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Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin α 5 β 1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori -induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling. Helicobacter targets integrin Integrins, an important family of cell adhesion receptors involved in a variety of signalling processes, are targeted by a number of bacterial and viral pathogens for adhesion or invasion. An integrin has now been identified as the receptor for the gastric pathogen Helicobacter pylori . The pathogen's CagL pilus protein docks onto the host cell surface receptor integrin α 5 β 1 ; this triggers the injection of the oncoprotein CagA (cytotoxin-associated gene A) into the host cells. This work points to CagL as a possible drug target for treating gastric diseases caused by some H. pylori strains. Integrins are cell adhesion receptors involved in a variety of signalling processes and are targeted by a number of bacterial and viral pathogens for adhesion or invasion. The gastric pathogen Helicobacter pylori 's pilus protein CagL interacts with integrin, which subsequently triggers translocation and phoshorylation of the bacterial effector CagA.

The SPACE trial is a multinational, prospective, randomised study to test the hypothesis that carotid artery stenting is not inferior to carotid endarterectomy for treating patients with severe symptomatic carotid artery stenosis. We did not prove non-inferiority of carotid artery stenting compared with carotid endarterectomy for the 30-day complication rate, and we now report the results at 2 years. Between March, 2001, and February, 2006, patients with symptomatic, severe (≥70%) carotid artery stenosis were recruited to this non-inferiority trial and randomly assigned with a block randomisation design to have carotid artery angioplasty with stenting or carotid artery endarterectomy. 2-year endpoints include several clinical endpoints and the incidence of recurrent carotid stenosis of at least 70%. Clinical and vascular follow-up was done by a certified neurologist. Analyes were by intention to treat and per protocol. This trial is registered with ISRCTN, number 57874028.12. 1 214 patients were randomly assigned (613 were randomly assigned to carotid angioplasty with stenting and 601 were randomly assigned to carotid endarterectomy). In both the intention-to-treat and per-protocol analyses the Kaplan-Meier estimates of ipsilateral ischaemic strokes up to 2 years after the procedure and any periprocedural stroke or death do not differ between the carotid artery stenting and the carotid endarterectomy groups (intention to treat 9·5% vs 8·8%; hazard ratio (HR) 1·10, 95%CI 0·75 to 1·61; log-rank p=0·62; per protocol 9·4% vs 7·8%; HR 1·23, 95%CI 0·82 to 1·83; log-rank p=0·31). In both the intention-to-treat and per-protocol populations, recurrent stenosis of 70% or more is significantly more frequent in the carotid artery stenting group compared with the carotid endarterectomy group, with a life-table estimate of 10·7% versus 4·6% (p=0·0009) and 11·1% versus 4·6% (p=0·0007), respectively. Only two incidences of recurrent stenoses after carotid artery stenting led to neurological symptoms. After 2 years' follow-up, the rate of recurrent ipsilateral ischaemic strokes reported in the SPACE trial is similar for both treatment groups. The incidence of recurrent carotid stenosis at 2 years, as defined by ultrasound, is significantly higher after carotid artery stenting. However, it cannot be excluded that the degree of in-stent stenosis is slightly overestimated by conventional ultrasound criteria. Federal Ministry of Education and Research; German Research Foundation; The German Society of Neurology; The German Society of Neuroradiology; The German Radiological Society; Boston Scientific; Guidant; Sanofi-Aventis.

Ever since the discovery of endogenous host defense antimicrobial peptides it has been discussed how these evolutionary conserved molecules avoid to induce resistance and to remain effective. Human ß-defensin 1 (hBD1) is an ubiquitously expressed endogenous antimicrobial peptide that exhibits qualitatively distinct activities between its oxidized and reduced forms. Here, we explore these antimicrobial mechanisms. Surprisingly, using electron microscopy we detected a so far unknown net-like structure surrounding bacteria, which were treated with the reduced but not the oxidized form of hBD1. A transmigration assay demonstrated that hBD1-derived nets capture bacteria and inhibit bacterial transmigration independent of bacterial killing. The presence of nets could completely prevent migration of hBD1 resistant pathogens and are stable in the presence of human duodenal secretion with a high amount of proteases. In contrast to HD6, cysteins are necessary for net formation. This redox-dependent function serves as an additional mechanism of action for hBD1 and differs from net formation by other defensins such as Paneth cell-derived human α-defensin 6 (HD6). While hBD1red and hBD1ox have distinct antimicrobial profiles and functions, only the reduced form provides additional host protection by entrapping bacteria in extracellular net structures preventing bacterial invasion. Better understanding of the modes of action of endogenous host peptides will help to find new antimicrobial strategies.

Life-cycle transitions connecting larval and juvenile stages in metazoans are orchestrated by neuroendocrine signals including neuropeptides and hormones. In marine invertebrate life cycles, which often consist of planktonic larval and benthic adult stages, settlement of the free-swimming larva to the sea floor in response to environmental cues is a key life cycle transition. Settlement is regulated by a specialized sensory–neurosecretory system, the larval apical organ. The neuroendocrine mechanisms through which the apical organ transduces environmental cues into behavioral responses during settlement are not yet understood. Here we show that myoinhibitory peptide (MIP)/allatostatin-B, a pleiotropic neuropeptide widespread among protostomes, regulates larval settlement in the marine annelid Platynereis dumerilii . MIP is expressed in chemosensory–neurosecretory cells in the annelid larval apical organ and signals to its receptor, an orthologue of the Drosophila sex peptide receptor, expressed in neighboring apical organ cells. We demonstrate by morpholino-mediated knockdown that MIP signals via this receptor to trigger settlement. These results reveal a role for a conserved MIP receptor–ligand pair in regulating marine annelid settlement.

The stone-like otoliths from the ears of teleost fishes are involved in balance and hearing and consist of calcium carbonate crystallites embedded in a protein framework. We report that a previously unknown gene, starmaker, is required in zebrafish for otolith morphogenesis. Reduction of starmaker activity by injection of modified antisense oligonucleotides causes a change in the crystal lattice structure and thus a change in otolith morphology. The expression pattern of starmaker, along with the presence of the protein on the growing otolith, suggest that the expression levels of starmaker control the shape of the otoliths.

Biofilm formation has been studied in much detail for a variety of bacterial species, as it plays a major role in the pathogenicity of bacteria. However, only limited information is available for the development of archaeal communities that are frequently found in many natural environments. We have analyzed biofilm formation in three closely related hyperthermophilic crenarchaeotes: Sulfolobus acidocaldarius, S. solfataricus and S. tokodaii. We established a microtitre plate assay adapted to high temperatures to determine how pH and temperature influence biofilm formation in these organisms. Biofilm analysis by confocal laser scanning microscopy demonstrated that the three strains form very different communities ranging from simple carpet-like structures in S. solfataricus to high density tower-like structures in S. acidocaldarius in static systems. Lectin staining indicated that all three strains produced extracellular polysaccharides containing glucose, galactose, mannose and N-acetylglucosamine once biofilm formation was initiated. While flagella mutants had no phenotype in two days old static biofilms of S. solfataricus, a UV-induced pili deletion mutant showed decreased attachment of cells. The study gives first insights into formation and development of crenarchaeal biofilms in extreme environments.

Protoliths of highly metamorphosed gneisses from the Erzgebirge are deduced from the morphology, age and chemistry of zircons as well as from whole rock geochemistry and are compared with lower-grade rocks of Lusatia. Gneisses with similar structural appearance and/or geochemical pattern may have quite different protoliths. The oldest rocks in the Erzgebirge are paragneisses representing meta-greywackes and meta-conglomerates. The youngest group of zircon of meta-greywackes that did not undergo Pb loss represents the youngest igneous component for source rocks (about 575 Ma). Similar ages and zircon morphology reflect the subordinate formation of new zircon grains or only zircon rims in the augengneiss from Bärenstein and Wolkenstein, which probably represent metamorphic equivalents to Lower Cambrian two-mica granodiorites from Lusatia. Bulk rock chemistry, intense fracturing and high U and Th concentrations of zircons suggest deformation-induced and fluid-enhanced recrystallisation of zircon grains. Temperatures during tectonic overprinting—too low to reset zircon ages—indicate mid- or upper crustal levels for shearing recorded in these augengneisses. Lower Cambrian (~540 Ma) granodiorites are widespread in Lusatia but are exclusively represented by the Freiberg gneiss dome in the Eastern Erzgebirge. Ordovician protolith ages were recorded by zircons from the augengneisses of the Reitzenhain–Catherine dome and the Schwarzenberg dome (Western Erzgebirge) documenting significant regional differences between the eastern and the western Erzgebirge (~540 vs. ~490 Ma). In the Western Erzgebirge, most meta-volcanic rocks (muscovite gneisses) and meta-granites (mainly red augengneisses) yield Ordovician zircon ages, whereas in the Eastern part, similar rocks mainly recorded Lower Cambrian protolith ages. Zircon overprinting was highest within discrete tectonic zones where the combination of fluid infiltration and deformation induced variable degrees of recrystallisation and formation of a new augengneiss structure. Variable degrees of Pb loss caused age shifts that do not correspond to changes in zircon morphology but may be associated with U and Th enrichments. Major changes in bulk rock composition appear to be restricted to discrete zones and to (U)HP nappes, whereas gneisses with a MP–MT metamorphic overprint basically show no geochemical modifications.

Startle responses triggered by aversive stimuli including predators are widespread across animals. These coordinated whole-body actions require the rapid and simultaneous activation of a large number of muscles. Here we study a startle response in a planktonic larva to understand the whole-body circuit implementation of the behaviour. Upon encountering water vibrations, larvae of the annelid Platynereis close their locomotor cilia and simultaneously raise the parapodia. The response is mediated by collar receptor neurons expressing the polycystins PKD1-1 and PKD2-1. CRISPR-generated PKD1-1 and PKD2-1 mutant larvae do not startle and fall prey to a copepod predator at a higher rate. Reconstruction of the whole-body connectome of the collar-receptor-cell circuitry revealed converging feedforward circuits to the ciliary bands and muscles. The wiring diagram suggests circuit mechanisms for the intersegmental and left-right coordination of the response. Our results reveal how polycystin-mediated mechanosensation can trigger a coordinated whole-body effector response involved in predator avoidance.

Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are used to prevent ischaemic stroke in patients with stenosis of the internal carotid artery. Better knowledge of risk factors could improve assignment of patients to these procedures and reduce overall risk. We aimed to assess the risk of stroke or death associated with CEA and CAS in patients with different risk factors. We analysed data from 1196 patients randomised to CAS or CEA in the Stent-Protected Angioplasty versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial. The primary outcome event was death or ipsilateral stroke (ischaemic or haemorrhagic) with symptoms that lasted more than 24 h between randomisation and 30 days after therapy. Six predefined variables were assessed as potential risk factors for this outcome: age, sex, type of qualifying event, side of intervention, degree of stenosis, and presence of high-grade contralateral stenosis or occlusion. The SPACE trial is registered at Current Controlled Trials, with the international standard randomised controlled trial number ISRCTN57874028. Risk of ipsilateral stroke or death increased significantly with age in the CAS group (p=0·001) but not in the CEA group (p=0·534). Classification and regression tree analysis showed that the age that gave the greatest separation between high-risk and low-risk populations who had CAS was 68 years: the rate of primary outcome events was 2·7% (8/293) in patients who were 68 years old or younger and 10·8% (34/314) in older patients. Other variables did not differ between the CEA and CAS groups. Of the predefined covariates, only age was significantly associated with the risk of stroke and death. The lower risk after CAS versus CEA in patients up to 68 years of age was not detectable in older patients. This finding should be interpreted with caution because of the drawbacks of post-hoc analyses.

Acute bacterial meningitis is a life-threatening disease in humans. Discussed as entry sites for pathogens into the brain are the blood-brain and the blood-cerebrospinal fluid barrier (BCSFB). Although human brain microvascular endothelial cells (HBMEC) constitute a well established human in vitro model for the blood-brain barrier, until now no reliable human system presenting the BCSFB has been developed. Here, we describe for the first time a functional human BCSFB model based on human choroid plexus papilloma cells (HIBCPP), which display typical hallmarks of a BCSFB as the expression of junctional proteins and formation of tight junctions, a high electrical resistance and minimal levels of macromolecular flux when grown on transwell filters. Importantly, when challenged with the zoonotic pathogen Streptococcus suis or the human pathogenic bacterium Neisseria meningitidis the HIBCPP show polar bacterial invasion only from the physiologically relevant basolateral side. Meningococcal invasion is attenuated by the presence of a capsule and translocated N. meningitidis form microcolonies on the apical side of HIBCPP opposite of sites of entry. As a functionally relevant human model of the BCSFB the HIBCPP offer a wide range of options for analysis of disease-related mechanisms at the choroid plexus epithelium, especially involving human pathogens.