Fluorescent Discrimination between Traces of Chemical Warfare Agents and Their Mimics

An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the inthe- field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.Ministerio de Economía y Competitividad, Spain (Project CTQ2012- 31611), Junta de Castilla y León, Consejería de Educación y Cultura y Fondo Social Europeo (Project BU246A12-1), the European Commission, Seventh Framework Programme (Project SNIFFER FP7-SEC-2012-312411) and the Swedish Ministry of Defence (no. A403913

Molecular evolution of a chordate specific family of G protein-coupled receptors

<p>Abstract</p> <p>Background</p> <p>Chordate evolution is a history of innovations that is marked by physical and behavioral specializations, which led to the development of a variety of forms from a single ancestral group. Among other important characteristics, vertebrates obtained a well developed brain, anterior sensory structures, a closed circulatory system and gills or lungs as blood oxygenation systems. The duplication of pre-existing genes had profound evolutionary implications for the developmental complexity in vertebrates, since mutations modifying the function of a duplicated protein can lead to novel functions, improving the evolutionary success.</p> <p>Results</p> <p>We analyzed here the evolution of the GPRC5 family of G protein-coupled receptors by comprehensive similarity searches and found that the receptors are only present in chordates and that the size of the receptor family expanded, likely due to genome duplication events in the early history of vertebrate evolution. We propose that a single GPRC5 receptor coding gene originated in a stem chordate ancestor and gave rise by duplication events to a gene family comprising three receptor types (GPRC5A-C) in vertebrates, and a fourth homologue present only in mammals (GPRC5D). Additional duplications of GPRC5B and GPRC5C sequences occurred in teleost fishes. The finding that the expression patterns of the receptors are evolutionarily conserved indicates an important biological function of these receptors. Moreover, we found that expression of GPRC5B is regulated by vitamin A <it>in vivo</it>, confirming previous findings that linked receptor expression to retinoic acid levels in tumor cell lines and strengthening the link between the receptor expression and the development of a complex nervous system in chordates, known to be dependent on retinoic acid signaling.</p> <p>Conclusions</p> <p>GPRC5 receptors, a class of G protein-coupled receptors with unique sequence characteristics, may represent a molecular novelty that helped non-chordates to become chordates.</p

Multidimensional Scaling Reveals the Main Evolutionary Pathways of Class A G-Protein-Coupled Receptors

Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families

Improving virtual screening of G protein-coupled receptors via ligand-directed modeling

G protein-coupled receptors (GPCRs) play crucial roles in cell physiology and pathophysiology. There is increasing interest in using structural information for virtual screening (VS) of libraries and for structure-based drug design to identify novel agonist or antagonist leads. However, the sparse availability of experimentally determined GPCR/ligand complex structures with diverse ligands impedes the application of structure-based drug design (SBDD) programs directed to identifying new molecules with a select pharmacology. In this study, we apply ligand-directed modeling (LDM) to available GPCR X-ray structures to improve VS performance and selectivity towards molecules of specific pharmacological profile. The described method refines a GPCR binding pocket conformation using a single known ligand for that GPCR. The LDM method is a computationally efficient, iterative workflow consisting of protein sampling and ligand docking. We developed an extensive benchmark comparing LDM-refined binding pockets to GPCR X-ray crystal structures across seven different GPCRs bound to a range of ligands of different chemotypes and pharmacological profiles. LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases. In all cases, the LDM-refined models had superior performance in enriching for the chemotype of the refinement ligand. This likely contributes to the LDM success in all cases of inhibitor-bound to agonist-bound binding pocket refinement, a key task for GPCR SBDD programs. Indeed, agonist ligands are required for a plethora of GPCRs for therapeutic intervention, however GPCR X-ray structures are mostly restricted to their inactive inhibitor-bound state

Exiles in British sociology

We have all seen them, foreheads wrinkled like a ploughed field, pastel-shaded check summer shirts worn in winter, desks festooned with yellowed index cards covered in hieroglyphics, books like yours only in plainer covers and read more carefully, filthy cigarettes, an accent growing thicker with age. But we have all seen them too, the luxuriant thatch at seventy, the jacket and tie, the tidy desk, the London club and the house in the country, the pipe, the disdain for small talk made all the more intimidating by an English acquired somewhere between grammar school and Oxford. Self-contained in a way only the uprooted can be, mysterious because you never knew what questions to ask them, emissaries from worlds they have lost and you have never known: the Polish gentry, the central European peasantry, Jewish merchants, German workers and, most puzzling of all, the continental European middle class

Whole Brain Size and General Mental Ability: A Review

We review the literature on the relation between whole brain size and general mental ability (GMA) both within and between species. Among humans, in 28 samples using brain imaging techniques, the mean brain size/GMA correlation is 0.40 (N = 1,389; p < 10−10); in 59 samples using external head size measures it is 0.20 (N = 63,405; p < 10−10). In 6 samples using the method of correlated vectors to distill g, the general factor of mental ability, the mean r is 0.63. We also describe the brain size/GMA correlations with age, socioeconomic position, sex, and ancestral population groups, which also provide information about brain–behavior relationships. Finally, we examine brain size and mental ability from an evolutionary and behavior genetic perspective