A talin mutant that impairs talin-integrin binding in platelets decelerates αIIbβ3 activation without pathological bleeding

Tight regulation of integrin affinity is critical for hemostasis. A final step of integrin activation is talin binding to 2 sites within the integrin β cytoplasmic domain. Binding of talin to a membrane-distal NPxY sequence facilitates a second, weaker interaction of talin with an integrin membrane-proximal region (MPR) that is critical for integrin activation. To test the functional significance of these distinct interactions on platelet function in vivo, we generated knock-in mice expressing talin1 mutants with impaired capacity to interact with the β3 integrin MPR (L325R) or NPLY sequence (W359A). Both talin1(L325R) and talin1(W359A) mice were protected from experimental thrombosis. Talin1(L325R) mice, but not talin(W359A) mice, exhibited a severe bleeding phenotype. Activation of αIIbβ3 was completely blocked in talin1(L325R) platelets, whereas activation was reduced by approximately 50% in talin1(W359A) platelets. Quantitative biochemical measurements detected talin1(W359A) binding to β3 integrin, albeit with a 2.9-fold lower affinity than wild-type talin1. The rate of αIIbβ3 activation was slower in talin1(W359A) platelets, which consequently delayed aggregation under static conditions and reduced thrombus formation under physiological flow conditions. Together our data indicate that reduction of talin-β3 integrin binding affinity results in decelerated αIIbβ3 integrin activation and protection from arterial thrombosis without pathological bleeding

Dynamical response of a Bose-Einstein condensate to a discontinuous change in internal state

A two-photon transition is used to convert an arbitrary fraction of the 87Rb atoms in a |F=1,m_f=-1> condensate to the |F=2,m_f=1> state. Transferring the entire population imposes a discontinuous change on the condensate's mean-field repulsion, which leaves a residual ringing in the condensate width. A calculation based on Gross-Pitaevskii theory agrees well with the observed behavior, and from the comparison we obtain the ratio of the intraspecies scattering lengths for the two states, a_|1,-1> / a_|2,1> = 1.062(12).Comment: 4 pages, 3 figure

Functional redundancy between RAP1 isoforms in murine platelet production and function

RAP GTPases, important regulators of cellular adhesion, are abundant signaling molecules in the platelet/megakaryocytic lineage. However, mice lacking the predominant isoform, RAP1B, display a partial platelet integrin activation defect and have a normal platelet count, suggesting the existence of a RAP1-independent pathway to integrin activation in platelets and a negligible role for RAP GTPases in megakaryocyte biology. To determine the importance of individual RAP isoforms on platelet production and on platelet activation at sites of mechanical injury or vascular leakage, we conditionally deleted Rap1a and/or Rap1b in the megakaryocytic lineage (mKO). Interestingly, Rap1a/b-mKO mice displayed a marked macrothrombocytopenia due to impaired pro- platelet formation by megakaryocytes. In platelets, RAP isoforms had both redundant and isoform-ˇspecific functions. Deletion of RAP1B, but not RAP1A, significantly reduced α- granule secretion and activation of the cytoskeleton regulator RAC1. Both isoforms significantly contributed to thromboxane A2 generation and the inside-out activation of platelet integrins. Combined deficiency of RAP1A and RAP1B markedly impaired platelet aggregation, spreading and clot retraction. Consistently, thrombus formation in physiological flow conditions was abolished in Rap1a/b-mKO, but not Rap1a-mKO or Rap1b-mKO platelets. Rap1a/b-mKO mice were strongly protected from experimental thrombosis and exhibited a severe defect in hemostasis after mechanical injury. Surprisingly, Rap1a/b-mKO platelets were indistinguishable from controls in their ability to prevent blood-lymphatic mixing during development and hemorrhage at sites of inflammation. In summary, our studies demonstrate an essential role for RAP1 signaling in platelet integrin activation and a critical role in platelet production. While important for hemostatic/thrombotic plug formation, platelet RAP1 signaling is dispensable for vascular integrity during development and inflammation

Position-aware activity recognition with wearable devices

Reliable human activity recognition with wearable devices enables the development of human-centric pervasive applications. We aim to develop a robust wearable-based activity recognition system for real life situations where the device position is up to the user or where a user is unable to collect initial training data. Consequently, in this work we focus on the problem of recognizing the on-body position of the wearable device ensued by comprehensive experiments concerning subject-specific and cross-subjects activity recognition approaches that rely on acceleration data. We introduce a device localization method that predicts the on-body position with an F-measure of 89% and a cross-subjects activity recognition approach that considers common physical characteristics. In this context, we present a real world data set that has been collected from 15 participants for 8 common activities were they carried 7 wearable devices in different on-body positions. Our results show that the detection of the device position consistently improves the result of activity recognition for common activities. Regarding cross-subjects models, we identified the waist as the most suitable device location at which the acceleration patterns for the same activity across several people are most similar. In this context, our results provide evidence for the reliability of physical characteristics based cross-subjects models

A fast recoiling silk-like elastomer facilitates nanosecond nematocyst discharge

Background: The discharge of the Cnidarian stinging organelle, the nematocyst, is one of the fastest processes in biology and involves volume changes of the highly pressurised (150 bar) capsule of up to 50%. Hitherto, the molecular basis for the unusual biomechanical properties of nematocysts has been elusive, as their structure was mainly defined as a stress-resistant collagenous matrix. Results: Here, we characterise Cnidoin, a novel elastic protein identified as a structural component of Hydra nematocysts. Cnidoin is expressed in nematocytes of all types and immunostainings revealed incorporation into capsule walls and tubules concomitant with minicollagens. Similar to spider silk proteins, to which it is related at sequence level, Cnidoin possesses high elasticity and fast coiling propensity as predicted by molecular dynamics simulations and quantified by force spectroscopy. Recombinant Cnidoin showed a high tendency for spontaneous aggregation to bundles of fibrillar structures. Conclusions: Cnidoin represents the molecular factor involved in kinetic energy storage and release during the ultra-fast nematocyst discharge. Furthermore, it implies an early evolutionary origin of protein elastomers in basal metazoans