Shared and Distinctive Ultrastructural Abnormalities Expressed by Megakaryocytes in Bone Marrow and Spleen From Patients With Myelofibrosis

Numerous studies have documented ultrastructural abnormalities in malignant megakaryocytes from bone marrow (BM) of myelofibrosis patients but the morphology of these cells in spleen, an important extramedullary site in this disease, was not investigated as yet. By transmission-electron microscopy, we compared the ultrastructural features of megakaryocytes from BM and spleen of myelofibrosis patients and healthy controls. The number of megakaryocytes was markedly increased in both BM and spleen. However, while most of BM megakaryocytes are immature, those from spleen appear mature with well-developed demarcation membrane systems (DMS) and platelet territories and are surrounded by platelets. In BM megakaryocytes, paucity of DMS is associated with plasma (thick with protrusions) and nuclear (dilated with large pores) membrane abnormalities and presence of numerous glycosomes, suggesting a skewed metabolism toward insoluble polyglucosan accumulation. By contrast, the membranes of the megakaryocytes from the spleen were normal but these cells show mitochondria with reduced crests, suggesting deficient aerobic energy-metabolism. These distinctive morphological features suggest that malignant megakaryocytes from BM and spleen express distinctive metabolic impairments that may play different roles in the pathogenesis of myelofibrosis

Measurement of D*+/- meson production in jets from pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

This paper reports a measurement of D*+/- meson production in jets from proton-proton collisions at a center-of-mass energy of sqrt(s) = 7 TeV at the CERN Large Hadron Collider. The measurement is based on a data sample recorded with the ATLAS detector with an integrated luminosity of 0.30 pb^-1 for jets with transverse momentum between 25 and 70 GeV in the pseudorapidity range |eta| < 2.5. D*+/- mesons found in jets are fully reconstructed in the decay chain: D*+ -> D0pi+, D0 -> K-pi+, and its charge conjugate. The production rate is found to be N(D*+/-)/N(jet) = 0.025 +/- 0.001(stat.) +/- 0.004(syst.) for D*+/- mesons that carry a fraction z of the jet momentum in the range 0.3 < z < 1. Monte Carlo predictions fail to describe the data at small values of z, and this is most marked at low jet transverse momentum.Comment: 10 pages plus author list (22 pages total), 5 figures, 1 table, matches published version in Physical Review

Inhibition of TGF-β1 signaling restores both microenvironmental and stem cells abnormalities in the Gata-1low Mouse Model of Myelofibrosis

Primary myelofibrosis (PMF) is characterized by abnormal megakaryocyte (Mk) development, fibrosis and ineffective hematopoiesis in the marrow and hematopoiesis in extramedullary sites [1]. Studies in animal models have suggested that fibrosis is established by fibroblasts activated by TGF-β1 released by the abnormal Mk. Increased levels of TGF-β1 expression in Mk have been implicated in the development of PMF. To clarify whether TGF-β1 alterations are involved in the development of PMF in Gata1low mice, the TGF-β1 content of Mk from the marrow and spleen from PMF patients and Gata1low mice was compared, the TGF-β1 pathway of the marrow and spleen of the Gata1low mouse PMF model was profiled and the consequences of pharmacological inhibition of TGF-β1 signaling, obtained through treatment with SB431542, was determined. Bone marrow (BM) sections from PMF patients contain 4-times more Mk than those from normal donors and great numbers of Mk are also detectable in their spleen. In addition, Mk from both BM and spleen of PMF patients reacted 34-times more intensely than normal Mk with the TGF-β1 antibody. Similarly the number of Mk in BM and spleen of Gata-1low mice was 2-3- fold greater than normal and these cells reacted 3-8-times more intensely with the TGF-β1 antibody than wild-type(wt)Mk. These results were confirmed by immunoelectron- microscopy. On average, one Mk from wild-type and Gata1low mice contained 10.3±2.2 and 54.3±6.5 immunogold-particles per area (p&lt;0.01). SB431542-treatment reduced the intensity of TGF-β1 staining of Gata1low Mk both in BM (5.3±1.1) and spleen (9.2±0.7) compared to Mk both in BM (18.9±0.8) and spleen (24.3±0.9) of Gata- 1low vehicle-treated mice, while had modest effects on the expression of VEGF and CXCL12. Inhibition of TGF-β1 signaling activates hematopoiesis in BM while reducing extramedullary hematopoiesis in spleen of Gata-1low mice. In addition, it reduced fibrosis, vessel microdensity, increases Ptl counts and decreases WBC and poikilocytes in the blood of Gata1low mice suggesting a potential benefit for treatments targeting microenvironment abnormalities in PMF

Search for supersymmetry in final states with jets, missing transverse momentum and one isolated lepton in sqrt{s} = 7 TeV pp collisions using 1 fb-1 of ATLAS data

We present an update of a search for supersymmetry in final states containing jets, missing transverse momentum, and one isolated electron or muon, using 1.04 fb^-1 of proton-proton collision data at sqrt{s} = 7 TeV recorded by the ATLAS experiment at the LHC in the first half of 2011. The analysis is carried out in four distinct signal regions with either three or four jets and variations on the (missing) transverse momentum cuts, resulting in optimized limits for various supersymmetry models. No excess above the standard model background expectation is observed. Limits are set on the visible cross-section of new physics within the kinematic requirements of the search. The results are interpreted as limits on the parameters of the minimal supergravity framework, limits on cross-sections of simplified models with specific squark and gluino decay modes, and limits on parameters of a model with bilinear R-parity violation.Comment: 18 pages plus author list (30 pages total), 9 figures, 4 tables, final version to appear in Physical Review

Reducing heterotic M-theory to five dimensional supergravity on a manifold with boundary

This paper constructs the reduction of heterotic $M$-theory in eleven dimensions to a supergravity model on a manifold with boundary in five dimensions using a Calabi-Yau three-fold. New results are presented for the boundary terms in the action and for the boundary conditions on the bulk fields. Some general features of dualisation on a manifold with boundary are used to explain the origin of some topological terms in the action. The effect of gaugino condensation on the fermion boundary conditions leads to a `twist' in the chirality of the gravitino which can provide an uplifting mechanism in the vacuum energy to cancel the cosmological constant after moduli stabilisation.Comment: 16 pages, RevTe

Thrombotic events in models GATA-1 low myelofibrosis characterized by altered localization of P-selectin during megakaryocyte development

Patients with primary myelofibrosis (PMF) have increased risk for bleeding and thrombosis. It is debated whether propensity to thrombosis is due to increased numbers of platelet microparticles and/or to pathological platelet-neutrophil interactions.This interactions are mediated by P-selectin and even though the megakaryocytes(Mk)of MF patients express normal levels of P-selectin,it remains abnormally localized to the DMS rather than being assembled into the a-granules in platelets.Mice carrying the hypomorphic Gata1low mutation express the same Mk abnormalities presented by PMF patients,including abnormal P-selectin localization to the DMS and develop with age myelofibrosis,that closely resembles human PMF.The aim of this study was to determine whether Gata1low mice would develop thrombosis with age and,in this case,the role played by P-selectin in the development of the trait.To this aim,Gata1low mice were crossed with P-selnull mice according to standard genetic protocols and Gata1lowP-selWT,Gata1lowP-selnull and Gata1WTP-selnull or Gata1WTP-selWT littermates obtained.Platelet count,hematocrit as well as platelet microparticle levels were determined on all the different mutants.It was shown that platelet counts are reduced in Gata1low mice.Moreover,platelet microparticles are reduced in Gata1low mice and P-selectin positive platelet microparticles were not found.The presence of thrombosis was determined by immunohistological staining of organs.Gata1low mice with or without the P-selectin null trait had a prolonged bleeding time and thrombosis was seen adult and old Gata1low mice,but the Gata1low/P-selnull mice were rescued.Thus,presence of the P-selectin null trait rescued Gata1low mice from the thrombotic phenotype,but did not change level of platelet microparticles.All these data indicate that abnormal localization of P-selectin,induced by the Gata1low mutation,and thus, increased pathological interactions with leucocytes,is responsible for the increased presence of thrombosis seen in these mice

Measurement of tau polarization in W->taunu decays with the ATLAS detector in pp collisions at sqrt(s) = 7 TeV

In this paper, a measurement of tau polarization in W->taunu decays is presented. It is measured from the energies of the decay products in hadronic tau decays with a single final state charged particle. The data, corresponding to an integrated luminosity of 24 pb^-1, were collected by the ATLAS experiment at the Large Hadron Collider in 2010. The measured value of the tau polarization is Ptau = -1.06 +/- 0.04 (stat) + 0.05 (syst) - 0.07 (syst), in agreement with the Standard Model prediction, and is consistent with a physically allowed 95% CL interval [-1,-0.91]. Measurements of tau polarization have not previously been made at hadron colliders.Comment: 10 pages plus author list (25 pages total), 4 figures, 4 tables, revised author list, matches published EPJC versio

Readiness of the ATLAS liquid argon calorimeter for LHC collisions

The ATLAS liquid argon calorimeter has been operating continuously since August 2006. At this time, only part of the calorimeter was readout, but since the beginning of 2008, all calorimeter cells have been connected to the ATLAS readout system in preparation for LHC collisions. This paper gives an overview of the liquid argon calorimeter performance measured in situ with random triggers, calibration data, cosmic muons, and LHC beam splash events. Results on the detector operation, timing performance, electronics noise, and gain stability are presented. High energy deposits from radiative cosmic muons and beam splash events allow to check the intrinsic constant term of the energy resolution. The uniformity of the electromagnetic barrel calorimeter response along eta (averaged over phi) is measured at the percent level using minimum ionizing cosmic muons. Finally, studies of electromagnetic showers from radiative muons have been used to cross-check the Monte Carlo simulation. The performance results obtained using the ATLAS readout, data acquisition, and reconstruction software indicate that the liquid argon calorimeter is well-prepared for collisions at the dawn of the LHC era.ATLAS Collaboration, for complete list of authors see http://dx.doi.org/10.1140/epjc/s10052-010-1354-y</p

X-Ray Detection of a Pre-Supernova Evolution for the SN 1993J Progenitor

We report on the first detection of a pre-supernova (SN) evolution in the X-ray regime. The results are based on ROSAT observations of SN 1993J ranging from six days to five years after the outburst. The X-ray observations are used to probe the SN shell interaction with the ambient circumstellar matter (CSM). After exploring various scenarios that might explain the observed X-ray lightcurve with a t^-0.27 rate of decline, we present a coherent picture in terms of the interaction of the SN shock front with the CSM deposited by the progenitor's stellar wind. During the observed period, the SN shell has reached a radius of 3x10^17 cm from the site of the explosion, corresponding to ~10^4 years in the progenitors stellar wind history. Our analysis shows that the mass-loss rate of the progenitor has decreased constantly from \dot{M} = 4x10^-4 to 4x10^-5 M_sun/yr (v_w/10 km/s) during the late stage of the evolution. Assuming a spherically symmetric expansion, the circumstellar matter density profile is found to be significantly flatter (\rho_csm \propto r^-1.63) than expected for a constant mass-loss rate and constant wind velocity profile (r^-2). The observed evolution either reflects a decrease in the mass-loss rate, an increase in the wind speed or a combination of both, indicating that the progenitor likely was making a transition from the red to the blue supergiant phase during the late stage of its evolution.Comment: 5 pages, 3 figures, accepted for publication in the Astrophysical Journal Letter

Search for diphoton events with large missing transverse momentum in 1 fb^-1 of 7 TeV proton-proton collision data with the ATLAS detector

A search for diphoton events with large missing transverse momentum has been performed using 1.07 fb^-1 of proton-proton collision data at sqrt(s) = 7 TeV recorded with the ATLAS detector. No excess of events was observed above the Standard Model prediction and 95% Confidence Level (CL) upper limits are set on the production cross section for new physics: sigma < (22-129) fb in the context of a generalised model of gauge-mediated supersymmetry breaking (GGM) with a bino-like lightest neutralino, sigma < (27-91) fb in the context of a minimal model of gauge-mediated supersymmetry breaking (SPS8) and (15-27) fb in the context of a specific model with one universal extra dimension (UED). A 95% CL lower limit of 805 GeV, for bino masses above 50 GeV, is set on the GGM gluino mass. Lower limits of 145 TeV and 1.23 TeV are set on the SPS8 breaking scale Lambda and on the UED compactification scale 1/R, respectively. These limits provide the most stringent tests of these models to date.Comment: 8 pages plus author list (20 pages total), 6 figures, 2 tables, matches published version in Physics Letters