Enzymatic competition: Modeling and verification with timed hybrid petri nets

International audienceThe formalism of hybrid functional petri nets (HFPN) has proved its convenience for simulating biological systems. The drawback of the noticeable expressiveness of HFPN is the difficulty to perform formal verifications of dynamical properties. In this article, we propose a model-checking procedure for timed hybrid petri nets (THPN), a sub-class of HFPN. This procedure is based on the translation of the THPN model and of the studied property into real-time automata. It is applied to model enzymatic competitions existing in amphibian metamorphosis

Nouvelles données sur les fontaines lyonnaises et l’approvisionnement en eau de la Presqu’île durant l’Antiquité

Remployés dans un mur de cave médiévale, quatre imposants blocs d’architecture ont été mis au jour à l’occasion de la fouille de la place d’Albon (Lyon 2e) durant l’hiver 2015-2016. Identifiés comme des éléments de fontaine, ils sont probablement à mettre en relation avec une conduite d’adduction en terre cuite mise au jour à proximité immédiate. Ces découvertes récentes sont l’occasion de reprendre les données sur les fontaines publiques lyonnaises, en présentant notamment un nouvel élément (re)découvert à Fourvière et en proposant une série d’observations quant à l’objet de leur mise en place. Nous en profiterons pour discuter des perspectives de recherche autour de la question de l’approvisionnement en eau dans la Presqu’île lyonnaise : captage ou puisage, répartition et distribution.Reused in a wall of a medieval cellar, four large stone blocks were uncovered during the excavation of the Place d’Albon (Lyon 2nd) in winter 2015-2016. Identified as elements of a fountain, they probably correspond to a terra cotta adduction conduit uncovered nearby. These recent discoveries provide an opportunity to reanalyze the data on public fountains in Lyon, while presenting a new element (re)discovered in Fourvière, and while presenting observations concerning the reasons for their installation. We will also discuss the research perspectives on the question of water procurement in the Lyon Presqu’île: catchment or drawing, allocation and distribution.Bei der Grabung auf dem Place d’Albon (Lyon 2e) im Winter 2015-2016 wurden in einem mittelalterlichen Keller vier imposante, als Spolien wiederverwendete Steinblöcke freigelegt. Sie wurden als Elemente eines Brunnen identifiziert und dürften mit einer in unmittelbarer Nähe gefundenen Tonrohrleitung in Verbindung zu bringen sein. Diese neuen Entdeckungen bieten Gelegenheit die bereits bekannten Daten über die öffentlichen Brunnen Lugdunums und einen in Fourvière (wieder)entdeckten Fund zu präsentieren und eine Reihe von Betrachtungen bezüglich der Errichtung der Brunnen vorzuschlagen. Wie nutzen die Gelegenheit, um die Forschungsperspektiven um die Frage der Wasserversorgung der Presqu’île de Lyon zu diskutieren : Gewinnung des Wassers aus Quellen oder aus Brunnen, Verteilung des Wassers

Correspondence between discrete and piecewise linear models of gene regulatory networks

International audienceWe know that some proteins can regulate the expression of genes in a living organism. The regulation of gene expression occurs through networks of regulatory interactions in a non linear way between DNA, RNA, proteins and some molecules, called genetic regulatory networks. It is becoming clear that mathematical models and tools are required to analyze these complex systems. In the course of his study on gene regulatory networks R. Thomas proposed a discrete framework that mimics the qualitative evolution of such systems. Such discrete models are of great importance because kinetic parameters are often non measurable in vivo and available data are often of qualitative nature. Then Snoussi proved consistency between the discrete approach of R. Thomas and Piecewise Linear Differential Equation Systems, which are easy to construct from interaction graph and thresholds of interactions. Our work focuses on the relationships between both approaches: we will prove a result of correspondence between the two models. Finally, we will give some short description of a Maple program which can compute a discrete path, given the ordinary differential equation and starting box

Evaluation of time profile reconstruction from complex two-color microarray designs

<p>Abstract</p> <p>Background</p> <p>As an alternative to the frequently used "reference design" for two-channel microarrays, other designs have been proposed. These designs have been shown to be more profitable from a theoretical point of view (more replicates of the conditions of interest for the same number of arrays). However, the interpretation of the measurements is less straightforward and a reconstruction method is needed to convert the observed ratios into the genuine profile of interest (e.g. a time profile). The potential advantages of using these alternative designs thus largely depend on the success of the profile reconstruction. Therefore, we compared to what extent different linear models agree with each other in reconstructing expression ratios and corresponding time profiles from a complex design.</p> <p>Results</p> <p>On average the correlation between the estimated ratios was high, and all methods agreed with each other in predicting the same profile, especially for genes of which the expression profile showed a large variance across the different time points. Assessing the similarity in profile shape, it appears that, the more similar the underlying principles of the methods (model and input data), the more similar their results. Methods with a dye effect seemed more robust against array failure. The influence of a different normalization was not drastic and independent of the method used.</p> <p>Conclusion</p> <p>Including a dye effect such as in the methods lmbr_dye, anovaFix and anovaMix compensates for residual dye related inconsistencies in the data and renders the results more robust against array failure. Including random effects requires more parameters to be estimated and is only advised when a design is used with a sufficient number of replicates. Because of this, we believe lmbr_dye, anovaFix and anovaMix are most appropriate for practical use.</p

