4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1

In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation of chromosomal maintenance 1 protein (CRM1), also known as exportin 1 (XPO1), a host cell protein exploited by IAV during replication. 4-OI-mediated deactivation of CRM1 resulted in the accumulation of the IAV nucleoprotein, the Rev protein of feline immunodeficiency virus, as well as the natural CRM1 cargos p53 and p65, in the nucleus of treated cells. Further mechanism of action studies revealed that, similar to known CRM1 inhibitors, 4-OI modifies a key cysteine in the cargo binding pocket of CRM1 at position 528 through an alkylation reaction called 2,3-dicarboxypropylation. Subsequent studies in a cell line in which the cysteine at position 528 in CRM1 protein was substituted by a serine confirmed that modification of this residue was indeed the cause for the observed inhibitory effect induced by 4-OI on CRM1 function. Overall, this study demonstrated a mechanism through which 4-OI directly interferes with the replication cycle of CRM1-dependent viruses, which contributes to the understanding of the antiviral and anti-inflammatory properties of this multifaceted immuno-metabolite. IMPORTANCE Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.</p

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

Acciari, V. A., et al. (MAGIC Collaboration)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 Metsähovi, 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) γ-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+9-6 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.The financial support of the German BMBF and MPG; the Italian INFN and INAF; the Swiss National Fund SNF; the ERDF under the Spanish MINECO (FPA2017-87859-P, FPA2017-85668-P, FPA2017-82729-C6-2-R, FPA2017-82729-C6-6-R, FPA2017-82729-C6-5-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2017-87055-C2-2-P, FPA2017-90566-REDC); the Indian Department of Atomic Energy; the Japanese ICRR, the University of Tokyo, JSPS, and MEXT; the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-268/16.12.2019 and the Academy of Finland grant nr. 320045 is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia ‘Severo Ochoa’ SEV-2016-0588 and SEV-2015-0548, the Unidad de Excelencia ‘María de Maeztu’ MDM-2014-0369 and the ‘la Caixa’ Foundation (fellowship LCF/BQ/PI18/11630012), by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ

Detection of persistent VHE gamma-ray emission from PKS 1510-089 by the MAGIC telescopes during low states between 2012 and 2017

PKS 1510-089 is a flat spectrum radio quasar strongly variable in the optical and GeV range. To date, very high-energy (VHE, > 100 GeV) emission has been observed from this source either during long high states of optical and GeV activity or during short flares. Aims. We search for low-state VHE gamma-ray emission from PKS 1510-089. We characterize and model the source in a broadband context, which would provide a baseline over which high states and flares could be better understood. Methods. PKS 1510-089 has been monitored by the MAGIC telescopes since 2012. We use daily binned Fermi-LAT flux measurements of PKS 1510-089 to characterize the GeV emission and select the observation periods of MAGIC during low state of activity. For the selected times we compute the average radio, IR, optical, UV, X-ray, and gamma-ray emission to construct a low-state spectral energy distribution of the source. The broadband emission is modeled within an external Compton scenario with a stationary emission region through which plasma and magnetic fields are flowing. We also perform the emission-model-independent calculations of the maximum absorption in the broad line region (BLR) using two different models. Results. The MAGIC telescopes collected 75 hr of data during times when the Fermi-LAT flux measured above 1 GeV was below 3? × 10 -8 ? cm -2 ? s -1 , which is the threshold adopted for the definition of a low gamma-ray activity state. The data show a strongly significant (9.5¿) VHE gamma-ray emission at the level of (4.27 ± 0.61 stat ) × 10 -12 ? cm -2 ? s -1 above 150 GeV, a factor of 80 lower than the highest flare observed so far from this object. Despite the lower flux, the spectral shape is consistent with earlier detections in the VHE band. The broadband emission is compatible with the external Compton scenario assuming a large emission region located beyond the BLR. For the first time the gamma-ray data allow us to place a limit on the location of the emission region during a low gamma-ray state of a FSRQ. For the used model of the BLR, the 95% confidence level on the location of the emission region allows us to place it at a distance > 74% of the outer radius of the BLR. © ESO 2018.The financial support of the German BMBF and MPG, the Italian INFN and INAF, the Swiss National Fund SNF, the ERDF under the Spanish MINECO (FPA2015-69818-P, FPA2012-36668, FPA2015-68378-P, FPA2015-69210-C6-2-R, FPA2015-69210-C6-4-R, FPA2015-69210-C6-6-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2015-71662-C2-2-P, CSD2009-00064), and the Japanese JSPS and MEXT is gratefully acknowledged. This work was also supported by the Spanish Centro de Exce-lencia “Severo Ochoa” SEV-2012-0234 and SEV-2015-0548, and Unidad de Excelencia “María de Maeztu” MDM-2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382, and by the Brazilian MCTIC, CNPq and FAPERJ. IA acknowledges support from a Ramón y Cajal grant of the Ministerio de Economía, Industria, y Competitividad (MINECO) of Spain. Acquisition and reduction of the POLAMI and MAPCAT data was supported in part by MINECO through grants AYA2010-14844, AYA2013-40825-P, and AYA2016-80889-P, and by the Regional Government of Andalucía through grant P09-FQM-4784.Peer Reviewe

Periastron Observations of TeV Gamma-Ray Emission from a Binary System with a 50-year Period

We report on observations of the pulsar / Be star binary system PSR J2032+4127 / MT91 213 in the energy range between 100 GeV and 20 TeV with the VERITAS and MAGIC imaging atmospheric Cherenkov telescope arrays. The binary orbit has a period of approximately 50 years, with the most recent periastron occurring on 2017 November 13. Our observations span from 18 months prior to periastron to one month after. A new, point-like, gamma-ray source is detected, coincident with the location of PSR J2032+4127 / MT91 213. The gamma-ray light curve and spectrum are well-characterized over the periastron passage. The flux is variable over at least an order of magnitude, peaking at periastron, thus providing a firm association of the TeV source with the pulsar / Be star system. Observations prior to periastron show a cutoff in the spectrum at an energy around 0.5 TeV. This result adds a new member to the small population of known TeV binaries, and it identifies only the second source of this class in which the nature and properties of the compact object are firmly established. We compare the gamma-ray results with the light curve measured with the X-ray Telescope (XRT) on board the Neil Gehrels Swift Observatory and with the predictions of recent theoretical models of the system. We conclude that significant revision of the models is required to explain the details of the emission we have observed, and we discuss the relationship between the binary system and the overlapping steady extended source, TeV J2032+4130

Detection of the blazar S4 0954+65 at very-high-energy with the MAGIC telescopes during an exceptionally high optical state

The very high energy (VHE ¿ 100 GeV) -ray MAGIC observations of the blazar S4 0954+65, were triggered by an exceptionally high flux state of emission in the optical. This blazar has a disputed redshift of z = 0.368 or z ¿ 0.45 and an uncertain classification among blazar subclasses. The exceptional source state described here makes for an excellent opportunity to understand physical processes in the jet of S4 0954+65 and thus contribute to its classification. Methods. We investigated the multiwavelength (MWL) light curve and spectral energy distribution (SED) of the S4 0954+65 blazar during an enhanced state in February 2015 and have put it in context with possible emission scenarios. We collected photometric data in radio, optical, X-ray, and ¿-ray. We studied both the optical polarization and the inner parsec-scale jet behavior with 43 GHz data. Results. Observations with the MAGIC telescopes led to the first detection of S4 0954+65 at VHE. Simultaneous data with Fermi-LAT at high energy ¿-ray(HE, 100 MeV < E < 100 GeV) also show a period of increased activity. Imaging at 43 GHz reveals the emergence of a new feature in the radio jet in coincidence with the VHE flare. Simultaneous monitoring of the optical polarization angle reveals a rotation of approximately 100. Conclusions. The high emission state during the flare allows us to compile the simultaneous broadband SED and to characterize it in the scope of blazar jet emission models. The broadband spectrum can be modeled with an emission mechanism commonly invoked for flat spectrum radio quasars (FSRQs), that is, inverse Compton scattering on an external soft photon field from the dust torus, also known as external Compton. The light curve and SED phenomenology is consistent with an interpretation of a blob propagating through a helical structured magnetic field and eventually crossing a standing shock in the jet, a scenario typically applied to FSRQs and low-frequency peaked BL Lac objects (LBL). © ESO 2018.The financial support of the German BMBF and MPG, the Italian INFN and INAF, the Swiss National Fund SNF, the ERDF under the Spanish MINECO (FPA2015-69818-P, FPA2012-36668, FPA2015-68378-P, FPA2015-69210-C6-2-R, FPA2015-69210-C6-4-R, FPA2015-69210-C6-6-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2015-71662-C2-2-P, CSD2009-00064), and the Japanese JSPS and MEXT is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia “Severo Ochoa” SEV-2012-0234 and SEV-2015-0548, and Unidad de Excelencia “María de Maeztu” MDM-2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ. IA acknowledges support by a Ramón y Cajal grant of the Ministerio de Economía, Industria y Competitividad (MINECO) of Spain. The research at the IAA–CSIC was supported in part by the MINECO through grants AYA2016–80889–P, AYA2013–40825–P, and AYA2010–14844, and by the regional government of Andalucía through grant P09–FQM–4784.Peer Reviewe

