A Temporal Logic Based Theory of Test Coverage and Generation

This paper presents a theory of test coverage and generation from specifications written in extended finite state machines (EFSMs). We investigate a family of coverage criteria based on the information of control flow and data flow in EFSMs and characterize them using the temporal logic CTL. We discuss the complexity of minimal cost test generation and describe a simple heuristic which uses the capability of model checkers to construct counterexamples. Our approach extends the range of applications of model checking from automatic verification of finite state systems to automatic test generation from finite state systems

Production of Extracellular Traps against Aspergillus fumigatus In Vitro and in Infected Lung Tissue Is Dependent on Invading Neutrophils and Influenced by Hydrophobin RodA

Aspergillus fumigatus is the most important airborne fungal pathogen causing life-threatening infections in immunocompromised patients. Macrophages and neutrophils are known to kill conidia, whereas hyphae are killed mainly by neutrophils. Since hyphae are too large to be engulfed, neutrophils possess an array of extracellular killing mechanisms including the formation of neutrophil extracellular traps (NETs) consisting of nuclear DNA decorated with fungicidal proteins. However, until now NET formation in response to A. fumigatus has only been demonstrated in vitro, the importance of neutrophils for their production in vivo is unclear and the molecular mechanisms of the fungus to defend against NET formation are unknown. Here, we show that human neutrophils produce NETs in vitro when encountering A. fumigatus. In time-lapse movies NET production was a highly dynamic process which, however, was only exhibited by a sub-population of cells. NETosis was maximal against hyphae, but reduced against resting and swollen conidia. In a newly developed mouse model we could then demonstrate the existence and measure the kinetics of NET formation in vivo by 2-photon microscopy of Aspergillus-infected lungs. We also observed the enormous dynamics of neutrophils within the lung and their ability to interact with and phagocytose fungal elements in situ. Furthermore, systemic neutrophil depletion in mice almost completely inhibited NET formation in lungs, thus directly linking the immigration of neutrophils with NET formation in vivo. By using fungal mutants and purified proteins we demonstrate that hydrophobin RodA, a surface protein making conidia immunologically inert, led to reduced NET formation of neutrophils encountering Aspergillus fungal elements. NET-dependent killing of Aspergillus-hyphae could be demonstrated at later time-points, but was only moderate. Thus, these data establish that NET formation occurs in vivo during host defence against A. fumigatus, but suggest that it does not play a major role in killing this fungus. Instead, NETs may have a fungistatic effect and may prevent further spreading

ACE (I/D) polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

<p>Abstract</p> <p>Background</p> <p>The role of angiotensin-converting enzyme (<it>ACE</it>) gene insertion/deletion (<it>I/D</it>) polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial.</p> <p>Methods</p> <p>PubMed was searched and a database of 58 studies with detailed information regarding <it>ACE I/D </it>polymorphism and response to treatment in coronary artery disease was created. Eligible studies were synthesized using meta-analysis methods, including cumulative meta-analysis. Heterogeneity and study quality issues were explored.</p> <p>Results</p> <p>Forty studies involved invasive treatments (coronary angioplasty or coronary artery by-pass grafting) and 18 used conservative treatment options (including anti-hypertensive drugs, lipid lowering therapy and cardiac rehabilitation procedures). Clinical outcomes were investigated by 11 studies, while 47 studies focused on surrogate endpoints. The most studied outcome was the restenosis following coronary angioplasty (34 studies). Heterogeneity among studies (p < 0.01) was revealed and the risk of restenosis following balloon angioplasty was significant under an additive model: the random effects odds ratio was 1.42 (95% confidence interval:1.07–1.91). Cumulative meta-analysis showed a trend of association as information accumulates. The results were affected by population origin and study quality criteria. The meta-analyses for the risk of restenosis following stent angioplasty or after angioplasty and treatment with angiotensin-converting enzyme inhibitors produced non-significant results. The allele contrast random effects odds ratios with the 95% confidence intervals were 1.04(0.92–1.16) and 1.10(0.81–1.48), respectively. Regarding the effect of <it>ACE I/D </it>polymorphism on the response to treatment for the rest outcomes (coronary events, endothelial dysfunction, left ventricular remodeling, progression/regression of atherosclerosis), individual studies showed significance; however, results were discrepant and inconsistent.</p> <p>Conclusion</p> <p>In view of available evidence, genetic testing of <it>ACE I/D </it>polymorphism prior to clinical decision making is not currently justified. The relation between <it>ACE </it>genetic variation and response to treatment in CAD remains an unresolved issue. The results of long-term and properly designed prospective studies hold the promise for pharmacogenetically tailored therapy in CAD.</p

