Recent development and biomedical applications of probabilistic Boolean networks

in Cell Communication and Signaling (2013), 11(46),

Probabilistic Boolean network (PBN) modelling is a semi-quantitative approach widely used for the study of the topology and dynamic aspects of biological systems. The combined use of rule-based ... [more ▼]

Probabilistic Boolean network (PBN) modelling is a semi-quantitative approach widely used for the study of the topology and dynamic aspects of biological systems. The combined use of rule-based representation and probability makes PBN appealing for large-scale modelling of biological networks where degrees of uncertainty need to be considered. A considerable expansion of our knowledge in the field of theoretical research on PBN can be observed over the past few years, with a focus on network inference, network intervention and control. With respect to areas of applications, PBN is mainly used for the study of gene regulatory networks though with an increasing emergence in signal transduction, metabolic, and also physiological networks. At the same time, a number of computational tools, facilitating the modelling and analysis of PBNs, are continuously developed. A concise yet comprehensive review of the state-of-the-art on PBN modelling is offered in this article, including a comparative discussion on PBN versus similar models with respect to concepts and biomedical applications. Due to their many advantages, we consider PBN to stand as a suitable modelling framework for the description and analysis of complex biological systems, ranging from molecular to physiological levels. [less ▲]

Fast reconstruction of compact context-specific metabolic network models

E-print/Working paper (2013)

Systemic approaches to the study of a biological cell or tissue rely increasingly on the use of context-specific metabolic network models. The reconstruction of such a model from high-throughput data can ... [more ▼]

Systemic approaches to the study of a biological cell or tissue rely increasingly on the use of context-specific metabolic network models. The reconstruction of such a model from high-throughput data can routinely involve large numbers of tests under different conditions and extensive parameter tuning, which calls for fast algorithms. We present FASTCORE, a generic algorithm for reconstructing context-specific metabolic network models from global genome-wide metabolic network models such as Recon X. FASTCORE takes as input a core set of reactions that are known to be active in the context of interest (e.g., cell or tissue), and it searches for a flux consistent subnetwork of the global network that contains all reactions from the core set and a minimal set of additional reactions. Our key observation is that a minimal consistent reconstruction can be defined via a set of sparse modes of the global network, and FASTCORE iteratively computes such a set via a series of linear programs. Experiments on liver data demonstrate speedups of several orders of magnitude, and significantly more compact reconstructions, over a chief rival method. Given its simplicity and its excellent performance, FASTCORE can form the backbone of many future metabolic network reconstruction algorithms. [less ▲]

A balancing act: Parameter estimation for biological models with steady-state measurements

in Proceedings of 11th Conference on Computational Methods in Systems Biology (CMSB'13) (2013)

Systems analysis of transcription factor activities in environments with stable and dynamic oxygen concentrations

in Open Biology (2012), 2(7), 120091

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless ... [more ▼]

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless, statistical approaches to infer TF activities have yielded non-trivial and verifiable predictions for individual TFs. Here, global statistical modelling identifies changes in TF activities from transcript profiles of Escherichia coli growing in stable (fixed oxygen availabilities) and dynamic (changing oxygen availability) environments. A core oxygen-responsive TF network, supplemented by additional TFs acting under specific conditions, was identified. The activities of the cytoplasmic oxygen-responsive TF, FNR, and the membrane-bound terminal oxidases implied that, even on the scale of the bacterial cell, spatial effects significantly influence oxygen-sensing. Several transcripts exhibited asymmetrical patterns of abundance in aerobic to anaerobic and anaerobic to aerobic transitions. One of these transcripts, ndh, encodes a major component of the aerobic respiratory chain and is regulated by oxygen-responsive TFs ArcA and FNR. Kinetic modelling indicated that ArcA and FNR behaviour could not explain the ndh transcript profile, leading to the identification of another TF, PdhR, as the source of the asymmetry. Thus, this approach illustrates how systematic examination of regulatory responses in stable and dynamic environments yields new mechanistic insights into adaptive processes. [less ▲]

Analysing the role of UVB-induced translational inhibition and PP2Ac deactivation in NF-kappaB signalling using a minimal mathematical model.

in PLoS ONE (2012), 7(7), 40274

Activation of nuclear factor kappaB (NF-kappaB) by interleukin-1beta (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kappaB ... [more ▼]

Activation of nuclear factor kappaB (NF-kappaB) by interleukin-1beta (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kappaB dependent resynthesis of its own inhibitor IkappaBalpha. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-kappaB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of IkappaBalpha recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKKbeta phosphorylation is shown to be a decisive process in IkappaBalpha degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of IkappaBalpha recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of IkappaBalpha. This shows that the processes leading to activation of transcription factor NF-kappaB upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting. [less ▲]

A study of the PDGF signaling pathway with PRISM

in Proceedings of the 3rd Workshop on Computational Models for Cell Processes (2011), EPTCS 67

Mathematical modeling of the central carbohydrate metabolism in Arabidopsis reveals a substantial regulatory influence of vacuolar invertase on whole plant carbon metabolism.

in Plant Physiology (2010), 153(1), 260-72

A mathematical model representing metabolite interconversions in the central carbohydrate metabolism of Arabidopsis (Arabidopsis thaliana) was developed to simulate the diurnal dynamics of primary carbon ... [more ▼]

A mathematical model representing metabolite interconversions in the central carbohydrate metabolism of Arabidopsis (Arabidopsis thaliana) was developed to simulate the diurnal dynamics of primary carbon metabolism in a photosynthetically active plant leaf. The model groups enzymatic steps of central carbohydrate metabolism into blocks of interconverting reactions that link easily measurable quantities like CO(2) exchange and quasi-steady-state levels of soluble sugars and starch. When metabolite levels that fluctuate over diurnal cycles are used as a basic condition for simulation, turnover rates for the interconverting reactions can be calculated that approximate measured metabolite dynamics and yield kinetic parameters of interconverting reactions. We used experimental data for Arabidopsis wild-type plants, accession Columbia, and a mutant defective in vacuolar invertase, AtbetaFruct4, as input data. Reducing invertase activity to mutant levels in the wild-type model led to a correct prediction of increased sucrose levels. However, additional changes were needed to correctly simulate levels of hexoses and sugar phosphates, indicating that invertase knockout causes subsequent changes in other enzymatic parameters. Reduction of invertase activity caused a decline in photosynthesis and export of reduced carbon to associated metabolic pathways and sink organs (e.g. roots), which is in agreement with the reported contribution of vacuolar invertase to sink strength. According to model parameters, there is a role for invertase in leaves, where futile cycling of sucrose appears to have a buffering effect on the pools of sucrose, hexoses, and sugar phosphates. Our data demonstrate that modeling complex metabolic pathways is a useful tool to study the significance of single enzyme activities in complex, nonintuitive networks. [less ▲]

Mechanism of PP2A-mediated IKK beta dephosphorylation: a systems biological approach.

in BMC Systems Biology (2009), 3

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an ... [more ▼]

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha. RESULTS: To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality. CONCLUSION: The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies. [less ▲]

Analyse der evolutiven Adaptation am Beispiel einer pyruvat-auxotrophen Escherichia coli-Mutante

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 ▲]

Modeling and Analysis of UVB Influence on IL-1 induced NF-kappaB Signaling

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 ▲]