Biomarkers of the L-arginine / dimethylarginine / nitric oxide pathway in people with chronic airflow obstruction and obstructive sleep apnoea

Background: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are common chronic diseases that are associated with chronic and intermittent hypoxemia, respectively. Patients affected by the overlap of COPD and OSA have a particularly unfavourable prognosis. The L-arginine/nitric oxide (NO) pathway plays an important role in regulating pulmonary vascular function. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) interfere with NO production. Methods: We analysed the serum concentrations of ADMA, SDMA, L-arginine, L-citrulline, and L-ornithine in a large sample of the Icelandic general population together with chronic airflow obstruction (CAO), a key physiological marker of COPD that was assessed by post-bronchodilator spirometry (FEV1/FVC 0.5. SDMA was significantly higher in individuals with CAO (0.518 [0.461–0.616] vs. 0.494 [0.441–0.565] µmol/L; p = 0.005), but ADMA was not. However, ADMA was significantly associated with decreasing FEV1 percent predicted among those with CAO (p = 0.002). ADMA was 0.50 (0.44–0.56) µmol/L in MAP ≤ 0.5 versus 0.52 (0.46–0.58) µmol/L in MAP > 0.5 (p = 0.008). SDMA was 0.49 (0.44–0.56) µmol/L versus 0.51 (0.46–0.60) µmol/L, respectively (p = 0.004). The highest values for ADMA and SDMA were observed in individuals with overlap of CAO and MAP > 0.5, which was accompanied by lower L-citrulline levels. Conclusions: The plasma concentrations of ADMA and SDMA are elevated in COPD patients with concomitant intermittent hypoxaemia. This may account for impaired pulmonary NO production, enhanced pulmonary vasoconstriction, and disease progression

New Hard-TeV Extreme Blazars Detected with the MAGIC Telescopes

Extreme high-frequency-peaked BL Lac objects (EHBLs) are blazars that exhibit extremely energetic synchrotron emission. They also feature nonthermal gamma-ray emission whose peak lies in the very high-energy (VHE, E > 100 GeV) range, and in some sources exceeds 1 TeV: this is the case for hard-TeV EHBLs such as 1ES 0229+200. With the aim of increasing the EHBL population, 10 targets were observed with the MAGIC telescopes from 2010 to 2017, for a total of 265 hr of good-quality data. The data were complemented by coordinated Swift observations. The X-ray data analysis confirms that all but two sources are EHBLs. The sources show only a modest variability and a harder-when-brighter behavior, typical for this class of objects. At VHE gamma-rays, three new sources were detected and a hint of a signal was found for another new source. In each case, the intrinsic spectrum is compatible with the hypothesis of a hard-TeV nature of these EHBLs. The broadband spectral energy distributions (SEDs) of all sources are built and modeled in the framework of a single-zone, purely leptonic model. The VHE gamma-ray-detected sources were also interpreted with a spine-layer model and a proton synchrotron model. The three models provide a good description of the SEDs. However, the resulting parameters differ substantially in the three scenarios, in particular the magnetization parameter. This work presents the first mini catalog of VHE gamma-ray and multiwavelength observations of EHBLs

MAGIC observations provide compelling evidence of hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