Measurement of the Extragalactic Background Light using MAGIC and Fermi-LAT gamma-ray observations of blazars up to z = 1

We present a measurement of the extragalactic background light (EBL) based on a joint likelihood analysis of 32 gamma-ray spectra for 12 blazars in the redshift range z = 0.03 to 0.944, obtained by the MAGIC telescopes and Fermi-LAT. The EBL is the part of the diffuse extragalactic radiation spanning the ultraviolet, visible and infrared bands. Major contributors to the EBL are the light emitted by stars through the history of the universe, and the fraction of it which was absorbed by dust in galaxies and re-emitted at longer wavelengths. The EBL can be studied indirectly through its effect on very-high energy photons that are emitted by cosmic sources and absorbed via photon-photon interactions during their propagation across cosmological distances. We obtain estimates of the EBL density in good agreement with state-of-the-art models of the EBL production and evolution. The 1-sigma upper bounds, including systematic uncertainties, are between 13% and 23% above the nominal EBL density in the models. No anomaly in the expected transparency of the universe to gamma rays is observed in any range of optical depth.We also perform a wavelength-resolved EBL determination, which results in a hint of an excess of EBL in the 0.18 - 0.62 $\mu$m range relative to the studied models, yet compatible with them within systematics.Comment: Accepted by MNRA

Study of the GeV to TeV morphology of the γ Cygni SNR (G 78.2+2.1) with MAGIC and Fermi-LAT: Evidence for cosmic ray escape

Context. Diffusive shock acceleration (DSA) is the most promising mechanism that accelerates Galactic cosmic rays (CRs) in the shocks of supernova remnants (SNRs). It is based on particles scattering caused by turbulence ahead and behind the shock. The turbulence upstream is supposedly generated by the CRs, but this process is not well understood. The dominant mechanism may depend on the evolutionary state of the shock and can be studied via the CRs escaping upstream into the interstellar medium (ISM). Aims. Previous observations of the γ Cygni SNR showed a difference in morphology between GeV and TeV energies. Since this SNR has the right age and is at the evolutionary stage for a significant fraction of CRs to escape, our aim is to understand γ-ray emission in the vicinity of the γ Cygni SNR. Methods. We observed the region of the γ Cygni SNR with the MAGIC Imaging Atmospheric Cherenkov telescopes between 2015 May and 2017 September recording 87 h of good-quality data. Additionally, we analysed Fermi-LAT data to study the energy dependence of the morphology as well as the energy spectrum in the GeV to TeV range. The energy spectra and morphology were compared against theoretical predictions, which include a detailed derivation of the CR escape process and their γ-ray generation. Results. The MAGIC and Fermi-LAT data allowed us to identify three emission regions that can be associated with the SNR and that dominate at different energies. Our hadronic emission model accounts well for the morphology and energy spectrum of all source components. It constrains the time-dependence of the maximum energy of the CRs at the shock, the time-dependence of the level of turbulence, and the diffusion coefficient immediately outside the SNR shock. While in agreement with the standard picture of DSA, the time-dependence of the maximum energy was found to be steeper than predicted, and the level of turbulence was found to change over the lifetime of the SNR. © 2023 EDP Sciences. All rights reserved

