Calibration of centre-of-mass energies at LEP 2 for a precise measurement of the W boson mass

The determination of the centre-of-mass energies for all LEP 2 running is presented. Accurate knowledge of these energies is of primary importance to set the absolute energy scale for the measurement of the W boson mass. The beam energy between 80 and 104 GeV is derived from continuous measurements of the magnetic bending field by 16 NMR probes situated in a number of the LEP dipoles. The relationship between the fields measured by the probes and the beam energy is defined in the NMR model, which is calibrated against precise measurements of the average beam energy between 41 and 61 GeV made using the resonant depolarisation technique. The validity of the NMR model is verified by three independent methods: the flux-loop, which is sensitive to the bending field of all the dipoles of LEP; the spectrometer, which determines the energy through measurements of the deflection of the beam in a magnet of known integrated field; and an analysis of the variation of the synchrotron tune with the total RF voltage. To obtain the centre-of-mass energies, corrections are then applied to account for sources of bending field external to the dipoles, and variations in the local beam energy at each interaction point. The relative error on the centre-of-mass energy determination for the majority of LEP 2 running is 1.2 x 10^{-4}, which is sufficiently precise so as not to introduce a dominant uncertainty on the W mass measurement.Comment: 79 pages, 45 figures, submitted to EPJ

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

OBJECTIVE—Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4+CD25+FOXP3+ T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs

Investigations of the LHC Emittance Blow-Up During the 2012 Proton Run

About 30 % of the potential luminosity performance is lost through the different phases of the LHC cycle, mainly due to transverse emittance blow-up. Measuring the emittance growth is a difficult task with high intensity beams and changing energies. Improvements of the LHC transverse profile instrumentation helped to study various effects. A breakdown of the growth through the different phases of the LHC cycle is given as well as a comparison with the data from the LHC experiments for transverse beam size. In 2012 a number of possible sources and remedies have been studied. Among these are intra beam scattering, 50 Hz noise and the effect of the transverse damper gain. The results of the investigations are summarized in this paper. Requirements for transverse profile instrumentation for post LHC long shutdown operation to finally tackle the emittance growth are given as well

Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft

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LEIR Commissioning

The Low Energy Ion Ring (LEIR) is a central piece of the injector chain for LHC ion operation, transforming long Linac 3 pulses into high density bunches needed for LHC. LEIR commissioning is scheduled to be completed at the time of the conference. A review of LEIR commissioning highlighting expected and unexpected problems and actions to tackle them will be given

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome

Background Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. Objective Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. Methods We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein. Results After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19+CD21-CD35- and CD21low

Status of the LEP2 Spectrometer Project

The LEP spectrometer has been conceived to provide a determination of the beam energy with a relative accuracy of 10-4 in the LEP2 physics region where insufficient polarisation levels prevent the application of the resonant depolarisation method. The setup consists of a steel bending magnet flanked by a triplet of Beam Position Monitors (BPM) at each side providing a measurement of changes in the bending angle when the beams are accelerated to physics energies. The goal for a 100 ppm relative precision on the beam energy involves a ± 1 micron BPM resolution and the calibration of the dipole bending strength to a 30 ppm accuracy. This paper reports on the results of the commissioning of the Spectrometer during the 1999 LEP Run and on the experience acquired on the behaviour of the several sub-systems with circulating beams

Molecular and functional heterogeneity of IL-10-producing CD4 + T cells

IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4 + T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3 neg CD4 + T cells that displays regulatory activity unlike other IL-10-producing CD4 + T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4 + T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3 neg CD4 + T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation