A Refinement Calculus for Logic Programs

Existing refinement calculi provide frameworks for the stepwise development of imperative programs from specifications. This paper presents a refinement calculus for deriving logic programs. The calculus contains a wide-spectrum logic programming language, including executable constructs such as sequential conjunction, disjunction, and existential quantification, as well as specification constructs such as general predicates, assumptions and universal quantification. A declarative semantics is defined for this wide-spectrum language based on executions. Executions are partial functions from states to states, where a state is represented as a set of bindings. The semantics is used to define the meaning of programs and specifications, including parameters and recursion. To complete the calculus, a notion of correctness-preserving refinement over programs in the wide-spectrum language is defined and refinement laws for developing programs are introduced. The refinement calculus is illustrated using example derivations and prototype tool support is discussed.Comment: 36 pages, 3 figures. To be published in Theory and Practice of Logic Programming (TPLP

Lessons from a Failed γ-Secretase Alzheimer Trial

γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill

A Case Study in Testing Distributed Systems

This paper describes a case study in the testing of distributed systems. The software under test is a middleware system developed in Java. The full test lifecycle is examined including unit testing, integration testing, and system testing. Where possible, traditional tools and techniques are used to carry out the testing. One aspect where this is not possible is the testing of the low-level concurrency, which is often overlooked when testing commercial distributed systems, since the middleware or application server is already developed by a third-party and is assumed to operate correctly. This paper examines testing the middleware system itself, and therefore, a method for testing the concurrency properties of the system is used. The testing revealed a number of faults and design weaknesses, and showed that, with some adaptation, traditional tools and techniques go a long way in the testing of distributed applications

The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD - Aβ plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial

Parkin interacts with Ambra1 to induce mitophagy

Mutations in the gene encoding Parkin are a major cause of recessive Parkinson's disease. Recent work has shown that Parkin translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy). However, the molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we investigated whether Parkin interacts with autophagy-regulating proteins. We purified Parkin and associated proteins from HEK293 cells using tandem affinity purification and identified the Parkin interactors using mass spectrometry. We identified the autophagy-promoting protein Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 activates autophagy in the CNS by stimulating the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex that is essential for the formation of new phagophores. We found Ambra1, like Parkin, to be widely expressed in adult mouse brain, including midbrain dopaminergic neurons. Endogenous Parkin and Ambra1 coimmunoprecipitated from HEK293 cells, SH-SY5Y cells, and adult mouse brain. We found no evidence for ubiquitination of Ambra1 by Parkin. The interaction of endogenous Parkin and Ambra1 strongly increased during prolonged mitochondrial depolarization. Ambra1 was not required for Parkin translocation to depolarized mitochondria but was critically important for subsequent mitochondrial clearance. In particular, Ambra1 was recruited to perinuclear clusters of depolarized mitochondria and activated class III PI3K in their immediate vicinity. These data identify interaction of Parkin with Ambra1 as a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy

Tool Support for Testing Java Monitors

The Java programming language supports monitors. Monitor implementations, like other concurrent programs, are hard to test due to the inherent non-determinism. This paper presents the ConAn (Concurrency Analyser) tool for generating drivers for the testing of Java monitors. To obtain adequate controllability over the interactions between Java threads, the generated driver contains processes that are synchronized by a clock. The driver automatically executes the calls in the test sequence in the prescribed order and compares the outputs against the expected outputs specified in the test sequence. The method and tool are illustrated in detail on an asymmetric producer-consumer monitor, and their application to two other monitors is discussed

The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications

BACKGROUND: Astrocytes, also called astroglia, maintain homoeostasis of the brain by providing trophic and metabolic support to neurons. They recycle neurotransmitters, stimulate synaptogenesis and synaptic neurotransmission, form part of the blood-brain barrier, and regulate regional blood flow. Although astrocytes have been known to display morphological alterations in Alzheimer's disease for more than a century, research has remained neurocentric. Emerging evidence suggests that these morphological changes reflect functional alterations that affect disease. RECENT DEVELOPMENTS: Genetic studies indicate that most of the risk of developing late onset Alzheimer's disease, the most common form of the disease, affecting patients aged 65 years and older, is associated with genes (ie, APOE, APOJ, and SORL) that are mainly expressed by glial cells (ie, astrocytes, microglia, and oligodendrocytes). This insight has moved the focus of research away from neurons and towards glial cells and neuroinflammation. Molecular studies in rodent models suggest a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease; however, these models might insufficiently mimic the human disease, because rodent astrocytes differ considerably in morphology, functionality, and gene expression. In-vivo studies using stem-cell derived human astrocytes are allowing exploration of the human disease and providing insights into the neurotoxic or protective contributions of these cells to the pathogenesis of disease. The first attempts to develop astrocytic biomarkers and targeted therapies are emerging. WHERE NEXT?: Single-cell transcriptomics allows the fate of individual astrocytes to be followed in situ and provides the granularity needed to describe healthy and pathological cellular states at different stages of Alzheimer's disease. Given the differences between human and rodent astroglia, study of human cells in this way will be crucial. Although refined single-cell transcriptomic analyses of human post-mortem brains are important for documentation of pathology, they only provide snapshots of a dynamic reality. Thus, functional work studying human astrocytes generated from stem cells and exposed to pathological conditions in rodent brain or cell culture are needed to understand the role of these cells in the pathogenesis of Alzheimer's disease. These studies will lead to novel biomarkers and hopefully a series of new drug targets to tackle this disease

Systematic Operational Profile Development for Software Components

An operational profile is a quantification of the expected use of a system. Determining an operational profile for software is a crucial and difficult part of software reliability assessment in general and it can be even more difficult for software components. This paper presents a systematic method for deriving an operational profile for software components. The method uses both actual usage data and intended usage assumptions to derive a usage structure, usage distribution and characteristics of parameters (including relationships between parameters). A usage structure represents the flow and interaction of operation calls. Statecharts are used to model the usage structures. A usage distribution represents probabilities of the operations. The method is illustrated on two Java classes but can be applied to any software component that is accessed through an Application Program Interface (API)

Exploring model-based development for the verification of real-time Java code

Many safety- and security-critical systems are real-time systems and, as a result, tools and techniques for verifying real-time systems are extremely important. Simulation and testing such systems can be exceedingly time-consuming and these techniques provide only probabilistic measures of correctness. There are a number of model-checking tools for real-time systems. However, they provide formal verification for models, not programs. To increase the confidence in real-time programs written in real-time Java, this paper takes a modelling approach to the design of such programs. First, models can be mechanically verified, to check whether they satisfy particular properties, by using current real-time model-checking tools. Then, programs are derived from the model by following a systematic approach. To illustrate the approach we use a nontrivial example: a gear controller