Méthodes qualitatives pour la construction et l'analyse des réseaux moléculaires SBGN

Two fundamental tasks of Systems Biology are the construction of molecular networks from experimental data, and their analysis with a view to discovering their emergent properties. With the increase of available experimental data, these two tasks can no longer be realized by hand. Based on this observation, numerous bioinformatics methods aiming at the automation of these two task have been developped.In parallel, standards aiming at defining and organizing terms of systems biology, or representing networks and mathematical models, have been developped. Among these standards, the Standard Biology Graphical Notation is composed of three languages that allow the representation of molecular networks. The two main SBGN languages are SBGN-PD for the representation of reaction networks, and SBGN-AF for the representation of influence graphs. The SBGN notation not only standardizes the representation of networks, but also gives the concepts of systems biology that are most often used to express knowledge of the field.Our work takes its root in this general background. We have developped a number of methods to construct molecular networks and analyze their dynamics. All the methods that we propose are based on qualitative formalisms, such as logics or automata networks. These formalisms have solid theoretical bases and can be used by numerous pieces of software. All our methods also rely on the biological concepts given by the SBGN standard, and can therefore be blended in the same theoretical framework.First, we introduce two sets of predicates that allow to translate any SBGN-PD or SBGN-AF network into a set of ground atoms. Then, we show how these sets of predicates can be used to reason on networks, by proposing a transformation method of SBGN-PD signaling networks into SBGN-AF influence graphs.Second, we present a first-order logic based method to construct signaling networks from experimental results. This method formalizes and automatizes biologists' reasoning using explicit reasoning rules.On the contrary to existing methods, it allows to take into account numerous types of experimental results while reconstructing precise molecular mecanisms.Third, we show a new method to compute the finite traces and attractor points of Boolean networks that model SBGN-AF networks and that are parameterized using general principles.Finally, we introduce two new qualitative semantics for the computation of the dynamics of SBGN-PD reaction networks. These semantics are expressed using automata networks. The first semantics extends the classical Boolean semantics by taking into account inhibitions. As to the second one, it relies on the concept of story which introduces a new point of view on reaction networks. Indeed, it allows to model different physical states of the same molecular entity using a unique variable.All the methods that we have developped show how qualitative formalisms can be used to reason on the relations represented by molecular networks in order to discorver new knowledge in systems biology.La construction des réseaux moléculaires à partir de résultats expérimentaux, ainsi que leur analyse en vue d'en exhiber des propriétés émergentes, sont deux tâches fondamentales de la biologie des systèmes. Avec l'augmentation du nombre de données expérimentales, elles ne peuvent plus être réalisées manuellement. Partant de ce constat, un certain nombre de méthodes bioinformatiques visant à les automatiser ont été développées.En parallèle du développement des méthodes, un certain nombre de standards ont vu le jour. Parmi ceux-ci, la Standard Biology Graphical Notation (SBGN) se compose de trois langages permettant la représentation des réseaux moléculaires.Les deux langages SBGN les plus couramment utilisés sont SBGN-PD pour la représentation des réseaux de réactions, et SBGN-AF pour celle des graphes d'influences. La notation SBGN, en plus de standardiser la représentation des réseaux, donne l'ensemble des concepts de la biologie des systèmes qui sont le plus souvent utilisés pour exprimer les connaissances du domaine.C'est dans ce cadre général que se placent l'ensemble de nos travaux. Nous avons développé un ensemble de méthodes pour la construction des réseaux moléculaires et l'analyse de leur dynamique. L'ensemble des méthodes que nous proposons reposent sur des formalismes qualitatifs, tels que la logique ou les réseaux d'automates. Ces formalismes on non seulement des bases théoriques solides, mais peuvent aussi être utilisés par de nombreux logiciels.L'ensemble de nos méthodes reposent également sur les concepts biologiques fournis par le standard SBGN, et peuvent ainsi être intégrées dans un même cadre théorique.Nous introduisons d'abord deux ensembles de prédicats qui permettent de traduire n'importe quel réseau SBGN-PD ou SBGN-AF sous la forme d'atomes instanciés. Nous montrons ensuite comment ces deux ensembles peuvent être utilisés pour raisonner automatiquement sur des réseaux moléculaires, en proposant une méthode de transformation automatique des réseaux de signalisation SBGN-PD en graphes d'influences SBGN-AF.Nous présentons ensuite une méthode de construction des réseaux de signalisation à partir de résultats expérimentaux, basée sur la logique du premier ordre. Cette méthode formalise et automatise le raisonnement réalisé par les biologistes à l'aide de règles de raisonnement explicites. Contrairement aux méthodes développées jusqu'à maintenant, celle que nous présentons prend en compte un grand nombre de types d'expériences, tout en permettant la reconstruction de mécanismes moléculaires précis.Puis nous montrons une nouvelle méthode pour le calcul des traces finies et des points attracteurs de réseaux Booléens modélisant des réseaux SBGN-AF et paramétrés à l'aide de principes généraux. Notre méthode repose sur l'utilisation de programmes logiques normaux du premier ordre, qui formalisent ces principes généraux.Enfin, nous proposons deux nouvelles sémantiques qualitatives pour le calcul de la dynamique des réseaux de réactions SBGN-PD, exprimées à l'aide de réseaux d'automates. La première de ces sémantiques étend la sémantique Booléenne des réseaux de réactions en prenant en compte les inhibitions. Quant à la deuxième, elle introduit le concept d'histoire (story) qui offre un nouveau point de vue sur les réseaux de réactions, en permettant de modéliser différents états physiques d'une même entité moléculaire par une seule variable.L'ensemble des méthodes que nous avons développées montrent comment les formalismes qualitatifs, et en particulier la logique, peuvent être utilisés pour raisonner à partir des relations représentées par les réseaux moléculaires, afin de découvrir de nouvelles connaissances en biologie des systèmes

