T cell specific adaptor protein (TSAd) promotes interaction of Nck with Lck and SLP-76 in T cells

Background: The Lck and Src binding adaptor protein TSAd (T cell specific adaptor) regulates actin polymerization in T cells and endothelial cells. The molecular details as to how TSAd regulates this process remain to be elucidated. Results: To identify novel interaction partners for TSAd, we used a scoring matrix-assisted ligand algorithm (SMALI), and found that the Src homology 2 (SH2) domain of the actin regulator Non-catalytic region of tyrosine kinase adaptor protein (Nck) potentially binds to TSAd phosphorylated on Tyr280 (pTyr280) and pTyr305. These predictions were confirmed by peptide array analysis, showing direct binding of recombinant Nck SH2 to both pTyr280 and pTyr305 on TSAd. In addition, the SH3 domains of Nck interacted with the proline rich region (PRR) of TSAd. Pull-down and immunoprecipitation experiments further confirmed the Nck-TSAd interactions through Nck SH2 and SH3 domains. In line with this Nck and TSAd co-localized in Jurkat cells as assessed by confocal microscopy and imaging flow cytometry. Co-immunoprecipitation experiments in Jurkat TAg cells lacking TSAd revealed that TSAd promotes interaction of Nck with Lck and SLP-76, but not Vav1. TSAd expressing Jurkat cells contained more polymerized actin, an effect dependent on TSAd exon 7, which includes interactions sites for both Nck and Lck. Conclusions: TSAd binds to and co-localizes with Nck. Expression of TSAd increases both Nck-Lck and Nck-SLP-76 interaction in T cells. Recruitment of Lck and SLP-76 to Nck by TSAd could be one mechanism by which TSAd promotes actin polymerization in activated T cells. © 2015 Hem et al

Economic evaluation of adverse events of dabrafenib plus trametinib versus nivolumab in patients with advanced BRAF-mutant cutaneous melanoma for adjuvant therapy in Germany

Background: Adjuvant treatment options have become the standard therapy for stage III and IV resectable cutaneous melanoma. Two recent studies led to the registration of dabrafenib and trametinib as targeted therapies for BRAF-mutated melanoma, and of immunotherapy with nivolumab irrespective of BRAF-mutation status. Both therapies have different spectrums of adverse events. Objective: To estimate the financial impact of side effects from the perspective of the German statutory sick funds to compare both therapeutic options and to relate the burden to the overall costs of the treatment. Study design and setting: Thirty-six adverse event categories for the combination of dabrafenib and trametinib (‘combi treatment’) and for nivolumab were extracted from the original publications of the studies named COMBI-AD and CheckMate 238. Patients and intervention: For all event categories a diagnosis and therapy recommendation were determined according to current national or international guidelines or from leading German textbooks. Main outcome measure: The resulting diagnostic steps, treatments, and therapies were evaluated with unit costs based on the German fee schedule for ambulatory physicians, the German G-DRG scheme, and the German drug price list. Results: The number of events with nivolumab per one hundred treatments amounted to 3.8 mandatory hospitalizations, 3.5 emergency care events and 0.8 life-threatening events. For the combi treatment, the respective number of events per one hundred treatments was 2.7, 1.8, and 0.5. The overall cost burden was calculated as €899 for nivolumab and €861 for combi-treatment. Conclusion: The treatment of adverse events resulting from adjuvant melanoma therapy showed comparable costs for both therapies

Semileptonic decays of baryons in a relativistic quark model

We calculate semileptonic decays of light and heavy baryons in a relativistically covariant constituent quark model. The model is based on the Bethe-Salpeter-equation in instantaneous approximation. It generates satisfactory mass spectra for mesons and baryons up to the highest observable energies. Without introducing additional free parameters we compute on this basis helicity amplitudes of electronic and muonic semileptonic decays of baryons. We thus obtain form factor ratios and decay rates in good agreement with experiment.Comment: 8 pages, 10 figures, 2 tables, typos remove

Dual character of the electronic structure in YBa2Cu4O8: conduction bands of CuO2 planes and CuO chains

We use microprobe Angle-Resolved Photoemission Spectroscopy (muARPES) to separately investigate the electronic properties of CuO2 planes and CuO chains in the high temperature superconductor, YBa2Cu4O8. In the CuO2 planes, a two dimensional (2D) electronic structure with nearly momentum independent bilayer splitting is observed. The splitting energy is 150 meV at (pi,0), almost 50% larger than in Bi2Sr2CaCu2O(8+d) and the electron scattering at the Fermi level in the bonding band is about 1.5 times stronger than in the antibonding band. The CuO chains have a quasi one dimensional (1D) electronic structure. We observe two 1D bands separated by ~ 550meV: a conducting band and an insulating band with an energy gap of ~ 240meV. We find that the conduction electrons are well confined within the planes and chains with a non-trivial hybridization.Comment: 4 pages, 4 figure

Ocean Dynamics and the Inner Edge of the Habitable Zone for Tidally Locked Terrestrial Planets

Recent studies have shown that ocean dynamics can have a significant warming effect on the permanent night sides of 1 to 1 tidally locked terrestrial exoplanets with Earth-like atmospheres and oceans in the middle of the habitable zone. However, the impact of ocean dynamics on the habitable zone's boundaries (inner edge and outer edge) is still unknown and represents a major gap in our understanding of this type of planets. Here we use a coupled atmosphere-ocean global climate model to show that planetary heat transport from the day to night side is dominated by the ocean at lower stellar fluxes and by the atmosphere near the inner edge of the habitable zone. This decrease in oceanic heat transport (OHT) at high stellar fluxes is mainly due to weakening of surface wind stress and a decrease in surface shortwave energy deposition. We further show that ocean dynamics have almost no effect on the observational thermal phase curves of planets near the inner edge of the habitable zone. For planets in the habitable zone's middle range, ocean dynamics moves the hottest spot on the surface eastward from the substellar point. These results suggest that future studies of the inner edge may devote computational resources to atmosphere-only processes such as clouds and radiation. For studies of the middle range and outer edge of the habitable zone, however, fully coupled ocean-atmosphere modeling will be necessary. Note that due to computational resource limitations, only one rotation period (60 Earth days) has been systematically examined in this study; future work varying rotation period as well as other parameters such as atmospheric mass and composition is required.Comment: 34 pages, 13 figures, and 1 tabl

Electrostatic Interactions of Asymmetrically Charged Membranes

We predict the nature (attractive or repulsive) and range (exponentially screened or long-range power law) of the electrostatic interactions of oppositely charged and planar plates as a function of the salt concentration and surface charge densities (whose absolute magnitudes are not necessarily equal). An analytical expression for the crossover between attractive and repulsive pressure is obtained as a function of the salt concentration. This condition reduces to the high-salt limit of Parsegian and Gingell where the interaction is exponentially screened and to the zero salt limit of Lau and Pincus in which the important length scales are the inter-plate separation and the Gouy-Chapman length. In the regime of low salt and high surface charges we predict - for any ratio of the charges on the surfaces - that the attractive pressure is long-ranged as a function of the spacing. The attractive pressure is related to the decrease in counter-ion concentration as the inter-plate distance is decreased. Our theory predicts several scaling regimes with different scaling expressions for the pressure as function of salinity and surface charge densities. The pressure predictions can be related to surface force experiments of oppositely charged surfaces that are prepared by coating one of the mica surfaces with an oppositely charged polyelectrolyte

SPH modelling of turbulent open channel flow over and within natural gravel beds with rough interfacial boundaries

Smoothed Particle Hydrodynamics (SPH) is brought to a level that can be applied to simulate turbulent open channel flows over and within natural porous gravel beds. For this, improvements have been made with regards to i) turbulence modelling, ii) open boundaries (inflow and outflow), and iii) treatment of the rough interface boundary between the porous bed and the overlying free-flow. Flow through the porous bed is simulated macroscopically, and the coefficients of the drag closure model are carefully determined at different layers of the flow; the effect of turbulence is taken into account using a three-layer mixing-length model; and a porous inflow boundary at the inlet as well as an imaginary pressure wall at the outlet are introduced to obtain the required steady and uniform flow conditions. The developed model is then used to simulate eight test cases with two bed conditions, each with four flow conditions. Through the velocity analysis, a nearly S-shaped distribution is observed within the roughness layer for the present test cases. The comparison of the results of the velocity and shear stress with a set of experimental data reveals that the SPH model with the present drag and turbulence closure models as well as the proposed inflow/outflow boundary techniques is capable of simulating complex turbulent channel flows over highly sheared natural porous beds