Efficient object-oriented integration and regression testing

International audienc

Test Generation for CEFSM Combining Specification and Fault Coverage

We discuss how specification coverage and fault coverage based test derivation strategies can be combined. In particular, the problem of deriving a test suffix, which raises tester confidence in the configuration of the system, reached after a test derived by a specification coverage criterion, is formalized and solved in the CEFSM setting. The traditional mutant-based test derivation approach is extended with nondeterministic mutants to cover more faults. An experimental tool and case study are reported

Symbolic Verification of Communication Protocols with Infinite State Spaces Using QDDs

peer reviewedWe study the verification of properties of communication protocols modeled by a finite set of finite-state machines that communicate by exchanging messages via unbounded FIFO queues. It is well-known that most interesting verification problems, such as deadlock detection, are undecidable for this class of systems. However, in practice, these verification problems may very well turn out to be decidable for a subclass containing most "real" protocols. Motivated by this optimistic (and, we claim, realistic) observation, we present an algorithm that may construct a finite and exact representation of the state space of a communication protocol, even if this state space is infinite. Our algorithm performs a loop-first search in the state space of the protocol being analyzed. A loop-first search is a search technique that attempts to explore first the results of successive executions of loops in the protocol description (code). A new data structure named Queue-content Decision Diagram (QDD) is introduced for representing (possibly infinite) sets of queue-contents. Operations for manipulating QDDs during a loop-first search are presented. A loop-first search using QDDs has been implemented, and experiments on several existing communication protocols with infinite state spaces have been performed. For these examples, our tool completed its search, and produced a finite symbolic representation for these infinite state spaces

A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization

Objective: Genetic variants of cardiac ion channels may influence cardiac repolarization. Thereby such variants may modulate the penetrance of primary electrical disorders, contribute to differences in susceptibility to drug-induced QT-prolongation between individuals, or contribute to rhythm disturbances in the context of structural heart disease. Since the current encoded by KCNH2 (HERG; I-Kr) is a primary determinant of repolarization, we conducted association studies between the respective alleles of the common amino acid-changing polymorphism at codon 897 (2690A>C; K897T) within HERG and rate-corrected QT interval (QTc). Methods and Results: Association analysis in Caucasian subjects (n=1030) revealed a significant association of this polymorphism with QTc (P=0.0025) with CC homozygotes having a significantly shorter QTc (388.5+/-2.9 ms) compared to AA homozygotes (398.5+/-0.9) and heterozygotes (AC, 397.2 +/- 1.2). The latter two genotypes were associated with comparable mean QTc's, suggesting that the 2690C-allele is recessive. After stratification by sex, the polymorphism was more predictive of QTc in females (P=0.0021), a finding that was replicated in a second population sample (n=352) from the same ethnic background (P=0.044). To assess whether this polymorphism could represent a 'functional' polymorphism, we compared the biophysical properties of K897- and T897-HERG channels by whole-cell voltage clamp. Compared to the K897 channel, the T897 channel displayed a shift of -7 mV in voltage dependence of activation and increased rates of current activation and deactivation. Conclusion: As confirmed in modeling studies, these changes are expected to shorten action potential duration by an increase in I-Kr. This recapitulates the shorter QTc in females homozygous for the 2690C-allele. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserve