The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein

The antimicrobial defence of Drosophila relies largely on the challenge-induced synthesis of an array of potent antimicrobial peptides by the fat body. The defence against Gram-positive bacteria and natural fungal infections is mediated by the Toll signalling pathway, whereas defence against Gram-negative bacteria is dependent on the Immune deficiency (IMD) pathway. Loss-of-function mutations in either pathway reduce the resistance to corresponding infections. The link between microbial infections and activation of these two pathways has remained elusive. The Toll pathway is activated by Gram-positive bacteria through a circulating Peptidoglycan recognition protein (PGRP-SA). PGRPs appear to be highly conserved from insects to mammals, and the Drosophila genome contains 13 members. Here we report a mutation in a gene coding for a putative transmembrane protein, PGRP-LC, which reduces survival to Gram-negative sepsis but has no effect on the response to Gram-positive bacteria or natural fungal infections. By genetic epistasis, we demonstrate that PGRP-LC acts upstream of the imd gene. The data on PGRP-SA with respect to the response to Gram-positive infections, together with the present report, indicate that the PGRP family has a principal role in sensing microbial infections in Drosophila.     

Structural basis for the selectivity of the external thioesterase of the surfactin synthetase

Non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) found in bacteria, fungi and plants use two different types of thioesterases for the production of highly active biological compounds. Type I thioesterases (TEI) catalyse the release step from the assembly line of the final product where it is transported from one reaction centre to the next as a thioester linked to a 4'-phosphopantetheine (4'-PP) cofactor that is covalently attached to thiolation (T) domains. The second enzyme involved in the synthesis of these secondary metabolites, the type II thioesterase (TEII), is a crucial repair enzyme for the regeneration of functional 4'-PP cofactors of holo-T domains of NRPS and PKS systems. Mispriming of 4'-PP cofactors by acetyl- and short-chain acyl-residues interrupts the biosynthetic system. This repair reaction is very important, because roughly 80% of CoA, the precursor of the 4'-PP cofactor, is acetylated in bacteria. Here we report the three-dimensional structure of a type II thioesterase from Bacillus subtilis free and in complex with a T domain. Comparison with structures of TEI enzymes shows the basis for substrate selectivity and the different modes of interaction of TEII and TEI enzymes with T domains. Furthermore, we show that the TEII enzyme exists in several conformations of which only one is selected on interaction with its native substrate, a modified holo-T domain.     

Local and Global Properties of the World

The essence of the method of physics is inseparably connected with the problem of interplay between local and global properties of the universe. In the present paper we discuss this interplay as it is present in three major departments of contemporary physics: general relativity, quantum mechanics and some attempts at quantizing gravity (especially geometrodynamics and its recent successors in the form of various pregeometry conceptions). It turns out that all big interpretative issues involved in this problem point towards the necessity of changing from the standard space-time geometry to some radically new, most probably non-local, generalization. We argue that the recent noncommutative geometry offers attractive possibilities, and gives us a conceptual insight into its algebraic foundations. Noncommutative spaces are, in general, non-local, and their applications to physics, known at present, seem very promising. One would expect that beneath the Planck threshold there reigns a "noncommutative pregeometry", and only when crossing this threshold does the usual space-time geometry emerges.     

Andalò di Negro’s De compositione astrolabii: a critical edition with English translation and notes

In this article, we publish the critical edition of Andalò di Negro’s De compositione astrolabii, with English translation and commentary. The mathematician and astronomer Andalò di Negro (Genoa ca. 1260–Naples 1334) presumably redacted this treatise on the astrolabe in the 1330s, while residing at the court of King Robert of Naples. The present edition has three purposes: first, to make available a text missing from the previous compilations of works by Andalò di Negro (ed. Bonus Opus preclarissimum astrolabij compositum a domino Andalo de nigro genuensi foeliciter incipit…Explicit tractatus astrolabij excellentissimi mathematici Andalonis genuensis, emendatus per celeberrimum et doctissimum astronomum magistrum Petrum Bonum Avogarium in foelici gymnasio ferrariensi. [Ferrara]: magister Johannes Picardus, 1475; Bertolotto II Trattato sull’Astrolabio di Andalò di Negro, riprodotto dall’edizione ferrarese del 1475, con prefazione del socio G. Bertolotto. Atti della società ligure di storia patria 25, 51–141, 1892; Fornaciari and Faracovi Trattato sull’astrolabio di Andalò di Negro, a cura di P.E. Fornaciari e O.P. Faracovi. Pubblicazione del Comune di Livorno in occasione della “Primavera della Scienza a Livorno” (febbraio-maggio 2005). Ospedaletto: Pacini editore, 2005); second, to revise a privately circulated edition of the text (Cesari L’astrolabio di Andalò di Negro, Parte I, edizione critica. Milano: s.n., 1984a; Practica Astrolabii di Andalò di Negro, Parte I. Edizione critica. Bergamo: Istituto Universitario di Bergamo, 1984b); and third, to help disseminating one of the rare Latin texts presenting the principles of the stereographic projection which underlie the construction of the astrolabe.

     

A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse

The mouse mutation fragilitas ossium (fro) leads to a syndrome of severe osteogenesis and dentinogenesis imperfecta with no detectable collagen defect. Positional cloning of the locus identified a deletion in the gene encoding neutral sphingomyelin phosphodiesterase 3 (Smpd3) that led to complete loss of enzymatic activity. Our knowledge of SMPD3 function is consistent with the pathology observed in mutant mice and provides new insight into human pathologies.     

Building the stemma codicum from geometric diagrams

In view of the progress made in recent decades in the fields of stemmatology and the analysis of geometric diagrams, the present article explores the possibility of establishing the stemma codicum of a handwritten tradition from geometric diagrams alone. This exploratory method is tested on Ibn al-Haytham’s Epistle on the Shape of the Eclipse, because this work has not yet been issued in a critical edition. Separate stemmata were constructed on the basis of the diagrams and the text, and a comparison showed no major differences. The greater reliability of a stemma codicum constructed on the basis of the diagrams rather than the text of a mathematical work is discussed, and preliminary conclusions are drawn.