects, and the implementation of PROMOT.
2000
Article
http://edoc.mpg.de/65144
Mathematical and Computer Modelling of Dynamical Systems, v.6, 283-307 (2000)
oai:edoc.mpg.de:651492004-09-0619:94
Aufbau und Funktion eines virtuellen biologischen Labors
Gilles, E. D.
expertsonly
2000
Article
http://edoc.mpg.de/65149
Chemie Ingenieur Technik, v.72, 924 (2000)
oai:edoc.mpg.de:651532004-10-1319:94
Signal transduction systems and their coupling to regulatory networks
Lengeler, J. W.
Gilles, E. D.
Jahreis, K.
Kremling, A.
expertsonly
Modern biotechnology will require increasingly a quantitative analysis of the complex behavior of cellular systems. The paper describes the definition of functional units as a basis for mathematical modeling of cellular systems.
Fraunhofer IRB Verlag
2000
Conference-Paper
http://edoc.mpg.de/65153
Brunner, H.: Proceedings of the 4th International Congress on Biochemical Engineering, Fraunhofer IRB Verlag, 309-313 (2000)
en
oai:edoc.mpg.de:651552004-02-2619:94
The organization of metabolic reaction networks: A signal-oriented approach to cellular models
Kremling, A.
Jahreis, K.
Lengeler, J. W.
Gilles, E. D.
expertsonly
Complex metabolic networks are characterized by a great number of elements and many regulatory loops. The description of these networks with mathematical models requires the definition of functional units, which group together several cellular processes. The presented approach is based on the idea that cellular functional units may directly be assigned to mathematical modeling objects. Since the proposed modeling objects have defined in- and outputs, they can be connected with other modeling objects until eventually the whole metabolism is covered. This modular approach guarantees a high transparency for biologist as well as for engineers. Three criteria are introduced to demarcate functional units. The criteria consider physiological pathways, the organization of the corresponding genes and the observation that cellular systems can be structured into units showing a hierarchy of signal transduction and processing. As an example the carbon catabolic reactions in Escherichia coli are discussed as members of a functional unit catabolism.
2000
Article
http://edoc.mpg.de/65155
Metabolic Engineering, v.2, 190-200 (2000)
oai:edoc.mpg.de:652592004-03-0119:94
The Behavior of the Iron(III)-Catalyzed Oxidation of Ethanol by Hydrogen Peroxide in a Fed-Batch reactor
Zeyer, K.-P.
Pushpavanam, S.
Mangold, M.
Gilles, E. D.
expertsonly
We present a theoretical (numerical) investigation of the exothermic iron-(III)-nitrate catalyzed oxidation of ethanol with hydrogen peroxide to ethanal and acetic acid. This reaction can display temperature and concentration oscillations when it is carried out in a continuous flow stirred tank reactor (CSTR) for some operating conditions. In this study we investigate the reaction when it is performed in a fed-batch reactor (FBR). The FBR can be interpreted as a mode of operation in between a CSTR and a batch reactor. The behavior of the reaction system is studied using two models. These differ in the degree of detail in evaluating properties. They hence have different degrees in complexity. The fed-batch mode of reactor operating is found to result in a significant improvement of the yield of ethanal, which is an intermediate product, in comparison to the batch and the CSTR modes of operation. The FBR mode of operation also introduces a rich variety of complex periodic states and chaos.
2000
Article
http://edoc.mpg.de/65259
Physical Chemistry Chemical Physics, v.2, 3605-3612 (2000)
oai:edoc.mpg.de:1119542004-04-0519:94
Sensitivitätsbasierte Erkennung gefährlicher Zustände in Reaktoren
Obertopp, T.
Alos, M. A.
Mangold, M.
Gilles, E. D.
expertsonly
This contribution deals with the model-based detection of hazardous states in chemical reactors. The runaway criteria known from literature are either not applicable on-line or they are only applicable to simple kinetics or a certain type of reactor. An intrinsic on-line runaway criterion has been developed based on parametric sensitivity. The power of the new early warning systems is shown for the continuous oxidation of ethanol by hydrogen peroxide.
1999
Article
http://edoc.mpg.de/111954
At - Automatisierungstechnik, v.47, 501-508 (1999)
de
oai:edoc.mpg.de:1119552004-03-1219:94
A new concept for operating simulated moving-bed processes
Kloppenburg, E.
Gilles, E. D.
expertsonly
1999
Article
http://edoc.mpg.de/111955
Chemical Engineering Technology, v.22, 813-817 (1999)
en
oai:edoc.mpg.de:1119572004-03-1219:94
Automatic control of the simulated moving bed process for C₈ aromatics separation using asymptotically exact input/output-linearization
Kloppenburg, E.
Gilles, E. D.
expertsonly
An approach to automatic control of the simulated moving bed process (SMB) applied to the separation of C₈ aromatics is presented. The principle of asymptotically exact input/output-linearization is used. The controller is based on a nonlinear state estimator using the true moving bed model (TMB). The estimator receives measurement data from four spectroscopic measurement cells. The problem of moving measurement positions with respect to the TMB model is adressed. An exactly linearizing feedback of the estimated states controller is shown in simulations using a detailed SMB model as a representative of the real process.
1999
Article
http://edoc.mpg.de/111957
Journal of Process Control, v.9, 41-50 (1999)
en
oai:edoc.mpg.de:1119652004-03-1219:94
Modeling and simulation of a chemical reactor for the production of acetic acid : III. dynamic phase transitions
Waschler, R.
Kienle, A.
Sviatnyi, S.
Gilles, E. D.
Anoprienko, A.
Osipova, T.
expertsonly
A special modeling and simulation approach is required to account for potential discrete events during the simulation of chemical plants. In the case of a reactor for the production of acetic acid discrete events may be caused by phase transitions or due to the extinction of the zero order reaction. It is shown how to handle such system discontinuities using an appropriate model formulation and exploiting the numerical methods of the simulatin environment DIVA. Simulation results illustrate the effects of discrete events in the reactor model.
Donetsk State Technical University
1999
Conference-Paper
http://edoc.mpg.de/111965
Informatics, Cybernetics and Computer Science (ICCS-98), Donetsk State Technical University, 102-109 (1999)
en
oai:edoc.mpg.de:1119712004-03-0519:94
The Iron (III)-catalyzed oxidation of ethanol by hydrogen peroxide: a thermokinetic oscillator
Zeyer, K.-P.
Mangold, M.
Obertopp, T.
Gilles, E. D.
expertsonly
We present an experimental and theoretical study of a laboratory scale continuous flow stirred tank reactor (CSTR) in which the exothermiciron(III)-nitrate catalyzed oxidation of ethanol with hydrogen peroxideto ethanal and acetic acid takes place. This reaction can display temperature and concentration oscillations when it is performed in a CSTR. A model is known in the literature, which is derived from a more detailed mechanism. We investigate the behavior of the system under different conditions using the volumetric flow of the cooling water as an experimental bifurcation parameter. The model is analyzed by one and two parameter continuation of stationary and periodic solutions. We characterize period doubling sequences to chaos, homoclinic orbits, and cross-shaped diagrams, which separate regions of oscillations and bistability.
1999
Article
http://edoc.mpg.de/111971
Journal of Physical Chemistry, v.103A, 5515-5522 (1999)
en
oai:edoc.mpg.de:1119762004-06-3019:94
An oscillating liquid-gas reaction with periodic evaporation : nonlinear analysis and experimental results
Zeyer, K. P.
Mangold, M.
Obertopp, T.
Gilles, E. D.
expertsonly
In this work we present theoretical and experimental studies of a laboratory scale continuous flow stirred tank reactor (CSTR) in which theiron-(III)-nitrate catalyzed oxidation of ethanol with hydrogen peroxide to ethanal and acetic acid takes place. This reaction displays temperature and concentration oscillations when it is performed in a CSTR. A liquid phase model is known in the literature derived from a more detailed mechanism. This model predicts the location of stationary solutions and bifurcations well, but the calculated reactor temperatures are high above the boiling point of the reaction mixture under certain conditions. Therefore, two different gas/liquid models were developed and compared with the experimental results.
1999
Article
http://edoc.mpg.de/111976
Chemical Engineering Science, v.54, 4845-4851 (1999)
en
oai:edoc.mpg.de:1139472004-03-2219:94
Computer modeling of chromatographic bioseparation
Spieker, A.
Kloppenburg, E.
Gilles, E. D.
expertsonly
Wiley-VCH
1998
InBook
http://edoc.mpg.de/113947
urn:ISBN:3-527-28876-7
Bioseparation and Bioprocessing, 329-362 (1998)
en
oai:edoc.mpg.de:1237242004-06-0619:94
An approach for dividing models of biological reaction networks into functional units
Ederer, M.
Sauter, T.
Bullinger, E.
Gilles, E. D.
Allgöwer, F.
expertsonly
Biological reaction networks consist of many substances and reactions between them. Like many other biological systems, they have a modular structure. Therefore, a division of a biological reaction network into smaller units highly facilitates its investigation. The authors propose an algorithm to divide an ordinary differential equation (ODE) model of a biological reaction network hierarchically into functional units. For every compound, an activity function dependent on concentration or concentration change rate is defined. After performing suitable simulations, distances between the compounds are computed by comparing the activities along the trajectories of the simulation. The distance information is used to generate a dendrogram revealing the internal structure of the reaction network. The algorithm identifies functional units in two models of different networks: catabolite repression in Escherichia coli and epidermal growth factor (EGF) signal transduction in mammalian cells.
2003
Article
http://edoc.mpg.de/123724
Simulation : Transactions of the Society for Modeling and Simulation, v.79, 703-716 (2003)
en
oai:edoc.mpg.de:1238372004-10-0619:94
Microaerophilic cooperation of reductive and oxidative pathways allows maximal photosynthetic membrane biosynthesis in Rhodospirillum rubrum
Grammel, H.
Gilles, E. D.
Ghosh, R.
expertsonly
The purple nonsulfur bacterium Rhodospirillum rubrum has been employed to study physiological adaptation to limiting oxygen tensions (microaerophilic conditions). R. rubrum produces maximal levels of photosynthetic membranes when grown with both succinate and fructose as carbon sources under microaerophilic conditions in comparison to the level (only about 20% of the maximum) seen in the absence of fructose. Employing a unique partial O₂ pressure (pO₂) control strategy to reliably adjust the oxygen tension to values below 0.5%, we have used bioreactor cultures to investigate the metabolic rationale for this effect. A metabolic profile of the central carbon metabolism of these cultures was obtained by determination of key enzyme activities under microaerophilic as well as aerobic and anaerobic phototrophic conditions. Under aerobic conditions succinate and fructose were consumed simultaneously, whereas oxygen-limiting conditions provoked the preferential breakdown of fructose. Fructose was utilized via the Embden-Meyerhof-Parnas pathway. High levels of pyrophosphate-dependent phosphofructokinase activity were found to be specific for oxygen-limited cultures. No glucose-6-phosphate dehydrogenase activity was detected under any conditions. We demonstrate that NADPH is supplied mainly by the pyridine-nucleotide transhydrogenase under oxygen-limiting conditions. The tricarboxylic acid cycle enzymes are present at significant levels during microaerophilic growth, albeit at lower levels than those seen under fully aerobic growth conditions. Levels of the reductive tricarboxylic acid cycle marker enzyme fumarate reductase were also high under microaerophilic conditions. We propose a model by which the primary "switching" of oxidative and reductive metabolism is performed at the level of the tricarboxylic acid cycle and suggest how this might affect redox signaling and gene expression in R. rubrum
2003
Article
http://edoc.mpg.de/123837
Applied and Environmental Microbiology, v.69, 6577-6586 (2003)
en
oai:edoc.mpg.de:1247852012-03-2819:94
Signal processing and flagellar motor switching during phototaxis of Halobacterium salinarum
Nutsch, T.
Marwan, W.
Oesterhelt, D.
Gilles, E. D.
expertsonly
Prokaryotic taxis, the active search of motile cells for the best environmental conditions, is one of the paradigms for signal transduction. The search algorithm implemented by the cellular biochemistry modulates the probability of switching the rotational direction of the flagellar motor, a nanomachine that propelsprokaryotic cells. On the basis of the well-known biochemical mechanisms of chemotaxis in Escherichia coli, kinetic modeling of the events leading from chemoreceptor activation by ligand binding to themotility response has been performed with great success. In contrast to Escherichia coli, Halobacterium salinarum, in addition, responds to visible light, which is sensed through specific photoreceptors of different wave length sensitivity (phototaxis). Light stimuli of defined intensity and time course can be controlled precisely, which facilitates input-output measurements used for system analysis of the molecular network connecting the sensory receptors to the flagellar motor switch. Here, we analyze the response of halobacterial cells to single and double-pulse light stimuli and present the first kinetic model for prokaryotic cells that couples the signal transduction pathway with the flagellar motor switch. Modeling based on experimental data supports the current biochemical model of halobacterial phototaxis. Moreover, the simulations demonstrate that motor switching occurs through subsequent rate-limiting steps, which are both under sensory control, suggesting that two signals maybe involved in halobacterial phototaxis.
2003
Article
http://edoc.mpg.de/124785
Genome Research, v.13, 2406-2412 (2003)
en
oai:edoc.mpg.de:1248042004-05-2619:94
Towards whole cell in silico models for cellular systems : model set-up and model validation
Kremling, A.
Bettenbrock, K.
Fischer, S.
Ginkel, M.
Sauter, T.
Gilles, E. D.
expertsonly
Based on recent developments for new measurement technologies that enable researches to get quantitative information on intracellular processes, the set-up of very detailed models describing metabolism as well as regulatory networks becomes very popular. However, biochemical networks are rather complex including many feed-forward and feedback loops. In this contribution we propose an interdisciplinary approach including the computerbased set-up of models and strategies to validate the models with apparent experiments. This approach will offer a new way to meaningful models that can be used to make simulations experiments analogous to real laboratory experiments. The approach is applied to the bacterium Escherichia coli: A mathematical model to describe carbon catabolite repression is developed and in part validated. The model is aggregated from functional units describing carbohydrate transport and degradation. All units are members of the crp modulon and are under control of aglobal signal transduction system which calculates the signals that turn on or off gene expression for the specific enzymes. Problems for parameter identification of whole cell models are discussed.
2003
Conference-Paper
http://edoc.mpg.de/124804
urn:ISBN:3-540-40342-6
Benvenuti, L. ; de Santis, A.; Farina, L.: Positive systems : proceedings of the First Multidisciplinary International Symposium on Positive Systems (POST 2003), 92-102 (2003)
en
oai:edoc.mpg.de:1248062004-07-0619:94
A dynamic model library for membrane reactors
Mangold, M.
Ginkel, M.
Gilles, E. D.
expertsonly
The objective of this contribution is to support the generation of dynamic fixed bed reactor and membrane reactor models by a computer aided modelling tool. This class of reactor models has been chosen because fixed bed reactors are an important reactor type in chemical industry, and because membrane reactors are a novel and promising reactor concept that is subject to much research work at the moment. The traditional approach to develop a model library of generic process unit models with adjustable parameters is not chosen here. Such process unit models tend to be complicated and hardly transparent, but nevertheless lack the flexibility necessary to formulate bigger classes of different reactor models. Instead, the elementary units in the library developed here consist of smaller building blocks below the level of process units. The structuring principle used to identify the elements of the library is a general concept that is not restricted to reactor models but also applicable to other chemical processes. The elements of the model library are small modelling entities like sinks or soure terms in the balance equations. Structuring the process models below the level of process units permits the flexible formulation of different models from a limited number of building blocks in the model library. The model developer creates a new process model by choosing model components from the library. He can concentrate on the physical assumptions behind his model and to a big extent is relieved from algebraic manipulations and from mechanical coding work. The model library is implemented in the process modelling tool ProMoT developed at our institute. ProMoT provides a object oriented modelling language and a graphical user interface. It permits the aggregation of building blocks to more highly structured units. Inheritance mechanisms can be used to create modified modelling units from existing ones. At the current stage of development, the model library for fixed bed and membrane reactors contains modules for the definition of dynamic models with one space coordinate. An extension to models with more than one space coordinate should be easily possible. Heterogeneous, homogeneous, and pseudohomogeneous models can be formulated. Modules for convective transport, for different types of diffusive transport (Fick diffusion, Stefan-Maxwell diffusion, surface diffusion), and for combined convective-dispersive transport according to the dusty gas model are available. The use of the model library will be illustrated by the example of the selective oxidation of hydrocarbons. Different types of reactors will be modeled and compared for this type of reaction: the conventional tubular fixed bed reactor, a membrane reactor with a porous non-reactive membrane, and a membrane reactor with a reactive membrane.
2003
Conference-Paper
http://edoc.mpg.de/124806
urn:ISBN:ISBN 84-88233-28-0
4th European Congress of Chemical Engineering (2003)
en
oai:edoc.mpg.de:1250612012-03-3019:94
Modular modeling of cellular systems with ProMoT/Diva
Ginkel, M.
Kremling, A.
Nutsch, T.
Rehner, Robert
Gilles, E. D.
expertsonly
Motivation: Need for software to setup and analyze complex mathematical models for cellular systems in a modular way, that also integrates the experimental environment of the cells. Results: A computer framework is described which allows the building of modularly structured models using an abstract, modular and general modeling methodology. With this methodology, reusable modeling entities are introduced which lead to the development of a modeling library within the modeling tool ProMot. The simulation environment Diva is used for numerical analysis and parameter identification of the models. The simulation environment provides a number of tools and algorithms to simulate and analyze complex biochemical networks. The described tools are the first steps towards an integrated computer-based modeling, simulation and visualization environment.
2003
Article
http://edoc.mpg.de/125061
Bioinformatics, v.19, 1169-1176 (2003)
en
oai:edoc.mpg.de:1947452004-09-1319:94
A coherent kinetic model of sensing and response in halobacterium salinarium phototaxis based on the mechanism of flagellar motor switching
Nutsch, T.
