Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent

Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer’s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization

Efficient Symmetry Reduction and the Use of State Symmetries for Symbolic Model Checking

One technique to reduce the state-space explosion problem in temporal logic model checking is symmetry reduction. The combination of symmetry reduction and symbolic model checking by using BDDs suffered a long time from the prohibitively large BDD for the orbit relation. Dynamic symmetry reduction calculates representatives of equivalence classes of states dynamically and thus avoids the construction of the orbit relation. In this paper, we present a new efficient model checking algorithm based on dynamic symmetry reduction. Our experiments show that the algorithm is very fast and allows the verification of larger systems. We additionally implemented the use of state symmetries for symbolic symmetry reduction. To our knowledge we are the first who investigated state symmetries in combination with BDD based symbolic model checking

A comparability study of 5 commercial KRAS tests

<p>Abstract</p> <p>Background</p> <p>Activating mutations in the <it>KRAS </it>gene occur frequently in human tumors, including colorectal carcinomas; most mutations occur in codons 12 and 13. Mutations in <it>KRAS </it>have been associated with poor response to anti-epidermal growth factor receptor antibodies. Therefore, an accurate and readily available analysis of <it>KRAS </it>mutational status is needed. The aim of this study was to evaluate concordance between <it>KRAS </it>assays performed by 6 different laboratories.</p> <p>Methods</p> <p>Forty formalin-fixed paraffin-embedded colorectal cancer tumor samples were obtained. Sample sections were submitted for <it>KRAS </it>mutation analysis to 5 independent commercial laboratories (Agencourt, Gentris, Genzyme, HistoGeneX, and Invitek) and to the Amgen DNA Sequencing Laboratory for direct polymerase chain reaction sequencing. The assay used by Invitek is no longer commercially available and has been replaced by an alternative technique. Results from the commercial services were compared with those from Amgen direct sequencing by κ statistics.</p> <p>Results</p> <p><it>KRAS </it>mutations were observed in codon 12 and/or 13 in 20 of 40 (50%) samples in Amgen direct sequencing assays. Results from HistoGeneX (κ = 0.95), Genzyme (κ = 0.94), and Agencourt (κ = 0.94) were in almost perfect agreement with these results, and the results from Gentris were in substantial agreement with the results from Amgen (κ = 0.75). The Invitek allele-specific assay demonstrated slight agreement (κ = 0.13).</p> <p>Conclusions</p> <p>This study provides data on the comparability of <it>KRAS </it>mutational analyses. The results suggest that most (but not all) commercial services provide analysis that is accurate and comparable with direct sequencing.</p

Warm Water and Cool Nests Are Best. How Global Warming Might Influence Hatchling Green Turtle Swimming Performance

For sea turtles nesting on beaches surrounded by coral reefs, the most important element of hatchling recruitment is escaping predation by fish as they swim across the fringing reef, and as a consequence hatchlings that minimize their exposure to fish predation by minimizing the time spent crossing the fringing reef have a greater chance of surviving the reef crossing. One way to decrease the time required to cross the fringing reef is to maximize swimming speed. We found that both water temperature and nest temperature influence swimming performance of hatchling green turtles, but in opposite directions. Warm water increases swimming ability, with hatchling turtles swimming in warm water having a faster stroke rate, while an increase in nest temperature decreases swimming ability with hatchlings from warm nests producing less thrust per stroke

Synthesis and Cytoprotective Characterization of 8- Hydroxyquinoline Betti Products

The 8-hydroxyquinoline pharmacophore scaffold has been shown to possess a range of activities as metal chelation, enzyme inhibition, cytotoxicity, and cytoprotection. Based on our previous findings we set out to optimize the scaffold for cytoprotective activity for its potential application in central nervous system related diseases. A 48-membered Betti-library was constructed by the utilization of formic acid mediated industrial-compatible coupling with sets of aromatic primary amines such as anilines, oxazoles, pyridines, and pyrimidines, with (hetero)aromatic aldehydes and 8-hydroxiquinoline derivatives. After column chromatography and re-crystallization, the corresponding analogues were obtained in yields of 13–90%. The synthesized analogs were optimized with the utilization of a cytoprotection assay with chemically induced oxidative stress, and the most active compounds were further tested in orthogonal assays, a real time cell viability method, a fluorescence-activated cell sorting (FACS)-based assay measuring mitochondrial membrane potential changes, and gene expression analysis. The best candidates showed potent, nanomolar activity in all test systems and support the need for future studies in animal models of central nervous system (CNS) disorders

'Pragmatics and discourse analysis' [Review]

Review of work in 201

Network analysis of human protein location

<p>Abstract</p> <p>Background</p> <p>Understanding cellular systems requires the knowledge of a protein's subcellular localization (SCL). Although experimental and predicted data for protein SCL are archived in various databases, SCL prediction remains a non-trivial problem in genome annotation. Current SCL prediction tools use amino-acid sequence features and text mining approaches. A comprehensive analysis of protein SCL in human PPI and metabolic networks for various subcellular compartments is necessary for developing a robust SCL prediction methodology.</p> <p>Results</p> <p>Based on protein-protein interaction (PPI) and metabolite-linked protein interaction (MLPI) networks of proteins, we have compared, contrasted and analysed the statistical properties across different subcellular compartments. We integrated PPI and metabolic datasets with SCL information of human proteins from LOCATE and GOA (Gene Ontology Annotation) and estimated three statistical properties: Chi-square (χ²) test, Paired Localisation Correlation Profile (PLCP) and network topological measures. For the PPI network, Pearson's chi-square test shows that for the same SCL category, twice as many interacting protein pairs are observed than estimated when compared to non-interacting protein pairs (χ²= 1270.19, <it>P-value </it>< 2.2 × 10^-16), whereas for MLPI, metabolite-linked protein pairs having the same SCL are observed 20% more than expected, compared to non-metabolite linked proteins (χ²= 110.02, <it>P-value </it>< 2.2 x10^-16). To address the issue of proteins with multiple SCLs, we have specifically used the PLCP (Pair Localization Correlation Profile) measure. PLCP analysis revealed that protein interactions are majorly restricted to the same SCL, though significant cross-compartment interactions are seen for nuclear proteins. Metabolite-linked protein pairs are restricted to specific compartments such as the mitochondrion (<it>P-value </it>< 6.0e-07), the lysosome (<it>P-value </it>< 4.7e-05) and the Golgi apparatus (<it>P-value </it>< 1.0e-15). These findings indicate that the metabolic network adds value to the information in the PPI network for the localisation process of proteins in human subcellular compartments.</p> <p>Conclusions</p> <p>The MLPI network differs significantly from the PPI network in its SCL distribution. The PPI network shows passive protein interaction, possibly due to its high false positive rate, across different subcellular compartments, which seem to be absent in the MLPI network, as the MLPI network has evolved to maintain high substrate specificity for proteins.</p

An outline of an asymmetric two-component theory of aspect

The paper presents the bases of an asymmetric two-component model of aspect. The main theoretical conclusion of the study is that (grammatical) viewpoint aspect and situation aspect are not independent aspectual levels, since the former often modifies the input situation aspect of the phrase/sentence. As it is shown, besides the arguments and adjuncts of the predicate, viewpoint aspect is also an important factor in compositionally marking situation aspect. The aspectual framework put forward in the paper is verified and illustrated on the basis of the aspectual system of Hungarian and some examples taken from English linguistic data