881 research outputs found

    Computational Techniques for the Structural and Dynamic Analysis of Biological Networks

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    The analysis of biological systems involves the study of networks from different omics such as genomics, transcriptomics, metabolomics and proteomics. In general, the computational techniques used in the analysis of biological networks can be divided into those that perform (i) structural analysis, (ii) dynamic analysis of structural prop- erties and (iii) dynamic simulation. Structural analysis is related to the study of the topology or stoichiometry of the biological network such as important nodes of the net- work, network motifs and the analysis of the flux distribution within the network. Dy- namic analysis of structural properties, generally, takes advantage from the availability of interaction and expression datasets in order to analyze the structural properties of a biological network in different conditions or time points. Dynamic simulation is useful to study those changes of the biological system in time that cannot be derived from a structural analysis because it is required to have additional information on the dynamics of the system. This thesis addresses each of these topics proposing three computational techniques useful to study different types of biological networks in which the structural and dynamic analysis is crucial to answer to specific biological questions. In particu- lar, the thesis proposes computational techniques for the analysis of the network motifs of a biological network through the design of heuristics useful to efficiently solve the subgraph isomorphism problem, the construction of a new analysis workflow able to integrate interaction and expression datasets to extract information about the chromo- somal connectivity of miRNA-mRNA interaction networks and, finally, the design of a methodology that applies techniques coming from the Electronic Design Automation (EDA) field that allows the dynamic simulation of biochemical interaction networks and the parameter estimation

    The Signaling Petri Net-Based Simulator: A Non-Parametric Strategy for Characterizing the Dynamics of Cell-Specific Signaling Networks

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    Reconstructing cellular signaling networks and understanding how they work are major endeavors in cell biology. The scale and complexity of these networks, however, render their analysis using experimental biology approaches alone very challenging. As a result, computational methods have been developed and combined with experimental biology approaches, producing powerful tools for the analysis of these networks. These computational methods mostly fall on either end of a spectrum of model parameterization. On one end is a class of structural network analysis methods; these typically use the network connectivity alone to generate hypotheses about global properties. On the other end is a class of dynamic network analysis methods; these use, in addition to the connectivity, kinetic parameters of the biochemical reactions to predict the network's dynamic behavior. These predictions provide detailed insights into the properties that determine aspects of the network's structure and behavior. However, the difficulty of obtaining numerical values of kinetic parameters is widely recognized to limit the applicability of this latter class of methods

    Topological analysis of metabolic and regulatory networks by decomposition methods

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    Die lebenden Organismen sind fĂŒr eine wissenschaftliche Analyse zu kompliziert, wenn man sie als Ganzes und in ihrer vollen KomplexitĂ€t betrachtet. Die vorliegende Arbeit behandelt die topologischen Eigenschaften von zwei wichtigen Teilen der lebenden Organismen: die metabolischen und die regulatorischen Systeme. Topolgische Eigenschaften sind solche, die durch die Netwerkstruktur bedingt werden. Ein Signalsystem ist eine spezielle Art von regulatorischem System. Zwischen den metabolischen und Signalnetzen gibt es wichtige Unterschiede, die ihre Behandlung in unterschiedlicher Weise erfordert. In der metabolischen Pfadanalyse ist das Konzept der elementaren Flussmoden bereits als ein passendes Instrument fĂŒr die Charakterisierung der einfachsten essentiellen Wege in biochemischen Systemen etabliert. Wir untersuchen die Eigenschaften und Vorteile dieses Konzepts in einigen besonderen FĂ€llen. Zuerst untersuchen wir die vielfach vorkommenden Enzyme mit niedriger SpezifitĂ€t (z.B. Nukleosiddiphosphokinase, Uridinkinase, Transketolase, Transaldolase). Sie können parallel verschiedene Substrate und Produkte umwandeln. Auch die Enzym-Mechanismen sind vielfĂ€ltig, wie wir mit dem Reaktionsschema fĂŒr bifunktionelle Enzyme veranschaulichen. Wir betrachten dabei nur den Fall, dass ein bestimmtes aktives Zentrum mehrere Reaktionen katalysiert. Der Fall, dass das studierte Enzym mehrere solche aktiven Zentren hat, kann in den Fall mehrerer Enzyme transformiert werden, die nur ein aktives Zentrum haben. Wenn eine Krankheit das Ausgangsenzym Ă€ndert, werden dann in der Analyse auch alle ersetzenden Enzyme geĂ€ndert. Es gibt zwei unterschiedliche Betrachtungsweisen, um multifunktionelle Enzyme zu beschreiben. Zum einen kann man die Gesamtreaktionen betrachten und zum anderen die elementaren Reaktionsschritte (Hemireaktionen, Halbreaktionen). FĂŒr Enzyme mit zwei oder mehr Funktionen ist es wichtig, nur linear unabhĂ€ngige Funktionen zu betrachten, weil sonst zyklische elementare Moden auftreten wĂŒrden, die keine Nettoumwandlung durchfĂŒhren. Jedoch ist die Wahl der linear unabhĂ€ngigen Funktionen nicht a priori eindeutig. Wir stellen eine Methode fĂŒr das Treffen dieser Wahl vor, indem wir die konvexe Basis des Hemireaktions-Systems betrachten. Eine formale Anwendung des Algorithmus fĂŒr das Berechnen der elementaren Flussmoden (Routen) erbringt das Resultat, dass die Zahl solcher Moden manchmal vom Niveau der Beschreibung abhĂ€ngt, wenn einige Reaktionen reversibel sind und die Produkte der multifunktionellen Enzyme externe Metabolite sind, oder einige multifunktionelle Enzyme zum Teil die gleichen Stoffwechselprodukte umwandeln. Jedoch kann dieses Problem durch eine geeignete Deutung der Definition der elementaren Moden und die korrekte Wahl der unabhĂ€ngigen Funktionen der Multifunktionsenzyme gelöst werden. Die Analyse wird durch einige kleinere Beispiele und ein grĂ¶ĂŸeres biochemisches Beispiel veranschaulicht, das aus dem Nukleotidmetabolismus stammt und die zwei Arten der Beschreibung fĂŒr Nukleosiddiphosphokinase und Adenylatekinase vergleicht. Der Nukleotidmetabolismus spielt eine wichtige Rolle in lebenden Organismen und ist gegenĂŒber allen möglichen Störungen in seiner internen Balance sehr empfindlich. GefĂ€hrliche Krankheiten können auftreten, wenn einige Enzyme nicht richtig funktionieren. Mit Hilfe des Konzeptes des elementaren Flussmodus erklĂ€ren wir das Auftreten und den Schweregrad von Krankheiten, die auf Enzymdefizienzen basieren. Wenn ein Enzym vollstĂ€ndig gehemmt wird, werden einige metabolische Wege blockiert. Wenn jedoch einige alternative Wege noch bestehen, ist die Krankheit weniger gefĂ€hrlich. Unsere Analyse ist darauf gerichtet, alternative Wege, wesentliche Enzyme und solche Enzyme, die immer zusammenarbeiten zu finden. Der letzte Begriff ist auch als "Enzyme subset" bekannt und stellt einen intermediĂ€ren Schritt im Algorithmus zur Berechnung der elementaren Flussmoden dar. Wir diskutieren bereits bekannte und bisher nur hypothetische Mechanismen einiger Krankheiten (proliferative Krankheiten, Immundefizienzen), die auf Störungen des Nukleotidmetabolismus oder seiner Ausbeutung durch Viren und Parasiten beruhen. Die meisten Strategien, die fĂŒr das BekĂ€mpfen solcher Krankheiten eingesetzt werden, basieren auf der Unterbrechung des Nukleotidmetabolismus an bestimmten Stellen. Diese Strategien können aber auch zur Akkumulation toxischer Stoffe fĂŒhren und dadurch Nebenwirkungen hervorrufen. Deswegen hilft ein besseres VerstĂ€ndnis dieses Systems, wirkungsvollere Medikamente zu entwickeln, und eine gute strukturelle Analyse kann viele experimentelle BemĂŒhungen ersparen. Konzepte aus der Theorie der Petri-Netze liefern zusĂ€tzliche Werkzeuge fĂŒr das Modellieren metabolischer Netzwerke. In Kapitel 4 werden die Ă€hnlichkeiten zwischen einigen Konzepten in der traditionellen biochemischen Modellierung und analogen