The contribution of surface residues to membrane binding and ligand transfer by the -tocopherol transfer protein ( -TTP)

Previous work has shown that the -tocopherol transfer protein ( -TTP) can bind to vesicular or immobilized phospholipid membranes. Revealing the molecular mechanisms by which -TTP associates with membranes is thought to be critical to understanding its function and role in the secretion of tocopherol from hepatocytes into the circulation. Calculations presented in the Orientations of Proteins in Membranes database have provided a testable model for the spatial arrangement of -TTP and other CRAL-TRIO family proteins with respect to the lipid bilayer. These calculations predicted that a hydrophobic surface mediates the interaction of -TTP with lipid membranes. To test the validity of these predictions, we used site-directed mutagenesis and examined the substituted mutants with regard to intermembrane ligand transfer, association with lipid layers and biological activity in cultured hepatocytes. Substitution of residues in helices A8 (F165A and F169A) and A10 (I202A, V206A and M209A) decreased the rate of intermembrane ligand transfer as well as protein adsorption to phospholipid bilayers. The largest impairment was observed upon mutation of residues that are predicted to be fully immersed in the lipid bilayer in both apo (open) and holo (closed) conformations such as Phe165 and Phe169. Mutation F169A, and especially F169D, significantly impaired -TTP-assisted secretion of -tocopherol outside cultured hepatocytes. Mutation of selected basic residues (R192H, K211A, and K217A) had little effect on transfer rates, indicating no significant involvement of nonspecific electrostatic interactions with membranes.

Measurement of the W+ W- cross section in sqrt(s) = 7 TeV pp collisions with ATLAS

This Letter presents a measurement of the W+ W- production cross section in sqrt(s) = 7  TeV pp collisions by the ATLAS experiment, using 34  pb(-1) of integrated luminosity produced by the Large Hadron Collider at CERN. Selecting events with two isolated leptons, each either an electron or a muon, 8 candidate events are observed with an expected background of 1.7 ± 0.6 events. The measured cross section is 41(-16)(+20)(stat) ± 5(syst)±1(lumi)  pb, which is consistent with the standard model prediction of 44 ± 3  pb calculated at next-to-leading order in QCD.

Search for a heavy particle decaying into an electron and a muon with the ATLAS detector in sqrt[s] = 7 TeV pp collisions at the LHC

This Letter presents the first search for a heavy particle decaying into an e ± μ(-/+) final state in sqrt[s] = 7 TeV pp collisions at the LHC. The data were recorded by the ATLAS detector during 2010 and correspond to a total integrated luminosity of 35 pb(-1). No excess above the standard model background expectation is observed. Exclusions at 95% confidence level are placed on two representative models. In an R-parity violating supersymmetric model, tau sneutrinos with a mass below 0.75 TeV are excluded, assuming all R-parity violating couplings are zero except λ(311)' = 0.11 and λ312 = 0.07. In a lepton flavor violating model, a Z'-like vector boson with masses of 0.70-1.00 TeV and corresponding cross sections times branching ratios of 0.175-0.183 pb is excluded. These results extend to higher mass R-parity violating sneutrinos and lepton flavor violating Z's than previous constraints from the Tevatron.

Measurement of dijet azimuthal decorrelations in pp collisions at sqrt(s)=7 TeV

Azimuthal decorrelations between the two central jets with the largest transverse momenta are sensitive to the dynamics of events with multiple jets. We present a measurement of the normalized differential cross section based on the full data set (∫Ldt=36  pb(-1)) acquired by the ATLAS detector during the 2010 sqrt(s)=7  TeV proton-proton run of the LHC. The measured distributions include jets with transverse momenta up to 1.3 TeV, probing perturbative QCD in a high-energy regime.

Search for supersymmetry using final states with one lepton, jets, and missing transverse momentum with the ATLAS detector in √s=7 TeV pp collisions

This Letter presents the first search for supersymmetry in final states containing one isolated electron or muon, jets, and missing transverse momentum from √s=7  TeV proton-proton collisions at the LHC. The data were recorded by the ATLAS experiment during 2010 and correspond to a total integrated luminosity of 35  pb(-1). No excess above the standard model background expectation is observed. Limits are set on the parameters of the minimal supergravity framework, extending previous limits. Within this framework, for A(0)=0 GeV, tanβ=3, and μ>0 and for equal squark and gluino masses, gluino masses below 700 GeV are excluded at 95% confidence level.

Search for diphoton events with large missing transverse energy in 7 TeV proton-proton collisions with the ATLAS detector

A search for diphoton events with large missing transverse energy is presented. The data were collected with the ATLAS detector in proton-proton collisions at √s=7 TeV at the CERN Large Hadron Collider and correspond to an integrated luminosity of 3.1 pb⁻¹. No excess of such events is observed above the standard model background prediction. In the context of a specific model with one universal extra dimension with compactification radius R and gravity-induced decays, values of 1/R<729 GeV are excluded at 95% C. L., providing the most sensitive limit on this model to date.

Search for a standard model Higgs boson in the H→ZZ→ℓ(+)ℓ(-)νν decay channel with the ATLAS detector

A search for a heavy standard model Higgs boson decaying via H→ZZ→→ℓ(+)ℓ(-)νν, where ℓ=e, μ, is presented. It is based on proton-proton collision data at √s=7 TeV, collected by the ATLAS experiment at the LHC in the first half of 2011 and corresponding to an integrated luminosity of 1.04 fb(-1). The data are compared to the expected standard model backgrounds. The data and the background expectations are found to be in agreement and upper limits are placed on the Higgs boson production cross section over the entire mass window considered; in particular, the production of a standard model Higgs boson is excluded in the region 340

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study

The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS).

Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα-CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.

Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia

Catheter ablation of ventricular tachycardia (VT) is effective and particularly useful in patients with frequent defibrillator interventions. Various substrate modification techniques have been described for unmappable or hemodynamically intolerable VT. Noninducibility is the most frequently used end point but is associated with significant limitations, so the optimal end point remains unclear. We hypothesized that elimination of local abnormal ventricular activities (LAVAs) during sinus rhythm or ventricular pacing would be a useful and effective end point for substrate-based VT ablation. As an adjunct to this strategy, we used a new high-density mapping catheter and frequently used epicardial mapping.