PMX-53 as a Dual CD88 antagonist and an Agonist for Mas-Related Gene 2 (MrgX2) in Human Mast Cells

Human mast cells express the G protein coupled receptor (GPCR) for C5a (CD88). Previous studies indicated that C5a could cause mast cell degranulation, at least in part, via a mechanism similar to that proposed for basic neuropeptides such as substance P, possibly involving Mas-related gene 2 (MrgX2). We therefore sought to more clearly define the receptor specificity for C5a-induced mast cell degranulation. We found that LAD2, a human mast cell line, and CD34+ cell-derived primary mast cells express functional MrgX1 and MrgX2 but the immature human mast cell line HMC-1 does not. A potent CD88 antagonist, PMX-53 (10 nM) inhibited C5ainduced Ca2+ mobilization in HMC-1 cells, but at higher concentrations (≥30 nM) it caused degranulation in LAD2 mast cells, CD34+ cell-derived mast cells, and RBL-2H3 cells stably expressing MrgX2. PMX-53 did not, however, activate RBL-2H3 cells expressing MrgX1. Although C5a induced degranulation in LAD2 and CD34+ cell-derived mast cells, it did not activate RBL-2H3 cells expressing MrgX1 or MrgX2. Replacement of Trp with Ala and Arg with dArg abolished the ability of PMX-53 to inhibit C5a-induced Ca2+ mobilization in HMC-1 cells and to cause degranulation in RBL-2H3 cells expressing MrgX2. These findings demonstrate that C5a does not use MrgX1 or MrgX2 for mast cell degranulation. Moreover, it reveals the novel finding that PMX-53 functions as a potent CD88 antagonist and a low-affinity agonist for MrgX2. Furthermore, Trp and Arg residues are required for the ability of PMX53 to act as both a CD88 antagonist and a MrgX2 agonist. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics

The Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation

J.C.Y. was funded by an MRC PhD studentship. D.J.B. is supported by a London Research Institute, Cancer Research UK Postdoctoral Fellowship award and M.W. is supported by Cancer Research UK. K.A. was supported by the Deutsche Forschungsgemeinschaft (AK 6/22-1 and AK 6/22-2) and the Center for Biological Signaling Studies in Freiburg (Germany). This work was supported by grants from the Wellcome Trust to G.F. and S.J.M

Vibration and stability of thin shell structures

SIGLEAvailable from British Library Document Supply Centre- DSC:D36637/81 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Othello the Traveller

In this study, I employ Francis Bacon's concept of simulation, or 'false profession,' to discuss Othello the traveller and the significance of his penchant for telling wondrous tales. Defined by Bacon as 'when a man industriously and expressly feigns and pretends to be that he is not' (Essays VI.19-20), simulation is a kind of affirmative untruth in which perpetrators invent false materials, embellish their achievements or exaggerate their talents in order to achieve self-promotional goals - actions akin to padding one's resumé today. Bacon terms this calculated mis-representation of the self a 'vice' that reveals to discerning auditors that which it would conceal, namely, faults or weaknesses in the teller (VI.20). Contradictions in Othello's marvellous truth-claims (e.g., about his past, his sword, his 'magical' handkerchief) expose a myth-making process by which, paradoxically, he overstates his foreign-ness in order to gain European admirers. In short, Othello does not fear being other; he fears not being other enough. Using travellers' tales and moving accounts of the 'battles, sieges, fortunes' that he has passed (1.3.131-32), Othello markets himself to Venice as culturally exotic and militarily indispensable, qualities which are ultimately revealed to have been overstated. This article contextualizes Othello using contemporary plays featuring that emerging figure of ridicule, the stock comic traveller, as well as within increasing early modern skepticism about travellers' tales, in order to propose that early audiences may have been prompted to interpret Othello's stories as narrative simulations forming a pseudo-exotic persona which secures him unwarranted prominence in Venetian society