Uniform Substitution for Differential Game Logic

This paper presents a uniform substitution calculus for differential game logic (dGL). Church's uniform substitutions substitute a term or formula for a function or predicate symbol everywhere. After generalizing them to differential game logic and allowing for the substitution of hybrid games for game symbols, uniform substitutions make it possible to only use axioms instead of axiom schemata, thereby substantially simplifying implementations. Instead of subtle schema variables and soundness-critical side conditions on the occurrence patterns of logical variables to restrict infinitely many axiom schema instances to sound ones, the resulting axiomatization adopts only a finite number of ordinary dGL formulas as axioms, which uniform substitutions instantiate soundly. This paper proves soundness and completeness of uniform substitutions for the monotone modal logic dGL. The resulting axiomatization admits a straightforward modular implementation of dGL in theorem provers

Constructive Hybrid Games

Hybrid games are models which combine discrete, continuous, and adversarial dynamics. Game logic enables proving (classical) existence of winning strategies. We introduce constructive differential game logic (CdGL) for hybrid games, where proofs that a player can win the game correspond to computable winning strategies. This is the logical foundation for synthesis of correct control and monitoring code for safety-critical cyber-physical systems. Our contributions include novel static and dynamic semantics as well as soundness and consistency.Comment: 60 pages, preprint, under revie

If blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes

AbstractLower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS–HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial

Use of Climate Information in Malaria Stratification/Early Warning Systems/Impact Assessment for Malaria Interventions

A report on the training workshop and stakeholder meeting hosted by the Tanzania Meteorological Agency in Dar es Salaam, Tanzania October 16th-18th 2013

Embedding CCSL into Dynamic Logic: A Logical Approach for the Verification of CCSL Specifications

International audienceThe Clock Constraint Specification Language (CCSL) is a clock-based specification language for capturing causal and chronometric constraints between events in Real-Time Embedded Systems (RTESs). Due to the limitations of the existing verification approaches, CCSL lacks a full verification support for 'unsafe CCSL specifications' and a unified proof framework. In this paper, we propose a novel verification approach based on theorem proving and SMT-checking. We firstly build a logic called CCSL Dynamic Logic (CDL), which extends the traditional dynamic logic with 'signals' and 'clock relations' as primitives, and with synchronous execution mechanism for modelling RTESs. Then we propose a sound and relatively complete proof system for CDL to provide the verification support. We show how CDL can be used to capture RTES and verify CCSL specifications by analyzing a simple case study

De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy Due to Impaired GABAergic Neurotransmission

Objective:Rare inherited missense variants inSLC32A1, the gene that encodes the vesicular gamma-aminobutyric acid(GABA) transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarifyif de novo missense variants inSLC32A1can also cause epilepsy with impaired neurodevelopment.Methods:Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathyand de novo missense variants inSLC32A1. To assess causality, we performed functional evaluation of the identifiedvariants in a murine neuronal cell culture model.Results:The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset epilepsy within thefirst 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functionalanalyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway,result in reduced quantal size, consistent with impairedfilling of synaptic vesicles with GABA. The fourth variant,located in the vesicular gamma-aminobutyric acid N-terminus, does not affect quantal size, but increases presynapticrelease probability, leading to more severe synaptic depression during high-frequency stimulation. Thus, variants invesicular gamma-aminobutyric acid can impair GABAergic neurotransmission through at least two mechanisms, byaffecting synaptic vesiclefilling and by altering synaptic short-term plasticity.Interpretation:This work establishes de novo missense variants inSLC32A1as a novel cause of a developmental andepileptic encephalopathy

Generalized Property-Directed Reachability for Hybrid Systems

Generalized property-directed reachability (GPDR) belongs to the family of the model-checking techniques called IC3/PDR. It has been successfully applied to software verification; for example, it is the core of Spacer, a state-of-the-art Horn-clause solver bundled with Z3. However, it has yet to be applied to hybrid systems, which involve a continuous evolution of values over time. As the first step towards GPDR- based model checking for hybrid systems, this paper formalizes HGPDR, an adaptation of GPDR to hybrid systems, and proves its soundness. We also implemented a semi-automated proof-of-concept verifier, which allows a user to provide hints to guide verification steps.Comment: To appear in VMCAI 202

Ordering variable for parton showers

The parton splittings in a parton shower are ordered according to an ordering variable, for example the transverse momentum of the daughter partons relative to the direction of the mother, the virtuality of the splitting, or the angle between the daughter partons. We analyze the choice of the ordering variable and conclude that one particular choice has the advantage of factoring softer splittings from harder splittings graph by graph in a physical gauge.Comment: 28 pages, 5 figure