Model Checking Synchronized Products of Infinite Transition Systems

Formal verification using the model checking paradigm has to deal with two aspects: The system models are structured, often as products of components, and the specification logic has to be expressive enough to allow the formalization of reachability properties. The present paper is a study on what can be achieved for infinite transition systems under these premises. As models we consider products of infinite transition systems with different synchronization constraints. We introduce finitely synchronized transition systems, i.e. product systems which contain only finitely many (parameterized) synchronized transitions, and show that the decidability of FO(R), first-order logic extended by reachability predicates, of the product system can be reduced to the decidability of FO(R) of the components. This result is optimal in the following sense: (1) If we allow semifinite synchronization, i.e. just in one component infinitely many transitions are synchronized, the FO(R)-theory of the product system is in general undecidable. (2) We cannot extend the expressive power of the logic under consideration. Already a weak extension of first-order logic with transitive closure, where we restrict the transitive closure operators to arity one and nesting depth two, is undecidable for an asynchronous (and hence finitely synchronized) product, namely for the infinite grid.Comment: 18 page

Model checking synchronized products of infinite transition systems

Abstract. Formal verification using the model checking paradigm has to deal with two aspects: The system models are structured, often as products of components, and the specification logic has to be expressive enough to allow the formalization of reachability properties. The present paper is a study on what can be achieved for infinite transition systems under these premises. As models we consider products of infinite transition systems with different synchronization constraints. We introduce finitely synchronized transition systems, i.e. product systems which contain only finitely many (parameterized) synchronized transitions, and show that the decidability of FO(R), first-order logic extended by reachability predicates, of the product system can be reduced to the decidability of FO(R) of the components. This result is optimal in the following sense: (1) If we allow semifinite synchronization, i.e. just in one component infinitely many transitions are synchronized, the FO(R)-theory of the product system is in general undecidable. (2) We cannot extend the expressive power of the logic under consideration. Already a weak extension of firstorder logic with transitive closure, where we restrict the transitive closure operators to arity one and nesting depth two, is undecidable for an asynchronous (and hence finitely synchronized) product, namely for the infinite grid. 1

The Caucal hierarchy of infinite graphs in terms of logic and higher-order pushdown automata

In this paper we give two equivalent characterizations of the Caucal hierarchy, a hierarchy of infinite graphs with a decidable monadic second-order (MSO) theory. It is obtained by iterating the graph transformations of unfolding and inverse rational mapping. The first characterization sticks to this hierarchical approach, replacing the language-theoretic operation of a rational mapping by an MSO-transduction and the unfolding by the treegraph operation. The second characterization is non-iterative. We show that the family of graphs of the Caucal hierarchy coincides with the family of graphs obtained as the ε-closure of configuration graphs of higher-order pushdown automata. While the different characterizations of the graph family show their robustness and thus also their importance, the characterization in terms of higher-order pushdown automata additionally yields that the graph hierarchy is indeed strict

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial

Drug-coated balloons (DCB) are a novel therapeutic strategy for small native coronary artery disease. However, their safety and efficacy is poorly defined in comparison with drug-eluting stents (DES).; BASKET-SMALL 2 was a multicentre, open-label, randomised non-inferiority trial. 758 patients with de-novo lesions (<3 mm in diameter) in coronary vessels and an indication for percutaneous coronary intervention were randomly allocated (1:1) to receive angioplasty with DCB versus implantation of a second-generation DES after successful predilatation via an interactive internet-based response system. Dual antiplatelet therapy was given according to current guidelines. The primary objective was to show non-inferiority of DCB versus DES regarding major adverse cardiac events (MACE; ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation) after 12 months. The non-inferiority margin was an absolute difference of 4% in MACE. This trial is registered with ClinicalTrials.gov, number NCT01574534.; Between April 10, 2012, and February 1, 2017, 382 patients were randomly assigned to the DCB group and 376 to DES group. Non-inferiority of DCB versus DES was shown because the 95% CI of the absolute difference in MACE in the per-protocol population was below the predefined margin (-3·83 to 3·93%, p=0·0217). After 12 months, the proportions of MACE were similar in both groups of the full-analysis population (MACE was 7·5% for the DCB group vs 7·3% for the DES group; hazard ratio [HR] 0·97 [95% CI 0·58-1·64], p=0·9180). There were five (1·3%) cardiac-related deaths in the DES group and 12 (3·1%) in the DCB group (full analysis population). Probable or definite stent thrombosis (three [0·8%] in the DCB group vs four [1·1%] in the DES group; HR 0·73 [0·16-3·26]) and major bleeding (four [1·1%] in the DCB group vs nine [2·4%] in the DES group; HR 0·45 [0·14-1·46]) were the most common adverse events.; In small native coronary artery disease, DCB was non-inferior to DES regarding MACE up to 12 months, with similar event rates for both treatment groups.; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Basel Cardiovascular Research Foundation, and B Braun Medical AG

Decision problems over infinite graphs : higher order pushdown systems and synchronized products

The extension of formal verification methods to infinite models requires classes of graphs which are finitely representable and for which the model checking problem is decidable. We consider three approaches to define classes of finitely representable graphs: internal representations as configuration graphs of higher-order pushdown systems, transformational representations by application of operations which preserve the decidability of the model checking problem, and by composition from components using synchronized products. In the first part of the thesis we show that the hierarchy of higher-order pushdown graphs coincides with the Caucal hierarchy of graphs. We thus obtain transformational representations of higher-order pushdown graphs and can conclude that they enjoy a decidable monadic second-order theory. In the second part of the thesis investigate synchronized products of finitely representable infinite graphs and show that the decidability of an extension of first-order logic with reachability predicates is preserved under the formation of finitely synchronized products. This result is complemented by undecidability results for extensions of the admissible product operations as well as the expressive power of the logic under consideration

The Caucal Hierarchy of Infinite Graphs in Terms of Logic

International audienc

Model Checking Synchronized Products of Infinite Transition Systems

Formal verification using the model-checking paradigm has to deal with two aspects. The systems models are structured, often as products of components, and the specification logic has to be expressive enough to allow the formalization of reachability properties. The present paper is a study on what can be achieved for infinite transition systems under these premises. As models we consider products of infinite transition systems with different synchronization constraints. We introduce finitely synchronized transition systems, i.e. product systems which contain only finitely many synchronized transitions, and show that the decidability of FO(R), first-order logic extended by reachability predicates, of the product system can be reduced to the decidability of FO(R) of the components in a FefermanVaught like style. This result is optimal in the following sense. (1) If we allow semifinite synchronization, i.e. just in one component infinitely many transitions are synchronized, the FO(R)-theory of the product system is in general undecidable. (2) We cannot extend the expressive power of the logic under consideration. Already a weak extension of first-order logic with transitive closure, where we restrict the transitive closure operators to arity one and nesting depth two, is undecidable for an asynchronous (and hence finitely synchronized) product, namely for the infinite grid