Improved molecular replacement by density- and energy-guided protein structure optimization

Molecular replacement procedures, which search for placements of a starting model within the crystallographic unit cell that best account for the measured diffraction amplitudes, followed by automatic chain tracing methods, have allowed the rapid solution of large numbers of protein crystal structures. Despite extensive work, molecular replacement or the subsequent rebuilding usually fail with more divergent starting models based on remote homologues with less than 30% sequence identity. Here we show that this limitation can be substantially reduced by combining algorithms for protein structure modelling with those developed for crystallographic structure determination. An approach integrating Rosetta structure modelling with Autobuild chain tracing yielded high-resolution structures for 8 of 13 X-ray diffraction data sets that could not be solved in the laboratories of expert crystallographers and that remained unsolved after application of an extensive array of alternative approaches. We estimate that the new method should allow rapid structure determination without experimental phase information for over half the cases where current methods fail, given diffraction data sets of better than 3.2?? resolution, four or fewer copies in the asymmetric unit, and the availability of structures of homologous proteins with >20% sequence identity.     

Relation between blockade of H3-noradrenaline uptake and pharmacological actions produced by phenothiazine derivatives

Zusammenfassung Es wurden eine Reihe von Phenothiazin-Derivaten auf ihr Vermögen die H³-Noradrenalinaufnahme in das Rattenherz zu blockieren getestet. Dabei hat sich ergeben, dass dieses Blockierungsvermögen weniger mit den antimotorischen oder Antihistamineigenschaften der Substanzen gekoppelt zu sein scheint, sondern eher mit deren antiadrenergischen Wirkungskomponenten.     

Evolution of cooperation without reciprocity.

A long-standing problem in biological and social sciences is to understand the conditions required for the emergence and maintenance of cooperation in evolving populations. For many situations, kin selection is an adequate explanation, although kin-recognition may still be a problem. Explanations of cooperation between non-kin include continuing interactions that provide a shadow of the future (that is, the expectation of an ongoing relationship) that can sustain reciprocity, possibly supported by mechanisms to bias interactions such as embedding the agents in a two-dimensional space or other context-preserving networks. Another explanation, indirect reciprocity, applies when benevolence to one agent increases the chance of receiving help from others. Here we use computer simulations to show that cooperation can arise when agents donate to others who are sufficiently similar to themselves in some arbitrary characteristic. Such a characteristic, or 'tag', can be a marking, display, or other observable trait. Tag-based donation can lead to the emergence of cooperation among agents who have only rudimentary ability to detect environmental signals and, unlike models of direct or indirect reciprocity, no memory of past encounters is required.     

1-(3′-methoxy-4′-hydroxy benzyl) 6–7 dimethoxy isoquinoline,a major metabolite of papaverine

Zusammenfassung An Glukorons?ure gebundenes 1-(3′-Methoxy-4′-hydroxy-phenyl)-6, 7-dimethoxy-chinolin ist als Metabolit des Papaverins beim Menschen und bei S?ugetieren erkannt und isoliert worden. Ein in den Lebermikrosomen enthaltenes Ferment, dassauerstoff-und TPNH-abh?ngig ist, bewirkt die Methoxylspaltung, und ein weiteres Ferment übertr?gt die Glukurons?ure aus ihrer Verbindung mit Uridinphosphat auf die entstandene phenolische Verbindung.      

Hydroxylation and N-demethylation of N,N-dimethyltryptamine

Zusammenfassung Der intermediäre Stoffwechsel des psychotropen N,N-Dimethyltryptamins wurde untersucht. N-Methyltryptamin, als Produkt der Demethylierung, und 6-Hydroxy-N,N-Dimethyltryptamin, als Produkt der Hydroxylierung, wurden nachgewiesen und papierchromatographisch charakterisiert. An weiteren Stoffwechselprodukten wurden nachgewiesen: N,N-Dimethyltryptamin-N-oxyd und sein 6-Hydroxy-Derivat (in vitro), sowie Tryptamin, Indol-3-essigsäure und 6-Hydroxyindol-3-essigsäure (in vivo).