Infection by the human immunodeficiency virus (HIV) either upregulates or downregulates the expression of several cytokines and interferons (IFNs) that use the Janus kinase/signal transducer and ...activator of transcription (JAK/STAT) pathway for signal transduction. However, very little is known on the state of activation of the JAK/STAT pathway after HIV infection either in vivo or in vitro. In this regard, we report here that a constitutive activation of a C-terminal truncated STAT5 (STAT5▵) and of STAT1α occurs in the majority (∼75%) of individuals with progressive HIV disease. We have further demonstrated that, among peripheral blood mononuclear cells (PBMCs), STAT5▵ is activated preferentially in CD4+ T cells. In contrast to a published report, expression of STATs from PBMCs of infected individuals was comparable with that of seronegative donors. In addition, in vitro infection of mitogen-activated PBMCs with a panel of laboratory-adapted and primary HIV strains characterized by differential usage of chemokine coreceptors did not affect STAT protein levels. However, enhanced activation of STAT was observed after in vitro infection of resting PBMCs and nonadherent PBMCs by different viral strains. Thus, constitutive STAT activation in CD4+T lymphocytes represents a novel finding of interest also as a potential new marker of immunological reconstitution of HIV-infected individuals.
MAGIC detection of GRB 201216C at z = 1.1 Acciari, V A; Agudo, I; Aniello, T ...
Monthly notices of the Royal Astronomical Society,
01/2024, Letnik:
527, Številka:
3
Journal Article
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ABSTRACT
Gamma-ray bursts (GRBs) are explosive transient events occurring at cosmological distances, releasing a large amount of energy as electromagnetic radiation over several energy bands. We ...report the detection of the long GRB 201216C by the MAGIC telescopes. The source is located at z = 1.1 and thus it is the farthest one detected at very high energies. The emission above 70 GeV of GRB 201216C is modelled together with multiwavelength data within a synchrotron and synchrotron self-Compton (SSC) scenario. We find that SSC can explain the broad-band data well from the optical to the very-high-energy band. For the late-time radio data, a different component is needed to account for the observed emission. Differently from previous GRBs detected in the very-high-energy range, the model for GRB 201216C strongly favours a wind-like medium. The model parameters have values similar to those found in past studies of the afterglows of GRBs detected up to GeV energies.
Aims. The BL Lac 1ES 2344+514 is known for temporary extreme properties characterised by a shift of the synchrotron spectral energy distribution (SED) peak energy ν synch, p above 1 keV. While those ...extreme states have only been observed during high flux levels thus far, additional multi-year observing campaigns are required to achieve a coherent picture. Here, we report the longest investigation of the source from radio to very high energy (VHE) performed so far, focussing on a systematic characterisation of the intermittent extreme states. Methods. We organised a monitoring campaign covering a 3-year period from 2019 to 2021. More than ten instruments participated in the observations in order to cover the emission from radio to VHE. In particular, sensitive X-ray measurements by XMM-Newton , NuSTAR , and AstroSat took place simultaneously with multi-hour MAGIC observations, providing an unprecedented constraint of the two SED components for this blazar. Results. While our results confirm that 1ES 2344+514 typically exhibits ν synch, p > 1 keV during elevated flux periods, we also find periods where the extreme state coincides with low flux activity. A strong spectral variability thus happens in the quiescent state, and is likely caused by an increase in the electron acceleration efficiency without a change in the electron injection luminosity. On the other hand, we also report a strong X-ray flare (among the brightest for 1ES 2344+514) without a significant shift of ν synch, p . During this particular flare, the X-ray spectrum is among the softest of the campaign. It unveils complexity in the spectral evolution, where the common harder-when-brighter trend observed in BL Lacs is violated. By combining Swift -XRT and Swift -UVOT measurements during a low and hard X-ray state, we find an excess of the UV flux with respect to an extrapolation of the X-ray spectrum to lower energies. This UV excess implies that at least two regions significantly contribute to the infrared/optical/ultraviolet/X-ray emission. Using the simultaneous MAGIC, XMM-Newton , NuSTAR , and AstroSat observations, we argue that a region possibly associated with the 10 GHz radio core may explain such an excess. Finally, we investigate a VHE flare, showing an absence of simultaneous variability in the 0.3−2 keV band. Using time-dependent leptonic modelling, we show that this behaviour, in contradiction to single-zone scenarios, can instead be explained by a two-component model.
ABSTRACT
In recent years, a new generation of optical intensity interferometers has emerged, leveraging the existing infrastructure of Imaging Atmospheric Cherenkov Telescopes (IACTs). The MAGIC ...telescopes host the MAGIC-SII system (Stellar Intensity Interferometer), implemented to investigate the feasibility and potential of this technique on IACTs. After the first successful measurements in 2019, the system was upgraded and now features a real-time, dead-time-free, 4-channel, GPU-based correlator. These hardware modifications allow seamless transitions between MAGIC’s standard very-high-energy gamma-ray observations and optical interferometry measurements within seconds. We establish the feasibility and potential of employing IACTs as competitive optical Intensity Interferometers with minimal hardware adjustments. The measurement of a total of 22 stellar diameters are reported, 9 corresponding to reference stars with previous comparable measurements, and 13 with no prior measurements. A prospective implementation involving telescopes from the forthcoming Cherenkov Telescope Array Observatory’s Northern hemisphere array, such as the first prototype of its Large-Sized Telescopes, LST-1, is technically viable. This integration would significantly enhance the sensitivity of the current system and broaden the UV-plane coverage. This advancement would enable the system to achieve competitive sensitivity with the current generation of long-baseline optical interferometers over blue wavelengths.
Aims. We have performed the first broadband study of Mrk 421 from radio to TeV gamma rays with simultaneous measurements of the X-ray polarization from IXPE. Methods. The data were collected as part ...of an extensive multiwavelength campaign carried out between May and June 2022 using MAGIC, Fermi -LAT, NuSTAR , XMM-Newton , Swift , and several optical and radio telescopes to complement IXPE data. Results. During the IXPE exposures, the measured 0.2–1 TeV flux was close to the quiescent state and ranged from 25% to 50% of the Crab Nebula without intra-night variability. Throughout the campaign, the very high-energy (VHE) and X-ray emission are positively correlated at a 4 σ significance level. The IXPE measurements reveal an X-ray polarization degree that is a factor of 2–5 higher than in the optical/radio bands; that implies an energy-stratified jet in which the VHE photons are emitted co-spatially with the X-rays, in the vicinity of a shock front. The June 2022 observations exhibit a rotation of the X-ray polarization angle. Despite no simultaneous VHE coverage being available during a large fraction of the swing, the Swift -XRT monitoring reveals an X-ray flux increase with a clear spectral hardening. This suggests that flares in high synchrotron peaked blazars can be accompanied by a polarization angle rotation, as observed in some flat spectrum radio quasars. Finally, during the polarization angle rotation, NuSTAR data reveal two contiguous spectral hysteresis loops in opposite directions (clockwise and counterclockwise), implying important changes in the particle acceleration efficiency on approximately hour timescales.
We present a novel approach to the determination of the pointing of Imaging Atmospheric Cherenkov Telescopes (IACTs) using the trajectories of the stars in their camera’s field of view. The method ...starts with the reconstruction of the star positions from the Cherenkov camera data, taking into account the point spread function of the telescope, to achieve a satisfying reconstruction accuracy of the pointing position. A simultaneous fit of all reconstructed star trajectories is then performed with the orthogonal distance regression (ODR) method. ODR allows us to correctly include the star position uncertainties and use the time as an independent variable. Having the time as an independent variable in the fit makes it better suitable for various star trajectories. This method can be applied to any IACT and requires neither specific hardware nor interface or special data-taking mode. In this paper, we use the Large-Sized Telescope (LST) data to validate it as a useful tool to improve the determination of the pointing direction during regular data taking. The simulation studies show that the accuracy and precision of the method are comparable with the design requirements on the pointing accuracy of the LST (≤14″). With the typical LST event acquisition rate of 10 kHz, the method can achieve up to 50 Hz pointing monitoring rate, compared to ??(1) Hz achievable with standard techniques. The application of the method to the LST prototype (LST-1) commissioning data shows the stable pointing performance of the telescope.
