Asymmetries of dual enlargement: from the Baltics to the Balkans

Dual enlargement of the EU and NATO has the potential to generate asymmetric security impacts within Euro-Atlantic region. The room for asymmetric impacts are between existing NATO and EU member states, between new and old NATO and EU members; between three security policies, between EU and NATO member states and those that will integrate in the year 2004

A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant

OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions

Do cravings predict smoking cessation in smokers calling a national quit line: secondary analyses from a randomised trial for the utility of ‘urges to smoke’ measures

BACKGROUND: Single-item urges to smoke measures have been contemplated as important measures of nicotine dependence This study aimed to prospectively determine the relationships between measures of craving to smoke and smoking cessation, and compare their ability to predict cessation with the Heaviness of Smoking Index, an established measure of nicotine dependence. METHODS: We conducted a secondary analysis of data from the randomised controlled PORTSSS trial. Measures of nicotine dependence, ascertained before making a quit attempt, were the HSI, frequency of urges to smoke (FUTS) and strength of urges to smoke (SUTS). Self-reported abstinence at six months after quitting was the primary outcome measure. Multivariate logistic regression and Receiver Operating Characteristic (ROC) analysis were used to assess associations and abilities of the nicotine dependence measures to predict smoking cessation. RESULTS: Of 2,535 participants, 53.5% were female; the median (Interquartile range) age was 38 (28–50) years. Both FUTS and HSI were inversely associated with abstinence six months after quitting; for each point increase in HSI score, participants were 16% less likely to have stopped smoking (OR 0.84, 95% C.I 0.78-0.89, p < 0.0001). Compared to participants with the lowest possible FUTS scores, those with greater scores had generally lower odds of cessation (p across frequency of urges categories=0.0026). SUTS was not associated with smoking cessation. ROC analysis suggested the HSI and FUTS had similar predictive validity for cessation. CONCLUSIONS: Higher FUTS and HSI scores were inversely associated with successful smoking cessation six months after quit attempts began and both had similar validity for predicting cessation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13011-015-0011-8) contains supplementary material, which is available to authorized users

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Victory is not possible : defeat is not an option ; the US, Iraq and the Middle East

Graeme P. Her

The causes and consequences of strategic failure in Afghanistan & Iraq

Graeme P. HerdParallel als Buch-Ausg. erschiene