We present an actor language which is an extension of a simple functional language, and provide an operational semantics for this extension. Actor configurations represent open distributed systems, by which we mean that the specification of an actor system explicitly takes into account the interface with external components. We study the composability of such systems. We define and study various notions of testing equivalence on actor expressions and configurations. The model we develop provides fairness. An important result is that the three forms of equivalence, namely, convex, must, and may equivalences, collapse to two in the presence of fairness. We further develop methods for proving laws of equivalence and provide example proofs to illustrate our methodology.
Abstract. This paper gives an overview of the Maude 2.0 system. We emphasize the full generality with which rewriting logic and membership equational logic are supported, operational semantics issues, the new built-in modules, the more general Full Maude module algebra, the new META-LEVEL module, the LTL model checker, and new implementation techniques yielding substantial performance improvements in rewriting modulo. We also comment on Maude's formal tool environment and on applications.
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Traditionally the view has been that direct expression of control and store mechanisms and clear mathematical semantics are incompatible requirements. This paper shows that adding objects with memory to the call-by-value lambda calculus results in a language with a rich equational theory, satisfying many of the usual laws. Combined with other recent work, this provides evidence that expressive, mathematically clean programming languages are indeed possible.
BackgroundChagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity.Methodology/Principal FindingsIn the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC50 < 10μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi.Conclusions/ SignificanceWe have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.
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We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage this data in order to move from a hit to a lead to a clinical candidate and potentially a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are herein reviewed. We suggest these computational approaches should be more optimally integrated in a workflow with experimental approaches to accelerate TB drug discovery.
Abstract. This paper describes the application of the Real-Time Maude tool and the Maude formal methodology to the specification and analysis of the AER/NCA suite of active network multicast protocol components. Because of the time-sensitive and resource-sensitive behavior and the composability of its components, AER/NCA poses challenging new problems for its formal specification and analysis. Real-Time Maude is a natural extension of the Maude rewriting logic language and tool for the specification and analysis of real-time object-based distributed systems. It supports a wide spectrum of formal methods, including: executable specification; symbolic simulation; and infinite-state model checking of temporal logic formulas. These methods complement those offered by finite-state model checkers and general-purpose theorem provers. RealTime Maude has proved to be well-suited to meet the AER/NCA modeling challenges, and its methods have been effective in uncovering subtle and important errors in the informal use case specification.
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