The Schnitzler syndrome

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections

Insights into the emission of the blazar 1ES 1011+496 through unprecedented broadband observations during 2011 and 2012

Context. 1ES 1011+496 (z = 0.212) was discovered in very high-energy (VHE, E > 100 GeV) gamma rays with MAGIC in 2007. The absence of simultaneous data at lower energies led to an incomplete characterization of the broadband spectral energy distribution (SED). Aims. We study the source properties and the emission mechanisms, probing whether a simple one-zone synchrotron self-Compton (SSC) scenario is able to explain the observed broadband spectrum.Methods. We analyzed data in the range from VHE to radio data from 2011 and 2012 collected by MAGIC, Fermi-LAT, Swift, KVA, OVRO, and Metsahovi in addition to optical polarimetry data and radio maps from the Liverpool Telescope and MOJAVE.Results. The VHE spectrum was fit with a simple power law with a photon index of 3.69 +/- 0.22 and a flux above 150 GeV of (1.46 +/- 0.16) x 10(-11) ph cm(-2) s(-1). The source 1ES 1011+496 was found to be in a generally quiescent state at all observed wavelengths, showing only moderate variability from radio to X-rays. A low degree of polarization of less than 10% was measured in optical, while some bright features polarized up to 60% were observed in the radio jet. A similar trend in the rotation of the electric vector position angle was found in optical and radio. The radio maps indicated a superluminal motion of 1.8 +/- 0.4 c, which is the highest speed statistically significant measured so far in a high-frequency-peaked BL Lac.Conclusions. For the first time, the high-energy bump in the broadband SED of 1ES 1011+496 could be fully characterized from 0.1 GeV to 1 TeV, which permitted a more reliable interpretation within the one-zone SSC scenario. The polarimetry data suggest that at least part of the optical emission has its origin in some of the bright radio features, while the low polarization in optical might be due to the contribution of parts of the radio jet with different orientations of the magnetic field with respect to the optical emission

Accelerating functional gene discovery in osteoarthritis

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease

Search for very high-energy gamma-ray emission from the microquasar Cygnus X-1 with the MAGIC telescopes

The microquasar Cygnus X-1 displays the two typical soft and hard X-ray states of a black hole transient. During the latter, Cygnus X-1 shows a one-sided relativistic radio-jet. Recent detection of the system in the high energy (HE; E greater than or similar to 60 MeV) gamma-ray range with FermiLAT associates this emission with the outflow. Former MAGIC observations revealed a hint of flaring activity in the very high-energy (VHE; E greater than or similar to 100 GeV) regime during this X-ray state. We analyse similar to 97 h of Cygnus X-1 data taken with the MAGIC telescopes between July 2007 and October 2014. To shed light on the correlation between hard X-ray and VHE gamma rays as previously suggested, we study each main X-ray state separately. We perform an orbital phase-folded analysis to look for variability in the VHE band. Additionally, to place this variability behaviour in a multiwavelength context, we compare our results with Fermi-LAT, AGILE, Swift-BAT, MAXI, RXTE-ASM, AMI and RATAN-600 data. We do not detect Cygnus X-1 in the VHE regime. We establish upper limits for each X-ray state, assuming a power-law distribution with photon index Gamma = 3.2. For steady emission in the hard and soft X-ray states, we set integral upper limits at 95 per cent confidence level for energies above 200 GeV at 2.6 x 10(-12) photons cm(-2) s(-1) and 1.0 x 10(-11) photons cm(-2) s(-1), respectively. We rule out steady VHE gamma-ray emission above this energy range, at the level of theMAGIC sensitivity, originating in the interaction between the relativistic jet and the surrounding medium, while the emission above this flux level produced inside the binary still remains a valid possibility

Observation of the black widow B1957+20 millisecond pulsar binary system with the MAGIC telescopes

B1957+20 is a millisecond pulsar located in a black-widow-type compact binary system with a low-mass stellar companion. The interaction of the pulsar wind with the companion star wind and/or the interstellar plasma is expected to create plausible conditions for acceleration of electrons to TeV energies and subsequent production of very high-energy gamma-rays in the inverse Compton process. We performed extensive observations with the Major Atmospheric Gamma Imaging Cherenkov Telescopes (MAGIC) telescopes of B1957+20. We interpret results in the framework of a few different models, namely emission from the vicinity of the millisecond pulsar, the interaction of the pulsar and stellar companion wind region or bow shock nebula. No significant steady very high-energy gamma-ray emission was found. We derived a 95 per cent confidence level upper limit of 3.0 x 10(-12) cm(-2) s(-1) on the average gamma-ray emission from the binary system above 200 GeV. The upper limits obtained with the MAGIC constrain, for the first time, different models of the high-energy emission in B1957+20. In particular, in the inner mixed wind nebula model with mono-energetic injection of electrons, the acceleration efficiency of electrons is constrained to be below similar to 2-10 per cent of the pulsar spin-down power. For the pulsar emission, the obtained upper limits for each emission peak are well above the exponential cut-off fits to the Fermi-LAT data, extrapolated to energies above 50 GeV. The MAGIC upper limits can rule out a simple power-law tail extension through the sub-TeV energy range for the main peak seen at radio frequencies

MAGIC observations of the microquasar V404 Cygni during the 2015 outburst

The microquasar V404 Cygni underwent a series of outbursts in 2015, June 15-31, during which its flux in hard X-rays (20-40 keV) reached about 40 times the Crab nebula flux. Because of the exceptional interest of the flaring activity from this source, observations at several wavelengths were conducted. The MAGIC telescopes, triggered by the INTEGRAL alerts, followed-up the flaring source for several nights during the period June 18-27, for more than 10 h. One hour of observation was simultaneously conducted on a giant 22 GHz radio flare and a hint of signal at GeV energies seen by Fermi-LAT. The MAGIC observations did not show significant emission in any of the analysed time intervals. The derived flux upper limit, in the energy range 200-1250 GeV, is 4.8 x 10(-12) photons cm(-2) s(-1). We estimate the gamma-ray opacity during the flaring period, which along with our non-detection points to an inefficient acceleration in the V404 Cyg jets if a very high energy emitter is located further than 1 x 10(10) cm from the compact object

Constraining Lorentz Invariance Violation Using the Crab Pulsar Emission Observed up to TeV Energies by MAGIC

Spontaneous breaking of Lorentz symmetry at energies on the order of the Planck energy or lower is predicted by many quantum gravity theories, implying non-trivial dispersion relations for the photon in vacuum. Consequently, gamma-rays of different energies, emitted simultaneously from astrophysical sources, could accumulate measurable differences in their time of flight until they reach the Earth. Such tests have been carried out in the past using fast variations of gamma-ray flux from pulsars, and more recently from active galactic nuclei and gamma-ray bursts. We present new constraints studying the gamma-ray emission of the galactic Crab Pulsar, recently observed up to TeV energies by the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) collaboration. A profile likelihood analysis of pulsar events reconstructed for energies above 400. GeV finds no significant variation in arrival time as their energy increases.. Ninety-five percent CL limits are obtained on the effective Lorentz invariance violating energy scale at the level of E-QG1 > 5.5 x 10(17) GeV (4.5 x 10(17) GeV) for a linear, and E-QG2 > 5.9 x 10(10) GeV (5.3 x 10(10) GeV) for a quadratic scenario, for the subluminal and the superluminal cases, respectively. A substantial part of this study is dedicated to calibration of the test statistic, with respect to bias and coverage properties. Moreover, the limits take into account systematic uncertainties, which are found to worsen the statistical limits by about 36%-42%. Our constraints would have been much more stringent if the intrinsic pulse shape of the pulsar between 200 GeV and 400 GeV was understood in sufficient detail and allowed inclusion of events well below 400 GeV

First multi-wavelength campaign on the gamma-ray-loud active galaxy IC 310

Context. The extragalactic very-high-energy gamma-ray sky is rich in blazars. These are jetted active galactic nuclei that are viewed at a small angle to the line-of-sight. Only a handful of objects viewed at a larger angle are so far known to emit above 100 GeV. Multi-wavelength studies of such objects up to the highest energies provide new insights into the particle and radiation processes of active galactic nuclei.Aims. We aim to report the results from the first multi-wavelength campaign observing the TeV detected nucleus of the active galaxy IC 310, whose jet is observed at a moderate viewing angle of 10 degrees-20 degrees.Methods. The multi-instrument campaign was conducted between 2012 November and 2013 January, and involved observations with MAGIC, Fermi, INTEGRAL, Swift, OVRO, MOJAVE and EVN. These observations were complemented with archival data from the AllWISE and 2MASS catalogs. A one-zone synchrotron self-Compton model was applied to describe the broadband spectral energy distribution.Results. IC 310 showed an extraordinary TeV flare at the beginning of the campaign, followed by a low, but still detectable TeV flux. Compared to previous measurements in this energy range, the spectral shape was found to be steeper during the low emission state. Simultaneous observations in the soft X-ray band showed an enhanced energy flux state and a harder-when-brighter spectral shape behavior. No strong correlated flux variability was found in other frequency regimes. The broadband spectral energy distribution obtained from these observations supports the hypothesis of a double-hump structure.Conclusions. The harder-when-brighter trend in the X-ray and VHE emission, observed for the first time during this campaign, is consistent with the behavior expected from a synchrotron self-Compton scenario. The contemporaneous broadband spectral energy distribution is well described with a one-zone synchrotron self-Compton model using parameters that are comparable to those found for other gamma-ray-emitting misaligned blazars

Observations of Sagittarius A* during the pericenter passage of the G2 object with MAGIC

Context. We present the results of a multi-year monitoring campaign of the Galactic center (GC) with the MAGIC telescopes. These observations were primarily motivated by reports that a putative gas cloud (G2) would be passing in close proximity to the super-massive black hole (SMBH), associated with Sagittarius A*, located at the center of our galaxy. This event was expected to give astronomers a unique chance to study the effect of in-falling matter on the broad-band emission of a SMBH.Aims. We search for potential flaring emission of very-high-energy (VHE; >= 100 GeV) gamma rays from the direction of the SMBH at the GC due to the passage of the G2 object. Using these data we also study the morphology of this complex region.Methods. We observed the GC region with the MAGIC Imaging Atmospheric Cherenkov Telescopes during the period 2012-2015, collecting 67 h of good-quality data. In addition to a search for variability in the flux and spectral shape of the GC gamma-ray source, we use a point-source subtraction technique to remove the known gamma-ray emitters located around the GC in order to reveal the TeV morphology of the extended emission inside that region.Results. No effect of the G2 object on the VHE gamma-ray emission from the GC was detected during the 4 yr observation campaign. We confirm previous measurements of the VHE spectrum of Sagittarius A*, and do not detect any significant variability of the emission from the source. Furthermore, the known VHE gamma-ray emitter at the location of the supernova remnant G0.9+0.1 was detected, as well as the recently discovered VHE source close to the GG radio arc