IFN-gamma induces transcription of several IFN-stimulated genes (ISGs). Recently, the IFN-gamma-dependent Janus kinase (JAK)/STAT pathway has been shown to mediate the activation of some ISGs, by the ...sequential phosphorylation of two JAK kinases (JAK1 and JAK2) and of STAT1. Given that the JAK/STAT is the major, but not the only pathway linked to the IFN-gammaR, aim of our work was to investigate the signal-transduction pathway(s) by which IFN-gamma exerts its effects on acute replication of HIV in monocytic cells. To this end, we utilized clones previously derived from the U937 promonocytic cell line, differing for their efficient (plus clones) or inefficient (minus clones) abilities of supporting HIV replication. Unlike IFN-alpha, IFN-gamma did not inhibit HIV replication in plus clones, whereas virus production in minus cells was efficiently inhibited by both types of IFN. Plus clones generated a JAK/STAT signal-transduction pathway in response to IFN-alpha, but not IFN-gamma. In contrast, minus clones responded to either cytokines. The functional defect of plus clones in response to IFN-gamma was correlated to a selective defect of IFN-gammaR2, but not IFN-gammaR1, membrane expression. Surprisingly enough, IFN-gamma stimulation of plus clones induced IFN-stimulated gene factor 3 (ISGF3gamma). These results strongly support the hypothesis that the JAK/STAT pathway is responsible for the antiretroviral effect of IFN-gamma, and further provide evidence for a potential second pathway triggered by IFN-gamma in the absence of IFN-gammaR2 chain cell surface expression and involving ISGF3gamma.
Leader binding protein-1 (LBP-1)/late SV40 factor (LSF) and ying yang-1 (YY1) transcription factors are involved in the regulation of HIV expression. In particular, YY1 and LBP-1 have been shown to ...cooperate in repressing HIV-1-long terminal repeat reporter gene expression by in vitro cotransfection experiments. However, no information is available on the levels of expression and activation of these transcription factors in PBMC of HIV-infected individuals. Therefore, we have evaluated the expression and DNA binding activity of YY1 and LBP-1 (LSF) in PBMC of HIV-infected individuals before, during, and after administration of IL-2 in association with antiretroviral therapy (ART), a regimen under consideration for broad clinical use in this disease based on its ability to stably raise the absolute number of circulating CD4+ T lymphocytes. Both YY1- and LBP-1 (LSF)-DNA binding were profoundly down-modulated during administration of IL-2/ART, and a proteolytic activity probably responsible for the reduced expression of the two cellular transcription factors was found activated in PBMC of individuals receiving the immunotherapeutic regimen. This study is the first evidence of modulation of cellular transcription factors following IL-2/ART administration and provides a potential correlate of the transient raises in plasma viremia early reported in patients receiving IL-2 in the absence of ART, thus underscoring the importance of always administering this cytokine to HIV-infected individuals together with potent antiretrovirals.
The susceptibility of HIV-1 to chemokine-mediated inhibition may be lost as a consequence of the expanded usage of chemokine co-receptors frequently occurring in clade B isolates obtained from ...individuals with advanced disease. Since chemokine-based immune intervention is under intense investigation, it is crucial to determine its potential effect on primary dualtropic HIV isolates characterized by simultaneous utilization of CCR5 and CXCR4 chemokine co-receptors (R5X4 viruses). In the present study, the CCR5 binding chemokine regulated upon activation normal T cell expressed and secreted (RANTES) strongly inhibited the replication of two of eight primary R5X4 viruses in mitogen-activated primary peripheral blood mononuclear cells (PBMC). The CXCR4 antagonist AMD3100 efficiently suppressed the replication of other two HIV isolates, whereas the remaining four viruses were partially inhibited by treatment with either RANTES or AMD3100. The potency of chemokine-mediated inhibition was influenced by PBMC donor variability, but it was usually independent from the levels of expression of CCR5 or CXCR4. Dual co-receptor usage was maintained by the viruses after two serial passages on U87.CD4 astrocytic cell lines expressing exclusively either CCR5 or CXCR4. The gp120 env variable domains were sequenced before and after passages on U87.CD4 cells. Virus replication into U87.CD4-CXCR4 cells did not result in changes in the V3 region but perturbed the dominant env V4 sequence. Interestingly, double passage onto U87.CD4-CXCR4 cells determined the loss of susceptibility to RANTES inhibition. In conclusion, interference with CCR5 may efficiently inhibit the replication of at least some dualtropic HIV-1 strains, whereas forced CXCR4 usage may result in viral escape from CCR5-dependent inhibitory effects.
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