Towards a logic-based method to infer provenance-aware molecular networks

International audienceProviding techniques to automatically infer molecular networks is particularly important to understand complex relationships between biological objects. We present a logic-based method to infer such networks and show how it allows inferring signalling networks from the design of a knowledge base. Provenance of inferred data has been carefully collected, allowing quality evaluation. More precisely, our method (i) takes into account various kinds of biological experiments and their origin; (ii) mimics the scientist's reasoning within a first-order logic setting; (iii) specifies precisely the kind of interaction between the molecules; (iv) provides the user with the provenance of each interaction; (v) automatically builds and draws the inferred network

Reusability and composability in process description maps: RAS-RAF-MEK-ERK signalling.

peer reviewedDetailed maps of the molecular basis of the disease are powerful tools for interpreting data and building predictive models. Modularity and composability are considered necessary network features for large-scale collaborative efforts to build comprehensive molecular descriptions of disease mechanisms. An effective way to create and manage large systems is to compose multiple subsystems. Composable network components could effectively harness the contributions of many individuals and enable teams to seamlessly assemble many individual components into comprehensive maps. We examine manually built versions of the RAS-RAF-MEK-ERK cascade from the Atlas of Cancer Signalling Network, PANTHER and Reactome databases and review them in terms of their reusability and composability for assembling new disease models. We identify design principles for managing complex systems that could make it easier for investigators to share and reuse network components. We demonstrate the main challenges including incompatible levels of detail and ambiguous representation of complexes and highlight the need to address these challenges

Towards a logic-based method to infer provenance-aware molecular networks

International audienceProviding techniques to automatically infer molecular networks is particularly important to understand complex relationships between biological objects. We present a logic-based method to infer such networks and show how it allows inferring signalling networks from the design of a knowledge base. Provenance of inferred data has been carefully collected, allowing quality evaluation. More precisely, our method (i) takes into account various kinds of biological experiments and their origin; (ii) mimics the scientist's reasoning within a first-order logic setting; (iii) specifies precisely the kind of interaction between the molecules; (iv) provides the user with the provenance of each interaction; (v) automatically builds and draws the inferred network

SBGN Bricks Ontology as a tool to describe recurring concepts in molecular networks.

A comprehensible representation of a molecular network is key to communicating and understanding scientific results in systems biology. The Systems Biology Graphical Notation (SBGN) has emerged as the main standard to represent such networks graphically. It has been implemented by different software tools, and is now largely used to communicate maps in scientific publications. However, learning the standard, and using it to build large maps, can be tedious. Moreover, SBGN maps are not grounded on a formal semantic layer and therefore do not enable formal analysis. Here, we introduce a new set of patterns representing recurring concepts encountered in molecular networks, called SBGN bricks. The bricks are structured in a new ontology, the Bricks Ontology (BKO), to define clear semantics for each of the biological concepts they represent. We show the usefulness of the bricks and BKO for both the template-based construction and the semantic annotation of molecular networks. The SBGN bricks and BKO can be freely explored and downloaded at sbgnbricks.org

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe