Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes.

Radioiodinated recombinant human interferon-gamma (IFN gamma) bound to human monocytes, U937, and HL60 cells in a specific, saturable, and reversible manner. At 4 degrees C, the different cell types bound 3,000-7,000 molecules of IFN gamma, and binding was of comparable affinity (Ka = 4-12 X 10(8) M-1). No change in the receptor was observed after monocytes differentiated to macrophages or when the cell lines were pharmacologically induced to differentiate. The functional relevance of the receptor was validated by the demonstration that receptor occupancy correlated with induction of Fc receptors on U937. Binding studies using U937 permeabilized with digitonin showed that only 46% of the total receptor pool was expressed at the cell surface. The receptor appears to be a protein, since treatment of U937 with trypsin or pronase reduced 125I-IFN gamma binding by 87 and 95%, respectively. At 37 degrees C, ligand was internalized, since 32% of the cell-associated IFN gamma became resistant to trypsin stripping. Monocytes degraded 125I-IFN gamma into trichloroacetic acid-soluble counts at 37 degrees C but not at 4 degrees C, at an approximate rate of 5,000 molecules/cell per h. The receptor was partially characterized by SDS-polyacrylamide gel electrophoresis analysis of purified U937 membranes that had been incubated with 125I-IFN gamma. After cross-linking, the receptor-ligand complex migrated as a broad band that displayed an Mr of 104,000 +/- 18,000 at the top and 84,000 +/- 6,000 at the bottom. These results thereby define and partially characterize the IFN gamma receptor of human mononuclear phagocytes.

IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice

To determine the effect of aging on IFN-gamma-induced MHC class II antigen expression, we produced bone marrow¿derived macrophages in vitro. In these conditions, we analyzed the effect of aging on the genomic expression of macrophages without the influence of other cell types that may be affected by aging. Although macrophages from young and aged mice showed an identical degree of differentiation, after incubation with IFN-gamma, the expression at the cell surface of the IA complex and the levels of IAbeta protein and mRNA were lower in aged macrophages. Moreover, the transcription of the IAbeta gene was impaired in aged macrophages. The amount of transcription factors that bound to the W and X, but not to the Y, boxes of the IAbeta promoter gene was lower in aged macrophages. Similar levels of CIITA mRNA were found after IFN-gamma treatment of both young and aged macrophages. This shows that neither the initial cascade that starts after the interaction of IFN-gamma with the receptor nor the second signals involved in the expression of CIITA are impaired in aged macrophages. These data indicate that aging is associated with low levels of MHC class II gene induction by IFN-gamma because of impaired transcription.

Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.

Interferon-gamma release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis.

Background: Despite the widespread use of interferon-gamma release assays (IGRAs), their role in diagnosing tuberculosis and targeting preventive therapy in HIV-infected patients remains unclear. We conducted a comprehensive systematic review to contribute to the evidence-based practice in HIV-infected people. Methodology/Principal Findings: We searched MEDLINE, Cochrane, and Biomedicine databases to identify articles published between January 2005 and July 2011 that assessed QuantiFERON H -TB Gold In-Tube (QFT-GIT) and T-SPOT H .TB (T-SPOT.TB) in HIV-infected adults. We assessed their accuracy for the diagnosis of tuberculosis and incident active tuberculosis, and the proportion of indeterminate results. The search identified 38 evaluable studies covering a total of 6514 HIV-infected participants. The pooled sensitivity and specificity for tuberculosis were 61% and 72% for QFT-GIT, and 65% and 70% for T-SPOT.TB. The cumulative incidence of subsequent active tuberculosis was 8.3% for QFT-GIT and 10% for T-SPOT.TB in patients tested positive (one study each), and 0% for QFT-GIT (two studies) and T-SPOT.TB (one study) respectively in those tested negative. Pooled indeterminate rates were 8.2% for QFT-GIT and 5.9% for T-SPOT.TB. Rates were higher in high burden settings (12.0% for QFT-GIT and 7.7% for T-SPOT.TB) than in low-intermediate burden settings (3.9% for QFT-GIT and 4.3% for T-SPOT.TB). They were also higher in patients with CD4 + T-cell count, 200 (11.6% for QFT-GIT and 11.4% for T-SPOT.TB) than in those with CD4 + T-cell count $ 200 (3.1% for QFT-GIT and 7.9% for T-SPOT.TB). Conclusions/Significance: IGRAs have suboptimal accuracy for confirming or ruling out active tuberculosis disease in HIV-infected adults. While their predictive value for incident active tuberculosis is modest, a negative QFT-GIT implies a very low short- to medium-term risk. Identifying the factors associated with indeterminate results will help to optimize the use of IGRAs in clinical practice, particularly in resource-limited countries with a high prevalence of HIV-coinfection.

Planificació del procés de producció en sèrie d'un silenciós d'escapament per a un turisme de gamma mitjana

A partir d'un disseny d'un silenciós, s'estudien tots els processos i la maquinària necessària per a implantar la fabricació en sèrie del producte, i d'aquesta manera es poden donar unes pautes generals per la fàbrica que haurà d'acollir aquest procés.

The star forming region Monoceros R2 as a gamma-ray source

After the release of the gamma-ray source catalog produced by the Fermi satellite during its first two years of operation, a significant fraction of sources still remain unassociated at lower energies. In addition to well-known high-energy emitters (pulsars, blazars, supernova remnants, etc.), theoretical expectations predict new classes of gamma-ray sources. In particular, gamma-ray emission could be associated with some of the early phases of stellar evolution, but this interesting possibility is still poorly understood. Aims: The aim of this paper is to assess the possibility of the Fermi gamma-ray source 2FGL J0607.5-0618c being associated with the massive star forming region Monoceros R2. Methods: A multi-wavelength analysis of the Monoceros R2 region is carried out using archival data at radio, infrared, X-ray, and gamma-ray wavelengths. The resulting observational properties are used to estimate the physical parameters needed to test the different physical scenarios. Results: We confirm the 2FGL J0607.5-0618c detection with improved confidence over the Fermi two-year catalog. We find that a combined effect of the multiple young stellar objects in Monoceros R2 is a viable picture for the nature of the source.

Very-High-Energy gamma rays from a Distant Quasar: How Transparent Is the Universe?

The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.

The changing milliarcsecond radio morphology of the gamma-ray binary LS 5039

LS 5039 is one of the few TeV emitting X-ray binaries detected so far. The powering source of its multiwavelength emission can be accretion in a microquasar scenario or wind interaction in a young nonaccreting pulsar scenario. Aims.To present new high-resolution radio images and compare them with the expected behavior in the different scenarios. Methods.We analyze Very Long Baseline Array (VLBA) radio observations that provide morphological and astrometric information at milliarcsecond scales. Results.We detect a changing morphology between two images obtained five days apart. In both runs there is a core component with a constant flux density, and an elongated emission with a position angle (PA) that changes by 12 $\pm$ $3\degr$ between both runs. The source is nearly symmetric in the first run and asymmetric in the second one. The astrometric results are not conclusive. Conclusions.A simple and shockless microquasar scenario cannot easily explain the observed changes in morphology. An interpretation within the young nonaccreting pulsar scenario requires the inclination of the binary system to be very close to the upper limit imposed by the absence of X-ray eclipses.

Spectral energy distribution of the gamma-ray microquasar LS 5039

The microquasar LS 5039 has recently been detected as a source of very high energy (VHE) $\gamma$-rays. This detection, that confirms the previously proposed association of LS 5039 with the EGRET source 3EG~J1824$-$1514, makes of LS 5039 a special system with observational data covering nearly all the electromagnetic spectrum. In order to reproduce the observed spectrum of LS 5039, from radio to VHE $\gamma$-rays, we have applied a cold matter dominated jet model that takes into account accretion variability, the jet magnetic field, particle acceleration, adiabatic and radiative losses, microscopic energy conservation in the jet, and pair creation and absorption due to the external photon fields, as well as the emission from the first generation of secondaries. The radiative processes taken into account are synchrotron, relativistic Bremsstrahlung and inverse Compton (IC). The model is based on a scenario that has been characterized with recent observational results, concerning the orbital parameters, the orbital variability at X-rays and the nature of the compact object. The computed spectral energy distribution (SED) shows a good agreement with the available observational data.

Hepatocyte nuclear factor-4 alpha regulates the human apolipoprotein AV gene: Identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism.

Gamma-ray emission from microquasars: a numerical model for LSI+61º303

We explore the possible association between the microquasar LSI +61°303 and the EGRET source 2CG 135+01/3EG J0241+6103 by studying, with a detailed numerical model, whether this system can produce the emission and the variability detected by EGRET (>100 MeV) through inverse Compton (IC) scattering. Our numerical approach considers a population of relativistic electrons entrained in a cylindrical inhomogeneous jet, interacting with both the radiation and the magnetic fields, taking into account the Thomson and Klein-Nishina regimes of interaction. Our results reproduce the observed spectral characteristics and variability at γ-rays, thus strengthening the identification of LSI +61°303 as a high-energy γ-ray source.

MAGIC TeV Gamma-Ray Observations of Markarian 421 during Multiwavelength Campaigns in 2006

Wide-range spectral coverage of blazar-type active galactic nuclei is of paramount importance for understanding the particle acceleration mechanisms assumed to take place in their jets. The Major Atmospheric Gamma Imaging Cerenkov (MAGIC) telescope participated in three multiwavelength (MWL) campaigns, observing the blazar Markarian (Mkn) 421 during the nights of April 28 and 29, 2006, and June 14, 2006. Aims. We analyzed the corresponding MAGIC very-high energy observations during 9 nights from April 22 to 30, 2006 and on June 14, 2006. We inferred light curves with sub-day resolution and night-by-night energy spectra. Methods. MAGIC detects γ-rays by observing extended air showers in the atmosphere. The obtained air-shower images were analyzed using the standard MAGIC analysis chain. Results. A strong γ-ray signal was detected from Mkn 421 on all observation nights. The flux (E > 250 GeV) varied on night-by-night basis between (0.92±0.11) × 10-10 cm-2 s-1 (0.57 Crab units) and (3.21±0.15) × 10-10 cm-2 s-1 (2.0 Crab units) in April 2006. There is a clear indication for intra-night variability with a doubling time of 36± min on the night of April 29, 2006, establishing once more rapid flux variability for this object. For all individual nights γ-ray spectra could be inferred, with power-law indices ranging from 1.66 to 2.47. We did not find statistically significant correlations between the spectral index and the flux state for individual nights. During the June 2006 campaign, a flux substantially lower than the one measured by the Whipple 10-m telescope four days later was found. Using a log-parabolic power law fit we deduced for some data sets the location of the spectral peak in the very-high energy regime. Our results confirm the indications of rising peak energy with increasing flux, as expected in leptonic acceleration models.

Discovery of a High-Energy Gamma-Ray-Emitting Persistent Microquasar

Microquasars are stellar x-ray binaries that behave as a scaled down version of extragalactic quasars. The star LS 5039 is a new microquasar system with apparent persistent ejection of relativistic plasma at a 3 kiloparsec distance from the sun. It may also be associated with a gamma-ray source discovered by the Energetic Gamma Ray Experiment Telescope (EGRET) on board the COMPTON-Gamma Ray Observatory satellite. Before the discovery of LS 5039, merely a handful of microquasars had been identified in the Galaxy, and none of them was detected in high-energy gamma-rays.

Gamma-ray emission from massive young stellar objects

Context.Massive stars form in dense and massive molecular cores. The exact formation mechanism is unclear, but it is possible that some massive stars are formed by processes similar to those that produce the low-mass stars, with accretion/ejection phenomena occurring at some point of the evolution of the protostar. This picture seems to be supported by the detection of a collimated stellar wind emanating from the massive protostar IRAS 16547-4247. A triple radio source is associated with the protostar: a compact core and two radio lobes. The emission of the southern lobe is clearly non-thermal. Such emission is interpreted as synchrotron radiation produced by relativistic electrons locally accelerated at the termination point of a thermal jet. Since the ambient medium is determined by the properties of the molecular cloud in which the whole system is embedded, we can expect high densities of particles and infrared photons. Because of the confirmed presence of relativistic electrons, inverse Compton and relativistic Bremsstrahlung interactions are unavoidable. Aims.We aim to make quantitative predictions of the spectral energy distribution of the non-thermal spots generated by massive young stellar objects, with emphasis on the particular case of IRAS 16547-4247. Methods.We study the high-energy emission generated by the relativistic electrons which produce the non-thermal radio source in IRAS 16547-4247. We also study the result of proton acceleration at the terminal shock of the thermal jet and make estimates of the secondary gamma rays and electron-positron pairs produced by pion decay. Results.We present spectral energy distributions for the southern lobe of IRAS 16547-4247, for a variety of conditions. We show that high-energy emission might be detectable from this object in the gamma-ray domain. The source may also be detectable in X-rays through long exposures with current X-ray instruments. Conclusions.Gamma-ray telescopes such as GLAST, and even ground-based Cherenkov arrays of new generation can be used to study non-thermal processes occurring during the formation of massive stars.

A microquasar model applied to unidentified gamma-ray sources

Among unidentified gamma-ray sources in the galactic plane, there are some that present significant variability and have been proposed to be high-mass microquasars. To deepen the study of the possible association between variable low galactic latitude gamma-ray sources and microquasars, we have applied a leptonic jet model based on the microquasar scenario that reproduces the gamma-ray spectrum of three unidentified gamma-ray sources, 3EG J1735-1500, 3EG J1828+0142 and GRO J1411-64, and is consistent with the observational constraints at lower energies. We conclude that if these sources were generated by microquasars, the particle acceleration processes could not be as efficient as in other objects of this type that present harder gamma-ray spectra. Moreover, the dominant mechanism of high-energy emission should be synchrotron self-Compton (SSC) scattering, and the radio jets may only be observed at low frequencies. For each particular case, further predictions of jet physical conditions and variability generation mechanisms have been made in the context of the model. Although there might be other candidates able to explain the emission coming from these sources, microquasars cannot be excluded as counterparts. Observations performed by the next generation of gamma-ray instruments, like GLAST, are required to test the proposed model.