References of "Allgöwer, Frank"
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See detailHeterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli
Schliemann, Monica ULiege; Bullinger, Eric ULiege; Borchers, Steffen et al

in BMC Systems Biology (2011), 5

Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate ... [more ▼]

Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. Results This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. Conclusions Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity. [less ▲]

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See detailComparative assessment of old and new suboptimal control schemes on three example processes
Journee, Michel ULiege; Schweickhardt, Tobias; Allgöwer, Frank

in International Journal of Tomography and Statistics (2007), 6(S07), 45--50

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See detailSteady state and (bi-) stability evaluation of simple protease signalling networks
Eissing, Thomas; Waldherr, Steffen; Allgöwer, Frank et al

in Biosystems (2007), 90(3), 591-601

Signal transduction networks are complex, as are their mathematical models. Gaining a deeper understanding requires a system analysis. Important aspects are the number, location and stability of steady ... [more ▼]

Signal transduction networks are complex, as are their mathematical models. Gaining a deeper understanding requires a system analysis. Important aspects are the number, location and stability of steady states. In particular, bistability has been recognised as an important feature to achieve molecular switching. This paper compares different model structures and analysis methods particularly useful for bistability analysis. The biological applications include proteolytic cascades as, for example, encountered in the apoptotic signalling pathway or in the blood clotting system. We compare three model structures containing zero-order, inhibitor and cooperative ultrasensitive reactions, all known to achieve bistability. The combination of phase plane and bifurcation analysis provides an illustrative and comprehensive understanding of how bistability can be achieved and indicates how robust this behaviour is. Experimentally, some so-called "inactive" components were shown to have a residual activity. This has been mostly ignored in mathematical models. Our analysis reveals that bistability is only mildly affected in the case of zero-order or inhibitor ultrasensitivity. However, the case where bistability is achieved by cooperative ultrasensitivity is severely affected by this perturbation. (c) 2007 Elsevier Ireland Ltd. All rights reserved. [less ▲]

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See detailResponse to bistability in apoptosis: Roles of Bax, Bcl-2, and mitochondrial permeability transition pores
Eissing, Thomas; Waldherr, Steffen; Allgöwer, Frank et al

in Biophysical Journal (2007), 92(9), 3332-3334

Recently, a mathematical model of the mitochondrial apoptotic pathway was proposed. In that study, the robustness of different simplified signaling models with respect to parameter changes was also ... [more ▼]

Recently, a mathematical model of the mitochondrial apoptotic pathway was proposed. In that study, the robustness of different simplified signaling models with respect to parameter changes was also investigated. It was found that bistability achieved via cooperative ultrasensitivity is ‘‘much more robust’’ than other mechanisms such as inhibitor ultrasensitivity. We reinvestigate this interesting finding to reveal that it does not hold in such generality. Our results indicate that mechanisms other than cooperative ultrasensitivity, such as inhibitor ultrasensitivity, can confer a similar robust bistable performance. Thereby, these findings are not restricted to apoptosis signaling, but relevant to bistable signaling in general. In addition, example calculations indicate the potential practical relevance of inhibitor ultrasensitivity for generating robustness in apoptosis signaling. [less ▲]

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See detailResults towards identifiability properties of biochemical reaction networks
Farina, Marcello; Findeisen, Rolf; Bullinger, Eric ULiege et al

in Proc. of the 45th IEEE Conference on Decision and Control, San Diego, USA (2006, December)

In this paper we consider the question of parameter identifiability for biochemical reaction networks, as typically encountered in systems biology. Specifically, we are interested in deriving conditions ... [more ▼]

In this paper we consider the question of parameter identifiability for biochemical reaction networks, as typically encountered in systems biology. Specifically, we are interested in deriving conditions on the biochemical reaction network and on the measured outputs that guarantee identifiability of the parameters. Taking the specific system structure of biochemical reaction networks into account, we derive sufficient conditions for local parameter identifiability based on a suitable system expansion which does not any more directly depend on the parameters. Rather, as shown, the problem of identifiability can be recast as the question of observability of the (parameter free) expanded system. The conditions derived are exemplified considering a simple example [less ▲]

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See detailComparative assessment of old and new suboptimal control schemes on three example processes
Journee, Michel ULiege; Schweickhardt, T.; Allgöwer, Frank

in Proceedings of the 13th IFAC Workshop on Control Applications of Optimisation, Paris (2006)

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See detailSensitivity analysis of programmed cell death and implications for crosstalk phenomena during tumor necrosis factor stimulation
Eissing, Thomas; Waldherr, Steffen; Gondro, Cedric et al

in Proc. of the 2006 IEEE Conference on Control Applications (2006)

Different methods for analyzing the sensitivity of the direct signal transduction pathway of receptor-induced apoptosis to parameter changes are presented. Apoptosis is a form of programmed cell death ... [more ▼]

Different methods for analyzing the sensitivity of the direct signal transduction pathway of receptor-induced apoptosis to parameter changes are presented. Apoptosis is a form of programmed cell death, removing unwanted cells within multicellular organisms to maintain a proper balance between cell reproduction and death. The results indicate the importance of controlling activated caspases by direct inhibition to prevent apoptosis. A misregulation of IAP molecules, one of the main inhibitors, appears to be especially critical. The results indicate how an increased production of this molecule promotes survival and might promote cancer progression, while a reduced degradation might not, thereby providing insight of potential pharmaceutical relevance and also stimulating experimental verification. The different engineering methods applied, nicely complement each other to provide valuable insight into this important process. Because IAPs, among others, are also an important connection to other signaling pathways, the results will enable a more efficient extension of the current model. This is outlined at the example of tumor necrosis factor induced signaling pathways [less ▲]

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See detailRobustness properties of apoptosis models with respect to parameter variations and intrinsic noise
Eißing, Thomas; Allgöwer, Frank; Bullinger, Eric ULiege

in IEE Proceedings. Systems Biology (2005), 152(4), 221228

Analyses of different robustness aspects for models of the direct signal transduction pathway of receptor-induced apoptosis is presented. Apoptosis is a form of programmed cell death, removing unwanted ... [more ▼]

Analyses of different robustness aspects for models of the direct signal transduction pathway of receptor-induced apoptosis is presented. Apoptosis is a form of programmed cell death, removing unwanted cells within multicellular organisms to maintain a proper balance between cell reproduction and death. Its signalling pathway includes an activation feedback loop that generates bistable behaviour, where the two steady states can be seen as `life' and `death'. Inherent robustness, widely recognised in biological systems, is of major importance in apoptosis signalling, as it guarantees the same cell fate for similar conditions. First, the influence of the stochastic nature of reactions indicating a role for inhibition reactions as noise filters and justifying a deterministic approach in the further analyses is evaluated. Second, the robustness of the bistable threshold with respect to parameter changes is evaluated by statistical methods, showing the need to balance both the forward and the back part of the activation loop. These analyses can also discriminate between the models favouring the model consistent with novel biological findings. The parameter robustness analyses are also applicable to other signal transduction networks, as several have been shown to display bistable behaviour. These methods therefore have a range of possible applications in systems biology not only to measure robustness, but also for model discrimination. [less ▲]

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See detailAdaptive lambda-tracking for nonlinear higher relative degree systems
Bullinger, Eric ULiege; Allgöwer, Frank

in Automatica (2005), 41(7), 1191-1200

This paper proposes a relatively simple adaptive controller for nonlinear systems with higher relative degree. The controller achieves lambda-tracking for a large class of nonlinear systems, i.e. it ... [more ▼]

This paper proposes a relatively simple adaptive controller for nonlinear systems with higher relative degree. The controller achieves lambda-tracking for a large class of nonlinear systems, i.e. it asymptotically stabilizes the system up to an error of at most lambda which is chosen by the user. Only little information on the system is needed in the sense that no model needs to be known for the controller design, but only structural information like the relative degree and a lower bound on the positive high-frequency gain. The zero-dynamics does not need to be asymptotically stable, boundedness is sufficient. The controller consists of a high-gain observer, a high-gain observer-state feedback and a common adaptation of both high-gain parameters. The adaptation increases the gains of the observer and the state-feedback whenever the control objective, namely that the tracking error is of magnitude not larger than lambda, is not attained. It is proved that the controller's adaptation converges and the control objective is achieved at least asymptotically. (c) 2005 Elsevier Ltd. All rights reserved. [less ▲]

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See detailIntegration und Interaktion: Möglichkeiten des Einsatzes von Notebooks und Internet in der regelungstechnischen Lehre
Schumm, Peter; Bullinger, Eric ULiege; Schweickhardt, Tobias et al

in at - Automatisierungstechnik (2004), vol.52, no.2

Since a few years high-schools are testing the use of notebooks for teaching purposes and already use them quite successfully. A new approach is to use them also for academic education. In the first part ... [more ▼]

Since a few years high-schools are testing the use of notebooks for teaching purposes and already use them quite successfully. A new approach is to use them also for academic education. In the first part of this article an overview will be given about the concepts of the BMBF-sponsored project Notebook University. The second part describes how notebooks are used in the e-learning project to support the teaching of control theory [less ▲]

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See detailBistability analyses of a caspase activation model for receptor-induced apoptosis
Eissing, Thomas; Conzelmann, Holger; Gilles, Ernst Dieter et al

in Journal of Biological Chemistry (2004), 279(35), 36892-36897

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 ... [more ▼]

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. [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), 1773-1785

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 oil 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 oil linear and nonlinear models are discussed. [less ▲]

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

in IEE Proceedings. Systems Biology (2004), 1(1), 159-169

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 detailAn approach for dividing models of biological reaction networks into functional units
Ederer, Michael; Sauter, Thomas; Bullinger, Eric ULiege et al

in Simulation: Trans. Society for Modeling and Simulation International (2003), 79(12), 703-716

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 ... [more ▼]

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. [less ▲]

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See detailA note on stability, robustness and performance of output feedback nonlinear model predictive control
Imsland, Lars; Findeisen, Rolf; Bullinger, Eric ULiege et al

in Journal of Process Control (2003), 13(7), 633-644

In recent years. nonlinear model predictive control (NMPC) schemes have been derived that guarantee stability of the closed loop under the assumption of full state information. However, only limited ... [more ▼]

In recent years. nonlinear model predictive control (NMPC) schemes have been derived that guarantee stability of the closed loop under the assumption of full state information. However, only limited advances have been made with respect to output feedback in the framework of nonlinear predictive control. This paper combines stabilizing instantaneous state feedback NMPC schemes with high-gain observers to achieve output feedback stabilization. For a uniformly observable MIMO system class it is shown that the resulting closed loop is asymptotically stable. Furthermore, the output feedback NMPC scheme recovers the performance of the state feedback in the sense that the region of attraction and the trajectories of the state feedback scheme can be recovered to any degree of accuracy for large enough observer gains, thus leading to semi-regional results. Additionally, it is shown that the output feedback controller is robust with respect to static sector bounded nonlinear input uncertainties. (C) 2003 Elsevier Ltd. All rights reserved. [less ▲]

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See detailDer Einsatz neuer Medien in der regelungstechnischen Ausbildung
Schumm, Peter; Bullinger, Eric ULiege; Schweickhardt, Tobias et al

in Proceedings of GMA-Kongress (2003)

This paper reviews the use of new media for teaching of control engineering.

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See detailSome further results on adaptive lambda-tracking for linear systems with high relative degree
Bullinger, Eric ULiege; Findeisen, Rolf; Kraus, Frantisek et al

in Proc. of the 2000 American Control Conf. (2000)

Several adaptive controllers which universally achieve the so-called lambda -tracking have been proposed in the literature. From a practical point of view, previous results are not usable for systems with ... [more ▼]

Several adaptive controllers which universally achieve the so-called lambda -tracking have been proposed in the literature. From a practical point of view, previous results are not usable for systems with a high relative degree because of bad numerical conditioning. The paper presents a modified approach overcoming this numerical problem while achieving the same robust stability properties. Stability and convergence of the adaptation is proven for tracking a large class of reference trajectories. The design of the controller is very simple and intuitive, only few parameters have to be tuned and little structural information about the system to be controlled is needed [less ▲]

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See detailPiecewise constant high-gain adaptive lambda-tracking for higher relative degree linear systems
Bullinger, Eric ULiege; Ilchmann, chim; Allgöwer, Frank

in Proceedings of the 14th IFAC World Congress (1999), 5

In this paper we present an adaptive high-gain observer-based controller for linear, minimum-phase systems with known relative degree larger than one and known sign of the high-frequency gain. The ... [more ▼]

In this paper we present an adaptive high-gain observer-based controller for linear, minimum-phase systems with known relative degree larger than one and known sign of the high-frequency gain. The adaptation scheme does not use any identification mechanism and is universal in the sense that it is independent of the system the controller is designed for. We prove that for any bounded and sufficiently smooth reference signal the modulus of the tracking error becomes smaller than an arbitrary small but fixed error bound lambda if t tends to infinity. All states of the nonlinear closed-loop system remain bounded [less ▲]

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See detailA simple adaptive observer for nonlinear systems
Bullinger, Eric ULiege; Ilchmann, Achim; Allgöwer, Frank

in IFAC Nonlinear Control Systems Design, NOLCOS98 (1998)

We present a high-gain observer for nonlinear uniformly observable SISO systems for which the high-gain parameter is determined adaptively online. The adaptation scheme is simple and universal in the ... [more ▼]

We present a high-gain observer for nonlinear uniformly observable SISO systems for which the high-gain parameter is determined adaptively online. The adaptation scheme is simple and universal in the sense that it is independent of the system the observer is designed for. Unlike in an earlier approach, the gain is adapted continuously in the present paper. This further simplifies the adaptation law and also leads to lower values of the high-gain parameter. We prove that the observer output error becomes smaller than a user specified bound for large times and that the adaptation converges. The observer is applied to a generic bioreactor [less ▲]

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See detailAn adaptive high-gain observer for nonlinear systems
Bullinger, Eric ULiege; Allgöwer, Frank

in 36th IEEE Conf. on Decision and Control (1997)

In this paper we present a high-gain observer for a general class of nonlinear SISO systems for which the high-gain parameter is determined on-line in an adaptive fashion. The adaptation scheme is simple ... [more ▼]

In this paper we present a high-gain observer for a general class of nonlinear SISO systems for which the high-gain parameter is determined on-line in an adaptive fashion. The adaptation scheme is simple and universal in the sense that it is independent of the system the observer is designed for. We prove that the observer output error becomes smaller than a user specified bound for large times and that the adaptation converges. The assumptions required for the adaptive high-gain observer are the same as for the nonadaptive high-gain observer, namely that the system is uniformly observable for any u(t) [less ▲]

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