Marwan, W.
Oesterhelt, D.
Gilles, E. D.
expertsonly
Halobacterium salinarium shows a qualitatively different swimming behavior than E. coli, what demands a different mechanism of flagellar motor switching. In this study we postulate general properties of the switching mechanism in Halobacteria, derived from experimental findings and present a detailed model that quantitatively reproduces various different experimental results with the same set of parameters. Even seemingly paradox findings are accomplished by the presented model.
Russian Academy of Sciences, Sibirian Branch, Institute of Cytology and Genetics, Laboratory of Theoretical Genetics
2004
Conference-Paper
http://edoc.mpg.de/194745
Proceedings of the Fourth International Conference on Bioinformatics of Genome Regulation and Structure : BGRS' 2004 : Novosibirsk, Russia : July 25 - 30, 2004, Russian Academy of Sciences, Sibirian Branch, Institute of Cytology and Genetics, Laboratory of Theoretical Genetics, 113-116 (2004)
en
oai:edoc.mpg.de:2075952005-02-0519:94
Mathematical Modeling of Complex Regulatory Networks
Stelling, J.
Gilles, E. D.
expertsonly
Cellular regulation comprises overwhelmingly complex interactions between genes and proteins that ultimately will only be rendered understandable by employing formal approaches. Developing large-scale mathematical models of such systems in an efficient and reliable way, however, requires careful evaluation of structuring principles for the models, of the description of the system dynamics, and of the experimental data basis for adjusting the models to reality. We discuss these three aspects of model development using the example of cell cycle regulation in yeast and suggest that capturing complex dynamic networks is feasible despite incomplete (quantitative) biological knowledge.
2004
Article
http://edoc.mpg.de/207595
IEEE Transactions on Nanobioscience, v.3, 172-179 (2004)
en
oai:edoc.mpg.de:2076232005-02-0719:94
Robustness properties of circadian clock architectures
Stelling, J.
Gilles, E. D.
Doyle III, F. J.
expertsonly
Robustness, a relative insensitivity to perturbations, is a key characteristic of living cells. However, the specific structural characteristics that are responsible for robust performance are not clear, even in genetic circuits of moderate complexity. Formal sensitivity analysis allows the investigation of robustness and fragility properties of mathematical models representing regulatory networks, but it yields only local properties with respect to a particular choice of parameter values. Here, we show that by systematically investigating the parameter space, more global properties linked to network structure can be derived. Our analysis focuses on the genetic oscillator responsible for generating circadian rhythms in Drosophila as a prototypic dynamical cellular system. Analysis of two mathematical models of moderate complexity shows that the tradeoff between robustness and fragility is largely determined by the regulatory structure. Rank-ordered sensitivities, for instance, allow the correct identification of protein phosphorylation as an influential process determining the oscillator's period. Furthermore, sensitivity analysis confirms the theoretical insight that hierarchical control might be important for achieving robustness. The complex feedback structures encountered in vivo, however, do not seem to enhance robustness per se but confer robust precision and adjustability of the clock while avoiding catastrophic failure.
2004
Article
http://edoc.mpg.de/207623
Proceedings of the National Academy of Sciences U.S.A., v.101, 13210-13215 (2004)
en
oai:edoc.mpg.de:2078992005-02-1019:94
Bistability Analyses of a Caspase Activation Model for Receptor-induced Apoptosis
Eissing, T.
Conzelmann, H.
Gilles, E. D.
Allgöwer, F.
Bullinger, E.
Scheurich, P.
expertsonly
Apoptosis is an important physiological process crucially involved in development and homeostasis of multicellular organisms. Although the major signaling pathways have been unraveled, a detailed mechanistic understanding of the complex underlying network remains elusive. We have translated here the current knowledge of the molecular mechanisms of the death-receptor-activated caspase cascade into a mathematical model. A reduction down to the apoptotic core machinery enables the application of analytical mathematical methods to evaluate the system behavior within a wide range of parameters. Using parameter values from the literature, the model reveals an unstable status of survival indicating the need for further control. Based on recent publications we tested one additional regulatory mechanism at the level of initiator caspase activation and demonstrated that the resulting system displays desired characteristics such as bistability. In addition, the results from our model studies allowed us to reconcile the fast kinetics of caspase 3 activation observed at the single cell level with the much slower kinetics found at the level of a cell population.
2004
Article
http://edoc.mpg.de/207899
The Journal of Biological Chemistry, v.279, 36892-36897 (2004)
en
oai:edoc.mpg.de:2079372005-02-1919:94
Analysis of two-component signal transduction by mathematical modeling using the KdpD/KdpE system of Escherichia coli
Kremling, A.
Heermann, R.
Centler, F.
Jung, K.
Gilles, E. D.
expertsonly
A mathematical model for the KdpD/KdpE two-component system is presented and its dynamical behavior is analyzed. KdpD and KdpE regulate expression of the kdpFABC operon encoding the high affinity K+ uptake system KdpFABC of E. coli. The model is validated in a two step procedure: (i) the elements of the signal transduction part are reconstructed in vitro. Experiments with the purified sensor kinase and response regulator in presence or absenceof DNA fragments comprising the response regulator binding-site are performed. (ii) The mRNA and molecule number of KdpFABC are determined in vivo at various extracellular K+ concentrations. Based on the identified parameters for the in vitro system it is shown, that different time hierarchies appear which are used for model reduction. Then the model is transformed in such a way that a singular perturbation problem is formulated. The analysis of the in vivo system shows that the modelcan be separated into two parts (submodels which are called functional units) that are connected only in a unidirectional way. Hereby one submodel represents signal transduction while the second submodel describes the response regulator-DNA binding.
2004
Article
http://edoc.mpg.de/207937
Biosystems, v.78, 23-37 (2004)
en
oai:edoc.mpg.de:2079542005-05-2519:94
Web-based visualisation of the transcriptional control network of Escherichia coli
Sosa, N.
Kremling, A.
Ratsch, E.
Rojas, I.
expertsonly
Transcription is one of the basic processes of gene expression, controlled by a complex network of biochemical reactions. Despite its importance, most work on the visualisation of biochemical networks focuses on the representation of metabolic pathways. The visualisation of the complex networks controlling transcription requires the implementation of a hierarchical approach that allows the display of the structure of each regulatory region with its transcription factors and regulated operons. This paper presents a web-based application for the visualisation of transcriptional control networks. It takes as case study the organism Escherichia coli. The definition of the visual components implemented is mainly based on those proposed by Shen-Orr et al., 2002, slightly extended to visualise complex networks.
2004
Article
http://edoc.mpg.de/207954
In Silico Biology, v.4 (2004)
en
oai:edoc.mpg.de:2079552005-02-1119:94
A benchmark for methods in reverse engineering and model discrimination : problem formulation and solutions
Kremling, A.
Fischer, S.
Gadkar, K.
Doyle, F. J.
Sauter, T.
Bullinger, E.
Allgoewer, F.
Gilles, E. D.
expertsonly
A benchmark problem is described for the reconstruction and analysis of biochemical networks given sampled experimental data. The growth of the organisms is described in a bio-reactor where one substrate is fed into the reactor with a given feed rate and feed concentration. Measurements for some intracellular components are provided representing a small biochemical network. Problems of reverse engineering, parameter estimation, and identifiability are addressed. The contribution mainly focuses on the problem of model discrimination. If two or more model variants describe the available experimental data, a new experiment must be designed to discriminate between the hypothetical models. For the problem presented the feed rate and feed concentration of a bioreactor system are available as control inputs. To verify calculated input profiles an interactive web-site http://www.sysbio.de/projects/benchmark/ is provided. Several solutions based on linear and nonlinear models are discussed.
2004
Article
http://edoc.mpg.de/207955
Genome Research, v.14, 1773-1785 (2004)
en
oai:edoc.mpg.de:2079602005-02-1119:94
Metabolic design based on a coupled gene expression-metabolic network model of tryptophan production in Escherichia coli
Schmid, J. W.
Mauch, K.
Reuss, M.
Gilles, E. D.
Kremling, A.
expertsonly
The presumably high potential of a holistic design approach for complex biochemical reaction networks is exemplified here for the network of tryptophan biosynthesis from glucose, a system whose components have been investigated thoroughly before. A dynamic model that combines the behavior of the trp operon gene expression with the metabolic network of central carbon metabolism and tryptophan biosynthesis is investigated. This model is analyzed in terms of metabolic fluxes, metabolic control, and nonlinear optimization. We compare two models for a wild-type strain and another model for a tryptophan producer. An integrated optimization of the whole network leads to a significant increase in tryptophan production rate for all systems under study. This enhancement is well above the increase that can be achieved by an optimization of subsystems. A constant ratio of control coefficients on tryptophan synthesis rate has been identified for the models regarding or disregarding trp operon expression. Although we found some examples where flux control coefficients even contradict the trends of enzyme activity changes in an optimized profile, flux control can be used as an indication for enzymes that have to be taken into account in optimization.
2004
Article
http://edoc.mpg.de/207960
Metabolic Engineering, v.6, 364-377 (2004)
en
oai:edoc.mpg.de:2079612005-02-1119:94
Workbench zur Modellbildung, Simulation und Analyse zellulärer Systeme
Kremling, A.
Ginkel, M.
Klamt, S.
Gilles, E. D.
expertsonly
Die aktuelle Forschung in der molekularen Genetik und die Erfolge bei der Analyse von Genexpression und Proteinfunktion führen zu einer bisher unerreichten Fülle von Informationen über biologische Phänomene. Werkzeuge, die eine quantitative Beschreibung und Analyse ermöglichen haben dabei eine entscheidende Bedeutung. Der Beitrag stellt Werkzeuge zur Modellerstellung, -simulation und -analyse vor, die bereits für eine Anzahl von biologischen Modellsystemen (Bakterien, Hefen) angewendet wurden. Das Werkzeug ProMoT dient zur automatischen Erstellung der Modellgleichungen, die anschliessend vom Gleichungsloeser Diva numerisch untersucht werden koennen. Eine Analyse der Modellstruktur sowie die Berechnung von stationären Flüssen ist mit dem FluxAnalyzer möglich.
2004
Article
http://edoc.mpg.de/207961
it - Information Technology, v.46, 12-19 (2004)
de
oai:edoc.mpg.de:2079742005-02-1119:94
Reduction of Mathematical Models of Signal Transduction Networks : Simulation-Based Approach Applied to EGF Receptor Signalling
Conzelmann, H.
Saez-Rodriguez, J.
Sauter, T.
Bullinger, E.
Allgöwer, F.
Gilles, E. D.
expertsonly
Biological systems and, in particular, cellular signal transduction pathways are characterized by their high complexity. Mathematical models describing these processes might be of great help to gain qualitative and, mostimportantly, quantitative knowledge about such complex systems. However, a detailed mathematical description of these systems leads to nearly unmanageably large models, especially when combining models of different signaling pathways to study cross-talk phenomena. Therefore, simplification of models becomes very important. Different methods are available for model reduction of biological models. Importantly, most of the common model reduction methods cannot be applied to cellular signal transduction pathways. Using as an example the EGF (Epidermal Growth Factor) signaling pathway, we discuss how quantitative methods like system analysis andsimulation studies can help to suitably reduce models and additionally give new insights into the signal transmission and processing of the cell.
2004
Article
http://edoc.mpg.de/207974
Systems Biology, v.1, 159-169 (2004)
en
oai:edoc.mpg.de:2079762005-02-1919:94
Komplexität in Technik und Biologie
Gilles, E. D.
expertsonly
Viele Veränderungen unseres täglichen Lebens sind dadurch bedingt, dass die Komplexität technischer Prozesse immer weiter wächst. Ein typisches Beispiel ist das Internet, das mit seinen vielfältigen Möglichkeiten die traditionellen Lebensgewohnheiten nachhaltig verändert. Weitere Beispiele sind Verkehrssysteme und hochautomatisierte industrielle Produktions- und Fertigungsprozesse. Deren zunehmende Komplexität stellt natürlich neue und erhöhte Anforderungen an die Ingenieur- und Systemwissenschaften. So sind Methoden und Werkzeuge zu entwickeln, die es gestatten, komplexe technische Prozesse so zu gestalten, dass sie bestimmte strukturelle Eigenschaften aufweisen. Eine besonders wichtige Struktureigenschaft ist die Robustheit. Der Entwurf eines komplexen Systems muss sicherstellen, dass dessen erwünschte Funktionalität möglichst auch dann aufrecht erhalten wird, wenn sowohl Fehlerquellen im Innern als auch Störungen in der Umgebung wirksam werden. Bei der Sicherstellung einer robusten Funktionalität kommt der Sensortechnik, der Signalübertragung und vor allem der Regelung eine zentrale Bedeutung zu.
2004
Article
http://edoc.mpg.de/207976
Akademie-Journal : Magazin der Union der Deutschen Akademien der Wissenschaften, 55-61 (2004)
de
oai:edoc.mpg.de:2079862005-02-1419:94
Robustness of Cellular Functions
Stelling, J.
Sauer, U.
Szallasi, Z.
Doyle III, F. J.
Doyle, J.
expertsonly
Robustness, the ability to maintain performance in the face of perturbations and uncertainty, is a long-recognized key property of living systems. Owing to intimate links to cellular complexity, however, its molecular and cellular basis has only recently begun to be understood. Theoretical approaches to complex engineered systems can provide guidelines for investigating cellular robustness because biology and engineering employ a common set of basic mechanisms in different combinations. Robustness may be a key to understanding cellular complexity, elucidating design principles, and fostering closer interactions between experimentation and theory.
2004
Article
http://edoc.mpg.de/207986
Cell, v.118, 675-685 (2004)
en
oai:edoc.mpg.de:2079942005-02-1419:94
Mathematical models in microbial systems biology
Stelling, J.
expertsonly
Systems biology aims at an understanding of the genotype–phenotype relations brought about by cellular networks. Mathematical models as formal representations are central for handling the associated complexity. Recently, model-based analysis of microorganisms has begun, for instance, to reveal functional modules in metabolic and transcriptional networks, to predict cellular behavior from genome-scale physicochemical constraints, and to suggest novel design principles for well-studied bacterial subsystems such as chemotaxis. Guided by common themes such as modularity, optimality and robustness, iterative model development promises further progress towards a system-level understanding.
2004
Article
http://edoc.mpg.de/207994
Current Opinion in Microbiology, v.7, 513-518 (2004)
en
oai:edoc.mpg.de:2079952005-02-1419:94
Modular Analysis of Signal Transduction Networks
Saez-Rodriguez, J.
Kremling, A.
Conzelmann, H.
Bettenbrock, K.
Gilles, E. D.
expertsonly
This paper introduces compelling problems of biological systems and signaling networks to show how engineering tools can be applied to the analysis of the cellular machinery. The mechanisms that cells have developed to process information are described, and the decomposition of signalling networks into subsystems is discussed. A novel criterion for defining modules based on the absence of retroactivity is also presented, and some simple criteria for the analysis of the resulting units are introduced. Two simple examples, two-component signaling and MAPK cascade, and a more complicated example, EGF signaling, were reviewed. An important point to discuss in model analysis for cellular system is the availability of experimental data that is sufficient to verify the model structure and model parameters.
2004
Article
http://edoc.mpg.de/207995
IEEE Control Systems Magazine, v.24, 35-52 (2004)
en
oai:edoc.mpg.de:2080142005-11-2319:94
Minimal cut sets in biochemical reaction networks
Klamt, S.
Gilles, E. D.
expertsonly
Motivation: Structural studies of metabolic networks yield deeper insight into topology, functionality and capabilities of the metabolisms of different organisms. Here, we address the analysis of potential failure modes in metabolic networks whose occurrence will render the network structurally incapable of performing certain functions. Such studies will help to identify crucial parts in the network structure and to find suitable targets for repressing undesired metabolic functions.
Results: We introduce the concept of minimal cut sets for biochemical networks. A minimal cut set (MCS) is a minimal (irreducible) set of reactions in the network whose inactivation will definitely lead to a failure in certain network functions. We present an algorithm which enables the computation of the MCSs in a given network related to user-defined objective reactions. This algorithm operates on elementary modes. A number of potential applications are outlined, including network verifications, phenotype predictions, assessing structural robustness and fragility, metabolic flux analysis and target identification in drug discovery. Applications are illustrated by the MCSs in the central metabolism of Escherichia coli for growth on different substrates.
2004
Article
http://edoc.mpg.de/208014
urn:ISSN:1367-4803
Bioinformatics, v.20, 226-234 (2004)
en
oai:edoc.mpg.de:2080452005-02-1919:94
Time hierarchies in the Escherichia coli carbohydrate uptake and metabolism
Kremling, A.
Fischer, S.
Sauter, T.
Bettenbrock, K.
Gilles, E. D.
expertsonly
The analysis of metabolic pathways with mathematical models contributes to the better understanding of the behavior of metabolic processes. This paper presents the analysis of a mathematical model for carbohydrate uptake and metabolism in Escherichia coli. It is shown that the dynamic processes cover a broad time span from some milliseconds to several hours. Based on this analysis the fast processes could be described with steady-state characteristic curves. A subsequent robustness analysis of the model parameters shows that the fast part of the system may act as a filter for the slow part of the system; the sensitivities of the fast system are conserved. From these findings it is concluded that the slow part of the system shows some robustness against changes in parameters of the fast subsystem, i.e. if a parameter shows no sensitivity for the fast part of the system, it will also show no sensitivity for the slow part of the system.
2004
Article
http://edoc.mpg.de/208045
Biosystems, v.73, 57-71 (2004)
en
oai:edoc.mpg.de:2080542005-02-1419:94
A model library for membrane reactors implemented in the process modelling tool ProMoT
Mangold, M.
Ginkel, M.
Gilles, E. D.
expertsonly
A model library for spatially distributed membrane reactor models is presented. The structure of the library is guided by a general modelling concept for the systematic formulation of chemical engineering process models. Therefore, the building blocks in the library can also be used to model related processes like fixed bed reactors or adsorption columns. The library is implemented in the process modelling tool (ProMoT), whose key features are presented. The use of the library is illustrated by the example of the selective oxidation of hydrocarbons in two types of membrane reactors.
2004
Article
http://edoc.mpg.de/208054
Computers & Chemical Engineering, v.28, 319-332 (2004)
en
oai:edoc.mpg.de:2083532012-03-0519:94
Computation of elementary modes : a unifying framework and the new binary approach
Gagneur, J.
Klamt, S.
expertsonly
Background: Metabolic pathway analysis has been recognized as a central approach to the structural analysis of metabolic networks. The concept of elementary (flux) modes provides a rigorous formalism to describe and assess pathways and has proven to be valuable for many applications. However, computing elementary modes is a hard computational task. In recent years we assisted in a multiplication of algorithms dedicated to it. We require a summarizing point of view and a continued improvement of the current methods.
Results: We show that computing the set of elementary modes is equivalent to computing the set of extreme rays of a convex cone. This standard mathematical representation provides a unified framework that encompasses the most prominent algorithmic methods that compute elementary modes and allows a clear comparison between them. Taking lessons from this benchmark, we here introduce a new method, the binary approach, which computes the elementary modes as binary patterns of participating reactions from which the respective stoichiometric coefficients can be computed in a post-processing step. We implemented the binary approach in FluxAnalyzer 5.1, a software that is free for academics. The binary approach decreases the memory demand up to 96% without loss of speed giving the most efficient method available for computing elementary modes to date.
Conclusions: The equivalence between elementary modes and extreme ray computations offers opportunities for employing tools from polyhedral computation for metabolic pathway analysis. The new binary approach introduced herein was derived from this general theoretical framework and facilitates the computation of elementary modes in considerably larger networks.
© 2004 Gagneur and Klamt; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
2004
Article
http://edoc.mpg.de/208353
BMC Bioinformatics, v.5 (2004)
en
oai:edoc.mpg.de:2084542005-02-2219:94
Mathematical modeling of signaling cascades : principles and future prospects
Schöberl, B.
Ginkel, M.
Gilles, E. D.
Müller, G.
expertsonly
Birkhäuser
2004
InBook
http://edoc.mpg.de/208454
urn:ISBN:3-7643-6925-6
Function and Regulation of Cellular Systems : Experiments and Models, 73-87 (2004)
en
oai:edoc.mpg.de:2084712005-04-2719:94
Comparison of network-based pathway analysis methods
Papin, J. A.
Stelling, J.
Price, N. D.
Klamt, S.
Schuster, S.
Palsson, B. O.
expertsonly
Network-based definitions of biochemical pathways have emerged in recent years. These pathway definitions insist on the balanced use of a whole network of biochemical reactions. Two such related definitions, elementary modes and extreme pathways, have generated novel hypotheses regarding biochemical network function. The relationship between these two approaches can be illustrated by comparing and contrasting the elementary modes and extreme pathways of previously published metabolic reconstructions of the human red blood cell (RBC) and the human pathogen Helicobacter pylori. Descriptions of network properties generated by using these two approaches in the analysis of realistic metabolic networks need careful interpretation.
2004
Article
http://edoc.mpg.de/208471
Trends in Biotechnology, v.22, 400-405 (2004)
en
oai:edoc.mpg.de:2153452005-08-0819:94
Integral approximation : an approach to reduced models for particulate processes
Motz, S.
Mannal, S.
Gilles, E. D.
expertsonly
In this contribution, a model reduction technique for population balance systems describing particulate processes is presented. This technique is based on integral approximation and allows the derivation of highly accurate moment models. In contrast to other model reduction methods which can be found in literature, this integral approximation technique can be applied for arbitrarily complex phenomena specifications. The applicability of the presented method will be demonstrated for different example processes by comparing the dynamic behavior of the original population balance models with those of the derived reduced models of moments.
2004
Article
http://edoc.mpg.de/215345
info:doi/10.1016/j.ces.2003.08.027
Chemical Engineering Science, v.59, 987-1000 (2004)
en
oai:edoc.mpg.de:2287952005-11-0219:94
Dissecting the Puzzle of Life : Modularization of Signal Transduction Networks
Saez-Rodriguez, J.
Kremling, A.
Gilles, E. D.
expertsonly
Cells have developed complex control networks which allow them to sense and response to changes in their environment. Although they have different underlying biochemical mechanisms, signal transduction units in prokaryotes and eukaryotes fulfill similar tasks, such as switching on or off a required process or amplifying a certain signal.
The growing amount of data available allows the development of increasingly complex models which offer a detailed picture of signaling networks, but the properties of these systems as a whole become difficult to grasp. A sound strategy to untangle this complexity is a decomposition into smaller units or modules. How modules should be delimited, however, remains an unanswered question. We propose that units without retroactive effects might be an interesting
criterion. In this contribution this issue will be explored through several examples, starting with a simple two-component system in E. coli up to the complex Epidermal Growth Factor signaling pathway in human cells.
2005
Article
http://edoc.mpg.de/228795
Computers & Chemical Engineering, v.29, 619-629 (2005)
en
oai:edoc.mpg.de:2399392007-02-1219:94
Generalized concept of minimal cut sets in biochmical networks
Klamt, S.
expertsonly
2006
Article
http://edoc.mpg.de/239939
Biosystems, v.83, 233-247 (2006)
en
oai:edoc.mpg.de:2399402012-04-2319:94
Algorithmic approaches for computing elementary modes in large biochemical reaction networks
Klamt, S.
Gagneur, J.
von Kamp, A.
expertsonly
2005
Article
http://edoc.mpg.de/239940
IEE Proceedings - Systems Biology, v.152, 249-255 (2005)
en
oai:edoc.mpg.de:2399422005-09-0119:94
Mathematical Model of rpoS Regulation in E. coli
Backfisch, T.
Pruteanu, M.
Hengge, R.
Gilles, E. D.
expertsonly
This contribution presents a mathematical model of rpoS regulation in E. coli. It is well known that many stress signals cause increases in cellular σS (RpoS) level and activate σS-dependent responses via reprogramming of RNA polymerase. Despite this general knowlegde about the importance of σS, its regulation and the ways leading to σS activation by specific stress signals are still incompletely understood. Therefore experiments and modeling have to cooperate to yield deeper insight, to evaluate hypotheses and to aid in planning further experiments. The model used here concentrates on regulation of rpoS expression (transcription, translation, proteolysis and competition of sigma subunits for RNA polymerase). The parameters of the model are estimated using in vitro data and steady-state as well as dynamic in vivo measurements. In combination with experimental efforts, the model allows testing of hypotheses and deeper insight into rpoS regulation. Here the importance of sigma factor competition and translational and proteolytic regulation is addressed.
2005
Conference-Paper
http://edoc.mpg.de/239942
FOSBE 2005 (Foundations of Systems Biology in Engineering) : Plenary & Contributed Papers, 239-242 (2005)
en
oai:edoc.mpg.de:2399592006-11-2919:94
A quantitative approach to catabolite repression in Escherichia coli
Bettenbrock, K.
Fischer, S.
Kremling, A.
Jahreis, K.
Sauter, T.
Gilles, E. D.
expertsonly
A dynamic mathematical model was developed to describe the uptake of various carbohydrates (glucose, lactose, glycerol, sucrose and galactose) in E.coli. For validation a number of isogenic strains with defined mutations were used. By considering metabolic reactions as well as signal transduction processes influencing the relevant pathways, we were able to describe quantitatively the phenomenon of catabolite repression in E.coli. We verified model predictions by measuring time courses of several extra- and intracellular components such as glycolytic intermediates, EIIA^Crr phosphorylation level, both LacZ and PtsG concentrations and total cAMP concentrations under various growth conditions. The entire database consists of 18 experiments performed with 9 different strains. The model describes the expression of 17 key enzymes, 38 enzymatic reactions and the dynamic behavior of more than 50 metabolites. The different phenomena effecting the EIIA^Crr phosphorylation level, the key regulation molecule for inducer exclusion and catabolite repression in enteric bacteria, can now be explained quantitatively.
2006
Article
http://edoc.mpg.de/239959
Journal of Biological Chemistry, v.281, 2578-2584 (2006)
en
oai:edoc.mpg.de:2399662012-03-0519:94
A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks
Conzelmann, H.
Saez-Rodriguez, J.
Sauter, T.
Kholodenko, B. N.
Gilles, E. D.
expertsonly
2006
Article
http://edoc.mpg.de/239966
BMC Bioinformatics, v.7 (2006)
en
oai:edoc.mpg.de:2399842006-05-0319:94
Metabolic networks : Biology meets engineering sciences
Kremling, A.
Stelling, J.
Bettenbrock, K.
Fischer, S.
Gilles, E. D.
expertsonly
A hallmark of systems biology is the interdisciplinary approach to the complexity of biological systems, in which mathematical modeling constitutes an important part. Here, we use the example of sugar metabolism in the simple bacterium Escherichia coli and its associated control to illustrate the process of model development. Even for this well--characterized biological system, a close interaction between experimentation and theoretical analysis revealed novel, unexpected features. Additionally, the example shows how concepts from engineering sciences can facilitate the formal investigation of biological networks. More generally, we argue that analogies between complex biological and technical systems such as modular structures and common design principles provide crystallization points for fruitful research in both domains.