Context. Certain types of supernova remnants (SNRs) in our Galaxy are assumed to be PeVatrons, capable of accelerating cosmic rays (CRs) to ∼ PeV energies. However, conclusive observational evidence for this has not yet been found. The SNR G106.3+2.7, detected at 1- 100 TeV energies by different γ-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape, which can be divided into a head and a tail region with different physical conditions. However, in which region the 100 TeV emission is produced has not yet been identified because of the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear as to whether the origin of the γ-ray emission is leptonic or hadronic. Aims. With the better angular resolution provided by new MAGIC data compared to earlier γ-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1 resolution at TeV energies. Methods. We observed the SNR G106.3+2.7 using the MAGIC telescopes for 121.7 h in total - after quality cuts - between May 2017 and August 2019. The analysis energy threshold is ∼0.2 TeV, and the angular resolution is 0.07-0.1. We examined the γ-ray spectra of different parts of the emission, whilst benefitting from the unprecedented statistics and angular resolution at these energies provided by our new data. We also used measurements at other wavelengths such as radio, X-rays, GeV γ-rays, and 10 TeV γ-rays to model the emission mechanism precisely. Results. We detect extended γ-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detect a significant γ-ray emission with energies above 6.0 TeV from only the tail region suggests that the emissions above 10 TeV detected with air shower experiments (Milagro, HAWC, Tibet ASγ and LHAASO) are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of ∼1 PeV for that region. Such high-energy emission in this middle-aged SNR (4-10 kyr) can be explained by considering a scenario where protons escaping from the SNR in the past interact with surrounding dense gases at present. Conclusions. The γ-ray emission region detected with the MAGIC telescopes in the SNR G106.3+2.7 is extended and spatially coincident with the radio continuum morphology. The multi-wavelength spectrum of the emission from the tail region suggests proton acceleration up to ∼PeV, while the emission mechanism of the head region could either be hadronic or leptonic

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

Testing emission models on the extreme blazar 2WHSP J073326.7+515354 detected at very high energies with the MAGIC telescopes

Extreme high-energy-peaked BL Lac objects (EHBLs) are an emerging class of blazars. Their typical two-hump-structured spectral energy distribution (SED) peaks at higher energies with respect to conventional blazars. Multiwavelength (MWL) observations constrain their synchrotron peak in the medium to hard X-ray band. Their gamma-ray SED peaks above the GeV band, and in some objects it extends up to several TeV. Up to now, only a few EHBLs have been detected in the TeV gamma-ray range. In this paper, we report the detection of the EHBL 2WHSP J073320,7+515354, observed and detected during 2018 in TeV gamma rays with the MAGIC telescopes. The broad-band SED is studied within an MWL context, including an analysis of the Fermi-LAT data over 10 yr of observation and with simultaneous Swift-XRT, Swift-UVOT, and KVA data. Our analysis results in a set of spectral parameters that confirms the classification of the source as an EIME. In order to investigate the physical nature of this extreme emission, different theoretical frameworks were tested to model the broadband SED. The hard TeV spectrum of 2WHSP J073326.7+515354 sets the SED far from the energy equipartition regime in the standard one-zone leptonic scenario of blazar emission. Conversely, more complex models of the jet, represented by either a two-zone spine-layer model or a hadronic emission model, better represent the broad-hand SED

Constraints on Gamma-Ray and Neutrino Emission from NGC 1068 with the MAGIC Telescopes

Starburst galaxies and star-forming active galactic nuclei are among the candidate sources thought to contribute appreciably to the extragalactic gamma-ray and neutrino backgrounds. NGC 1068 is the brightest of the star-forming galaxies found to emit gamma-rays from 0.1 to 50 GeV. Precise measurements of the high-energy spectrum are crucial to study the particle accelerators and probe the dominant emission mechanisms. We have carried out 125 hr of observations of NGC 1068 with the MAGIC telescopes in order to search for gamma-ray emission in the very-high-energy band. We did not detect significant gamma-ray emission, and set upper limits at the 95% confidence level to the gamma-ray flux above 200 GeV f < 5.1. x. 10(-13) cm(-2) s(-1). This limit improves previous constraints by about an order of magnitude and allows us to put tight constraints on the theoretical models for the gamma-ray emission. By combining the MAGIC observations with the Fermi-LAT spectrum we limit the parameter space (spectral slope, maximum energy) of the cosmic ray protons predicted by hadronuclear models for the gamma-ray emission, while we find that a model postulating leptonic emission from a semi-relativistic jet is fully consistent with the limits. We provide predictions for IceCube detection of the neutrino signal foreseen in the hadronic scenario. We predict a maximal IceCube neutrino event rate of 0.07 yr(-1)