Monitoring of the radio galaxy M87 during a low emission state from 2012 to 2015 with MAGIC

M87 is one of the closest (z=0.00436) extragalactic sources emitting at very-high-energies (VHE, E > 100 GeV). The aim of this work is to locate the region of the VHE gamma-ray emission and to describe the observed broadband spectral energy distribution (SED) during the low VHE gamma-ray state. The data from M87 collected between 2012 and 2015 as part of a MAGIC monitoring programme are analysed and combined with multi-wavelength data from Fermi-LAT, Chandra, HST, EVN, VLBA and the Liverpool Telescope. The averaged VHE gamma-ray spectrum can be fitted from 100GeV to 10TeV with a simple power law with a photon index of (-2.41 $\pm$ 0.07), while the integral flux above 300GeV is $(1.44 \pm 0.13) \times 10^{-12} cm^{-2} s^{-1}$. During the campaign between 2012 and 2015, M87 is generally found in a low emission state at all observed wavelengths. The VHE gamma-ray flux from the present 2012-2015 M87 campaign is consistent with a constant flux with some hint of variability ($\sim3\sigma$) on a daily timescale in 2013. The low-state gamma-ray emission likely originates from the same region as the flare-state emission. Given the broadband SED, both a leptonic synchrotron self Compton and a hybrid photo-hadronic 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

First detection of VHE gamma-ray emission from TXS 1515-273, study of its X-ray variability and spectral energy distribution

We report here on the first multi-wavelength (MWL) campaign on the blazar TXS 1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma rays (VHE). Up until now, this blazar had not been the subject of any detailed MWL observations. It has a rather hard photon index at GeV energies and was considered a candidate extreme high-synchrotronpeaked source. MAGIC observations resulted in the first-time detection of the source in VHE with a statistical significance of 7.6$\sigma$. The average integral VHE flux of the source is 6 $\pm$ 1% of the Crab nebula flux above 400 GeV. X-ray coverage was provided by Swift-XRT, XMMNewton, and NuSTAR. The long continuous X-ray observations were separated by $\sim$ 9 h, both showing clear hour scale flares. In the XMM-Newton data, both the rise and decay timescales are longer in the soft X-ray than in the hard X-ray band, indicating the presence of a particle cooling regime. The X-ray variability timescales were used to constrain the size of the emission region and the strength of the magnetic field. The data allowed us to determine the synchrotron peak frequency and classify the source as a flaring high, but not extreme, synchrotron peaked object. Considering the constraints and variability patterns from the X-ray data, we model the broad-band spectral energy distribution. We applied a simple one-zone model, which could not reproduce the radio emission and the shape of the optical emission, and a two-component leptonic model with two interacting components, enabling us to reproduce the emission from radio to VHE band

Multiwavelength Observations of the Blazar VER J0521+211 during an Elevated TeV Gamma-Ray State

We report on a long-lasting, elevated gamma-ray flux state from VER J0521+211 observed by VERITAS, MAGIC, and Fermi-LAT in 2013 and 2014. The peak integral flux above 200 GeV measured with the nightly binned light curve is (8.8 ± 0.4) × 10-7 photons m-2 s-1, or ∼37% of the Crab Nebula flux. Multiwavelength observations from X-ray, UV, and optical instruments are also presented. A moderate correlation between the X-ray and TeV gamma-ray fluxes was observed, and the X-ray spectrum appeared harder when the flux was higher. Using the gamma-ray spectrum and four models of the extragalactic background light (EBL), a conservative 95% confidence upper limit on the redshift of the source was found to be z ≤ 0.31. Unlike the gamma-ray and X-ray bands, the optical flux did not increase significantly during the studied period compared to the archival low-state flux. The spectral variability from optical to X-ray bands suggests that the synchrotron peak of the spectral energy distribution (SED) may become broader during flaring states, which can be adequately described with a one-zone synchrotron self-Compton model varying the high-energy end of the underlying particle spectrum. The synchrotron peak frequency of the SED and the radio morphology of the jet from the MOJAVE program are consistent with the source being an intermediate-frequency-peaked BL Lac object