The P2Y12 receptor induces platelet aggregation through weak activation of the αIIbβ3 integrin – a phosphoinositide 3-kinase-dependent mechanism

AbstractHigh concentrations of adenosine-5′-diphosphate ADP are able to induce partial aggregation without shape change of P2Y1 receptor-deficient mouse platelets through activation of the P2Y12 receptor. In the present work we studied the transduction pathways selectively involved in this phenomenon. Flow cytometric analyses using R-phycoerythrin-conjugated JON/A antibody (JON/A-PE), an antibody which recognizes activated mouse αIIbβ3 integrin, revealed a low level activation of αIIbβ3 in P2Y1 receptor-deficient platelets in response to 100 μM ADP or 1 μM 2MeS-ADP. Adrenaline induced no such activation but strongly potentiated the effect of ADP in a dose-dependent manner. Global phosphorylation of 32P-labeled platelets showed that P2Y12-mediated aggregation was not accompanied by an increase in the phosphorylation of myosin light chain (P20) or pleckstrin (P47) and was not affected by the protein kinase C (PKC) inhibitor staurosporine. On the other hand, two unrelated phosphoinositide 3-kinase inhibitors, wortmannin and LY294002, inhibited this aggregation. Our results indicate that (i) the P2Y12 receptor is able to trigger a P2Y1 receptor-independent inside-out signal leading to αIIbβ3 integrin activation and platelet aggregation, (ii) ADP and adrenaline use different signaling pathways which synergize to activate the αIIbβ3 integrin, and (iii) the transduction pathway triggered by the P2Y12 receptor is independent of PKC but dependent on phosphoinositide 3-kinase

Common-envelope evolution with an asymptotic giant branch star

Common-envelope phases are decisive for the evolution of many binary systems. Of particular interest are cases with asymptotic giant branch (AGB) primary stars, because they are thought to be progenitors of various astrophysical transients. In three-dimensional hydrodynamic simulations with the moving-mesh code AREPO, we study the common-envelope evolution of a $1.0\,M_{\odot}$ early-AGB star with companions of different masses. Although the stellar envelope of the AGB star is less tightly bound than that of a red giant, we find that the release of orbital energy of the core binary is insufficient to eject more than about twenty percent of the envelope mass. Ionization energy released in the expanding envelope, however, can lead to complete envelope ejection. Because recombination proceeds largely at high optical depths in our simulations, it is likely that this effect indeed plays a significant role in the considered systems. The efficiency of mass loss and the final orbital separation of the core binary system depend on the mass ratio between the companion and the primary star. Our results suggest a linear relation between the ratio of final to initial orbital separation and this parameter.Comment: 12 pages, 9 figures, 5 tables; accepted for publication by A&

Bipolar planetary nebulae from common envelope evolution of binary stars

Asymmetric shapes and evidence for binary central stars suggest a common-envelope origin for many bipolar planetary nebulae. The bipolar components of the nebulae are observed to expand faster than the rest and the more slowly expanding material has been associated with the bulk of the envelope ejected during the common-envelope phase of a stellar binary system. Common-envelope evolution in general remains one of the biggest uncertainties in binary star evolution and the origin of the fast outflow has not been explained satisfactorily. We perform three-dimensional magnetohydrodynamic simulations of common-envelope interaction with the moving-mesh code AREPO. Starting from the plunge-in of the companion into the envelope of an asymptotic giant branch star and covering hundreds of orbits of the binary star system, we are able to follow the evolution to complete envelope ejection. We find that magnetic fields are strongly amplified in two consecutive episodes. First, when the companion spirals in the envelope and, second, when it forms a contact binary with the core of the former giant star. In the second episode, a magnetically-driven, high-velocity outflow of gas is launched self-consistently in our simulations. The outflow is bipolar and the gas is additionally collimated by the ejected common envelope. The resulting structure reproduces typical morphologies and velocities observed in young planetary nebulae. We propose that the magnetic driving mechanism is a universal consequence of common envelope interaction responsible for a substantial fraction of observed planetary nebulae. Such a mechanism likely also exists in the common-envelope phase of other binary stars that lead to the formation of Type Ia supernovae, X-ray binaries and gravitational-wave merger events.Comment: 9 pages, 11 figures; accepted for publication by A&

Does the Integration of Haptic and Visual Cues Reduce the Effect of a Biased Visual Reference Frame on the Subjective Head Orientation?

The selection of appropriate frames of reference (FOR) is a key factor in the elaboration of spatial perception and the production of robust interaction with our environment. The extent to which we perceive the head axis orientation (subjective head orientation, SHO) with both accuracy and precision likely contributes to the efficiency of these spatial interactions. A first goal of this study was to investigate the relative contribution of both the visual and egocentric FOR (centre-of-mass) in the SHO processing. A second goal was to investigate humans' ability to process SHO in various sensory response modalities (visual, haptic and visuo-haptic), and the way they modify the reliance to either the visual or egocentric FORs. A third goal was to question whether subjects combined visual and haptic cues optimally to increase SHO certainty and to decrease the FORs disruption effect.Thirteen subjects were asked to indicate their SHO while the visual and/or egocentric FORs were deviated. Four results emerged from our study. First, visual rod settings to SHO were altered by the tilted visual frame but not by the egocentric FOR alteration, whereas no haptic settings alteration was observed whether due to the egocentric FOR alteration or the tilted visual frame. These results are modulated by individual analysis. Second, visual and egocentric FOR dependency appear to be negatively correlated. Third, the response modality enrichment appears to improve SHO. Fourth, several combination rules of the visuo-haptic cues such as the Maximum Likelihood Estimation (MLE), Winner-Take-All (WTA) or Unweighted Mean (UWM) rule seem to account for SHO improvements. However, the UWM rule seems to best account for the improvement of visuo-haptic estimates, especially in situations with high FOR incongruence. Finally, the data also indicated that FOR reliance resulted from the application of UWM rule. This was observed more particularly, in the visual dependent subject. Conclusions: Taken together, these findings emphasize the importance of identifying individual spatial FOR preferences to assess the efficiency of our interaction with the environment whilst performing spatial tasks

In-situ characterization of the Hamamatsu R5912-HQE photomultiplier tubes used in the DEAP-3600 experiment

The Hamamatsu R5912-HQE photomultiplier-tube (PMT) is a novel high-quantum efficiency PMT. It is currently used in the DEAP-3600 dark matter detector and is of significant interest for future dark matter and neutrino experiments where high signal yields are needed. We report on the methods developed for in-situ characterization and monitoring of DEAP's 255 R5912-HQE PMTs. This includes a detailed discussion of typical measured single-photoelectron charge distributions, correlated noise (afterpulsing), dark noise, double, and late pulsing characteristics. The characterization is performed during the detector commissioning phase using laser light injected through a light diffusing sphere and during normal detector operation using LED light injected through optical fibres

Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa)

Peer reviewedPublisher PD

Inherited dysfunctional platelet P2Y12 receptor mutations associated with bleeding disorders

The platelet adenosine 5'-diphosphate (ADP) receptor P2Y12 (P2Y12R) plays a critical role in platelet aggregation. The present report illustrates an update of dysfunctional platelet P2Y12R mutations diagnosed with congenital lifelong bleeding problems. Described patients with heterozygous or homozygous substitution in the P2Y12R gene and qualitative abnormalities of the platelet P2Y12R are summarized. Recently, a further dysfunctional variant of P2Y12R has been identified in two brothers who presented with a lifelong severe bleeding disorder. During in vitro aggregation studies, the patient's platelets show a markedly reduced and rapid reversible ADP-promoted aggregation. A homozygous c.561T > A substitution that changes the codon for His187 to Gln (p.His187Gln) in the P2Y12R gene has been identified. This mutation causes no change in receptor expression but decreases the affinity of the ligand for the receptor, even at high concentrations. Structure modelling studies indicated that the p.His187Gln mutation, located in the fifth transmembrane spanning domain (TM5), impairs conformational changes of the receptor. Structural integrity of the TM5 region is necessary for agonist and antagonist binding and for correct receptor function

Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes

Long Lasting Egocentric Disorientation Induced by Normal Sensori-Motor Spatial Interaction

Perception of the cardinal directions of the body, right-left, up-down, ahead-behind, which appears so absolute and fundamental to the organisation of behaviour can in fact, be modified. Perhaps unsurprisingly, it has been shown that prolonged distorted perception of the orientation of body axes can be a consequence of disordered sensori-motor signals, including long-term prismatic adaptation and lesions of the central nervous system. We report the novel and surprising finding that a long-lasting distortion of perception of personal space can also be induced by an ecological pointing task without the artifice of distorting normal sensori-motor relationships.Twelve right-handed healthy adults performed the task of pointing with their arms, without vision, to indicate their subjective 'straight ahead', a task often used to assess the Egocentric Reference. This was performed before, immediately, and one day after a second task intended to 'modulate' perception of spatial direction. The 'modulating' task lasted 5 minutes and consisted of asking participants to point with the right finger to targets that appeared only in one (right or left) half of a computer screen. Estimates of the 'straight-ahead' during pre-test were accurate (inferior to 0.3 degrees deviation). Significantly, up to one day after performing the modulating task, the subjective 'straight-ahead' was deviated (by approximately 3.2 degrees) to the same side to which subjects had pointed to targets.These results reveal that the perception of directional axes for behaviour is readily influenced by interactions with the environment that involve no artificial distortion of normal sensori-motor-spatial relationships and does not necessarily conform to the cardinal directions as defined by the anatomy of orthostatic posture. We thus suggest that perceived space is a dynamic construction directly dependent upon our past experience about the direction and/or the localisation of our sensori-motor spatial interaction with environment