Applying SMT Solvers to the Test Template Framework

The Test Template Framework (TTF) is a model-based testing method for the Z notation. In the TTF, test cases are generated from test specifications, which are predicates written in Z. In turn, the Z notation is based on first-order logic with equality and Zermelo-Fraenkel set theory. In this way, a test case is a witness satisfying a formula in that theory. Satisfiability Modulo Theory (SMT) solvers are software tools that decide the satisfiability of arbitrary formulas in a large number of built-in logical theories and their combination. In this paper, we present the first results of applying two SMT solvers, Yices and CVC3, as the engines to find test cases from TTF's test specifications. In doing so, shallow embeddings of a significant portion of the Z notation into the input languages of Yices and CVC3 are provided, given that they do not directly support Zermelo-Fraenkel set theory as defined in Z. Finally, the results of applying these embeddings to a number of test specifications of eight cases studies are analysed.Comment: In Proceedings MBT 2012, arXiv:1202.582

Structural insights into heme binding to IL-36α proinflammatory cytokine

Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins

SERS-based monitoring of the intracellular pH in endothelial cells:the influence of the extracellular environment and tumour necrosis factor-alpha

The intracellular pH plays an important role in various cellular processes. In this work, we describe a method for monitoring of the intracellular pH in endothelial cells by using surface enhanced Raman spectroscopy (SERS) and 4-mercaptobenzoic acid (MBA) anchored to gold nanoparticles as pH-sensitive probes. Using the Raman microimaging technique, we analysed changes in intracellular pH induced by buffers with acid or alkaline pH, as well as in endothelial inflammation induced by tumour necrosis factor-alpha (TNF alpha). The targeted nanosensor enabled spatial pH measurements revealing distinct changes of the intracellular pH in endosomal compartments of the endothelium. Altogether, SERS-based analysis of intracellular pH proves to be a promising technique for a better understanding of intracellular pH regulation in various subcellular compartments.This work was supported by the National Center of Science (grant PRELUDIUM DEC-2012/05/N/ST4/00218) and by the European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, no. POIG.01.01.02-00-069/09). We also thank the University of Edinburgh School of Chemistry for the Neil Campbell Travel Award for supporting LJ. We also thank Joanna Jalmuzna from the Department of Mathematics and Computer Sciences, Jagiellonian University in Krakow for fitting the calibration curve using Gnuplot software

Site-specific interrogation of an ionic chiral fragment during photolysis using an X-ray free-electron laser

Short-wavelength free-electron lasers with their ultrashort pulses at high intensities have originated new approaches for tracking molecular dynamics from the vista of specific sites. X-ray pump X-ray probe schemes even allow to address individual atomic constituents with a ‘trigger’-event that preludes the subsequent molecular dynamics while being able to selectively probe the evolving structure with a time-delayed second X-ray pulse. Here, we use a linearly polarized X-ray photon to trigger the photolysis of a prototypical chiral molecule, namely trifluoromethyloxirane (C$_3$H$_3$F$_3$O), at the fluorine K-edge at around 700 eV. The created fluorine-containing fragments are then probed by a second, circularly polarized X-ray pulse of higher photon energy in order to investigate the chemically shifted inner-shell electrons of the ionic mother-fragment for their stereochemical sensitivity. We experimentally demonstrate and theoretically support how two-color X-ray pump X-ray probe experiments with polarization control enable XFELs as tools for chiral recognition

Site-specific interrogation of an ionic chiral fragment during photolysis using an X-ray free-electron laser

Gefördert durch den Publikationsfonds der Universität Kasse

Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus

We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR

Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection—A Randomized Trial

International audienceBackground & AimsTreatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.MethodsPatients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).ResultsRates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.ConclusionsReduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy