Alternative RNA Splicing of the NMDA Receptor NR1 mRNA in the Neurons of the Teleost Electrosensory System

The sequence for cDNA encoding the NMDA receptor subunit 1 (aptNR1) of the weakly electric fish Apteronotus leptorhynchus has been determined. The deduced amino acid sequence is approximately 88% identical to other vertebrate NR1 proteins, with sequence homology extending to the alternatively spliced cassettes N1 and C1. The fish and mammalian N1 and C1 splice cassettes are identical at 20 of 21 and 30 of 37 amino acid positions, respectively. We did not detect a C2 splice cassette in aptNR1 mRNA, but we did find two novel C-terminal alternative splice cassettes labeled C1' and C1". The relative levels of NR1 transcripts containing the N1 and C1 splice cassettes were determined by using RNase protection and in situ hybridization analysis. N1-containing mRNAs are more abundant in caudal brain regions, similar to the patterns reported for mammalian brain. In contrast, the relative levels of transcripts containing the C1 splice cassette are much lower in fish than in mammals, averaging only 9% for the whole brain. The levels of C1 splicing increased in more rostral brain regions. In situ hybridizations with N1- and C1-specific probes demonstrated that N1 cassette splicing occurs in most neurons but that C1 splicing is heterogeneous and is restricted to a subset of neuronal types in the electrosensory system

Quantitative Regular Expressions for Arrhythmia Detection Algorithms

Motivated by the problem of verifying the correctness of arrhythmia-detection algorithms, we present a formalization of these algorithms in the language of Quantitative Regular Expressions. QREs are a flexible formal language for specifying complex numerical queries over data streams, with provable runtime and memory consumption guarantees. The medical-device algorithms of interest include peak detection (where a peak in a cardiac signal indicates a heartbeat) and various discriminators, each of which uses a feature of the cardiac signal to distinguish fatal from non-fatal arrhythmias. Expressing these algorithms' desired output in current temporal logics, and implementing them via monitor synthesis, is cumbersome, error-prone, computationally expensive, and sometimes infeasible. In contrast, we show that a range of peak detectors (in both the time and wavelet domains) and various discriminators at the heart of today's arrhythmia-detection devices are easily expressible in QREs. The fact that one formalism (QREs) is used to describe the desired end-to-end operation of an arrhythmia detector opens the way to formal analysis and rigorous testing of these detectors' correctness and performance. Such analysis could alleviate the regulatory burden on device developers when modifying their algorithms. The performance of the peak-detection QREs is demonstrated by running them on real patient data, on which they yield results on par with those provided by a cardiologist.Comment: CMSB 2017: 15th Conference on Computational Methods for Systems Biolog

Molecular biology of the apteronotus NMDA receptor NR1 subunit

The complete sequences and expression patterns of the NR1 (aptNR1) subunit of the N-methyl-d-aspartate (NMDA) receptor and its alternative splice isoforms have been determined for the weakly electric fish Apteronotus leptorhynchus. The deduced amino acid sequence of aptNR1 is approximately 88 % identical to the NR1 sequences of other vertebrate. Two of the three alternative splice cassettes previously described for mammalian NR1s, N1 and C1, are present in aptNR1, but the third cassette, C2, is not found. In addition, two teleost-specific splice cassettes occur on the N-terminal side of the C1 sequence. The cellular patterns of aptNR1 expression, including the patterns of N1 and C1 splicing, have been mapped using the in situ hybridization technique. High levels of aptNR1 mRNA were detected throughout the central nervous system including most neurons of the electrosensory system, with the highest levels in electrosensory lateral line lobe pyramidal cells. Expression of the N1 splice isoform was higher in more caudal regions of the brain, and expression of the C1 splice isoform was higher in more rostral regions. The N1 splice isoform was present in almost all NR1-positive cells, in contrast to the C1 splice isoform which was restricted to a subset of NR1-positive cells. These results demonstrate that the NR1 subunit of the NMDA receptor is evolutionarily conserved across species and that regulation of alternative RNA splicing modulates the properties of NR1 in different neurons of the central nervous system of A. leptorhynchus

Lazy Abstraction-Based Controller Synthesis

We present lazy abstraction-based controller synthesis (ABCS) for continuous-time nonlinear dynamical systems against reach-avoid and safety specifications. State-of-the-art multi-layered ABCS pre-computes multiple finite-state abstractions of varying granularity and applies reactive synthesis to the coarsest abstraction whenever feasible, but adaptively considers finer abstractions when necessary. Lazy ABCS improves this technique by constructing abstractions on demand. Our insight is that the abstract transition relation only needs to be locally computed for a small set of frontier states at the precision currently required by the synthesis algorithm. We show that lazy ABCS can significantly outperform previous multi-layered ABCS algorithms: on standard benchmarks, lazy ABCS is more than 4 times faster

A Theory of Sampling for Continuous-time Metric Temporal Logic

This paper revisits the classical notion of sampling in the setting of real-time temporal logics for the modeling and analysis of systems. The relationship between the satisfiability of Metric Temporal Logic (MTL) formulas over continuous-time models and over discrete-time models is studied. It is shown to what extent discrete-time sequences obtained by sampling continuous-time signals capture the semantics of MTL formulas over the two time domains. The main results apply to "flat" formulas that do not nest temporal operators and can be applied to the problem of reducing the verification problem for MTL over continuous-time models to the same problem over discrete-time, resulting in an automated partial practically-efficient discretization technique.Comment: Revised version, 43 pages

RTLola Cleared for Take-Off: Monitoring Autonomous Aircraft

The autonomous control of unmanned aircraft is a highly safety-critical domain with great economic potential in a wide range of application areas, including logistics, agriculture, civil engineering, and disaster recovery. We report on the development of a dynamic monitoring framework for the DLR ARTIS (Autonomous Rotorcraft Testbed for Intelligent Systems) family of unmanned aircraft based on the formal specification language RTLola. RTLola is a stream-based specification language for real-time properties. An RTLola specification of hazardous situations and system failures is statically analyzed in terms of consistency and resource usage and then automatically translated into an FPGA-based monitor. Our approach leads to highly efficient, parallelized monitors with formal guarantees on the noninterference of the monitor with the normal operation of the autonomous system

Mightyl: A compositional translation from mitl to timed automata

Metric Interval Temporal Logic (MITL) was first proposed in the early 1990s as a specification formalism for real-time systems. Apart from its appealing intuitive syntax, there are also theoretical evidences that make MITL a prime real-time counterpart of Linear Temporal Logic (LTL). Unfortunately, the tool support for MITL verification is still lacking to this day. In this paper, we propose a new construction from MITL to timed automata via very-weak one-clock alternating timed automata. Our construction subsumes the well-known construction from LTL to Büchi automata by Gastin and Oddoux and yet has the additional benefits of being compositional and integrating easily with existing tools. We implement the construction in our new tool MightyL and report on experiments using Uppaal and LTSmin as back-ends