The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG <sub>4</sub> ) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG <sub>4</sub> -HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners

Limits on scalar leptoquark interactions and consequences for GUTs

A colored weak singlet scalar state with hypercharge 4/3 is one of the possible candidates for the explanation of the unexpectedly large forward-backward asymmetry in t tbar production as measured by the CDF and D0 experiments. We investigate the role of this state in a plethora of flavor changing neutral current processes and precision observables of down-quarks and charged leptons. Our analysis includes tree- and loop-level mediated observables in the K and B systems, the charged lepton sector, as well as the Z to b bbar decay width. We perform a global fit of the relevant scalar couplings. This approach can explain the (g-2)_mu anomaly while tensions among the CP violating observables in the quark sector, most notably the nonstandard CP phase (and width difference) in the Bs system cannot be fully relaxed. The results are interpreted in a class of grand unified models which allow for a light colored scalar with a mass below 1TeV. We find that the renormalizable SU(5) scenario is not compatible with our global fit, while in the SO(10) case the viability requires the presence of both the 126- and 120-dimensional representations.Comment: 26 pages, 7 figures; version as publishe

MINERvA neutrino detector response measured with test beam data

The MINERvA collaboration operated a scaled-down replica of the solid scintillator tracking and sampling calorimeter regions of the MINERvA detector in a hadron test beam at the Fermilab Test Beam Facility. This article reports measurements with samples of protons, pions, and electrons from 0.35 to 2.0 GeV/c momentum. The calorimetric response to protons, pions, and electrons are obtained from these data. A measurement of the parameter in Birks' law and an estimate of the tracking efficiency are extracted from the proton sample. Overall the data are well described by a Geant4-based Monte Carlo simulation of the detector and particle interactions with agreements better than 4%, though some features of the data are not precisely modeled. These measurements are used to tune the MINERvA detector simulation and evaluate systematic uncertainties in support of the MINERvA neutrino cross section measurement program.Comment: as accepted by NIM

wKinMut: An integrated tool for the analysis and interpretation of mutations in human protein kinases

BACKGROUND: Protein kinases are involved in relevant physiological functions and a broad number of mutations in this superfamily have been reported in the literature to affect protein function and stability. Unfortunately, the exploration of the consequences on the phenotypes of each individual mutation remains a considerable challenge. RESULTS: The wKinMut web-server offers direct prediction of the potential pathogenicity of the mutations from a number of methods, including our recently developed prediction method based on the combination of information from a range of diverse sources, including physicochemical properties and functional annotations from FireDB and Swissprot and kinase-specific characteristics such as the membership to specific kinase groups, the annotation with disease-associated GO terms or the occurrence of the mutation in PFAM domains, and the relevance of the residues in determining kinase subfamily specificity from S3Det. This predictor yields interesting results that compare favourably with other methods in the field when applied to protein kinases. Together with the predictions, wKinMut offers a number of integrated services for the analysis of mutations. These include: the classification of the kinase, information about associations of the kinase with other proteins extracted from iHop, the mapping of the mutations onto PDB structures, pathogenicity records from a number of databases and the classification of mutations in large-scale cancer studies. Importantly, wKinMut is connected with the SNP2L system that extracts mentions of mutations directly from the literature, and therefore increases the possibilities of finding interesting functional information associated to the studied mutations. CONCLUSIONS: wKinMut facilitates the exploration of the information available about individual mutations by integrating prediction approaches with the automatic extraction of information from the literature (text mining) and several state-of-the-art databases. wKinMut has been used during the last year for the analysis of the consequences of mutations in the context of a number of cancer genome projects, including the recent analysis of Chronic Lymphocytic Leukemia cases and is publicly available at http://wkinmut.bioinfo.cnio.es

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio