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See detailAnalyse der evolutiven Adaptation am Beispiel einer pyruvat-auxotrophen Escherichia coli-Mutante
Feuer, Ronny; Ederer, Michael; Gilles, Ernst Dieter et al

in Automatisierungstechnik (2008), 56

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 ... [more ▼]

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 pyruvateprototrophic 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. [less ▲]

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See detailCorrelation between growth rates, EIIACrr phosphorylation, and intracellular cyclic AMP levels in Escherichia coli K-12.
Bettenbrock, Katja; Sauter, Thomas UL; Jahreis, Knut et al

in Journal of Bacteriology (2007), 189(19), 6891-900

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 ... [more ▼]

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 phosphoenolpyruvate-dependent protein kinase enzyme IIA(Crr) (EIIA(Crr)) (= EIIA(Glc)) and catabolite repression mediated by the global regulator cyclic AMP (cAMP)-cAMP receptor protein (CRP). We measured in a systematic way the relation between cellular growth rates and the key parameters of catabolite repression, i.e., the phosphorylated EIIA(Crr) (EIIA(Crr) approximately P) level and the cAMP level, 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 EIIA(Crr) to EIIA(Crr) approximately 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. [less ▲]

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See detailMethods for analysis of evolutive adaptation of E. coli
Feuer, Ronny; Ederer, Michael; Trachtmann, Natalie et al

in Proceedings of the SICE Annual Conference, September 17-20, 2007 Kagawa University, Takamatsu City, Japan (2007)

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See detailModeling and Analysis of UVB Influence on IL-1 induced NF-kappaB Signaling
Witt, Johannes; Husser, Sebastian; Kulms, Dagmar et al

in Proceedings of the FOSBE, September 9-12, Stuttgart, Germany (2007)

Enhancement of UVB-induced apoptosis has recently been reported upon co-stimulation of cells with IL-1. The phenomenon has been shown to be NF-kappaB dependent and coincides with a sustained absence of ... [more ▼]

Enhancement of UVB-induced apoptosis has recently been reported upon co-stimulation of cells with IL-1. The phenomenon has been shown to be NF-kappaB dependent and coincides with a sustained absence of the inhibitor of NF-kappaB, IkappaBalpha. The exact mechanisms are the subject of present research. In order to investigate the behavior of IkappaBalpha, a mathematical model for the IL-1 receptor is developed based on ordinary differential equations. It is coupled with an existing NF-kappaB signaling module and parameterized using experimental and literature data. The model provides a more realistic input for the NF-kappaB module and is suitable for fitting the experimental data of IkappaBalpha following IL-1 stimulation. It is used to test and reject the hypothesis that the sustained absence of IkappaBalpha upon IL-1+UVB stimulation is due to an altered internalization behavior of the IL-1 receptor. [less ▲]

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See detailSensitivity analysis of programmed cell death and implications for crosstalk phenomena during Tumor Necrosis Factor stimulation
Eissing, Thomas; Bullinger, Eric; Waldherr, Steffen et al

in Proceedings of IEEE International Conference on Control Applications (CCA), October 4-6, 2006, Technische Universität München, Germany (2006)

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See detailA quantitative approach to catabolite repression in Escherichia coli.
Bettenbrock, Katja; Fischer, Sophia; Kremling, Andreas et al

in Journal of Biological Chemistry (2006), 281(5), 2578-84

A dynamic mathematical model was developed to describe the uptake of various carbohydrates (glucose, lactose, glycerol, sucrose, and galactose) in Escherichia coli. For validation a number of isogenic ... [more ▼]

A dynamic mathematical model was developed to describe the uptake of various carbohydrates (glucose, lactose, glycerol, sucrose, and galactose) in Escherichia 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, EII-ACrr phosphorylation level, both LacZ and PtsG concentrations, and total cAMP concentrations under various growth conditions. The entire data base consists of 18 experiments performed with nine 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 affecting the phosphorylation level of EIIACrr, the key regulation molecule for inducer exclusion and catabolite repression in enteric bacteria, can now be explained quantitatively. [less ▲]

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See detailA domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks.
Conzelmann, Holger; Saez-Rodriguez, Julio; Sauter, Thomas UL et al

in BMC Bioinformatics (2006), 7

BACKGROUND: Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of ... [more ▼]

BACKGROUND: Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of different states generated by feasible molecular species. The number of possible species grows exponentially with the number of different docking sites and can easily reach several millions. Models accounting for this combinatorial variety become impractical for many applications. RESULTS: Our results show that under realistic assumptions on domain interactions, the dynamics of signaling pathways can be exactly described by reduced, hierarchically structured models. The method presented here provides a rigorous way to model a large class of signaling networks using macro-states (macroscopic quantities such as the levels of occupancy of the binding domains) instead of micro-states (concentrations of individual species). The method is described using generic multidomain proteins and is applied to the molecule LAT. CONCLUSION: The presented method is a systematic and powerful tool to derive reduced model structures describing the dynamics of multiprotein complex formation accurately. [less ▲]

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See detailModeling the VPAC2-activated cAMP/PKA signaling pathway: from receptor to circadian clock gene induction.
Hao, Haiping; Zak, Daniel E.; Sauter, Thomas UL et al

in Biophysical Journal (2006), 90(5), 1560-71

Increasing evidence suggests an important role for VPAC2-activated signal transduction pathways in maintaining a synchronized biological clock in the suprachiasmatic nucleus (SCN). Activation of the VPAC2 ... [more ▼]

Increasing evidence suggests an important role for VPAC2-activated signal transduction pathways in maintaining a synchronized biological clock in the suprachiasmatic nucleus (SCN). Activation of the VPAC2 signaling pathway induces per1 gene expression in the SCN and phase-shifts the circadian clock. Mice without the VPAC2 receptor lack an overt, coherent circadian rhythm in clock gene expression, SCN neuron firing rate, and locomotor behavior. Using a systems approach, we have developed a kinetic model integrating VPAC2 signaling mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and leading to induced circadian clock gene expression. We fit the model to experimental data from the literature for cAMP accumulation, PKA activation, cAMP-response element binding protein phosphorylation, and per1 induction. By linking the VPAC2 model to a published circadian clock model, we also simulated clock phase shifts induced by vasoactive intestinal polypeptide (VIP) and matched experimental data for the VIP response. The simulated phase response curve resembled the hamster response to a related neuropeptide, GRP1-27, and light. Simulations using pulses of VIP revealed that the system response is extraordinarily robust to input signal duration, a result with physiologically relevant consequences. Lastly, simulations using varied receptor levels matched literature experimental data from animals overexpressing VPAC2 receptors. [less ▲]

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See detailDetailed Mathematical Modeling of Metabolic and Regulatory Networks
Sauter, Thomas UL; Bullinger, E.

in BIOforum Europe (2004), 02

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See detailReduction of mathematical models of signal transduction networks: simulation-based approach applied to EGF receptor signalling.
Conzelmann, H.; Saez-Rodriguez, J.; Sauter, Thomas UL et al

in Systems biology (2004), 1(1), 159-69

Biological systems and, in particular, cellular signal transduction pathways are characterised by their high complexity. Mathematical models describing these processes might be of great help to gain ... [more ▼]

Biological systems and, in particular, cellular signal transduction pathways are characterised by their high complexity. Mathematical models describing these processes might be of great help to gain qualitative and, most importantly, 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 signalling 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 epidermal growth factor (EGF) signalling pathway, we discuss how quantitative methods like system analysis and simulation studies can help to suitably reduce models and additionally give new insights into the signal transmission and processing of the cell. [less ▲]

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See detailTime hierarchies in the Escherichia coli carbohydrate uptake and metabolism.
Kremling, A.; Fischer, S.; Sauter, Thomas UL et al

in Bio Systems (2004), 73(1), 57-71

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 ... [more ▼]

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. [less ▲]

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See detailModeling and experimental validation of the signal transduction via the Escherichia coli sucrose phospho transferase system.
Sauter, Thomas UL; Gilles, E. D.

in Journal of Biotechnology (2004), 110(2), 181-99

Bacterial signal processing was investigated concerning the sucrose phosphotransferase system (sucrose PTS) in the bacterium Escherichia coli as an example. The about 20 different phosphotransferase ... [more ▼]

Bacterial signal processing was investigated concerning the sucrose phosphotransferase system (sucrose PTS) in the bacterium Escherichia coli as an example. The about 20 different phosphotransferase systems (PTSs) of the cell fulfill besides the transport of various carbohydrates, also the function of one signal processing system. Extra- and intracellular signals are converted within the PTS protein chain to important regulatory signals affecting, e.g. carbon metabolism and chemotaxis. A detailed dynamical model of the sucrose PTS was developed describing transport and signal processing function. It was formulated using a detailed description of complex formation and phosphate transfer between the chain proteins. Model parameters were taken from literature or were identified with own experiments. Simulation studies together with experimental hints showed that the dynamic behavior of phosphate transfer in the PTS runs within 1 s. Therefore a description of steady state characteristics is sufficient for describing the signaling properties of the sucrose PTS. A steady state characteristic field describes the degree of phosphorylation of the PTS protein EIIACrr as a function of the input variables extracellular sucrose concentration and intracellular phosphoenolpyruvate (PEP):pyruvate ratio. The model has been validated with different experiments performed in a CSTR using a sucrose positive E. coli W3110 derivative. A method for determining intracellular metabolite concentrations has been developed. A sample preparation technique using a boiling ethanol buffer solution was successfully applied. The PTS output signal degree of phosphorylation of EIIACrr was also measured. Steady state conditions with varying dilution rate and dissolved oxygen concentration and dynamical variations applying different stimuli to the culture were considered. Pulse, and stop feeding experiments with limiting sucrose concentrations were performed. Simulation and experimental results matched well. The same holds for the expanded sucrose PTS and glycolysis model. [less ▲]

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See detailA benchmark for methods in reverse engineering and model discrimination: problem formulation and solutions.
Kremling, Andreas; Fischer, Sophia; Gadkar, Kapil et al

in Genome Research (2004), 14(9), 1773-85

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 bioreactor in which one ... [more ▼]

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 bioreactor in which 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. [less ▲]

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See detailTowards whole cell "in silico" models for cellular systems: model set-up and model validation
Kremling, A.; Bettenbrock, K.; Fischer, S. et al

in Lecture Notes in Control and Information Sciences: Proceedings of the first multidisciplinary international symposium on Positive Systems (2004)

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See detailDie bakterielle Signalverarbeitung am Beispiel des Sucrose Phosphotransferasesystems in Escherichia coli : Modellierung und experimentelle Überprüfung
Sauter, Thomas UL

Doctoral thesis (2003)

Bacterial signal processing was investigated concerning the sucrose phosphotransferase system (sucrose PTS) in the bacterium Escherichia coli as an example. The about 20 different phosphotransferase ... [more ▼]

Bacterial signal processing was investigated concerning the sucrose phosphotransferase system (sucrose PTS) in the bacterium Escherichia coli as an example. The about 20 different phosphotransferase systems (PTSs) of the cell fulfil besides the transport of various carbohydrates, also the function of one signal processing system. Extra- and intracellular signals are converted within the PTS protein chain to important regulatory signals affecting e.g. carbon metabolism and chemotaxis. A detailed dynamical model of the sucrose PTS was developed describing transport and signal processing function. It was formulated using a detailed description of complex formation and phosphate transfer between the chain proteins. Model parameters were taken from literature or were identified with own experiments. Using a formal algorithm including cluster analysis, PTS and glycolysis could be identified as biological functional units with limited autonomy. Simulation studies together with experimental hints showed that the dynamic behaviour of phosphate transfer in the PTS runs within one second. Therefore a description of steady state characteristics is sufficient for describing the signaling properties of the sucrose PTS. A steady state characteristic field describes the degree of phosphorylation of the PTS protein EIIACrr as a function of the input variables extracellular sucrose concentration and intracellular PEP:pyruvate ratio. The model has been validated with different experiments performed in a CSTR using an sucrose positive Escherichia coli W3110 derivative. A method for determining intracellular metabolite concentrations has been developed. A sample preparation technique using a boiling ethanol buffer solution was successfully applied. The PTS output signal degree of phosphorylation of EIIACrr was also measured. Steady state conditions with varying dilution rate and dissolved oxygen concentration and dynamical variations applying different stimuli to the culture were considered. Pulse, and stop feeding experiments with limiting sucrose concentrations were performed. Simulation and experimental results matched well. The same holds for the expanded sucrose PTS and glycolysis model. [less ▲]

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See detailAn approach for dividing models of biological reaction networks into functional units
Ederer, M.; Sauter, Thomas UL; Bullinger, E. et al

in Simulation (2003), 79

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See detailBiosystems Engineering: Applying methods from systems theory to biological systems
Kremling, A.; Sauter, Thomas UL; Bullinger, E. et al

in Proceedings of the 2nd International Conference on Systems Biology 4.-7.11.2001, Pasadena (2001)

Detailed reference viewed: 74 (0 UL)