Transient Emission From Dissipative Fronts in Magnetized, Relativistic Outflows. II. Synchrotron Flares

The time dependent synchrotron emission from relativistic jets, and the relation between the synchrotron and ERC emission is considered within the framework of the radiative front model. The timescale and profile of the optically thin emission are shown to be determined, in this model, by the shock formation radius, the thickness of expelled fluid slab and the variation of the front's parameters due to its transverse expansion. For a range of reasonable conditions, a variety of flare shapes can be produced, varying from roughly symmetric with exponential rises and decays, as often seen in blazars, to highly asymmetric with a fast rise and a much slower, power law decay, as seen in GRB afterglows. The onset, duration, and fluence of low-frequency (below the initial turnover frequency) and hard gamma-ray (above the initial gamma-spheric energy) outbursts are limited by opacity effects; the emission at these energies is quite generally delayed and, in the case of sufficiently short length outbursts, severely attenuated. The observational consequences are discussed. One distinctive prediction of this model is that in a single, powerful source, the upper cutoff of the gamma-ray spectrum should be correlated with the timescale of the outburst and with the amplitude of variations at long wavelengths (typically radio to millimeter).Comment: AAS LaTex, 14 pgs, accepted to A

Hard X-ray detection of the high redshift quasar 4C 71.07

BATSE/OSSE observations of the high redshift quasar 4C 71.07 indicate that this is the brightest and furthest AGN so far detected above 20 keV. BATSE Earth occultation data have been used to search for emission from 4C 71.07 from nearly 3 years of observation. The mean source flux over the whole period in the BATSE energy range 20-100 keV is (13.2 +/- 1.06) x 10^(-11) erg cm^(-2) s^(-1) corresponding to a luminosity of 2 x 10^(48) erg s^(-1). The BATSE light curve over the 3 years of observations shows several flare-like events, one of which (in January 1996) is associated with an optical flare (R=16.1) but with a delay of 55 days. The OSSE/BATSE spectral analysis indicates that the source is characterized by a flat power spectrum (Gamma about 1.1 - 1.3) when in a low state; this spectral form is consistent within errors with the ASCA and ROSAT spectra. This means that the power law observed from 0.1 to 10 keV extends up to at least 1 MeV but steepens soon after to meet EGRET high energy data. BATSE data taken around the January 1996 flare suggests that the spectrum could be steeper when the source is in a bright state. The nuF-nu representation of the source is typical of a low frequency peaked/gamma-ray dominated blazar, with the synchrotron peak in the mm-FIR band and the Compton peak in the MeV band. The BATSE and OSSE spectral data seem to favour a model in which the high energy flux is due to the sum of the synchrotron self-Compton and the external Compton contributions; this is also supported by the variability behaviour of the source.Comment: 19 pages, LaTeX, plus 4 .ps figures. accepted by Astrophysical Journa

Failure of Fibrotic Liver Regeneration in Mice Is Linked to a Severe Fibrogenic Response Driven by Hepatic Progenitor Cell Activation

Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 ± 355 IU/L compared to 93 ± 65 IU/L in nonfibrotic livers), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis

Rms-flux relation in the optical fast variability data of BL Lacertae object S5 0716+714

The possibility that BL Lac S5 0716+714 exhibits a linear root mean square (rms)-flux relation in its IntraDay Variability (IDV) is analysed. The results may be used as an argument in the existing debate regarding the source of optical IDV in Active Galactic Nuclei. 63 time series in different optical bands were used. A linear rms-flux relation at a confidence level higher than 65% was recovered for less than 8% of the cases. We were able to check if the magnitude is log-normally distributed for eight timeseries and found, with a confidence > 95%, that this is not the case.Comment: Accepted by Astrophysics and Space Scienc

Gamma-loud quasars: a view with BeppoSAX

We present $Beppo$SAX observations of the $\gamma$-ray emitting quasars 0836+710, 1510-089 and 2230+114. All the objects have been detected in the PDS up to 100 keV and have extremely flat power-law spectra above 2 keV ($\alpha _x$=0.3--0.5). 0836+710 shows absorption higher than the galactic value and marginal evidence for the presence of the redshifted 6.4 keV Iron line. 1510-089 shows a spectral break around 1 keV, with the low energy spectrum steeper ($\alpha_l$=1.6) than the high energy power-law ($\alpha_h$=0.3). The data are discussed in the light of current Inverse Compton models for the high energy emission.Comment: 4 pages, 2 figures, to appear in the proceedings of the conference "X-Ray Astronomy '99", Bologna, Italy, September 199

Loss of Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter-dependency between Akt-1 and heme oxygenase-1

