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Olaf Wolkenhauer

About Olaf Wolkenhauer:

SEEK ID: https://fairdomhub.org/people/10

Location: Germany

Expertise: Data analysis Mathematical modelling Bioinformatics Systems biology, dynamics of biological networks, dynamics and control of biological networks

Tools: quantitative western blot analysis, Stochastic models, quantitative western blot analyses, differential algebraic equations, stimulus response experiments, Mathematica, Matlab, ODE, Computational and theoretical biology

ORCID: Not specified

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INCOME

The project "INtegrative COllaborative modeling in systems MEdicine" aims at connecting different heterogenous datasets and individual models within systems medicine.

Programme: e:med

Public web page: Not specified

BESTER

Bioprocesses for the optimized, integrated production of butyl esters from sustainable resources (BESTER)

Industrial Biotechnology is a key enabling technology to produce a plethora of different bio-based products from sustainable resources and a driver for developing the bio-based economy in Europe. Systems biology and Synthetic biology are recent additions to the biotechnology toolbox that in interplay with bioprocess and chemical process technology can help developing competitive industrial
...

Programme: Era CoBioTech

Public web page: https://www.cobiotech.eu/call-information

iRhythmics

The project addresses the generation and establishment of programmed pacemaker cells for an in vitro drug testing possibility to perform predictive tests. This may lead to an improved treatment of cardiac arrhythmias or an accurate identification of potential drug molecules at a very early stage of development. Important benefits will arise in verifying the safety of a wide variety of medicines while reducing animal testing.

This project is funded by the European Social Fund (ESF) program of the
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Programme: Independent Projects

Public web page: Not specified

SYSTERACT

There is an urgent need for novel antibiotics to fight life-threatening infections and to counteract the increasing problem of propagating antibiotic resistance. Recently, new molecular genetic and biochemical tools have provided insight into the enormous unexploited genetic pool of environmental microbial biodiversity for new antibiotic compounds. New tools for more efficiently lifting this hidden treasure are needed to strengthen competitiveness of European industry, as well as for a cost-saving
...

Programme: ERASysAPP

Public web page: https://www.erasysapp.eu/calls/2nd-call/systeract

HUMET Startup

Aim of HUMET Startup Project is to make an inventory of expertise, research goals, resources etc. of the HUMET Coaliytion of the Willing.

Programme: HUMET

Public web page: Not specified

COSMIC

Systems Biology of Clostridium acetobutylicum - a possible answer to dwindling crude oil reserves

Programme: SysMO

Public web page: http://www.sysmo.net/index.php?index=54

BaCell-SysMO

BaCell-SysMO 2
Modelling carbon core metabolism in Bacillus subtilis – Exploring the contribution of protein complexes in core carbon and nitrogen metabolism.

Bacillus subtilis is a prime model organism for systems biology approaches because it is one of the most advanced models for functional genomics. Furthermore, comprehensive information on cell and molecular biology, physiology and genetics is available and the European Bacillus community (BACELL) has a well-established reputation for applying
...

Programme: SysMO

Public web page: http://www.sysmo.net/index.php?index=53

University of Rostock

Country:  Germany

City: Rostock

Web page: http://www.uni-rostock.de

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Model of the pH-induced metabolic shift in phosphate-limited continuous cultures of C. acetobutylicum assuming a phenotypic switch
COSMIC

This model assumes a phenotypic switch between an acid- and solvent-forming population caused by the changing pH levels. The two phenotypes differ in their transcriptomic, proteomic, and ,thus, their metabolomic profile. Because the growth rates of these phenotypes depends on the extracellular pH, the initiation of the pH-shift results in a significant decline of the acidogenic population. Simultaneously, the solvent-forming population rises and establishes an new steady state.

The model is build
...

Creators: Thomas Millat, Graeme Thorn, Olaf Wolkenhauer, John King

Contributor: Thomas Millat

Harmonizing semantic annotations for computational models in biology
FAIRDOM

Abstract

Not specified

Authors: Maxwell Lewis Neal, Matthias König, David Nickerson, Göksel Mısırlı, Reza Kalbasi, Andreas Dräger, Koray Atalag, Vijayalakshmi Chelliah, Michael T Cooling, Daniel L Cook, Sharon Crook, Miguel de Alba, Samuel H Friedman, Alan Garny, John H Gennari, Padraig Gleeson, Martin Golebiewski, Mike Hucka, Nick Juty, Chris Myers, Brett G Olivier, Herbert M Sauro, Martin Scharm, Jacky Snoep, Vasundra Toure, Anil Wipat, Olaf Wolkenhauer, Dagmar Waltemath

Date Published: 21st Nov 2018

Journal: Not specified

A shift in the dominant phenotype governs the pH-induced metabolic switch of Clostridium acetobutylicumin phosphate-limited continuous cultures
COSMIC

Abstract (Expand)

In response to changing extracellular pH levels, phosphate-limited continuous cultures of Clostridium acetobutylicum reversibly switches its metabolism from the dominant formation of acids to the … prevalent production of solvents. Previous experimental and theoretical studies have revealed that this pH-induced metabolic switch involves a rearrangement of the intracellular transcriptomic, proteomic and metabolomic composition of the clostridial cells. However, the influence of the population dynamics on the observations reported has so far been neglected. Here, we present a method for linking the pH shift, clostridial growth and the acetone-butanol-ethanol fermentation metabolic network systematically into a model which combines the dynamics of the external pH and optical density with a metabolic model. Furthermore, the recently found antagonistic expression pattern of the aldehyde/alcohol dehydrogenases AdhE1/2 and pH-dependent enzyme activities have been included into this combined model. Our model predictions reveal that the pH-induced metabolic shift under these experimental conditions is governed by a phenotypic switch of predominantly acidogenic subpopulation towards a predominantly solventogenic subpopulation. This model-driven explanation of the pH-induced shift from acidogenesis to solventogenesis by population dynamics casts an entirely new light on the clostridial response to changing pH levels. Moreover, the results presented here underline that pH-dependent growth and pH-dependent specific enzymatic activity play a crucial role in this adaptation. In particular, the behaviour of AdhE1 and AdhE2 seems to be the key factor for the product formation of the two phenotypes, their pH-dependent growth, and thus, the pH-induced metabolic switch in C. acetobutylicum.

Authors: None

Date Published: 3rd May 2013

Journal: Appl. Microbiol. Biotechnol.

Integrative modelling of pH-dependent enzyme activity and transcriptomic regulation of the acetone-butanol-ethanol fermentation of Clostridium acetobutylicum in continuous culture
COSMIC

Abstract (Expand)

In a continuous culture under phosphate limitation the metabolism of Clostridium acetobutylicum depends on the external pH level. By comparing seven steady-state conditions between pH 5.7 and pH 4.5 … we show that the switch from acidogenesis to solventogenesis occurs between pH 5.3 and pH 5.0 with an intermediate state at pH 5.1. Here, an integrative study is presented investigating how a changing external pH level affects the clostridial acetone–butanol–ethanol (ABE) fermentation pathway. This is of particular interest as the biotechnological production of n-butanol as biofuel has recently returned into the focus of industrial applications. One prerequisite is the furthering of the knowledge of the factors determining the solvent production and their integrative regulations. We have mathematically analysed the influence of pH-dependent specific enzyme activities of branch points of the metabolism on the product formation. This kinetic regulation was compared with transcriptomic regulation regarding gene transcription and the proteomic profile. Furthermore, both regulatory mechanisms were combined yielding a detailed projection of their individual and joint effects on the product formation. The resulting model represents an important platform for future developments of industrial butanol production based on C. acetobutylicum.

