The role of Drosophila Piezo in mechanical nociception

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.     

Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain

The vertebrate hindbrain develops in a segmental pattern, with distinctive groups of neurons originating from different segments. We report here that members of the Hox-2 cluster of murine homoeobox genes are expressed in segment-specific patterns in the developing hindbrain, with successive genes having boundaries at two-segment intervals. These data indicate that Hox genes specify segment phenotype, a role analogous to that of their Drosophila homologues.     

Carbon dioxide release from the North Pacific abyss during the last deglaciation

Atmospheric carbon dioxide concentrations were significantly lower during glacial periods than during intervening interglacial periods, but the mechanisms responsible for this difference remain uncertain. Many recent explanations call on greater carbon storage in a poorly ventilated deep ocean during glacial periods, but direct evidence regarding the ventilation and respired carbon content of the glacial deep ocean is sparse and often equivocal. Here we present sedimentary geochemical records from sites spanning the deep subarctic Pacific that--together with previously published results--show that a poorly ventilated water mass containing a high concentration of respired carbon dioxide occupied the North Pacific abyss during the Last Glacial Maximum. Despite an inferred increase in deep Southern Ocean ventilation during the first step of the deglaciation (18,000-15,000 years ago), we find no evidence for improved ventilation in the abyssal subarctic Pacific until a rapid transition approximately 14,600 years ago: this change was accompanied by an acceleration of export production from the surface waters above but only a small increase in atmospheric carbon dioxide concentration. We speculate that these changes were mechanistically linked to a roughly coeval increase in deep water formation in the North Atlantic, which flushed respired carbon dioxide from northern abyssal waters, but also increased the supply of nutrients to the upper ocean, leading to greater carbon dioxide sequestration at mid-depths and stalling the rise of atmospheric carbon dioxide concentrations. Our findings are qualitatively consistent with hypotheses invoking a deglacial flushing of respired carbon dioxide from an isolated, deep ocean reservoir, but suggest that the reservoir may have been released in stages, as vigorous deep water ventilation switched between North Atlantic and Southern Ocean source regions.     

Dissecting anxiety-related QTLs in mice by univariate and multivariate mapping

To detect genes underlying anxiety-related traits in mice,we performed univariate and multivariate QTL mapping analyses of phenotypes obtained from 71 mice of the BXD recombinant inbred (RI) strains (n=528 mice) and their parental strains (C57BL/6J and DBA/2J).Separate and joint mapping analyses were carried out using a linkage map composed of 506 simple sequence repeats (SSRs).The main QTL effects,interactions between pairs of QTLs (epistasis),and their environmental interactions were estimated.The results showed that anxiety-related traits were influenced by multiple QTLs (five main effect QTLs and three epistatic QTLs).Ten potential anxiety-related candidate genes within the QTL intervals on chromosomes 5,13 and 15 were identified.Some of these genes have been reported previously to be associated with the anxiety response.Based on our results,it is suggested that the multivariate QTL mapping approach improves the statistical power for detecting QTL and the precision of parameter estimation.Moreover,multivariate mapping can also detect pleiotropic QTL effects.     

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.     

Three-dimensional structure of calmodulin

The three-dimensional structure of calmodulin has been determined crystallographically at 3.0 A resolution. The molecule consists of two globular lobes connected by a long exposed alpha-helix. Each lobe binds two calcium ions through helix-loop-helix domains similar to those of other calcium-binding proteins. The long helix between the lobes may be involved in interactions of calmodulin with drugs and various proteins.     

A preliminary assessment of the techniques for measuring primary production in macrophytic marine algae

Résumé En employant les méthodes de la production d'oxygène et de l'assimilation du¹⁴C, on a estimé la productivité primaire de l'algue,Caulerpa prolifera, in situ à profondeurs variés aux îles Canaries. On a jugé les mérites respectives des 2 techniques et a comparé les résultats avec ceux des autres auteurs.

---

---

This work is part of a programme of investigation of the ecological distribution and primary productivity of benthic marine macrophytes in the Canary Island region.     

Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H

The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway. This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase. This, in turn, generates C3b, which mediates many of the biological functions of complement. Factor H, the main regulator of this activation, prevents formation and promotes dissociation of the C3 convertase enzyme, and, together with factor I, mediates the proteolytic inactivation of C3b. Factor H deficiency, described in 29 individuals from 12 families and in pigs, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H-deficient humans and pigs. Although MPGN has been reported in other conditions in which uncontrolled activation of C3 occurs, the role of C3 dysregulation in the pathogenesis of MPGN is not understood. Here we show that mice deficient in factor H (Cfh(-/-) mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh(-/-) mice. Thus, uncontrolled C3 activation in vivo is essential for the development of MPGN associated with deficiency of factor H.