Aims - Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-ß (TGF-ß) signalling, which is known to be elevated in preeclampsia. Methods and results - Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Aktdn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Aktmyr) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Aktmyr to mice significantly reduced circulating sEng, whereas Aktdn promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Aktmyr failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng. Conclusion - The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction

Heme oxygenase-1 and carbon monoxide in pulmonary medicine

Heme oxygenase-1 (HO-1), an inducible stress protein, confers cytoprotection against oxidative stress in vitro and in vivo. In addition to its physiological role in heme degradation, HO-1 may influence a number of cellular processes, including growth, inflammation, and apoptosis. By virtue of anti-inflammatory effects, HO-1 limits tissue damage in response to proinflammatory stimuli and prevents allograft rejection after transplantation. The transcriptional upregulation of HO-1 responds to many agents, such as hypoxia, bacterial lipopolysaccharide, and reactive oxygen/nitrogen species. HO-1 and its constitutively expressed isozyme, heme oxygenase-2, catalyze the rate-limiting step in the conversion of heme to its metabolites, bilirubin IXα, ferrous iron, and carbon monoxide (CO). The mechanisms by which HO-1 provides protection most likely involve its enzymatic reaction products. Remarkably, administration of CO at low concentrations can substitute for HO-1 with respect to anti-inflammatory and anti-apoptotic effects, suggesting a role for CO as a key mediator of HO-1 function. Chronic, low-level, exogenous exposure to CO from cigarette smoking contributes to the importance of CO in pulmonary medicine. The implications of the HO-1/CO system in pulmonary diseases will be discussed in this review, with an emphasis on inflammatory states

Relativistic jet motion in the core of the radio-loud quasar J1101+7225

Multi-epoch GHz Very Long Baseline Interferometry (VLBI) data of the radio-loud quasar J1101+7225 were analyzed to estimate the proper motion of extended optically thin jet components. Two components separated from the core could be mapped at 1.66 GHz, which is consistent with earlier observations. In one case we found evidence of high apparent superluminal motion (beta_app= 22.5+/-4) at large (deprojected) distances to the core (22 mas ~ 4 kpc at z= 1.46). Typically in other quasars such high separation velocities are only found much closer to the core component. Furthermore the Doppler factor, the magnetic field strength, and the angular size of the optically thick core were derived using published X-ray data. Analysis of 5 GHz VLBI data reveals the existence of further jet components within the central 5 mas. Additionally the data published so far on the GHz-spectrum were discussed at all angular resolutions. J1101+7225 turns out to be a standard quasar for studying different aspects of radio jet kinematics out to kpc-scales.Comment: 8 pages, 5 figures, accepted by A&

Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

Background: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3-/-) or c-Jun-NH2-terminal kinase-1 (jnk1-/-) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3-/- or jnk1-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GAFF45α. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusion: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. © 2008 Dolinay et al

Apoptosis and the activity of ceramide, Bax and Bcl-2 in the lungs of neonatal rats exposed to limited and prolonged hyperoxia

BACKGROUND: The aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1β and the expression of 2 proto-oncogenes that appear to modulate apoptosis (Bax and Bcl-2). METHODS: Newborn rats were placed in chambers containing room air or oxygen above 90% for 7 days. The rats were sacrificed at 3, 7 or 14 days and their lungs removed. Sections were fixed, subjected to TUNEL, Hoechst, and E-Cadherin Staining. Sections were also incubated with anti-Bcl-2 and anti-Bax antisera. Bcl-2 and Bax were quantitated by immunohistochemistry. Lipids were extracted, and ceramide measured through a modified diacylglycerol kinase assay. RT-PCR was utilized to assess IL-1β expression. RESULTS: TUNEL staining showed significant apoptosis in the hyperoxia-exposed lungs at 3 days only. Co-staining of the apoptotic cells with Hoechst, and E-Cadherin indicated that apoptotic cells were mainly epithelial cells. The expression of Bax and ceramide was significantly higher in the hyperoxia-exposed lungs at 3 and 14 days of age, but not at 7 days. Bcl-2 was significantly elevated in the hyperoxia-exposed lungs at 3 and 14 days. IL-1β expression was significantly increased at 14 days. CONCLUSION: Exposure of neonatal rat lung to hyperoxia results in early apoptosis documented by TUNEL assay. The early rise in Bax and ceramide appears to overcome the anti-apoptotic activity of Bcl-2. Further exposure did not result in late apoptotic changes. This suggests that apoptotic response to hyperoxia is time sensitive. Prolonged hyperoxia results in acute lung injury and the shifting balance of ceramide, Bax and Bcl-2 may be related to the evolution of the inflammatory process