On the Hybrid Extension of CTL and CTL+

The paper studies the expressivity, relative succinctness and complexity of satisfiability for hybrid extensions of the branching-time logics CTL and CTL+ by variables. Previous complexity results show that only fragments with one variable do have elementary complexity. It is shown that H1CTL+ and H1CTL, the hybrid extensions with one variable of CTL+ and CTL, respectively, are expressively equivalent but H1CTL+ is exponentially more succinct than H1CTL. On the other hand, HCTL+, the hybrid extension of CTL with arbitrarily many variables does not capture CTL*, as it even cannot express the simple CTL* property EGFp. The satisfiability problem for H1CTL+ is complete for triply exponential time, this remains true for quite weak fragments and quite strong extensions of the logic

On the Expressive Power of Hybrid Branching-Time Logics

Hybrid branching-time logics are a powerful extension of branching-time logics like CTL, CTL^* or even the modal mu-calculus through the addition of binders, jumps and variable tests. Their expressiveness is not restricted by bisimulation-invariance anymore. Hence, they do not retain the tree model property, and the finite model property is equally lost. Their satisfiability problems are typically undecidable, their model checking problems (on finite models) are decidable with complexities ranging from polynomial to non-elementary time. In this paper we study the expressive power of such hybrid branching-time logics beyond some earlier results about their invariance under hybrid bisimulations. In particular, we aim to extend the hierarchy of non-hybrid branching-time logics CTL, CTL^+, CTL^* and the modal mu-calculus to their hybrid extensions. We show that most separation results can be transferred to the hybrid world, even though the required techniques become a bit more involved. We also present some collapse results for restricted classes of models that are especially worth investigating, namely linear, tree-shaped and finite models

Enriched MU-Calculi Module Checking

The model checking problem for open systems has been intensively studied in the literature, for both finite-state (module checking) and infinite-state (pushdown module checking) systems, with respect to Ctl and Ctl*. In this paper, we further investigate this problem with respect to the \mu-calculus enriched with nominals and graded modalities (hybrid graded Mu-calculus), in both the finite-state and infinite-state settings. Using an automata-theoretic approach, we show that hybrid graded \mu-calculus module checking is solvable in exponential time, while hybrid graded \mu-calculus pushdown module checking is solvable in double-exponential time. These results are also tight since they match the known lower bounds for Ctl. We also investigate the module checking problem with respect to the hybrid graded \mu-calculus enriched with inverse programs (Fully enriched \mu-calculus): by showing a reduction from the domino problem, we show its undecidability. We conclude with a short overview of the model checking problem for the Fully enriched Mu-calculus and the fragments obtained by dropping at least one of the additional constructs

Towards Cancer Hybrid Automata

This paper introduces Cancer Hybrid Automata (CHAs), a formalism to model the progression of cancers through discrete phenotypes. The classification of cancer progression using discrete states like stages and hallmarks has become common in the biology literature, but primarily as an organizing principle, and not as an executable formalism. The precise computational model developed here aims to exploit this untapped potential, namely, through automatic verification of progression models (e.g., consistency, causal connections, etc.), classification of unreachable or unstable states and computer-generated (individualized or universal) therapy plans. The paper builds on a phenomenological approach, and as such does not need to assume a model for the biochemistry of the underlying natural progression. Rather, it abstractly models transition timings between states as well as the effects of drugs and clinical tests, and thus allows formalization of temporal statements about the progression as well as notions of timed therapies. The model proposed here is ultimately based on hybrid automata, and we show how existing controller synthesis algorithms can be generalized to CHA models, so that therapies can be generated automatically. Throughout this paper we use cancer hallmarks to represent the discrete states through which cancer progresses, but other notions of discretely or continuously varying state formalisms could also be used to derive similar therapies.Comment: In Proceedings HSB 2012, arXiv:1208.315

Basins of Attraction, Commitment Sets and Phenotypes of Boolean Networks

The attractors of Boolean networks and their basins have been shown to be highly relevant for model validation and predictive modelling, e.g., in systems biology. Yet there are currently very few tools available that are able to compute and visualise not only attractors but also their basins. In the realm of asynchronous, non-deterministic modeling not only is the repertoire of software even more limited, but also the formal notions for basins of attraction are often lacking. In this setting, the difficulty both for theory and computation arises from the fact that states may be ele- ments of several distinct basins. In this paper we address this topic by partitioning the state space into sets that are committed to the same attractors. These commitment sets can easily be generalised to sets that are equivalent w.r.t. the long-term behaviours of pre-selected nodes which leads us to the notions of markers and phenotypes which we illustrate in a case study on bladder tumorigenesis. For every concept we propose equivalent CTL model checking queries and an extension of the state of the art model checking software NuSMV is made available that is capa- ble of computing the respective sets. All notions are fully integrated as three new modules in our Python package PyBoolNet, including functions for visualising the basins, commitment sets and phenotypes as quotient graphs and pie charts

HBsAg-vectored DNA vaccines elicit concomitant protective responses to multiple CTL epitopes relevant in human disease.

Vaccines capable of controlling neoplastic and infectious diseases which depend on the cellular immune response for their resolution, have proven difficult to develop. We, and others, have previously demonstrated that the potent immunogenicity of hepatitis B surface antigen (HBsAg), the already- licensed human vaccine for hepatitis B infection, may be exploited to deliver foreign antigens for cytotoxic T-lymphocyte (CTL) induction. In this study we demonstrate that recombinant (r) HBsAg DNA delivering a CTL polyepitope appended at the C' terminus elicits concomitant responses to multiple epitopes restricted through a diversity of MHC class I haplotypes, which are relevant in a number of human diseases. We show that the rHBsAg DNA vaccine elicits concomitant protection against neoplastic and infectious disease. These studies vindicate the use of HBsAg as a powerful vector to deliver CTL responses to foreign antigens, and have implications for a multi-disease vaccine applicable to the HLA-polymorphic human population