Konzepten aus der Petri-Netztheorie besprochen. Zum Beispiel entspricht die stochiometrische Matrix eines metabolischen Netzwerkes der Inzidenzmatrix des Petri-Netzes. Die Flussmoden und die Erhaltungs-Relationen haben die T-Invarianten beziehungsweise P-Invarianten als GegenstĂŒcke. Wir decken die biologische Bedeutung einiger weiterer Begriffe aus der Theorie der Petri-Netze auf, nĂ€mlich "traps", "{siphons", "deadlocks" und "Lebendigkeit". Wir konzentrieren uns auf der topologischen Analyse anstatt auf die Analyse des dynamischen Verhaltens. Die geeignete Behandlung der externen Stoffwechselprodukte wird ebenfalls besprochen. Zur Illustration werden einige einfache theoretische Beispiele vorgestellt. Außerdem werden einige Petri-Netze prĂ€sentiert, die konkreten biochemischen Netzen entsprechen, um unsere Resultate zu belegen. Zum Beispiel wird die Rolle der Triosephosphatisomerase (TPI) im Metabolismus von Trypanosoma brucei ausgewertet, indem "traps" und "siphons" ermittelt werden. Alle behandelten Eigenschaften von Petri-Netzen werden anhand eines Systems illustriert, das aus dem Nukleotidmetabolismus stammt. WĂ€hrend viele BemĂŒhungen fĂŒr das Zerlegen metabolischer Systeme, (elementare Flußmoden, extreme Wege) erfolgt sind, sind bisher unseres Wissens keine Versuche in dieser Richtung fĂŒr SignalĂŒbertragungssysteme unternommen worden. Eine spezielle Eigenschaft von Signalnetzwerken in lebenden Zellen ist, dass Aktivierungen, Hemmungen und biochemische Reaktionen normalerweise gleichzeitig anwesend sind. Selbst wenn sie nicht Reaktionen enthalten, machen Mehrfach-Aktivierungen oder Mehrfach-Hemmungen die Netzwerke in hohem Grade verzweigt. Es ist eine schwierige und sehr zeitraubende Aufgabe, alle Faktoren, die einen Einfluss auf ein gegebenes Ziel haben, ohne eine automatische Methode zu ermitteln. Bereits in Kapitel 1 heben wir die Ă€hnlichkeiten und Unterschiede zwischen den metabolischen und Signal-Netzwerken hervor. In Kapitel 5 errichten wir einen Rahmen und prĂ€sentieren einen Algorithmus fĂŒr die Zerlegung von Signalnetzwerken in kleinere Einheiten, die einfacher zu studieren und zu verstehen sind. Zwei FĂ€lle werden untersucht: ein einfacheres, wenn nur monomolekulare Aktivierungen oder Reaktionen anwesend sind, und ein komplizierterer Fall, wenn die Aktivierungen und die Reaktionen multimolekular sein können. Ihre Beschreibung erfordert unterschiedliche Methoden: klassische Graphen bzw. Petrinetze. Wir besprechen die Probleme, die in unserem Modell wegen des Vorhandenseins von Hemmungen oder von unbekannten Effekten im Netz auftreten. Der vorgeschlagene Algorithmus ermittelt die Faktoren, die zusammenwirken und die Zielsubstanzen, die auf dem gleichen Weg beeinflusst werden. Die Zyklen, die im System auftreten, und mögliche fehlende Reaktionen werden ebenfalls ermittelt . Theoretische Beispiele veranschaulichen unsere Resultate. Anhand der T-Zell-Antigen-Rezeptor-Signalkaskade zeigen wir, wie die Methoden in realen Systemen angewendet werden können.The living organisms are too complex when considering them as a whole. The present thesis deals with the topological properties of two important parts of living organisms: the metabolic and the regulatory systems. The topological properties are those features that are determined by the network structure. A classification in metabolic and regulatory systems is often used. A signalling system is a special kind of regulatory system. Between metabolic and signalling networks, there are important differences that impose their treatment in different ways. In metabolic pathway analysis, the elementary flux mode concept is already established as a proper tool for identifying the smallest essential routes in biochemical systems. We examine its features and advantages in some particular cases. Firstly, many enzymes operate with low specificity (e.g. nucleoside diphosphokinase, uridine kinase, transketolase, transaldolase), so that various substrates and products can be converted. Also the enzymatic mechanisms are diverse, as we have illustrated with reaction schemes for bifunctional enzymes. Therefore, there are two different approaches to describe multifunctional enzymes (We considered only the case when a certain active site hosts several reactions. The case when the studied enzyme has several such active sites can be transformed into that of several enzymes having only one active site. If a disease alters the initial enzyme, also all substituting enzymes are altered.): in terms of overall reactions and in terms of reactions steps (hemi-reactions, half-reactions). For enzymes with two or more functions, it is important to consider only linearly independent functions, because otherwise cyclic elementary modes would occur which do not perform any net transformation. However, the choice of linearly independent functions is not a priori unique. In Chapter 2, we give a method for making this choice unique by considering the convex basis of the hemi-reactions system. The set of linearly independent functions provided by our algorithm coincides, in the case of transketolase in pentose phosphate pathway, with the set of linearly independent functions mentioned in literature. A formal application of the algorithm for computing elementary flux modes (pathways) yields the result that the number of such modes sometimes depends on the level of description if some reactions are reversible and the products of the multifunctional enzymes are external metabolites or some multifunctional enzymes partly share the same metabolites. However, this problem can be solved by appropriate interpretation of the definition of elementary modes and the correct choice of independent functions of multifunctional enzymes. The analysis is illustrated by a biochemical example taken from nucleotide metabolism, comparing the two ways of description for nucleoside diphosphokinase and adenylate kinase, and by several smaller examples. The nucleotide metabolism plays an important role in living organisms and is very sensitive to any perturbations in its internal balance. Dangerous diseases may occur if some enzymes do not work properly. With the help of elementary flux mode concept, we explain the occurrence and severity of diseases based on enzyme deficiencies. If an enzyme is completely inhibited, some metabolic routes are blocked. If, however, some alternative routes still exist, the disease is less dangerous. In Chapter 3, we focus on finding alternative routes, essential enzymes and enzymes operating together. The latter notion is also known as ,,enzyme subset`` and represents an intermediary step in calculating the elementary flux modes. The known or hypothesised mechanisms of several disorders, occurred due to the malfunctioning of nucleotide metabolism (proliferative diseases, immunodeficiency diseases) or due to its hijacking by viruses and parasites, are given. Most strategies adopted for curing such diseases are based on nucleotide metabolism interruption. Therefore, a better understanding of this system helps developing more effective drugs and a good structural analysis can spare many experimental efforts. Petri net concepts provide additional tools for the modelling of metabolic networks. In Chapter 4, the similarities between the counterparts in traditional biochemical modelling and Petri net theory are discussed. For example, the stoichiometry matrix of a metabolic network corresponds to the incidence matrix of the Petri net. The flux modes and conservation relations have the T-invariants, respectively, P-invariants as counterparts. We reveal the biological meaning of some notions specific to the Petri net framework (traps, siphons, deadlocks, liveness). We focus on the topological analysis rather than on the analysis of the dynamic behaviour. The treatment of external metabolites is discussed. Some simple theoretical examples are presented for illustration. Also the Petri nets corresponding to some biochemical networks are built to support our results. For example, the role of triose phosphate isomerase (TPI) in Trypanosoma brucei metabolism is evaluated by detecting siphons and traps. All Petri net properties treated in above-mentioned chapter (4) are exemplified on a system extracted from nucleotide metabolism. While for decomposing metabolic systems, many efforts have been done (elementary flux modes, convex basis, extreme pathways), for signalling maps, as far as we know, no attempt in this direction has been made. A special characteristic of signalling networks is that activations, inhibitions, and biochemical reactions are normally present in parallel. Even if they do not contain reactions, multi-part activations or inhibitions make them highly branched. To detect all factors that have an influence on a given target, without using an automatic method, is a difficult and very time-consuming effort. Already in Chapter 1 (Backgrounds), we highlight the similarities and differences between metabolic and signalling networks. In Chapter 5, we build a framework and algorithm for decomposing signalling networks in smaller units, which are easier to study and understand. Two cases are investigated: a simpler one, when only monomolecular activations or reactions are present, and a more complex case, when the activations and reactions can be multimolecular. Their description requires different instruments: classical graphs and Petri nets, respectively. We discuss the problems that occur in our model due to the presence of some inhibitions or unknown effects in the network. The algorithm that we propose detects the factors that are acting together and the targets that are affected on the same route. The cycles that occur in the system are also highlighted. We point out possible missing reactions. Theoretical examples illustrate out findings. Using the T cell antigen-receptor signalling cascade, we show how it can be applied to real systems