Monitoring of the radio galaxy M 87 during a low -emission state from m 2012 to 2015 with MAGIC

M 87 is one of the closest (z = 0.004 36) extragalactic sources emitting at very high energies (VHF, E > 100 GeV). The aim of this work is to locale the region of the VHF gamma-ray emission and to describe the observed broad-band spectral energy distribution (SED) during the low VHF gamma-ray state. The data from M 87 collected between 2012 and 2015 as part of a MAGIC monitoring programme are analysed and combined with multiwavelength data from Fermi-LAT, Chandra, HST, FVN, VLBA, and the Liverpool Telescope. The averaged VHE gamma-ray spectrum can be fitted from 100 GeV to 10 TeV with a simple power law with a photon index of (-2.41 0.07), while the integral flux above 300 GeV is (1.44 0.13) x 10-12 cm 2 s I. During the campaign between 2012 and 2015, M87 is generally found in a low-emission state at all observed wavelengths. The VIIE gamma-ray flux from the present 2012-2015M 87 campaign is consistent with a constant flux with some hint of variability ( 3 a) on a daily time-scale in 2013. The low-state gamma-ray emission likely originates from the same region as the flare-state emission. Given the broad-band SED, both a leptonic synchrotron self-Compton and a hybrid photohadronic model reproduce the available data well, even if the latter is preferred. We note, however, that the energy stored in the magnetic field in the leptonic scenario is very low, suggesting a matter-dominated emission region

Search for Very High-energy Emission from the Millisecond Pulsar PSR J0218+4232

PSR J0218+4232 is one of the most energetic millisecond pulsars known and has long been considered as one of the best candidates for very high-energy (VHE; >100 GeV) gamma-ray emission. Using 11.5 yr of Fermi Large Area Telescope (LAT) data between 100 MeV and 870 GeV, and similar to 90 hr of Major Atmospheric Gamma Imaging Cherenkov (MAGIC) observations in the 20 GeV to 20 TeV range, we searched for the highest energy gamma-ray emission from PSR J0218+4232. Based on the analysis of the LAT data, we find evidence for pulsed emission above 25 GeV, but see no evidence for emission above 100 GeV (VHE) with MAGIC. We present the results of searches for gamma-ray emission, along with theoretical modeling, to interpret the lack of VHE emission. We conclude that, based on the experimental observations and theoretical modeling, it will remain extremely challenging to detect VHE emission from PSR J0218+4232 with the current generation of Imaging Atmospheric Cherenkov Telescopes, and maybe even with future ones, such as the Cherenkov Telescope Array

Multiwavelength variability and correlation studies of Mrk 421 during historically low X-ray and γ-ray activity in 2015-2016

We report a characterization of the multiband flux variability and correlations of the nearby (z = 0.031) blazar Markarian 421 (Mrk 421) using data from Metsahovi, Swift, Fermi-LAT, MAGIC, FACT, and other collaborations and instruments from 2014 November till 2016 June. Mrk 421 did not show any prominent flaring activity, but exhibited periods of historically low activity above 1 TeV (F->1 TeV 0.1 TeV) gamma-rays, which, despite the low activity, show a significant positive correlation with no time lag. The HRkeV and HRTeV show the harder-when-brighter trend observed in many blazars, but the trend flattens at the highest fluxes, which suggests a change in the processes dominating the blazar variability. Enlarging our data set with data from years 2007 to 2014, we measured a positive correlation between the optical and the GeV emission over a range of about 60 d centred at time lag zero, and a positive correlation between the optical/GeV and the radio emission over a range of about 60 d centred at a time lag of 43(-6)(+9) d. This observation is consistent with the radio-bright zone being located about 0.2 parsec downstream from the optical/GeV emission regions of the jet. The flux distributions are better described with a lognormal function in most of the energy bands probed, indicating that the variability in Mrk 421 is likely produced by a multiplicative process