Boolean Models of Biosurfactants Production in Pseudomonas fluorescens

Cyclolipopeptides (CLPs) are biosurfactants produced by numerous Pseudomonas fluorescens strains. CLP production is known to be regulated at least by the GacA/GacS two-component pathway, but the full regulatory network is yet largely unknown. In the clinical strain MFN1032, CLP production is abolished by a mutation in the phospholipase C gene () and not restored by complementation. Their production is also subject to phenotypic variation. We used a modelling approach with Boolean networks, which takes into account all these observations concerning CLP production without any assumption on the topology of the considered network. Intensive computation yielded numerous models that satisfy these properties. All models minimizing the number of components point to a bistability in CLP production, which requires the presence of a yet unknown key self-inducible regulator. Furthermore, all suggest that a set of yet unexplained phenotypic variants might also be due to this epigenetic switch. The simplest of these Boolean networks was used to propose a biological regulatory network for CLP production. This modelling approach has allowed a possible regulation to be unravelled and an unusual behaviour of CLP production in P. fluorescens to be explained

Epigenetic acquisition of inducibility of type III cytotoxicity in P. aeruginosa

BACKGROUND: Pseudomonas aeruginosa, an opportunistic pathogen, is often encountered in chronic lung diseases such as cystic fibrosis or chronic obstructive pneumonia, as well as acute settings like mechanical ventilation acquired pneumonia or neutropenic patients. It is a major cause of mortality and morbidity in these diseases. In lungs, P. aeruginosa settles in a biofilm mode of growth with the secretion of exopolysaccharides in which it is encapsulated, enhancing its antibiotic resistance and contributing to the respiratory deficiency of patients. However, bacteria must first multiply to a high density and display a cytotoxic phenotype to avoid the host's defences. A virulence determinant implicated in this step of infection is the type III secretion system (TTSS), allowing toxin injection directly into host cells. At the beginning of the infection, most strains isolated from patients' lungs possess an inducible TTSS allowing toxins injection or secretion upon in vivo or in vitro activation signals. As the infection persists most of the bacteria permanently loose this capacity, although no mutations have been evidenced. We name "non inducible" this phenotype. As suggested by the presence of a positive feedback circuit in the regulatory network controlling TTSS expression, it may be due to an epigenetic switch allowing heritable phenotypic modifications without genotype's mutations. RESULTS: Using the generalised logical method, we designed a minimal model of the TTSS regulatory network that could support the epigenetic hypothesis, and studied its dynamics which helped to define a discriminating experimental scenario sufficient to validate the epigenetic hypothesis. A mathematical framework based on formal methods from computer science allowed a rigorous validation and certification of parameters of this model leading to epigenetic behaviour. Then, we demonstrated that a non inducible strain of P. aeruginosa can stably acquire the capacity to be induced by calcium depletion for the TTSS after a short pulse of a regulatory protein. Finally, the increased cytotoxicity of a strain after this epigenetic switch was demonstrated in vivo in an acute pulmonary infection model. CONCLUSION: These results may offer new perspectives for therapeutic strategies to prevent lethal infections by P. aeruginosa by reverting the epigenetic inducibility of type III cytotoxicity

Modelling of complex biological systems in the context of genomics: an account of a multidisciplinary thematic seminar held in Montpellier (France) in April 2005

International audienceno abstrac

A stochastic automaton shows how enzyme assemblies may contribute to metabolic efficiency

<p>Abstract</p> <p>Background</p> <p>The advantages of grouping enzymes into metabolons and into higher order structures have long been debated. To quantify these advantages, we have developed a stochastic automaton that allows experiments to be performed in a virtual bacterium with both a membrane and a cytoplasm. We have investigated the general case of transport and metabolism as inspired by the phosphoenolpyruvate:sugar phosphotransferase system (PTS) for glucose importation and by glycolysis.</p> <p>Results</p> <p>We show that PTS and glycolytic metabolons can increase production of pyruvate eightfold at low concentrations of phosphoenolpyruvate. A fourfold increase in the numbers of enzyme EI led to a 40% increase in pyruvate production, similar to that observed <it>in vivo </it>in the presence of glucose. Although little improvement resulted from the assembly of metabolons into a hyperstructure, such assembly can generate gradients of metabolites and signaling molecules.</p> <p>Conclusion</p> <p><it>in silico </it>experiments may be performed successfully using stochastic automata such as HSIM (Hyperstructure Simulator) to help answer fundamental questions in metabolism about the properties of molecular assemblies and to devise strategies to modify such assemblies for biotechnological ends.</p

Computing with bacterial constituents, cells and populations: from bioputing to bactoputing

The relevance of biological materials and processes to computing—aliasbioputing—has been explored for decades. These materials include DNA, RNA and proteins, while the processes include transcription, translation, signal transduction and regulation. Recently, the use of bacteria themselves as living computers has been explored but this use generally falls within the classical paradigm of computing. Computer scientists, however, have a variety of problems to which they seek solutions, while microbiologists are having new insights into the problems bacteria are solving and how they are solving them. Here, we envisage that bacteria might be used for new sorts of computing. These could be based on the capacity of bacteria to grow, move and adapt to a myriad different fickle environments both as individuals and as populations of bacteria plus bacteriophage. New principles might be based on the way that bacteria explore phenotype space via hyperstructure dynamics and the fundamental nature of the cell cycle. This computing might even extend to developing a high level language appropriate to using populations of bacteria and bacteriophage. Here, we offer a speculative tour of what we term bactoputing, namely the use of the natural behaviour of bacteria for calculating