Integrase strand-transfer inhibitors for treatment of early HIV infection : A case series

This study evaluated whether the interval from the first clinic visit until the start of antiretroviral treatment (ART) was correlated with common parameters of immunological recovery among patients with early HIV infection (EHI).We reviewed the medical records of patients with EHI who started ART using integrase strand-transfer inhibitors (ISTIs) within the first 6 months after diagnosis. Simple linear regression analyses were performed to determine whether the interval from the first visit to the start of ART was correlated with 1-year changes in CD4+ cell count, CD8+ cell count, CD4+ percentage, and CD4+/CD8+ ratio.Fifty-three patients with probable or definite EHI started ART using ISTIs between April 2014 and August 2016. Forty-nine patients completed 1 year of follow-up, including 48 men. The routes of HIV transmission were 1 case of needle sharing, 5 cases of heterosexual activity, and 43 cases of men who had sex with men. None of the immunological recovery parameters were correlated with time to the start of ART (CD4+ cell count: R = .12, P = .42; CD8+ cell count: R = .107, P = .5; CD4+ percentage: R = .14, P = .34; CD4+/CD8+ ratio: R = .23, P = .14). Furthermore, subgroup sensitivity analyses failed to detect significant correlations based on definite or probable diagnoses, treatment using elvitegravir or dolutegravir, or the time from HIV diagnosis to ART initiation.This series of EHI cases indicate that using ART with ISTI-based regimens is efficacious and well-tolerated. However, earlier initiation of treatment was not significantly correlated with common parameters of immunological recovery

Upper atmospheres and ionospheres of planets and satellites

The upper atmospheres of the planets and their satellites are more directly exposed to sunlight and solar wind particles than the surface or the deeper atmospheric layers. At the altitudes where the associated energy is deposited, the atmospheres may become ionized and are referred to as ionospheres. The details of the photon and particle interactions with the upper atmosphere depend strongly on whether the object has anintrinsic magnetic field that may channel the precipitating particles into the atmosphere or drive the atmospheric gas out to space. Important implications of these interactions include atmospheric loss over diverse timescales, photochemistry and the formation of aerosols, which affect the evolution, composition and remote sensing of the planets (satellites). The upper atmosphere connects the planet (satellite) bulk composition to the near-planet (-satellite) environment. Understanding the relevant physics and chemistry provides insight to the past and future conditions of these objects, which is critical for understanding their evolution. This chapter introduces the basic concepts of upper atmospheres and ionospheres in our solar system, and discusses aspects of their neutral and ion composition, wind dynamics and energy budget. This knowledge is key to putting in context the observations of upper atmospheres and haze on exoplanets, and to devise a theory that explains exoplanet demographics.Comment: Invited Revie

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.. The Spanish Ministry of Economy and Competitiveness supported EF-S and VG (BFU2016–78265-P), PA (BFU2016– 79313-P and MDM-2016–0687), and AM-V (BFU2015–64408-P). AM-V was also supported by the Instituto de Salud Carlos III (PI11/ 00072) and RPV-M (CPII16/00004, PI14/00949 and PI17/00011). All projects were cofinanced by the Fondo Social Europeo (FEDER). AM-V is a member of the GENIE and EU-ROS Cost Actions of the European Union and RPV-M is a Marie Curie Fellow (CIG322034, EU)

Measurement of the Crab Nebula spectrum over three decades in energy with the MAGIC telescopes

The MAGIC stereoscopic system collected 69 hours of Crab Nebula data between October 2009 and April 2011. Analysis of this data sample using the latest improvements in the MAGIC stereoscopic software provided an unprecedented precision of spectral and night-by-night light curve determination at gamma rays. We derived a differential spectrum with a single instrument from 50 GeV up to almost 30 TeV with 5 bins per energy decade. At low energies, MAGIC results, combined with Fermi-LAT data, show a flat and broad Inverse Compton peak. The overall fit to the data between 1 GeV and 30 TeV is not well described by a log-parabola function. We find that a modified log-parabola function with an exponent of 2.5 instead of 2 provides a good description of the data ($\chi^2=35/26$). Using systematic uncertainties of red the MAGIC and Fermi-LAT measurements we determine the position of the Inverse Compton peak to be at (53 $\pm$ 3stat + 31syst -13syst) GeV, which is the most precise estimation up to date and is dominated by the systematic effects. There is no hint of the integral flux variability on daily scales at energies above 300 GeV when systematic uncertainties are included in the flux measurement. We consider three state- of-the-art theoretical models to describe the overall spectral energy distribution of the Crab Nebula. The constant B-field model cannot satisfactorily reproduce the VHE spectral measurements presented in this work, having particular difficulty reproducing the broadness of the observed IC peak. Most probably this implies that the assumption of the homogeneity of the magnetic field inside the nebula is incorrect. On the other hand, the time-dependent 1D spectral model provides a good fit of the new VHE results when considering a 80 {\mu}G magnetic field. However, it fails to match the data when including the morphology of the nebula at lower wavelengths.Comment: accepted by JHEAp, 9 pages, 6 figure

Limits to dark matter annihilation cross-section from a combined analysis of MAGIC and Fermi-LAT observations of dwarf satellite galaxies

We present the first joint analysis of gamma-ray data from the MAGIC Cherenkov telescopes and the Fermi Large Area Telescope (LAT) to search for gamma-ray signals from dark matter annihilation in dwarf satellite galaxies. We combine 158 hours of Segue 1 observations with MAGIC with 6-year observations of 15 dwarf satellite galaxies by the Fermi-LAT. We obtain limits on the annihilation cross-section for dark matter particle masses between 10 GeV and 100 TeV - the widest mass range ever explored by a single gamma-ray analysis. These limits improve on previously published Fermi-LAT and MAGIC results by up to a factor of two at certain masses. Our new inclusive analysis approach is completely generic and can be used to perform a global, sensitivity-optimized dark matter search by combining data from present and future gamma-ray and neutrino detectors.Comment: 19 pages, 3 figures. V2: Few typos corrected and references added. Matches published version JCAP 02 (2016) 03

MAGIC observations of MWC 656, the only known Be/BH system

Context: MWC 656 has recently been established as the first observationally detected high-mass X-ray binary system containing a Be star and a black hole (BH). The system has been associated with a gamma-ray flaring event detected by the AGILE satellite in July 2010. Aims: Our aim is to evaluate if the MWC 656 gamma-ray emission extends to very high energy (VHE > 100 GeV) gamma rays. Methods. We have observed MWC 656 with the MAGIC telescopes for $\sim$23 hours during two observation periods: between May and June 2012 and June 2013. During the last period, observations were performed contemporaneously with X-ray (XMM-Newton) and optical (STELLA) instruments. Results: We have not detected the MWC 656 binary system at TeV energies with the MAGIC Telescopes in either of the two campaigns carried out. Upper limits (ULs) to the integral flux above 300 GeV have been set, as well as differential ULs at a level of $\sim$5% of the Crab Nebula flux. The results obtained from the MAGIC observations do not support persistent emission of very high energy gamma rays from this system at a level of 2.4% the Crab flux.Comment: Accepted for publication in A&A. 5 pages, 2 figures, 2 table

Investigating the peculiar emission from the new VHE gamma-ray source H1722+119

The MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes observed the BL Lac object H1722+119 (redshift unknown) for six consecutive nights between 2013 May 17 and 22, for a total of 12.5 h. The observations were triggered by high activity in the optical band measured by the KVA (Kungliga Vetenskapsakademien) telescope. The source was for the first time detected in the very high energy (VHE, $E > 100$ GeV) $\gamma$-ray band with a statistical significance of 5.9 $\sigma$. The integral flux above 150 GeV is estimated to be $(2.0\pm 0.5)$ per cent of the Crab Nebula flux. We used contemporaneous high energy (HE, 100 MeV $< E < 100$ GeV) $\gamma$-ray observations from Fermi-LAT (Large Area Telescope) to estimate the redshift of the source. Within the framework of the current extragalactic background light models, we estimate the redshift to be $z = 0.34 \pm 0.15$. Additionally, we used contemporaneous X-ray to radio data collected by the instruments on board the Swift satellite, the KVA, and the OVRO (Owens Valley Radio Observatory) telescope to study multifrequency characteristics of the source. We found no significant temporal variability of the flux in the HE and VHE bands. The flux in the optical and radio wavebands, on the other hand, did vary with different patterns. The spectral energy distribution (SED) of H1722+119 shows surprising behaviour in the $\sim 3\times10^{14} - 10^{18}$ Hz frequency range. It can be modelled using an inhomogeneous helical jet synchrotron self-Compton model.Comment: 12 pages, 5 figures, 2 table