Dépliages et interprétation abstraite pour réseaux de régulation biologiques paramétrés

The analysis of dynamics of biological regulatory networks, notably signalling and gene regulatory networks, faces the uncertainty of the exact computational model. Indeed, most of the knowledge available concerns the existence of (possibly indirect) interactions between biological entities (species), e.g. proteins, RNAs, genes, etc. The details on how different regulators of a same target cooperate, and even more so on consistent rates for those interactions, however, are rarely available. In this regard, qualitative modelling approaches in the form of discrete regulatory networks, such as Boolean and Thomas networks, offer an appropriate level of abstraction for the biological regulatory network dynamics. As discrete regulatory networks are based on an influence graph, they require few additional parameters compared to classical quantitative models. Nevertheless, determining the discrete parameters is a well known challenge, and a major bottleneck for providing robust predictions from computational models.The influence graph of a regulatory network establishes dependencies for the evolution of each specie, specified by the directed edges of the graph. The dependencies alone, however, do not suffice to specify the logical function governing the evolution of a specie. Instead the logical functions associated to each specie, constrained by the influence graph, are encoded within the parameters of a discrete regulatory network. The space of admissible logical functions is then represented by a parametric regulatory network. On the one hand, parametric regulatory networks can be used for identification of parameter values for which the resulting discrete regulatory network satisfies given (dynamical) properties. Parameter identification of regulatory networks can thus be seen as a particular instance of model synthesis, in the constrained setting of the underlying influence graph. On the other hand, parametric regulatory networks may be analysed as a stand-alone model, for making predictions that are robust with respect to variability in the network.The analysis of parametric regulatory network dynamics is hampered by dual combinatorial explosion, of the state space and of the parameter space. In this thesis, we develop novel methods of parametric regulatory network analysis, in the form of specialised semantics, aimed at alleviating the combinatorial explosion. First, we introduce abstract interpretation for the set of admissible parameter evaluations (parametrisations).The abstraction allows us to represent any set of parametrisations by a constant size encoding, at the cost of a conservative over-approximation. Second, we lift partial order semantics in the form of unfolding from Petri nets to parametric regulatory networks. The influence graphs of biological regulatory networks tend to be relatively sparse, allowing for a lot of concurrency. This can be harnessed by partial order reduction methods to produce concise state space representations.The two approaches are aimed at tackling both aspects of the dual combinatorial explosion and are introduced in a compatible manner, allowing one to employ them simultaneously. Such application is supported by a prototype implementation used to conduct experiments on various parametric regulatory networks. We further consider refinements of the methods, such as an on-the-run model reduction method lifted to parametric regulatory networks from automata networks.L'analyse de la dynamique des réseaux de régulation biologique, notamment des réseaux de signalisation et de régulation génique, fait face à l'incertitude du modèle de calcul exact. En effet, la plupart des connaissances disponibles concernent l'existence d'interactions (éventuellement indirectes) entre des entités biologiques (espèces), par ex. protéines, ARN, gènes, etc. Les détails sur la manière dont les différents régulateurs d'une même cible coopèrent, et plus encore sur les taux cohérents pour ces interactions, sont cependant rarement disponibles. A cet égard, des approches de modélisation qualitative sous forme de réseaux de régulation discrets, tels que les réseaux booléens et Thomas, offrir un niveau d'abstraction approprié pour la dynamique du réseau de régulation biologique. Les réseaux de régulation discrets étant basés sur un graphe d'influence, ils nécessitent peu de paramètres supplémentaires par rapport aux modèles quantitatifs classiques. Néanmoins, la détermination des paramètres discrets est un défi bien connu et un goulot d'étranglement majeur pour fournir des prédictions robustes à partir de modèles informatiques.Le graphe d'influence d'un réseau de régulation établit des dépendances pour l'évolution de chaque espèce, spécifiées par les arêtes dirigées du graphe. Les dépendances seules, cependant, ne suffisent pas pour spécifier la fonction logique régissant l'évolution d'une espèce. Au lieu de cela, les fonctions logiques associées à chaque espèce, contraintes par le graphe d'influence, sont codées dans les paramètres d'un réseau de régulation discret. L'espace des fonctions logiques admissibles est alors représenté par un réseau de régulation paramétrique. D'une part, les réseaux de régulation paramétriques peuvent être utilisés pour l'identification de valeurs de paramètres pour lesquelles le réseau de régulation discret résultant satisfait des propriétés (dynamiques) données. L'identification des paramètres des réseaux de régulation peut ainsi être vue comme un exemple particulier de synthèse de modèle, dans le cadre contraint du graphe d'influence sous-jacent. D'autre part, les réseaux de régulation paramétriques peuvent être analysés comme un modèle autonome, pour faire des prédictions robustes vis-à-vis de la variabilité du réseau.L'analyse de la dynamique du réseau de régulation paramétrique est entravée par la double explosion combinatoire, de l'espace d'états et de l'espace des paramètres. Dans cette thèse, nous développons de nouvelles méthodes d'analyse de réseau de régulation paramétrique, sous forme de sémantique spécialisée, visant à atténuer l'explosion combinatoire. Tout d'abord, nous introduisons une interprétation abstraite de l'ensemble des évaluations de paramètres admissibles (paramétrisations). L'abstraction permet de représenter n'importe quel ensemble de paramétrisations par un encodage de taille constante, au prix d'une sur-approximation conservatrice. Deuxièmement, nous élevons la sémantique d'ordre partiel sous la forme d'un déploiement des réseaux de Petri vers des réseaux de régulation paramétriques. Les graphiques d'influence des réseaux de régulation biologique ont tendance à être relativement clairsemés, ce qui permet une grande concurrence. Cela peut être exploité par des méthodes de réduction d'ordre partiel pour produire des représentations d'espace d'état concises.Les deux approches visent à aborder les deux aspects de la double explosion combinatoire et sont introduites de manière compatible, ce qui permet de les utiliser simultanément. Une telle application est soutenue par une implémentation prototype utilisée pour mener des expériences sur divers réseaux de régulation paramétriques. Nous considérons en outre des raffinements des méthodes, comme une méthode de réduction de modèle à la volée portée aux réseaux de régulation paramétriques à partir de réseaux d'automates

Relating the Chondrocyte Gene Network to Growth Plate Morphology: From Genes to Phenotype

During endochondral ossification, chondrocyte growth and differentiation is controlled by many local signalling pathways. Due to crosstalks and feedback mechanisms, these interwoven pathways display a network like structure. In this study, a large-scale literature based logical model of the growth plate network was developed. The network is able to capture the different states (resting, proliferating and hypertrophic) that chondrocytes go through as they progress within the growth plate. In a first corroboration step, the effect of mutations in various signalling pathways of the growth plate network was investigated

Information-theoretic approach to the study of control systems

We propose an information-theoretic framework for analyzing control systems based on the close relationship of controllers to communication channels. A communication channel takes an input state and transforms it into an output state. A controller, similarly, takes the initial state of a system to be controlled and transforms it into a target state. In this sense, a controller can be thought of as an actuation channel that acts on inputs to produce desired outputs. In this transformation process, two different control strategies can be adopted: (i) the controller applies an actuation dynamics that is independent of the state of the system to be controlled (open-loop control); or (ii) the controller enacts an actuation dynamics that is based on some information about the state of the controlled system (closed-loop control). Using this communication channel model of control, we provide necessary and sufficient conditions for a system to be perfectly controllable and perfectly observable in terms of information and entropy. In addition, we derive a quantitative trade-off between the amount of information gathered by a closed-loop controller and its relative performance advantage over an open-loop controller in stabilizing a system. This work supplements earlier results [H. Touchette, S. Lloyd, Phys. Rev. Lett. 84, 1156 (2000)] by providing new derivations of the advantage afforded by closed-loop control and by proposing an information-based optimality criterion for control systems. New applications of this approach pertaining to proportional controllers, and the control of chaotic maps are also presented.Comment: 18 pages, 7 eps figure

A uniform approach to the complexity and analysis of succinct systems

“ This thesis provides a unifying view on the succinctness of systems: the capability of a modeling formalism to describe the behavior of a system of exponential size using a polynomial syntax. The key theoretical contribution is the introduction of sequential circuit machines as a new universal computation model that focuses on succinctness as the central aspect. The thesis demonstrates that many well-known modeling formalisms such as communicating state machines, linear-time temporal logic, or timed automata exhibit an immediate connection to this machine model. Once a (syntactic) connection is established, many complexity bounds for structurally restricted sequential circuit machines can be transferred to a certain formalism in a uniform manner. As a consequence, besides a far-reaching unification of independent lines of research, we are also able to provide matching complexity bounds for various analysis problems, whose complexities were not known so far. For example, we establish matching lower and upper bounds of the small witness problem and several variants of the bounded synthesis problem for timed automata, a particularly important succinct modeling formalism. Also for timed automata, our complexity-theoretic analysis leads to the identification of tractable fragments of the timed synthesis problem under partial observability. Specifically, we identify timed controller synthesis based on discrete or template-based controllers to be equivalent to model checking. Based on this discovery, we develop a new model checking-based algorithm to efficiently find feasible template instantiations. From a more practical perspective, this thesis also studies the preservation of succinctness in analysis algorithms using symbolic data structures. While efficient techniques exist for specific forms of succinctness considered in isolation, we present a general approach based on abstraction refinement to combine off-the-shelf symbolic data structures. In particular, for handling the combination of concurrency and quantitative timing behavior in networks of timed automata, we report on the tool Synthia which combines binary decision diagrams with difference bound matrices. In a comparison with the timed model checker Uppaal and the timed game solver Tiga running on standard benchmarks from the timed model checking and synthesis domain, respectively, the experimental results clearly demonstrate the effectiveness of our new approach.Diese Dissertation liefert eine vereinheitlichende Sicht auf die Kompaktheit von Systemen: die Fähigkeit eines Modellierungsformalismus, das Verhalten eines Systems exponentieller Größe mit polynomieller Syntax zu beschreiben. Der wesentliche theoretische Beitrag ist die Einführung von sequenziellen Schaltkreis-Maschinen als neues universelles Berechnungsmodell, das sich auf den zentralen Aspekt der Kompaktheit konzentriert. Die Dissertation demonstriert, dass viele bekannte Modellierungsformalismen, wie z.B. kommunizierende Zustandsmaschinen, linear-Zeit temporale Logik (LTL) oder gezeitete Automaten eine direkte Verbindung zu diesem Maschinenmodell aufzeigen. Sobald eine (syntaktische) Verbindung hergestellt ist, können viele Komplexitätsschranken für strukturell beschränkte sequenzielle Schaltkreis-Maschinen für einen bestimmten Formalismus einheitlich übernommen werden. Neben einer weitreichenden Vereinheitlichung unabhängiger Forschungsrichtungen können auch zahlreiche Komplexitätsschranken für Analyse-Probleme etabliert werden, deren genaue Komplexität bisher noch nicht bekannt war. Zum Beispiel werden passende untere und obere Schranken des small witness Problems und mehrere Varianten des Synthese-Problems von Controllern mit beschränkter Größe für gezeitete Automaten bewiesen. Die theoretische Analyse deckt Fragmente geringerer Komplexität des partiell informierten Syntheseproblems für gezeitete Automaten auf. Es wird im Besonderen gezeigt, dass das gezeitete Syntheseproblem für diskrete oder Vorlagen-basierte Controller äquivalent zum Model Checking-Problem ist. Basierend auf dieser Einsicht wird ein neuartiger Model Checking-basierter Algorithmus zur effizienten Synthese von gültigen Instantiierungen von Vorlagen entwickelt. Der praktische Beitrag der Dissertation untersucht die Erhaltung von Kompaktheit in Analyse-Algorithmen durch die Benutzung symbolischer Datenstrukturen. Es wird ein allgemeiner Ansatz zur Kombination von Standard-Datenstrukturen vorgestellt, die jeweils bisher nur in Isolation verwendet werden konnten. Insbesondere wird für die Analyse von Netzwerken von gezeiteten Automaten das Tool Synthia vorgestellt, welches binäre Entscheidungs-Diagramme mit Differenzen-Matrizen verbindet. In einem experimentellen Vergleich mit den Tools Uppaal und Tiga wird klar die Effektivität des neuen Ansatzes belegt

Stability Analysis and Control of Several Classes of Logical Dynamic Systems and the Applications in Game Theory

With the rapid development of complex networks, logical dynamic systems have been commonly used mathematical models for simulating Genetic Regulatory Networks (GRNs) and Networked Evolutionary Games (NEGs), which have attracted considerable attention from biology, economy and many other fields. By resorting to the Semi-Tensor Product (STP) of matrices, logical dynamic systems can be equivalently converted into discrete time linear systems with algebraic forms. Based on that, this thesis analyzes the stability and studies the control design problems of several classes of logical dynamic systems. Moreover, the obtained results are applied to investigate the control and optimization problems of NEGs. The main results of this thesis are the following. • The stability and event-triggered control for a class of k-Valued Logical Networks (KVLNs) with time delays are studied. First, some necessary and sufficient con- ditions are obtained to detect the stability of Delayed k-Valued Logical Networks (DKVLNs). Second, the global stabilization problem under event-triggered control is considered, and some necessary and sufficient conditions are presented for the sta- bilization of Delayed k-Valued Logical Control Networks (DKVLCNs). Moreover, an algorithm is proposed to construct all the event-triggered state feedback controllers via antecedence solution technique. • The robust control invariance and robust set stabilization problems for a class of Mix- Valued Logical Control Networks (MVLCNs) with disturbances are studied. First, a calculation method for the Largest Robust Control Invariant Set (LRCIS) contained in a given set is introduced. Second, based on the Robust Control Invariant Subset (RCIS) obtained, the robust set stabilization of MVLCNs is discussed, and some new results are presented. Furthermore, the design algorithm of time-optimal state feedback stabilizers via antecedence solution technique is derived. • The robust set stability and robust set stabilization problems for a class of Probabilis- tic Boolean Control Networks (PBCNs) with disturbances are studied. An algorithm to determine the Largest Robust Invariant Set (LRIS) with probability 1 of a given set for a Probabilistic Boolean Network (PBN) is proposed, and the necessary and sufficient conditions to detect whether the PBN is globally finite-time stable to this invariant set with probability 1 are established. Then, the PBNs with control inputs are considered, and an algorithm for LRCIS with probability 1 is provided, based on which, some necessary and sufficient conditions for finite-time robust set stabiliza- tion with probability 1 of PBCNs are presented. Furthermore, the design scheme of time-optimal state feedback stabilizers via antecedence solution technique is derived. • The stabilization and set stabilization problems for a class of Switched Boolean Con- trol Networks (SBCNs) with periodic switching signal are studied. First, algebraic forms are constructed for SBCNs with periodic switching signal. Second, based on the algebraic formulations, the stabilization and set stabilization of SBCNs with peri- odic switching signal are discussed, and some new results are presented. Furthermore, constructive procedure of open loop controllers is given, and the design algorithms of switching-signal-dependent state feedback controllers via antecedence solution tech- nique are derived. • The dynamics and control problems for a class of NEGs with time-invariant delay in strategies are studied. First, algebraic forms are constructed for Delayed Networked Evolutionary Games (DNEGs). Second, based on the algebraic formulations, some necessary and sufficient conditions for the global convergence of desired strategy pro- file under a state feedback event-triggered controller are presented. Furthermore, the constructive procedure and the number of all valid event-triggered state feedback controllers are derived, which can make the game converge globally. • The evolutionary dynamics and optimization problems of the networked evolutionary boxed pig games with the mechanism of passive reward and punishment are studied. First, an algorithm is provided to construct the algebraic formulation for the dynamics of this kind of games. Then, the impact of reward and punishment parameters on the final cooperation level of the whole network is discussed

Tools and Algorithms for the Construction and Analysis of Systems

This open access book constitutes the proceedings of the 28th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2022, which was held during April 2-7, 2022, in Munich, Germany, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2022. The 46 full papers and 4 short papers presented in this volume were carefully reviewed and selected from 159 submissions. The proceedings also contain 16 tool papers of the affiliated competition SV-Comp and 1 paper consisting of the competition report. TACAS is a forum for researchers, developers, and users interested in rigorously based tools and algorithms for the construction and analysis of systems. The conference aims to bridge the gaps between different communities with this common interest and to support them in their quest to improve the utility, reliability, exibility, and efficiency of tools and algorithms for building computer-controlled systems

Tools and Algorithms for the Construction and Analysis of Systems

This open access book constitutes the proceedings of the 28th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2022, which was held during April 2-7, 2022, in Munich, Germany, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2022. The 46 full papers and 4 short papers presented in this volume were carefully reviewed and selected from 159 submissions. The proceedings also contain 16 tool papers of the affiliated competition SV-Comp and 1 paper consisting of the competition report. TACAS is a forum for researchers, developers, and users interested in rigorously based tools and algorithms for the construction and analysis of systems. The conference aims to bridge the gaps between different communities with this common interest and to support them in their quest to improve the utility, reliability, exibility, and efficiency of tools and algorithms for building computer-controlled systems

Foundations of Stochastic Thermodynamics

Small systems in a thermodynamic medium --- like colloids in a suspension or the molecular machinery in living cells --- are strongly affected by the thermal fluctuations of their environment. Physicists model such systems by means of stochastic processes. Stochastic Thermodynamics (ST) defines entropy changes and other thermodynamic notions for individual realizations of such processes. It applies to situations far from equilibrium and provides a unified approach to stochastic fluctuation relations. Its predictions have been studied and verified experimentally. This thesis addresses the theoretical foundations of ST. Its focus is on the following two aspects: (i) The stochastic nature of mesoscopic observations has its origin in the molecular chaos on the microscopic level. Can one derive ST from an underlying reversible deterministic dynamics? Can we interpret ST's notions of entropy and entropy changes in a well-defined information-theoretical framework? (ii) Markovian jump processes on finite state spaces are common models for bio-chemical pathways. How does one quantify and calculate fluctuations of physical observables in such models? What role does the topology of the network of states play? How can we apply our abstract results to the design of models for molecular motors? The thesis concludes with an outlook on dissipation as information written to unobserved degrees of freedom --- a perspective that yields a consistency criterion between dynamical models formulated on various levels of description.Comment: Ph.D. Thesis, G\"ottingen 2014, Keywords: Stochastic Thermodynamics, Entropy, Dissipation, Markov processes, Large Deviation Theory, Molecular Motors, Kinesi