On functional module detection in metabolic networks

Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady-state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

A case study in model-driven synthetic biology

We report on a case study in synthetic biology, demonstrating the modeldriven design of a self-powering electrochemical biosensor. An essential result of the design process is a general template of a biosensor, which can be instantiated to be adapted to specific pollutants. This template represents a gene expression network extended by metabolic activity. We illustrate the model-based analysis of this template using qualitative, stochastic and continuous Petri nets and related analysis techniques, contributing to a reliable and robust design

A bibliography on formal methods for system specification, design and validation

Literature on the specification, design, verification, testing, and evaluation of avionics systems was surveyed, providing 655 citations. Journal papers, conference papers, and technical reports are included. Manual and computer-based methods were employed. Keywords used in the online search are listed

Approaching the Coverability Problem Continuously

The coverability problem for Petri nets plays a central role in the verification of concurrent shared-memory programs. However, its high EXPSPACE-complete complexity poses a challenge when encountered in real-world instances. In this paper, we develop a new approach to this problem which is primarily based on applying forward coverability in continuous Petri nets as a pruning criterion inside a backward coverability framework. A cornerstone of our approach is the efficient encoding of a recently developed polynomial-time algorithm for reachability in continuous Petri nets into SMT. We demonstrate the effectiveness of our approach on standard benchmarks from the literature, which shows that our approach decides significantly more instances than any existing tool and is in addition often much faster, in particular on large instances.Comment: 18 pages, 4 figure

Static Analysis of Deterministic Negotiations

Negotiation diagrams are a model of concurrent computation akin to workflow Petri nets. Deterministic negotiation diagrams, equivalent to the much studied and used free-choice workflow Petri nets, are surprisingly amenable to verification. Soundness (a property close to deadlock-freedom) can be decided in PTIME. Further, other fundamental questions like computing summaries or the expected cost, can also be solved in PTIME for sound deterministic negotiation diagrams, while they are PSPACE-complete in the general case. In this paper we generalize and explain these results. We extend the classical "meet-over-all-paths" (MOP) formulation of static analysis problems to our concurrent setting, and introduce Mazurkiewicz-invariant analysis problems, which encompass the questions above and new ones. We show that any Mazurkiewicz-invariant analysis problem can be solved in PTIME for sound deterministic negotiations whenever it is in PTIME for sequential flow-graphs---even though the flow-graph of a deterministic negotiation diagram can be exponentially larger than the diagram itself. This gives a common explanation to the low-complexity of all the analysis questions studied so far. Finally, we show that classical gen/kill analyses are also an instance of our framework, and obtain a PTIME algorithm for detecting anti-patterns in free-choice workflow Petri nets. Our result is based on a novel decomposition theorem, of independent interest, showing that sound deterministic negotiation diagrams can be hierarchically decomposed into (possibly overlapping) smaller sound diagrams.Comment: To appear in the Proceedings of LICS 2017, IEEE Computer Societ

Delays in acyclical distributed decisionmaking organizations

Bibliography: leaf 6.Office of Naval Research contract N00014-84-K-0519 (NR 649-003) Office of Naval Research contract N00014-85-K-0782 (NR 964-001)by Victoria Y-Y Jin, Alexander H. Levis, Pascal A. Remy

The Hardness of Finding Linear Ranking Functions for Lasso Programs

Finding whether a linear-constraint loop has a linear ranking function is an important key to understanding the loop behavior, proving its termination and establishing iteration bounds. If no preconditions are provided, the decision problem is known to be in coNP when variables range over the integers and in PTIME for the rational numbers, or real numbers. Here we show that deciding whether a linear-constraint loop with a precondition, specifically with partially-specified input, has a linear ranking function is EXPSPACE-hard over the integers, and PSPACE-hard over the rationals. The precise complexity of these decision problems is yet unknown. The EXPSPACE lower bound is derived from the reachability problem for Petri nets (equivalently, Vector Addition Systems), and possibly indicates an even stronger lower bound (subject to open problems in VAS theory). The lower bound for the rationals follows from a novel simulation of Boolean programs. Lower bounds are also given for the problem of deciding if a linear ranking-function supported by a particular form of inductive invariant exists. For loops over integers, the problem is PSPACE-hard for convex polyhedral invariants and EXPSPACE-hard for downward-closed sets of natural numbers as invariants.Comment: In Proceedings GandALF 2014, arXiv:1408.5560. I thank the organizers of the Dagstuhl Seminar 14141, "Reachability Problems for Infinite-State Systems", for the opportunity to present an early draft of this wor