Springer
2005
InBook
http://edoc.mpg.de/239984
urn:ISBN:3-540-22968-X
Systems Biology : Definitions and Perspectives, 215-234 (2005)
en
oai:edoc.mpg.de:2399872005-11-0319:94
Domain-oriented and modular approaches to the reduction of mathematical models of signaling networks
Saez-Rodriguez, J.
Conzelmann, H.
Sauter, T.
Kholodenko, B. N.
Gilles, E. D.
expertsonly
A rigorous, detailed description of signaling networks gives rise to huge models, while an a priori simplified model relies on assumptions difficult to prove. Therefore, models which are manageable, yet retain the essential properties of the real network, are desirable. Herein, we first describe a method that addresses the combinatorial explosion of the number of states due to the ability of proteins to bind multiple partners via different domains. We show how a linear state transformation together with the application of the system-theoretical concept of observability allow a dramatic reduction of the number of states to be considered. Secondly, we present an approach for a further reduction o the models, based on a decomposition of the model into modules. The resulting subunits are analyzed via simulation studies, leading to the identification of less complex non-linear models showing approximately the same input/output behavior, which can replace the complex modules in the whole model.
Logos-Verlag
2005
Conference-Paper
http://edoc.mpg.de/239987
urn:ISBN:3-8325-1018-4
Kummer, U.; Pahle, J.; Surovtsova, I.; Zobeley, J.: 4th Workshop on Computation of Biochemical Pathways and Genetic Networks : a BioSim Event : Proceedings, Logos-Verlag, 13-20 (2005)
en
oai:edoc.mpg.de:2448802006-05-0319:94
Databases for Systems Biology
Eils, J.
Lawerenz, C.
Astrahantseff, K.
Ginkel, M.
Eils, R.
expertsonly
The ultimate goal of researchers in the interdisciplinary field of systems biology is to solve biological problems at the level of an entire system. Achieving this goal requires supporting the efforts of experimental biologists and computational modelers. Optimally, the phases of planning, actual experimentation, and data analysis (as well as model development, testing, and validation) would all be supported by one database solution. There is currently no integrative source for all information required in a computer-generated model of a biological system, and no system capable of providing support for all three phases of a systems biology endeavor. We present the concept of an integrative database for systems biology that functions as a data warehouse system and supports all three phases of a systems biology project.
This database system consists of three modules with different data models supporting the particular requirements of utilizing the three general types of data required: experimental data, components, and reactions of biological systems and mathematical models. The model and experiment modules are linked through the component/reaction module, eliminating the need to store complete information about any one entity more than once in the database. Complete functional models and simulations of particular interest are stored as SBML (Systems Biology Markup Language) files and linked to all necessary information within the database. This combination of modules tailored for dealing with the different data types and the interaction of these modules via links will meet the needs of researchers in the area of systems biology.
Elsevier
2005
InBook
http://edoc.mpg.de/244880
urn:ISBN:0-12-088786-X
Computational Systems Biology, 15-38 (2005)
en
oai:edoc.mpg.de:2514152012-03-0519:94
A methodology for the structural and functional analysis of signaling and regulatory networks
Klamt, S.
Saez-Rodriguez, J.
Lindquist, J.
Simeoni, L.
Gilles, E. D.
expertsonly
2006
Article
http://edoc.mpg.de/251415
BMC Bioinformatics, v.7 (2006)
en
oai:edoc.mpg.de:2869882013-02-0819:94
Signal transduction and regulation in bacteria
Gilles, E. D.
expertsonly
2006
Article
http://edoc.mpg.de/286988
Computers and Chemical Engineering, v.30, 1687-1699 (2006)
en
oai:edoc.mpg.de:2882952012-11-1219:94
The galactose switch in Kluyveromyces lactis depends on nuclear competition between Gal4 and Gal1 for Gal80 binding
Anders, A.
Lilie, H.
Franke, K.
Kapp, L.
Stelling, J.
Gilles, E. D.
Breunig, K. D.
expertsonly
2006
Article
http://edoc.mpg.de/288295
The Journal of Biological Chemistry, v.281, 29337-29348 (2006)
en
oai:edoc.mpg.de:2928702012-03-0619:94
Visual set-up of logical models of signaling and regulatory networks with ProMoT
Saez-Rodriguez, J.
Mirschel, S.
Hemenway, R.
Klamt, S.
Gilles, E. D.
Ginkel, M.
expertsonly
Background: The analysis of biochemical networks using a logical (Boolean) description is an important approach in Systems Biology. Recently, new methods have been proposed to analyze large signaling and regulatory networks using this formalism. Even though there is a large number of tools to set up models describing biological networks using a biochemical (kinetic) formalism, however, they do not support logical models.
Results: Herein we present a flexible framework for setting up large logical models in a visual manner with the software tool ProMoT. An easily extendible library, ProMoT's inherent modularity and object-oriented concept as well as adaptive visualization techniques provide a versatile environment. Both the graphical and the textual description of the logical model can be exported to different formats.
Conclusion: New features of ProMoT facilitate an efficient set-up of large Boolean models of biochemical interaction networks. The modeling environment is flexible; it can easily be adapted to specific requirements, and new extensions can be introduced. ProMoT is freely available from http://www.mpi-magdeburg.mpg.de/projects/promot/.
2006
Article
http://edoc.mpg.de/292870
BMC Bioinformatics, v.7 (2006)
en
oai:edoc.mpg.de:2938712012-03-0619:94
Structural and functional analysis of cellular networks with CellNetAnalyzer
Klamt, S.
Saez-Rodriguez, J.
Gilles, E. D.
expertsonly
Background
Mathematical modelling of cellular networks is an integral part of Systems Biology and requires appropriate software tools. An important class of methods in Systems Biology deals with structural or topological (parameter-free) analysis of cellular networks. So far, software tools providing such methods for both mass-flow (metabolic) as well as signal-flow (signalling and regulatory) networks are lacking.
Results
Herein we introduce CellNetAnalyzer, a toolbox for MATLAB facilitating, in an interactive and visual manner, a comprehensive structural analysis of metabolic, signalling and regulatory networks. The particular strengths of CellNetAnalyzer are methods for functional network analysis, i.e. for characterising functional states, for detecting functional dependencies, for identifying intervention strategies, or for giving qualitative predictions on the effects of perturbations. CellNetAnalyzer extends its predecessor FluxAnalyzer (originally developed for metabolic network and pathway analysis) by a new modelling framework for examining signal-flow networks. Two of the novel methods implemented in CellNetAnalyzer are discussed in more detail regarding algorithmic issues and applications: the computation and analysis (i) of shortest positive and shortest negative paths and circuits in interaction graphs and (ii) of minimal intervention sets in logical networks.
Conclusions
CellNetAnalyzer provides a single suite to perform structural and qualitative analysis of both mass-flow- and signal-flow-based cellular networks in a user-friendly environment. It provides a large toolbox with various, partially unique, functions and algorithms for functional network analysis. CellNetAnalyzer is freely available for academic use.
2007
Article
http://edoc.mpg.de/293871
BMC Systems Biology, v.1 (2007)
en
oai:edoc.mpg.de:3189302007-08-0719:94
Systems biology : An engineering perspective
Kremling, A.
Saez-Rodriguez, J.
expertsonly
2007
Article
http://edoc.mpg.de/318930
Journal of Biotechnology, v.129, 329-351 (2007)
en
oai:edoc.mpg.de:3189332008-03-1719:94
Comment on mathematical models which describe transcription and calculate the relationship between mRNA and protein expression ratio
Kremling, A.
expertsonly
2007
Article
http://edoc.mpg.de/318933
Biotechnology and Bioengineering, v.96, 815-819 (2007)
en
oai:edoc.mpg.de:3208832012-03-2619:94
Correlation between growth rates, EIIACrr phosphorylation, and intracellular cAMP levels in Escherichia coli K-12
Bettenbrock, K.
Sauter, T.
Jahreis, K.
Kremling, A.
Lengeler, J. W.
Gilles, E. D.
expertsonly
In Escherichia coli K-12, components of the phosphoenolpyruvate-dependent phosphotransferase systems (PTSs) represent a signal transduction system involved in the global control of carbon catabolism through inducer exclusion, mediated by EIIACrr (=EIIAGlc), and catabolite repression, mediated by the cAMP∙CRP global regulator. We measured, in a systematic way, the relation between cellular growth rates and the key parameters of catabolite repression, i.e. the EIIACrr~P level and the cAMP levels, using in vitro and in vivo assays. Different growth rates were obtained by using either various carbon sources, or by growing the cells with limited concentrations of glucose, sucrose, and mannitol, in continuous bioreactor experiments. The ratio of EIIACrr to EIIACrr~P and the intracellular cAMP concentrations, deduced from the activity of a cAMP.CRP-dependent promoter, correlated well with specific growth rates between 0.3 h-1 and 0.7 h-1, corresponding to generation times of about 138 and 60 min, respectively. Below and above this range, these parameters were increasingly uncoupled from the growth rate, which perhaps indicates an increasing role executed by other global control systems, in particular the stringent-relaxed response system.
2007
Article
http://edoc.mpg.de/320883
Journal of Bacteriology, v.189, 6891-6900 (2007)
en
oai:edoc.mpg.de:3208862008-01-1619:94
Reaction Rate of Small Diffusing Molecules on a Cylindrical Membrane
Straube, R.
Ward, M. J.
Falcke, M.
expertsonly
Biomembranes consist of a lipid bi-layer into which proteins are embedded to fulfill numerous tasks in localized regions of the membrane. Often, the proteins have to reach these regions by simple diffusion. Motivated by the observation that IP3 receptor channels (IP3R) form clusters on the surface of the endoplasmic reticulum (ER) during ATP-induced calcium release, the reaction rate of small diffusing molecules on a cylindrical membrane is calculated based on the Smoluchowski approach. In this way, the cylindrical topology of the tubular ER is explicitly taken into account. The problem can be reduced to the solution of the diffusion equation on a finite cylindrical surface containing a small absorbing hole. The solution is constructed by matching appropriate ‘inner’ and ‘outer’ asymptotic expansions. The asymptotic results are compared with those from numerical simulations and excellent agreement is obtained. For realistic parameter sets, we find reaction rates in the range of experimentally measured clustering rates of IP3R. This supports the idea that clusters are formed by a purely diffusion limited process.
2007
Article
http://edoc.mpg.de/320886
info:doi/10.1007/s10955-007-9371-4
Journal of Statistical Physics, v.129, 377-405 (2007)
en
oai:edoc.mpg.de:3209052008-01-1619:94
Reversible Clustering under the influence of a periodically modulated binding rate
Straube, R.
Falcke, M.
expertsonly
We study cluster-cluster aggregation and fragmentation with a periodically modulated binding rate. Using the Smoluchowski mean-field equations, we derive exact solutions for the cluster size distribution for two time courses of the binding rate: (i) harmonic modulations and (ii) on-off switching of the binding rate with dwell times τb and τf. In both cases, the asymptotic cluster size distribution is oscillatory in time. The formation of small-sized clusters is enhanced compared to a constant binding rate below a critical cluster size sc. There is another critical cluster size sp close to which the size distribution becomes quasistationary. We calculate analytically the dependence of the critical points sc and sp on the relevant system parameters for on-off switching of the binding rate. Our results are relevant whenever clustering can be externally controlled.
2007
Article
http://edoc.mpg.de/320905
info:doi/10.1103/PhysRevE.76.010402
Physical Review E, v.76 (2007)
en
oai:edoc.mpg.de:3209322012-03-0519:94
GSMN-TB : a web-based genome-scale network model of Mycobacterium tuberculosis metabolism
Beste, D. J.
Hooper, T.
Stewart, G.
Bonde, B.
Avignone-Rossa, C.
Bushell, M. E.
Wheeler, P.
Klamt, S.
Kierzek, A. M.
McFadden, J.
expertsonly
Background
An impediment to the rational development of novel drugs against tuberculosis (TB) is a general paucity of knowledge concerning the metabolism of Mycobacterium tuberculosis, particularly during infection. Constraint-based modeling provides a novel approach to investigating microbial metabolism but has not yet been applied to genome-scale modeling of M. tuberculosis.
Results
GSMN-TB, a genome-scale metabolic model of M. tuberculosis, was constructed, consisting of 849 unique reactions and 739 metabolites, and involving 726 genes. The model was calibrated by growing Mycobacterium bovis bacille Calmette Guérin in continuous culture and steady-state growth parameters were measured. Flux balance analysis was used to calculate substrate consumption rates, which were shown to correspond closely to experimentally determined values. Predictions of gene essentiality were also made by flux balance analysis simulation and were compared with global mutagenesis data for M. tuberculosis grown in vitro. A prediction accuracy of 78% was achieved. Known drug targets were predicted to be essential by the model. The model demonstrated a potential role for the enzyme isocitrate lyase during the slow growth of mycobacteria, and this hypothesis was experimentally verified. An interactive web-based version of the model is available.
Conclusion
The GSMN-TB model successfully simulated many of the growth properties of M. tuberculosis. The model provides a means to examine the metabolic flexibility of bacteria and predict the phenotype of mutants, and it highlights previously unexplored features of M. tuberculosis metabolism.
© 2007 Beste et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
2007
Article
http://edoc.mpg.de/320932
Genome Biology, v.8 (2007)
en
oai:edoc.mpg.de:3215242011-03-1019:94
Thermodynamically feasible kinetic models of reaction networks
Ederer, M.
Gilles, E. D.
expertsonly
2007
Article
http://edoc.mpg.de/321524
Biophysical Journal, v.92, 1846-1857 (2007)
de
oai:edoc.mpg.de:3221672012-03-0519:94
A logical model provides insights into T cell receptor signaling
Saez-Rodriguez, J.
Simeoni, L.
Lindquist, J.
Hemenway, R.
Bommhardt, U.
Arndt, B.
Haus, U. U.
Weismantel, R.
Gilles, E. D.
Klamt, S.
Schraven, B.
expertsonly
Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. Here, a methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. Our large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies) and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. Finally, we show that the logical model reveals key elements and potential failure modes in network functioning and provides candidates for missing links. In summary, our largescale logical model for T cell activation proved to be a promising in silico tool, and it inspires immunologists to ask new questions. We think that it holds valuable potential in foreseeing the effects of drugs and network modifications.
© 2007 Saez-Rodriguez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
2007
Article
http://edoc.mpg.de/322167
PLoS Computational Biology, v.3 (2007)
en
oai:edoc.mpg.de:3297392012-03-0619:94
Analysis of global control of Escherichia coli carbohydrate uptake
Kremling, A.
Bettenbrock, K.
Gilles, E. D.
expertsonly
Global control influences the regulation of many individual subsystems by superimposed regulator proteins. A prominent example is the control of carbohydrate uptake systems by the transcription factor Crp in Escherichia coli. A detailed understanding of the coordination of the control of individual transporters offers possibilities to explore the potential of microorganisms e.g. in biotechnology.
An o.d.e. based mathematical model is presented that maps a physiological parameter - the specific growth rate - to the sensor of the signal transduction unit, here a component of the bacterial phosphotransferase system (PTS), namely EIIA^Crr. The model describes the relation between the growth rate and the degree of phosphorylation of EIIA^Crr for a number of carbohydrates by a distinctive response curve, that differentiates between PTS transported carbohydrates and non-PTS carbohydrates. With only a small number of kinetic parameters, the model is able to describe a broad range of experimental steady-state and dynamical conditions. With a minor number of kinetic parameters, the model is able to describe a broad range of experimental steady-state and dynamical conditions.
2007
Article
http://edoc.mpg.de/329739
BMC Systems Biology, v.1 (2007)
en
oai:edoc.mpg.de:3312862012-03-0619:94
Host-pathogen systems biology : Logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction
Franke, R.
Mueller, M.
Wundrack, N.
Gilles, E. D.
Klamt, S.
Kaehne, T.
Naumann, M.
expertsonly
Background
The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen Helicobacter pylori can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The H. pylori effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by H. pylori infection, which might be of importance for tumour development
Results
A logical model of HGF and H. pylori induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and H. pylori induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cg1 (PLCg1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in H. pylori infected cells. The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor ag
ainst PLCg1. The in silico predictions for the knockout of two other network components were also verified experimentally.
Conclusions
This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an in silico prediction of a relevant target against pathogen infection.
© 2008 Franke et al; licensee BioMed Central Ltd.
[accessed June 6, 2008]
2008
Article
http://edoc.mpg.de/331286
BMC Systems Biology, v.2 (2008)
en
oai:edoc.mpg.de:3312892012-03-0519:94
Modeling the electron transport chain of purple non-sulfur bacteria
Klamt, S.
Grammel, H.
Straube, R.
Ghosh, R.
Gilles, E. D.
expertsonly
Purple non-sulfur bacteria (Rhodospirillaceae) have been extensively employed for studying principles of photosynthetic and respiratory electron transport phosphorylation and for investigating the regulation of gene expression in response to redox signals. Here, we use mathematical modeling to evaluate the steady-state behavior of the electron transport chain (ETC) in these bacteria under different environmental conditions. Elementary-modes analysis of a stoichiometric ETC model reveals nine operational modes. Most of them represent well-known functional states, however, two modes constitute reverse electron flow under respiratory conditions, which has been barely considered so far. We further present and analyze a kinetic model of the ETC in which rate laws of electron transfer steps are based on redox potential differences. Our model reproduces well-known phenomena of respiratory and photosynthetic operation of the ETC and also provides non-intuitive predictions. As one key result, model simulations demonstrate a stronger reduction of ubiquinone when switching from high-light to low-light conditions. This result is parameter insensitive and supports the hypothesis that the redox state of ubiquinone is a suitable signal for controlling photosynthetic gene expression.
© 2008 EMBO and Nature Publishing Group
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.
2008
Article
http://edoc.mpg.de/331289
Molecular Systems Biology, v.4 (2008)
en
oai:edoc.mpg.de:3370962012-03-0219:94
Profiling of external metabolites during production of hantavirus nucleocapsid protein with recombinant Saccharomyces cerevisiae
Antoniukas, L.
Grammel, H.
Sasnauskas, K.
Reichl, U.
expertsonly
Recombinant strains of Saccharomyces cerevisiae, producing hantavirus Puumala nucleocapsid protein for diagnostics and as a candidate vaccine were analyzed for uptake and excretion of intermediary metabolites during process optimization studies of fed-batch bioreactor cultures. Concentrations of glucose, maltose, galactose, pyruvate, acetaldehyde, ethanol, acetate, succinate and formaldehyde (used as a selection agent) were measured in the culture medium in order to find a metabolite pattern, indicative for the physiological state of the producer culture. When the inducer galactose was employed as a growth substrate, the metabolite profile of recombinant yeast cells was different from those of the non-recombinant original strain which excreted considerable amounts of metabolites with this substrate. In contrast, galactose-induced heterologous gene expression was indicated by the absence of excreted intermediary metabolites, except succinate. A model strain expressing a GFP fusion of hantavirus nucleocapsid protein differed in the excretion of metabolites from strains without GFP. In addition, the influence of alkali ions, employed for pH control is also demonstrated.
© Springer Science+Business Media B.V. 2007
[accessed June 6, 2008]
2008
Article
http://edoc.mpg.de/337096
Biotechnology Letters, v.30, 415-420 (2008)
en
oai:edoc.mpg.de:3452872012-03-0619:94
Reduced modeling of signal transduction - a modular approach
Koschorreck, M.
Conzelmann, H.
Ebert, S.
Ederer, M.
Gilles, E. D.
expertsonly
2007
Article
http://edoc.mpg.de/345287
BMC Bioinformatics, v.8 (2007)
en
oai:edoc.mpg.de:3630122009-03-2319:94
Computing knock-out strategies in metabolic networks
Haus, U.-U.
Klamt, S.
Stephen, T.
expertsonly
Given a metabolic network in terms of its metabolites and reactions, our goal is to efficiently compute the minimal knock-out sets of reactions required to block a given behavior. We describe an algorithm that improves the computation of these knock-out sets when the elementary modes (minimal functional subsystems) of the network are given. We also describe an algorithm that computes both the knock-out sets and the elementary modes containing the blocked reactions directly from the description of the network and whose worst-case computational complexity is better than the algorithms currently in use for these problems. Computational results are included.
Copyright © Mary Ann Liebert, Inc.
[accessed July 1, 2008]
2008
Article
http://edoc.mpg.de/363012
info:doi/10.1089/cmb.2007.0229
Journal of Computational Biology, v.15, 259-268 (2008)
en
oai:edoc.mpg.de:3664332009-05-2019:94
Redox state dynamics of ubiquinone-10 imply cooperative regulation of photosynthetic membrane expression in Rhodospirillum rubrum
Grammel, H.
Ghosh, R.
expertsonly
It is now well-established that for photosynthetic bacteria, the aerobic-to-microaerophilic transition activates the membrane-bound sensor kinase RegB, which subsequently phosphorylates the transcriptional activator RegA, thereby inducing elevated levels of intracellular photosynthetic membranes. The mechanism of RegB activation, in particular the role of ubiquinone-10 is controversial at present. One problem here is that very limited quantitative in vivo data for the response of the ubiquinone redox state to different cultivation conditions exist. Here, we utilize Rhodospirillum rubrum, to study the correlation of the quinone redox state to the expression level of photosynthetic membranes and determine an effective response function directly. Our results show that changes in the photosynthetic membrane levels between 50-95 % of that maximally attainable are associated with only a 2-fold change in the ubiquinol/ubiquinone ratio and are not necessarily proportional to either the total levels of quinone or [NAD(+)+NADH]. There is no correlation between the redox potentials of the quinone and pyridine nucleotide pools. Hill function analysis of the photosynthetic membrane induction in response to the quinone redox state suggests that the induction process is highly cooperative. Our results are probably generally applicable to quinone redox regulation in bacteria.
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
[accessed July 8, 2008]
2008
Article
http://edoc.mpg.de/366433
info:doi/doi:10.1128/JB.00423-08
Journal of Bacteriology, v.190, 4912-4921 (2008)
en
oai:edoc.mpg.de:3664522012-03-0519:94
Mathematical modeling and analysis of insulin clearance in vivo
Koschorreck, M.
Gilles, E. D.
expertsonly
Background:
Analyzing the dynamics of insulin concentration in the blood is necessary for a comprehensive understanding of the effects of insulin in vivo. Insulin removal from the blood has been addressed in many studies. The results are highly variable with respect to insulin clearance and the relative contributions of hepatic and renal insulin degradation.
Results:
We present a dynamic mathematical model of insulin concentration in the blood and of insulin receptor activation in hepatocytes. The model describes renal and hepatic insulin degradation, pancreatic insulin secretion and nonspecific insulin binding in the liver. Hepatic insulin receptor activation by insulin binding, receptor internalization and autophosphorylation is explicitly included in the model. We present a detailed mathematical analysis of insulin degradation and insulin clearance. Stationary model analysis shows that degradation rates, relative contributions of the different tissues to total insulin degradation and insulin clearance highly depend on the insulin concentration.
Conclusions:
This study provides a detailed dynamic model of insulin concentration in the blood and of insulin receptor activation in hepatocytes. Experimental data sets from literature are used for the model validation. We show that essential dynamic and stationary characteristics of insulin degradation are nonlinear and depend on the actual insulin concentration.
© 2008 Koschorreck and Gilles; licensee BioMed Central Ltd.
[accessed July 4, 2008]
2008
Article
http://edoc.mpg.de/366452
BMC Systems Biology, v.2 (2008)
en
oai:edoc.mpg.de:3664692008-07-1819:94
A feed-forward loop guarantees robust behavior in Echerichia coli carbohydrate uptake
Kremling, A.
Bettenbrock, K.
Gilles, E. D.
expertsonly
2008
Article
http://edoc.mpg.de/366469
info:doi/10.1093/bioinformatics/btn010
Bioinformatics, v.24, 704-710 (2008)
en
oai:edoc.mpg.de:3669932012-03-0219:94
Analyse der evolutiven Adaptation am Beispiel einer pyruvat-auxotrophen Escherichia coli-Mutante
Feuer, R.
Ederer, M.
Gilles, E. D.
Sprenger, G. A.
Sawodny, O.
Sauter, T.
expertsonly
Die biotechnische Herstellung von Substanzen mit Hilfe von Mikroorganismen ist ein wirtschaftlich wichtiges Einsatzgebiet der Systembiologie. In diesem Artikel wird ein pyruvat-auxotropher Escherichia coli-Stamm eingesetzt, um durch evolutive Adaptation alternative Stoffwechselwege zum Pyruvat zu aktivieren. Das Ergebnis der Experimente sind pyruvat-prototrophe Stämme, die mit ihren alternativen Stoffwechselwegen als Grundlage für Produktionstämme eingesetzt werden können, um später damit gezielt in diesen Wegen auftretende Zwischenprodukte industriell herzustellen. Mit Hilfe eines einfachen dynamischen Modells wird die evolutive Adaptation im Chemostat untersucht. Es können dabei Einstellregeln für die Zulaufkonzentration und Verdünnungsrate im Bioreaktor zur beschleunigten Gewinnung pyruvat-prototropher Stämme geschlussfolgert werden. Die Flussbilanzanalyse des metabolischen Netzwerkes des pyruvat-auxotrophen Stammes ergibt 20 verschiedene alternative Flussverteilungen. Zur übersichtlichen Darstellung solcher Flussverteilungen wird eine reduzierte Visualisierungsmethode vorgestellt.
The biotechnological production of substances with help of microorganisms is an economically important application of systems biology. In this paper a pyruvate-auxotrophic Escherichia coli-strain is utilized in order to activate alternative pyruvate synthesis pathways via evolutive adaptation. The outcome of the chemostat experiments are pyruvate-prototrophic strains. Due to the activated alternative synthesis pathways, these strains are a basis for future industrial production-strains in order to systematically produce the intermediate products on these pathways. By means of a simple dynamical model of a chemostat, the evolutive adaptation in chemostat mode is studied. Rules to adjust the feeding concentration and the dilution rate of the bioreactor could be obtained in order to accelerate the evolutive adaptation towards a pyruvate-prototrophic strain. A flux balance analysis of the metabolic network of the pyruvate-auxotrophic strain results in 20 different alternative pathways. For a well arranged presentation of those pathways a reduced visualization method is introduced.
© Oldenbourg Wissenschaftsverlag
[accessed July 10, 2008]
2008
Article
http://edoc.mpg.de/366993
Automatisierungstechnik, v.56, 257-268 (2008)
de
ResultSet_9uS1Jb0FXZP_range_100-130