The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation. STIM1 binds to novel proteins in human platelets.

Ca(2+) elevation is essential to platelet activation. STIM1 senses Ca(2+) in the endoplasmic reticulum and activates Orai channels allowing store-operated Ca(2+) entry (SOCE). STIM1 has also been reported to be present in the plasma membrane (PM) with its N-terminal region exposed to the outside medium but its role is not fully understood. We have examined the effects of the antibody GOK/STIM1, which recognises the N-terminal region of STIM1, on SOCE, agonist-stimulated Ca(2+) entry, surface exposure, in vitro thrombus formation and aggregation in human platelets. We also determined novel binding partners of STIM1 using proteomics. The dialysed GOK/STIM1 antibody failed to reduced thapsigargin- and agonist-mediated Ca(2+) entry in Fura2-labelled cells. Using flow cytometry we detect a portion of STIM1 to be surface-exposed. The dialysed GOK/STIM1 antibody reduced thrombus formation by whole blood on collagen-coated capillaries under flow and platelet aggregation induced by collagen. In immunoprecipitation experiments followed by proteomic analysis, STIM1 was found to extract a number of proteins including myosin, DOCK10, thrombospondin-1 and actin. These studies suggest that PM STIM1 may facilitate platelet activation by collagen through novel interactions at the plasma membrane while the essential Ca(2+)-sensing role of STIM1 is served by the protein in the ER

Bimodality and Gaps on Globular Cluster Horizontal Branches. II. The Cases of NGC 6229, NGC 1851 and NGC 2808

The outer-halo globular cluster NGC 6229 has a peculiar horizontal-branch (HB) morphology, with clear indications of a bimodal HB and a ``gap" on the blue HB. In this paper, we present extensive synthetic HB simulations to determine whether peculiar distributions in the underlying physical parameters are needed to explain the observed HB morphology. We find that a unimodal mass distribution along the HB can satisfactorily account for the observed HB bimodality, *provided* the mass dispersion is substantially larger than usually inferred for the Galactic globular clusters. In this case, NGC 6229 should have a well-populated, extended blue tail. A truly bimodal distribution in HB masses can also satisfactorily account for the observed HB morphology, although in this case the existence of an extended blue tail is not necessarily implied. The other two well-known bimodal-HB clusters, NGC 1851 and NGC 2808, are briefly analyzed. While the HB morphology of NGC 1851 can also be reproduced with a unimodal mass distribution assuming a large mass dispersion, the same is not true of NGC 2808, for which a bimodal, and possibly multimodal, mass distribution seems definitely required. The problem of gaps on the blue HB is also discussed. Applying the standard Hawarden (1971) and Newell (1973) chi-squared test, we find that the NGC 6229 gap is significant at the 99.7% level. However, in a set of 1,000 simulations, blue-HB gaps comparable to the observed one are present in ~ 6 - 9% of all cases. We employ a new and simple formalism, based on the binomial distribution, to explain the origin of this discrepancy, and conclude that Hawarden's method, in general, substantially overestimates the statistical significance of gaps.Comment: 50 pages (includes 5 tables and 18 multi-panel figures). Higher-resolution versions of Figs. 15a and 15b are available from the first author upon request. To appear in The Astrophysical Journa

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

ETUDE D'UNE NOUVELLE METHODE RADICALAIRE POUR LA DESOXYGENATION DES ALCOOLS. NOUVELLES APPROCHES RADICALAIRES (SYNTHESE DE -AMINOTETRALONES ET REDUCTION DE DERIVES IODES)

DEUX NOUVELLES APPROCHES RADICALAIRES ONT ETE MISE AU POINT AU COURS DE CE TRAVAIL DE THESE : UNE SYNTHESE DE -AMINOTETRALONES ET LA REDUCTION DE DERIVES IODES. UNE ETUDE APPROFONDIE D'UNE NOUVELLE METHODE RADICALAIRE POUR LA DESOXYGENATION DES ALCOHOLS A ETE EGALEMENT REALISEE. LE PREMIER SUJET EST UNE APPROCHE AUX -AMINOTETRALONES, QUI REPOSE SUR LA CHIMIE RADICALAIRE DES XANTHATES. ELLE IMPLIQUE DEUX REACTIONS RADICALAIRES SUCCESSIVES : ADDITION RADICALAIRE INTERMOLECULAIRE D'UN XANTHATE SUR UNE OLEFINE, SUIVIE D'UNE CYCLISATION RADICALAIRE SUR UN NOYAU AROMATIQUE. UNE MODIFICATION PRATIQUE DE LA REACTION CLASSIQUE DE BARTON-MCCOMBIE A ETE DEVELOPPE DANS UNE DEUXIEME PARTIE. CETTE REACTION CLASSIQUE TRES EFFICACE, UTILISE DES HYDRURES D'ETAIN COMME DONNEUR D'HYDROGENE, MAIS LA TOXICITE ET LES DIFFICULTES DE SEPARATION DES RESIDUS D'ETAIN REPRESENTENT DES LIMITATIONS SERIEUSES. LA NOUVELLE APPROCHE PERMET LA REDUCTION DES ALCOHOLS SECONDAIRES VIA LEURS XANTHATES OU LEURS DERIVES (TIOCARBONYL)IMIDAZOLIDES DANS DES CONDITIONS TRES DOUCES : ELLE S'EFFECTUE AU REFLUX DE L'ISOPROPANOL, SOLVANT QUI JOUE EN MEME TEMPS LE ROLE DE DONNEUR D'HYDROGENE. UNE NOUVELLE METHODE DE REDUCTION DES DERIVES IODES A ETE MISE AU POINT. LES COMPOSES IODES SONT IRRADIES PAR LA LUMIERE VISIBLE, A TEMPERATURE AMBIANTE EN PRESENCE D'UN BON DONNEUR D'HYDROGENE COMME LE THIOL. LES RENDEMENTS OBTENUS SONT BONS ET PEUVENT SOUVENT CONCURRENCER LA REDUCTION PAR L'HYDRURE DE TRI-N-BUTYLETAIN.PALAISEAU-Polytechnique (914772301) / SudocSudocFranceF