GRAIL, an omni-directional gravitational wave detector

A cryogenic spherical and omni-directional resonant-mass detector proposed by the GRAIL collaboration is described.Comment: 5 pages, 4 figs., contribution to proceedings GW Data Analysis Workshop, Paris, nov. 199

Correction: critical role for sec22b-dependent antigen cross-presentation in antitumor immunity

The authors regret that in the original version of their paper, they mistakenly used the phrase OVA-expressing cells instead of OVA-secreting cells in parts of the text and cited reference Boissonnas et al. (2007. http://dx.doi.org/10.1084/jem.20061890) instead of Zeelenberg et al. (2008. http://dx.doi.org/10.1158/0008-5472.CAN-07-3163) and Sedlik et al. (2014. http://dx.doi.org/10.3402/jev.v3.24646). The Results and discussion paragraph containing the corrected references and full bibliographic information appear below.Fil: Alloatti, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Rookhuizen, Derek C.. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Joannas, Leonel. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Carpier, Jean-Marie. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Iborra, Salvador. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Magalhaes, Joao G.. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Yatim, Nader. Institut Pasteur, Paris; FranciaFil: Kozik, Patrycja. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Sancho, David. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Albert, Matthew L.. Institut Pasteur, Paris; FranciaFil: Amigorena, Sebastian. Institute Curie. U-932 Immunity And Cancer; Franci

Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this “NOTCH2-BCR axis” in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity

Deep sea tests of a prototype of the KM3NeT digital optical module

The first prototype of a photo-detection unit of the future KM3NeT neutrino telescope has been deployed in the deepwaters of the Mediterranean Sea. This digital optical module has a novel design with a very large photocathode area segmented by the use of 31 three inch photomultiplier tubes. It has been integrated in the ANTARES detector for in-situ testing and validation. This paper reports on the first months of data taking and rate measurements. The analysis results highlight the capabilities of the new module design in terms of background suppression and signal recognition. The directionality of the optical module enables the recognition of multiple Cherenkov photons from the same (40)Kdecay and the localisation of bioluminescent activity in the neighbourhood. The single unit can cleanly identify atmospheric muons and provide sensitivity to the muon arrival directions

Detection potential of the KM3NeT detector for high-energy neutrinos from the Fermi bubbles

A recent analysis of the Fermi Large Area Telescope data provided evidence for a high-intensity emission of high-energy gamma rays with a E 2 spectrum from two large areas, spanning 50 above and below the Galactic centre (the ‘‘Fermi bubbles’’). A hadronic mechanism was proposed for this gamma-ray emission making the Fermi bubbles promising source candidates of high-energy neutrino emission. In this work Monte Carlo simulations regarding the detectability of high-energy neutrinos from the Fermi bubbles with the future multi-km3 neutrino telescope KM3NeT in the Mediterranean Sea are presented. Under the hypothesis that the gamma-ray emission is completely due to hadronic processes, the results indicate that neutrinos from the bubbles could be discovered in about one year of operation, for a neutrino spectrum with a cutoff at 100 TeV and a detector with about 6 km3 of instrumented volume. The effect of a possible lower cutoff is also considered.Published7–141.8. Osservazioni di geofisica ambientaleJCR Journalrestricte

Expansion cone for the 3-inch PMTs of the KM3NeT optical modules

[EN] Detection of high-energy neutrinos from distant astrophysical sources will open a new window on the Universe. The detection principle exploits the measurement of Cherenkov light emitted by charged particles resulting from neutrino interactions in the matter containing the telescope. A novel multi-PMT digital optical module (DOM) was developed to contain 31 3-inch photomultiplier tubes (PMTs). In order to maximize the detector sensitivity, each PMT will be surrounded by an expansion cone which collects photons that would otherwise miss the photocathode. Results for various angles of incidence with respect to the PMT surface indicate an increase in collection efficiency by 30% on average for angles up to 45 degrees with respect to the perpendicular. Ray-tracing calculations could reproduce the measurements, allowing to estimate an increase in the overall photocathode sensitivity, integrated over all angles of incidence, by 27% (for a single PMT). Prototype DOMs, being built by the KM3NeT consortium, will be equipped with these expansion cones.This work is supported through the EU, FP6 Contract no. 011937, FP7 grant agreement no. 212252, and the Dutch Ministry of Education, Culture and Science.Adrián Martínez, S.; Ageron, M.; Aguilar, JA.; Aharonian, F.; Aiello, S.; Albert, A.; Alexandri, M.... (2013). Expansion cone for the 3-inch PMTs of the KM3NeT optical modules. Journal of Instrumentation. 8(3):1-19. https://doi.org/10.1088/1748-0221/8/03/T03006S1198

Regulation of Germinal Center Antibody Responses by TLR Signaling in Dendritic Cells and B Cells

The ultimate goal of the immune system is to eliminate pathogens and establish an immunological memory for rapid response upon reinfection. It can be broadly divided into innate and adaptive compartments. Immediately or shortly after infection occurs, the innate immune system uses pattern recognition receptors (PRRs) to identify ancient conserved features of pathogens, for example, DNA, RNA and carbohydrate, termed pathogen associated molecular patters (PAMPs). Stimulation of PRRs by PAMPs triggers signaling events that both limit the spread of infection as well as inform the adaptive immune system to generate the appropriate type of immunological memory. For example, the adaptive system uses cellular immunity to eliminate pathogens such as Mycobacterium tuberculosis that reside within cells while it generates antibodies (humoral immunity) to neutralize and remove extracellular pathogens such as the bacteria Pseudomonas aeruginosa that causes pneumonia. Thus, innate responses provide the first wave of defense by containing infection while the slower acting adaptive response eliminates pathogens and programs the ability to respond more efficiently upon subsequent exposures. How innate signals sculpt adaptive responses is not well understood, and therefore, this thesis focuses on the ability of innate signaling by a family of PRRs known as toll-like receptors (TLRs) to program antibody responses. Ten and twelve TLRs have been identified in humans and mice, respectively, and they recognize a variety of PAMPs expressed by bacteria, viruses, fungi, and parasites including lipopolysaccharide (TLR4), flagellin (TLR5 and TLR11), and unmethylated CpG motifs in DNA (TLR9). Briefly, antibody responses may be broadly divided into those that require T cell help (T-dependent) and those that are independent of T cell help (T-independent). T-dependent antibody responses can occur either outside the B cell follicle (extrafollicular) or within the follicle in specialized transient structures termed germinal centers (GCs) that generate high affinity, long-lived humoral memory. To dissect how TLR signaling impacts GC antibody responses, I immunized mice with an oligovalent T-dependent protein antigen that was linked to either oligonucleotides containing (CpG) or lacking (nonCpG) a TLR9 ligand. In chapter two, I focus on the cellular contribution of TLR signaling to GC magnitude and quality by using a Cre recombinase system to selectively delete the TLR signaling adaptor MyD88 in either dendritic cells or B cells. This series of experiments revealed a division of labor for TLR signaling in DCs and B cells that controls GC magnitude and quality, respectively. In chapter three, I address the role of costimulation by the inducible costimulator (ICOS) on T cells and ICOS ligand (ICOSL) on B cells to direct the GC response against antigen linked to a TLR9 ligand. These experiments revealed that ICOSL acted B cell-extrinsically to impact GC quality and also unveiled a surprising B cell-intrinsic role for TLR9 signaling in affinity maturation. Collectively, these studies suggest that innate signals imprint the quality of T cell help that subsequently defines the antibody response and that they also act on B cells receiving TLR9 stimuli to directly enhance their affinity maturation. These results have implications in both human disease and rational vaccine design