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

Galanin and galanin receptor expression in neuroblastic tumours: correlation with their differentiation status

Neuroblastoma and its benign differentiated counterpart, ganglioneuroma, are paediatric neuroblastic tumours arising in the sympathetic nervous system. Their broad spectrum of clinical virulence is mainly related to heterogeneous biologic background and tumour differentiation. Neuroblastic tumours synthesize various neuropeptides acting as neuromodulators. Previous studies suggested that galanin plays a role in sympathetic tissue where it could be involved in differentiation and development. We investigated the expression and distribution of galanin and its three known receptors (Gal-R1, Gal-R2, Gal-R3) in 19 samples of neuroblastic tumours tissue by immunohistochemistry, in situ hybridization and fluorescent-ligand binding. This study provides clear evidence for galanin and galanin receptor expression in human neuroblastic tumours. The messengers coding for galanin, Gal-R1 and -R3 were highly expressed in neuroblastoma and their amount dramatically decreased in ganglioneuroma. In contrast, Gal-R2 levels remained unchanged. Double labelling studies showed that galanin was mainly co-expressed with its receptors whatever the differentiation stage. In neuroblastic tumours, galanin might promote cell-survival or counteract neuronal differentiation through the different signalling pathways mediated by galanin receptors. Finally, our results suggest that galanin influences neuroblastoma growth and development as an autocrine/paracrine modulator. These findings suggest potential critical implications for galanin in neuroblastic tumours development

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

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

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

Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis

<p>Abstract</p> <p>Background</p> <p>G protein coupled receptors (GPCRs) are one of the most widely studied gene superfamilies. Thousands of GPCR research studies have utilized heterologous expression systems such as human embryonic kidney cells (HEK293). Though often treated as 'blank slates', these cell lines nevertheless endogenously express GPCRs and related signaling proteins. The outcome of a given GPCR study can be profoundly influenced by this largely unknown complement of receptors and/or signaling proteins. Little easily accessible information exists that describes the expression profiles of the GPCRs in cell lines. What is accessible is often limited in scope - of the hundreds of GPCRs and related proteins, one is unlikely to find information on expression of more than a dozen proteins in a given cell line. Microarray technology has allowed rapid analysis of mRNA levels of thousands of candidate genes, but though often publicly available, the results can be difficult to efficiently access or even to interpret.</p> <p>Results</p> <p>To bridge this gap, we have used microarrays to measure the mRNA levels of a comprehensive profile of non-chemosensory GPCRs and over a hundred GPCR signaling related gene products in four cell lines frequently used for GPCR research: HEK293, AtT20, BV2, and N18.</p> <p>Conclusions</p> <p>This study provides researchers an easily accessible mRNA profile of the endogenous signaling repertoire that these four cell lines possess. This will assist in choosing the most appropriate cell line for studying GPCRs and related signaling proteins. It also provides a better understanding of the potential interactions between GPCRs and those signaling proteins.</p

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