Dual stimulation by autoantigen and CpG fosters the proliferation of exhausted rheumatoid factor-specific CD21low B cells in hepatitis C virus-cured mixed cryoglobulinemia

Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses. MethodsClonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination; proliferation and differentiation were then evaluated by flow cytometry. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR. DiscussionWe found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells

TGF DETECTION BY AGILE

We report the detection by the Astrorivelatore Gamma a Immagini Leggero (AGILE) satellite of terrestrial gamma ray flashes (TGFs) obtained with the minicalorimeter (MCAL) detector operating in the ..

AGILE TGFS AND GLOBAL LIGHTNING ACTIVITY

[1] The AGILE satellite detects Terrestrial Gamma-ray Flashes (TGFs) in the 0.35–100 MeV energy range using its Mini-Calorimeter (MCAL) instrument with an average detection rate of 10 TGFs/month. Thanks to its Low Earth Orbit with only 2.5 degree of inclination, AGILE guarantees an unprecedented exposure above the equator, where both lightning activity and TGF detection peak. Here we report the comparison between the AGILE TGFs detected between March 2009 and February 2010 and full climatology lightning worldwide distribution based on satellite optical observations from LIS (Lightning Imaging Sensor) and OTD (Optical Transient Detector) instruments. This approach is complementary to the one-to-one TGF/lightning correlations by ground-based sferics measurements. Based on mono and bi-dimensional Kolmogorov-Smirnov tests, we show that the AGILE TGFs and time-averaged global lightning in the equatorial area are not drawn from the same distribution. However, we find significant regional differences in the degree of correlation as well as in the TGF/lightning ratio. In the case of south east Asia we find a 87% probability for the TGF and lightning being samples of the same distribution. This result supports the idea that the physical conditions at play in TGF generation can have strong geographical and climatological modulation. Based on the assumption that the observed range of TGF/flash ratio holds at all latitudes we can estimate a global rate of ≃ 220 ÷ 570 TGFs per day. The observed TGF/flash geographical modulation as well as the TGF global rate estimate are in agreement with previous observations

The AGILE Mission

AGILE is an Italian Space Agency mission dedicated to observing the gamma-ray Universe. The AGILE's very innovative instrumentation for the first time combines a gamma-ray imager (sensitive in the energy range 30 MeV-50 GeV), a hard X-ray imager (sensitive in the range 18-60 keV), a calorimeter (sensitive in the range 350 keV-100 MeV), and an anticoincidence system. AGILE was successfully launched on 2007 April 23 from the Indian base of Sriharikota and was inserted in an equatorial orbit with very low particle background. Aims. AGILE provides crucial data for the study of active galactic nuclei, gamma-ray bursts, pulsars, unidentified gamma-ray sources, galactic compact objects, supernova remnants, TeV sources, and fundamental physics by microsecond timing. Methods. An optimal sky angular positioning (reaching 0.1 degrees in gamma- rays and 1-2 arcmin in hard X-rays) and very large fields of view (2.5 sr and 1 sr, respectively) are obtained by the use of Silicon detectors integrated in a very compact instrument. Results. AGILE surveyed the gamma- ray sky and detected many Galactic and extragalactic sources during the first months of observations. Particular emphasis is given to multifrequency observation programs of extragalactic and galactic objects. Conclusions. AGILE is a successful high-energy gamma-ray mission that reached its nominal scientific performance. The AGILE Cycle-1 pointing program started on 2007 December 1, and is open to the international community through a Guest Observer Program

Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

An X-ray burst from a magnetar enlightening the mechanism of fast radio bursts

Fast radio bursts (FRBs) are millisecond radio pulses originating from powerful enigmatic sources at extragalactic distances. Neutron stars with large magnetic fields (magnetars) have been considered as the sources powering the FRBs, but the connection requires further substantiation. Here we report the detection by the AGILE satellite on 28 April 2020 of an X-ray burst in temporal coincidence with a bright FRB-like radio burst from the Galactic magnetar SGR 1935+2154. The burst observed in the hard X-ray band (18-60 keV) lasted about 0.5 s, it is spectrally cut off above 80 keV and implies an isotropically emitted energy of about 1040 erg. This event demonstrates that a magnetar can produce X-ray bursts in coincidence with FRB-like radio bursts. It also suggests that FRBs associated with magnetars can emit X-ray bursts. We discuss SGR 1935+2154 in the context of FRBs with low-intermediate radio energies in the range 1038-1040 erg. Magnetars with magnetic fields B ≈ 1015 G may power these FRBs, and new data on the search for X-ray emission from FRBs are presented. We constrain the bursting X-ray energy of the nearby FRB 180916 to be less than 1046 erg, smaller than that observed in giant flares from Galactic magnetars

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe