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

Efficient Automata-based Planning and Control under Spatio-Temporal Logic Specifications

The use of spatio-temporal logics in control is motivated by the need to impose complex spatial and temporal behavior on dynamical systems, and to control these systems accordingly. Synthesizing correct-by-design control laws is a challenging task resulting in computationally demanding methods. We consider efficient automata-based planning for continuous-time systems under signal interval temporal logic specifications, an expressive fragment of signal temporal logic. The planning is based on recent results for automata-based verification of metric interval temporal logic. A timed signal transducer is obtained accepting all Boolean signals that satisfy a metric interval temporal logic specification, which is abstracted from the signal interval temporal logic specification at hand. This transducer is modified to account for the spatial properties of the signal interval temporal logic specification, characterizing all real-valued signals that satisfy this specification. Using logic-based feedback control laws, such as the ones we have presented in earlier works, we then provide an abstraction of the system that, in a suitable way, aligns with the modified timed signal transducer. This allows to avoid the state space explosion that is typically induced by forming a product automaton between an abstraction of the system and the specification.Comment: 8 pages - Accepted for Publication at ACC 202

Deriving real-time action systems with multiple time bands using algebraic reasoning

The verify-while-develop paradigm allows one to incrementally develop programs from their specifications using a series of calculations against the remaining proof obligations. This paper presents a derivation method for real-time systems with realistic constraints on their behaviour. We develop a high-level interval-based logic that provides flexibility in an implementation, yet allows algebraic reasoning over multiple granularities and sampling multiple sensors with delay. The semantics of an action system is given in terms of interval predicates and algebraic operators to unify the logics for an action system and its properties, which in turn simplifies the calculations and derivations

An Algebra of Synchronous Scheduling Interfaces

In this paper we propose an algebra of synchronous scheduling interfaces which combines the expressiveness of Boolean algebra for logical and functional behaviour with the min-max-plus arithmetic for quantifying the non-functional aspects of synchronous interfaces. The interface theory arises from a realisability interpretation of intuitionistic modal logic (also known as Curry-Howard-Isomorphism or propositions-as-types principle). The resulting algebra of interface types aims to provide a general setting for specifying type-directed and compositional analyses of worst-case scheduling bounds. It covers synchronous control flow under concurrent, multi-processing or multi-threading execution and permits precise statements about exactness and coverage of the analyses supporting a variety of abstractions. The paper illustrates the expressiveness of the algebra by way of some examples taken from network flow problems, shortest-path, task scheduling and worst-case reaction times in synchronous programming.Comment: In Proceedings FIT 2010, arXiv:1101.426

Fluid Model Checking

In this paper we investigate a potential use of fluid approximation techniques in the context of stochastic model checking of CSL formulae. We focus on properties describing the behaviour of a single agent in a (large) population of agents, exploiting a limit result known also as fast simulation. In particular, we will approximate the behaviour of a single agent with a time-inhomogeneous CTMC which depends on the environment and on the other agents only through the solution of the fluid differential equation. We will prove the asymptotic correctness of our approach in terms of satisfiability of CSL formulae and of reachability probabilities. We will also present a procedure to model check time-inhomogeneous CTMC against CSL formulae

Doctor of Philosophy

dissertationOver the past few decades, synthetic biology has generated great interest to biologists and engineers alike. Synthetic biology combines the research of biology with the engineering principles of standards, abstraction, and automated construction with the ultimate goal of being able to design and build useful biological systems. To realize this goal, researchers are actively working on better ways to model and analyze synthetic genetic circuits, groupings of genes that influence the expression of each other through the use of proteins. When designing and analyzing genetic circuits, researchers are often interested in building circuits that exhibit a particular behavior. Usually, this involves simulating their models to produce some time series data and analyzing this data to discern whether or not the circuit behaves appropriately. This method becomes less attractive as circuits grow in complexity because it becomes very time consuming to generate a sufficient amount of runs for analysis. In addition, trying to select representative runs out of a large data set is tedious and error-prone thereby motivating methods of automating this analysis. This has led to the need for design space exploration techniques that allow synthetic biologists to easily explore the effect of varying parameters and efficiently consider alternative designs of their systems. This dissertation attempts to address this need by proposing new analysis and verification techniques for synthetic genetic circuits. In particular, it applies formal methods such as model checking techniques to models of genetic circuits in order to ensure that they behave correctly and are as robust as possible for a variety of different inputs and/or parameter settings. However, model checking stochastic systems is not as simple as model checking deterministic systems where it is always known what the next state of the system will be at any given step. Stochastic systems can exhibit a variety of different behaviors that are chosen randomly with different probabilities at each time step. Therefore, model checking a stochastic system involves calculating the probability that the system will exhibit a desired behavior. Although it is often more difficult to work with the probabilities that stochastic systems introduce, stochastic systems and the models that represent them are becoming commonplace in many disciplines including electronic circuit design where as parts are being made smaller and smaller, they are becoming less reliable. In addition to stochastic model checking, this dissertation proposes a new incremental stochastic simulation algorithm (iSSA) based on Gillespie's stochastic simulation algorithm (SSA) that is capable of presenting a researcher with a simulation trace of the typical behavior of the system. Before the development of this algorithm, discerning this information was extremely error-prone as it involved performing many simulations and attempting to wade through the massive amounts of data. This algorithm greatly aids researchers in designing genetic circuits as it efficiently shows the researcher the most likely behavior of the circuit. Both the iSSA and stochastic model checking can be used in concert to give a researcher the likelihood that the system will exhibit its most typical behavior. Once the typical behavior is known, properties for nontypical behaviors can be constructed and their likelihoods can also be computed. This methodology is applied to several genetic circuits leading to new understanding of the effects of various parameters on the behavior of these circuits

Master of Science

thesisThis document describes an improved method of formal verification of complex analog/mixed-signal (AMS) circuits. Currently, in our LEMA tool, verification properties are encoded using labeled Petri net (LPN). These LPNs are generated manually, a tedious process that requires the user to have considerable familiarity with the tool. To eliminate this time-consuming process, our LEMA tool is extended to include a translator that converts properties written in a property specification language to LPNs. New methods are also implemented to separate the transient period from the stable output period, thus improving the generated model. Also, the current methodology generates the circuit models for the input values used during the simulation of the circuit. So, models generated for other control input values are not accurate. In this case, accuracy of the generated models is improved by using a linear abstraction method like interpolation