    Structural Vulnerability Analysis of Electric Power Distribution Grids

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    Power grid outages cause huge economical and societal costs. Disruptions in the power distribution grid are responsible for a significant fraction of electric power unavailability to customers. The impact of extreme weather conditions, continuously increasing demand, and the over-ageing of assets in the grid, deteriorates the safety of electric power delivery in the near future. It is this dependence on electric power that necessitates further research in the power distribution grid security assessment. Thus measures to analyze the robustness characteristics and to identify vulnerabilities as they exist in the grid are of utmost importance. This research investigates exactly those concepts- the vulnerability and robustness of power distribution grids from a topological point of view, and proposes a metric to quantify them with respect to assets in a distribution grid. Real-world data is used to demonstrate the applicability of the proposed metric as a tool to assess the criticality of assets in a distribution grid

    Ad hoc network security and modeling with stochastic petri nets

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    Advances in wireless technology and portable computing along with demands for high user mobility have provided a major promotion toward the development of ad hoc networks. These networks feature dynamic topology, self-organization, limited bandwidth and battery power of a node. Unlike the existing commercial wireless systems and fixed infrastructure networks, they do not rely on specialized routers for path discovery and traffic routing. Security is an important issue in such networks. Typically, mobile nodes are significantly more susceptible to physical attacks than their wired counterparts. This research intends to investigate the ad hoc network routing security by proposing a performance enhanced Secure ad hoc On-demand Routing protocol (SOR). Specifically, it presents a method to embed Security Level into ad hoc on-demand routing protocols using node-disjoint multipath, and to use maximum hopcount to restrict the number of routing packets in a specific area. The proposed scheme enables the use of security as a marked factor to improve the relevance of the routes discovered by ad hoc routing protocols. It provides customizable security to the flow of routing protocol messages. In general, SOR offers an alternative way to implement security in on-demand routing protocols. Ad hoc network is too complex to allow analytical study for explicit performance expressions. This research presents a Stochastic Petri net-based approach to modeling and analysis of mobile ad hoc network. This work illustrates how this model is built as a scalable model and used to exploit the characteristics of the networks. The proposed scheme is a powerful analytical model that can be used to derive network performance much more easily than a simulation-based approach. Furthermore, the proposed model is extended to study the performance of ad hoc network security by adding multipath selection and security measurement parameters. This research gives a quantificational measurement to analyze the performance of a modified SPN model under the effect of multipath and attack of a hypothetical compromised node

    IMPLEMENTATION AND UNIFORM MANAGEMENT OF MODELLING ENTITIES IN A MASSIVELY FEATURE-OBJECT ORIENTED ADVANCED CAD ENVIRONMENT

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    Today we are spectators of the transition process in computer aided design from traditional geometry based on design systems to advanced computer-based engineering systems. The key is the feature technology that allows both integrating and managing modelling entities in a coherent way. Feature technology is developing rapidly. New research topics and contexts are emerging from time to time. This paper introduces concept, design and technological feature-objects to support operational, structural and morphological modelling of mechanical products. First, the feature-centred approaches to conceptual design are summarized and evaluated. Then an implementation of concept feature-objects and the methodology for using them is presented. The strength of concept feature-objects is in their morphology inclusive nature. They appear as parametrized three-dimensional skeletons providing geometrical representations for the modelled engineering conceptions. A concept feature-object models the physical ports, contact surfaces related to ports, bones between ports, DOF of ports, relevant physical parameters, scientific and empirical descriptions of intentional transformations and environmental effects. Concept feature-objects are related to design feature-objects that, in turn, are constructed of a relevant set of technological feature-entities. Concept feature-objects refer to the configurable and parametrized design feature-objects through an indexing mechanism. The conceptions have been tested during the programming and further development of the authors' PRODES system

    A Risk Management Approach to Business Process Design

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