Authors: None

Date Published: 1st Feb 2013

Journal: Microbial Biotechnology

Simulations of stressosome activation emphasize allosteric interactions between RsbR and RsbT
BaCell-SysMO

Abstract (Expand)

Background The stressosome is a bacterial signalling complex that responds to environmental changes by initiating a protein partner switching cascade, which leads to the release of the alternative sigma … factor, sigmaB. Stress perception increases the phosphorylation of the stressosome sensor protein, RsbR, and the scaffold protein, RsbS, by the protein kinase RsbT. Subsequent dissociation of RsbT from the stressosome activates the sigmaB cascade. However, the sequence of physical events that occur in the stressosome during signal transduction is insufficiently understood. Results Here, we use computational modelling to correlate the structure of the stressosome with the efficiency of the phosphorylation reactions that occur upon activation by stress. In our model, the phosphorylation of any stressosome protein is dependent upon its nearest neighbours and their phosphorylation status. We compare different hypotheses about stressosome activation and find that only the model representing the allosteric activation of the kinase RsbT, by phosphorylated RsbR, qualitatively reproduces the experimental data. Conclusions Our simulations and the associated analysis of published data support the following hypotheses: (i) a simple Boolean model is capable of reproducing stressosome dynamics, (ii) different stressors induce identical stressosome activation patterns, and we also confirm that (i) phosphorylated RsbR activates RsbT, and (ii) the main purpose of RsbX is to dephosphorylate RsbS-P.

Authors: Ulf Liebal, Thomas Millat, Jon Marles-Wright, Rick Lewis, Olaf Wolkenhauer

Date Published: 2013

Journal: BMC Syst Biol

Proteolysis of beta-galactosidase following SigmaB activation in Bacillus subtilis
BaCell-SysMO

Abstract (Expand)

In Bacillus subtilis the σB mediated general stress response provides protection against various environmental and energy related stress conditions. To better understand the general stress response, … we need to explore the mechanism by which the components interact. Here, we performed experiments in B. subtilis wild type and mutant strains to test and validate a mathematical model of the dynamics of σB activity. In the mutant strain BSA115, σB transcription is inducible by the addition of IPTG and negative control of σB activity by the anti-sigma factor RsbW is absent. In contrast to our expectations of a continuous β-galactosidase activity from a ctc::lacZ fusion, we observed a transient activity in the mutant. To explain this experimental finding, we constructed mathematical models reflecting different hypotheses regarding the regulation of σB and β-galactosidase dynamics. Only the model assuming instability of either ctc::lacZ mRNA or β-galactosidase protein is able to reproduce the experiments in silico. Subsequent Northern blot experiments revealed stable high-level ctc::lacZ mRNA concentrations after the induction of the σB response. Therefore, we conclude that protein instability following σB activation is the most likely explanation for the experimental observations. Our results thus support the idea that B. subtilis increases the cytoplasmic proteolytic degradation to adapt the proteome in face of environmental challenges following activation of the general stress response. The findings also have practical implications for the analysis of stress response dynamics using lacZ reporter gene fusions, a frequently used strategy for the σB response.

Authors: Ulf Liebal, Praveen Kumar Sappa, Thomas Millat, Leif Steil, Georg Homuth, Uwe Voelker, Olaf Wolkenhauer

Date Published: 2012

Journal: Mol. BioSyst.

Modeling of cellular processes: methods, data, and requirements
BaCell-SysMO, COSMIC

Abstract (Expand)

Systems biology is a comprehensive quantitative analysis how the components of a biological system interact over time which requires an interdisciplinary team of investigators. System-theoretic methods … are applied to investigate the system's behavior. Using known information about the considered system, a conceptual model is defined. It is transferred in a mathematical model that can be simulated (analytically or numerically) and analyzed using system-theoretic tools. Finally, simulation results are compared with experimental data. However, assumptions, approximations, and requirements to available experimental data are crucial ingredients of this systems biology workflow. Consequently, the modeling of cellular processes creates special demands on the design of experiments: the quality, the amount, and the completeness of data. The relation between models and data is discussed in this chapter. Thereby, we focus on the requirements on experimental data from the perspective of systems biology projects.

Authors: None

Date Published: 11th Nov 2010

Journal: Methods Mol. Biol.

A systems biology approach to investigate the effect of pH-induced gene regulation on solvent production by Clostridium acetobutylicum in continuous culture
COSMIC

Abstract (Expand)

Background: Clostridium acetobutylicum is an anaerobic bacterium which is known for its solvent-producing capabilities, namely regarding the bulk chemicals acetone and butanol, the latter being a highly … efficient biofuel. For butanol production by C. acetobutylicum to be optimized and exploited on an industrial scale, the effect of pH-induced gene regulation on solvent production by C. acetobutylicum in continuous culture must be understood as fully as possible. Results: We present an ordinary differential equation model combining the metabolic network governing solvent production with regulation at the genetic level of the enzymes required for this process. Parameterizing the model with experimental data from continuous culture, we demonstrate the influence of pH upon fermentation products: at high pH (pH 5.7) acids are the dominant product while at low pH (pH 4.5) this switches to solvents. Through steady-state analyses of the model we focus our investigations on how alteration in gene expression of C. acetobutylicum could be exploited to increase butanol yield in a continuous culture fermentation. Conclusions: Incorporating gene regulation into the mathematical model of solvent production by C. acetobutylicum enables an accurate representation of the pH-induced switch to solvent production to be obtained and theoretical investigations of possible synthetic-biology approaches to be pursued. Steady-state analyses suggest that, to increase butanol yield, alterations in the expression of single solvent-associated genes are insufficient; a more complex approach targeting two or more genes is required.

Authors: None

Date Published: 2011

Journal: BMC Syst Biol

A mathematical analysis of nuclear intensity dynamics for Mig1-GFP under consideration of bleaching effects and background noise in Saccharomyces cerevisiae
COSMIC

Abstract (Expand)

Fluorescence microscopy is an imaging technique that provides insights into signal transduction pathways through the generation of quantitative data, such as the spatiotemporal distribution of GFP-tagged … proteins in signaling pathways. The data acquired are, however, usually a composition of both the GFP-tagged proteins of interest and of an autofluorescent background, which both undergo photobleaching during imaging. We here present a mathematical model based on ordinary differential equations that successfully describes the shuttling of intracellular Mig1-GFP under changing environmental conditions regarding glucose concentration. Our analysis separates the different bleaching rates of Mig1-GFP and background, and the background-to-Mig1-GFP ratio. By applying our model to experimental data, we can thus extract the Mig1-GFP signal from the overall acquired signal and investigate the influence of kinase and phosphatase on Mig1. We found a stronger regulation of Mig1 through its kinase than through its phosphatase when controlled by the glucose concentration, with a constant (de)phosphorylation rate independent of the glucose concentration. By replacing the term for decreasing excited Mig1-GFP concentration with a constant, we were able to reconstruct the dynamics of Mig1-GFP, as it would occur without bleaching and background noise. Our model effectively demonstrates how data, acquired with an optical microscope, can be processed and used for a systems biology analysis of signal transduction pathways.

Authors: Simone Frey, Kristin Sott, Maria Smedh, Thomas Millat, Peter Dahl, Olaf Wolkenhauer, Mattias Goksör

Date Published: 2011

Journal: Mol. BioSyst.

Ein Beitrag zu einer Theorie lebender Zellen (A Contribution towards a Theory of Living Cells)
BaCell-SysMO

Abstract (Expand)

The following article describes systems biology as a merger of systems theory with cell biology. The role of modelling in the description of living cells is discussed. As an example, an abstract … multiple-level model of a cell is developed. It is shown that a level of elementary cellular processes, realising cell functions, and a coordination-level are sufficient to create a system that is closed with respect to efficient causation. This form of self-organisation is thereby considered as basic criterion by which living systems, such as cells and organisms, are distinguished from machines and computers. Die causal closure of the cell is possible through the definition of the cell model as a cartesian closed category. It follows the conclusion that computer simulations of differential equations may be able to reproduce cellular processes but not this aspect of causal closure. The article ends with a discussion about the role of systems theory in the life sciences.

Authors: Olaf Wolkenhauer, Jan-Hendrik S. Hofmeyr

Date Published: 1st May 2008

Journal: at - Automatisierungstechnik

Dynamics of receptor and protein transducer homodimerisation
BaCell-SysMO

Abstract (Expand)

Background Signalling pathways are complex systems in which not only simple monomeric molecules interact, but also more complex structures that include constitutive or induced protein assemblies. In … particular, the hetero-and homo-dimerisation of proteins is a commonly encountered motif in signalling pathways. Several authors have suggested in recent times that dimerisation relates to a series of physical and biological outcomes used by the cell in the regulation of signal transduction. Results In this paper we investigate the role of homodimerisation in receptor-protein transducer interactions. Towards this end, mathematical modelling is used to analyse the features of such kind of interactions and to predict the behaviour of the system under different experimental conditions. A kinetic model in which the interaction between homodimers provokes a dual mechanism of activation (single and double protein transducer activation at the same time) is proposed. In addition, we analyse under which conditions the use of a power-law representation for the system is useful. Furthermore, we investigate the dynamical consequences of this dual mechanism and compare the performance of the system in different simulated experimental conditions. Conclusion The analysis of our mathematical model suggests that in receptor-protein interacting systems with dual mechanism there may be a shift between double and single activation in a way that intense double protein transducer activation could initiate and dominate the signal in the short term (getting a fast intense signal), while single protein activation could control the system in the medium and long term (when input signal is weaker and decreases slowly). Our investigation suggests that homodimerisation and oligomerisation are mechanisms used to enhance and regulate the dynamic properties of the initial steps in signalling pathways.

Authors: Julio Vera, Thomas Millat, Walter Kolch, Olaf Wolkenhauer

Date Published: 2008

Journal: BMC Syst Biol

Integration of sensitivity and bifurcation analysis to detect critical processes in a model combining signalling and cell population dynamics
BaCell-SysMO

Abstract (Expand)

In this article we present and test a strategy to integrate, in a sequential manner, sensitivity analysis, bifurcation analysis and predictive simulations. Our strategy uses some of these methods in a … coordinated way such that information, generated in one step, feeds into the definition of further analyses and helps refining the structure of the mathematical model. The aim of the method is to help in the designing of more informative predictive simulations, which focus on critical model parameters and the biological effects of their modulation. We tested our methodology with a multilevel model, accounting for the effect of erythropoietin (Epo)-mediated JAK2-STAT5 signalling in erythropoiesis. Our analysis revealed that time-delays associated with the proliferation-differentiation process are critical to induce pathological sustained oscillations, whereas the modulation of time-delays related to intracellular signalling and hypoxia-controlled physiological dynamics is not enough to induce self-oscillations in the system. Furthermore, our results suggest that the system is able to compensate (through the physiological-level feedback loop on hypoxia) the partial impairment of intracellular signalling processes (downregulation or overexpression of Epo receptor complex and STAT5), but cannot control impairment in some critical physiological-level processes, which provoke the emergence of pathological oscillations.

Authors: S. Nikolov, X. Lai, Ulf Liebal, Olaf Wolkenhauer, J. Vera

Date Published: 2010

Journal: Int. J. of Systems Sc.

The role of dynamic stimulation pattern in the analysis of bistable intracellular networks
BaCell-SysMO

Abstract (Expand)

Bistable systems play an important role in the functioning of living cells. Depending on the strength of the necessary positive feedback one can distinguish between (irreversible) "one-way … switch" or (reversible) "toggle-switch" type behavior. Besides the well- established steady-state properties, some important characteristics of bistable systems arise from an analysis of their dynamics. We demonstrate that a supercritical stimulus amplitude is not sufficient to move the system from the lower (off-state) to the higher branch (on-state) for either a step or a pulse input. A switching surface is identified for the system as a function of the initial condition, input pulse amplitude and duration (a supercritical signal). We introduce the concept of bounded autonomy for single level systems with a pulse input. Towards this end, we investigate and characterize the role of the duration of the stimulus. Furthermore we show, that a minimal signal power is also necessary to change the steady state of the bistable system. This limiting signal power is independent of the applied stimulus and is determined only by systems parameters. These results are relevant for the design of experiments, where it is often difficult to create a defined pattern for the stimulus. Furthermore, intracellular processes, like receptor internalization, do manipulate the level of stimulus such that level and duration of the stimulus is conducive to characteristic behavior.

Authors: Thomas Millat, Sree N Sreenath, Radina P Soebiyanto, Jayant Avva, Kwang-Hyun Cho, Olaf Wolkenhauer

Date Published: 17th Jan 2007

Journal: BioSystems

How quantitative measures unravel design principles in multi-stage phosphorylation cascades
BaCell-SysMO

Abstract (Expand)

We investigate design principles of linear multi-stage phosphorylation cascades by using quantitative measures for signaling time, signal duration and signal amplitude. We compare alternative pathway … structures by varying the number of phosphorylations and the length of the cascade. We show that a model for a weakly activated pathway does not reflect the biological context well, unless it is restricted to certain parameter combinations. Focusing therefore on a more general model, we compare alternative structures with respect to a multivariate optimization criterion. We test the hypothesis that the structure of a linear multi-stage phosphorylation cascade is the result of an optimization process aiming for a fast response, defined by the minimum of the product of signaling time and signal duration. It is then shown that certain pathway structures minimize this criterion. Several popular models of MAPK cascades form the basis of our study. These models represent different levels of approximation, which we compare and discuss with respect to the quantitative measures.

Authors: Simone Frey, Thomas Millat, Stefan Hohmann, Olaf Wolkenhauer

Date Published: 6th Sep 2007

Journal: J. Theor. Biol.

How mathematical modelling elucidates signalling in B. subtilis
BaCell-SysMO

Abstract (Expand)

Appropriate stimulus perception, signal processing and transduction ensure optimal adaptation of bacteria to environmental challenges. In the Gram-positive model bacterium Bacillus subtilis signalling …g networks and molecular interactions therein are well-studied, making this species a suitable candidate for the application of mathematical modelling. Here, we review systems biology approaches, focusing on chemotaxis, sporulation, σB-dependent general stress response and competence. Processes like chemotaxis and Z-ring assembly depend critically on the subcellular localization of proteins. Environmental response strategies, including sporulation and competence, are characterized by phenotypic heterogeneity in isogenic cultures. The examples of mathematical modelling also include investigations that have demonstrated how operon structure and signalling dynamics are intricately interwoven to establish optimal responses. Our review illustrates that these interdisciplinary approaches offer new insights into the response of B. subtilis to environmental challenges. These case studies reveal modelling as a tool to increase the understanding of complex systems, to help formulating hypotheses and to guide the design of more directed experiments that test predictions.

Authors: None

Date Published: 1st Jul 2010

Journal: Not specified

Improving the management of computational models.
FAIRDOM

Written by Martin Scharm (University of Rostock), Ron Henkel (University of Rostock), Dagmar Waltemath (University of Rostock), Olaf Wolkenhauer (University of Rostock, Stellenbosch University), and presented by Martin Scharm (University of Rostock) as part of the Reproducible and Citable Data and Models Workshop in Warnemünde, Germany. September 14th - 16th 2015.

Creators: Natalie Stanford, Dagmar Waltemath, Olaf Wolkenhauer, Ron Henkel, Martin Scharm (University of Rostock)

Contributor: Natalie Stanford

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