On the hierarchical classification of G Protein-Coupled Receptors

Motivation: G protein-coupled receptors (GPCRs) play an important role in many physiological systems by transducing an extracellular signal into an intracellular response. Over 50% of all marketed drugs are targeted towards a GPCR. There is considerable interest in developing an algorithm that could effectively predict the function of a GPCR from its primary sequence. Such an algorithm is useful not only in identifying novel GPCR sequences but in characterizing the interrelationships between known GPCRs. Results: An alignment-free approach to GPCR classification has been developed using techniques drawn from data mining and proteochemometrics. A dataset of over 8000 sequences was constructed to train the algorithm. This represents one of the largest GPCR datasets currently available. A predictive algorithm was developed based upon the simplest reasonable numerical representation of the protein's physicochemical properties. A selective top-down approach was developed, which used a hierarchical classifier to assign sequences to subdivisions within the GPCR hierarchy. The predictive performance of the algorithm was assessed against several standard data mining classifiers and further validated against Support Vector Machine-based GPCR prediction servers. The selective top-down approach achieves significantly higher accuracy than standard data mining methods in almost all cases

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

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

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

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

An exploration of educative praxis : Reflections on Marx’s concept praxis, informed by the Lacanian concepts act and event

This article explores an aspect of Karl Marx’s concept, praxis. Praxis is meaningful work, through which we fulfil ourselves by fulfilling others. The discussion draws on the author’s work with postgraduate student teachers, where both students and author were researching their own practice. Reflecting Marx’s conception of praxis as subjective fulfilment in the objective world, this activity was intended to trouble and complicate the categories ‘subjective’ and ‘objective’, whilst enabling students to become both more autonomous and other-oriented. The intention behind this article is to develop the theoretical vocabulary of praxis available to educational researchers and practitioners. Some ideas from Lacanian psychoanalysis are introduced, followed by extensive discussion of Slavoj Žižek’s concepts, ‘act’ and ‘event’. The key argument is that in a nascent educative praxis, ‘subjective’ and ‘objective’ perspectives can be understood not as fixed points of reference, but as dual orientations on a flow of signification. These ideas are developed alongside detailed examination of two university-based research sessions with student teachers. With reference to session activities, a rationale is provided for an emerging educative praxis, in which students explore creative tensions between ‘subjective’ and ‘objective’ perspectives on school-based practice