First detection of a VHE gamma-ray spectral maximum from a Cosmic source: H.E.S.S. discovery of the Vela X nebula

The Vela supernova remnant (SNR) is a complex region containing a number of sources of non-thermal radiation. The inner section of this SNR, within 2 degrees of the pulsar PSR B0833-45, has been observed by the H.E.S.S. gamma-ray atmospheric Cherenkov detector in 2004 and 2005. A strong signal is seen from an extended region to the south of the pulsar, within an integration region of radius 0.8 deg. around the position (RA = 08h 35m 00s, dec = -45 deg. 36' J2000.0). The excess coincides with a region of hard X-ray emission seen by the ROSAT and ASCA satellites. The observed energy spectrum of the source between 550 GeV and 65 TeV is well fit by a power law function with photon index = 1.45 +/- 0.09(stat) +/- 0.2(sys) and an exponential cutoff at an energy of 13.8 +/- 2.3(stat) +/- 4.1(sys) TeV. The integral flux above 1 TeV is (1.28 +/- 0.17 (stat) +/- 0.38(sys)) x 10^{-11} cm^{-2} s^{-1}. This result is the first clear measurement of a peak in the spectral energy distribution from a VHE gamma-ray source, likely related to inverse Compton emission. A fit of an Inverse Compton model to the H.E.S.S. spectral energy distribution gives a total energy in non-thermal electrons of ~2 x 10^{45} erg between 5 TeV and 100 TeV, assuming a distance of 290 parsec to the pulsar. The best fit electron power law index is 2.0, with a spectral break at 67 TeV.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and Astrophysics letter

Observations of Mkn 421 in 2004 with H.E.S.S. at large zenith angles

Mkn 421 was observed during a high flux state for nine nights in April and May 2004 with the fully operational High Energy Stereoscopic System (H.E.S.S.) in Namibia. The observations were carried out at zenith angles of 60$^\circ$--65$^\circ$, which result in an average energy threshold of 1.5 TeV and a collection area reaching 2~km$^2$ at 10~TeV. Roughly 7000 photons from Mkn~421 were accumulated with an average gamma-ray rate of 8 photons/min. The overall significance of the detection exceeds 100 standard deviations. The light-curve of integrated fluxes above 2~TeV shows changes of the diurnal flux up to a factor of 4.3. For nights of high flux, intra-night variability is detected with a decay time of less than 1 hour. The time averaged energy spectrum is curved and is well described by a power-law with a photon index \egamm and an exponential cutoff at \ecut~TeV and an average integral flux above 2~TeV of 3 Crab flux units. Significant variations of the spectral shape are detected with a spectral hardening as the flux increases. Contemporaneous multi-wavelength observations at lower energies (X-rays and gamma-rays above $\approx 300$~GeV) indicate smaller relative variability amplitudes than seen above 2~TeV during high flux state observed in April 2004.Comment: 5 pages, 4 figures, published in A&

Very high energy gamma rays from the direction of Sagittarius A*.

We report the detection of a point-like source of very high energy (VHE) -rays coincident within 1' of Sgr A *, obtained with the HESS array of Cherenkov telescopes. The -rays exhibit a power-law energy spectrum with a spectral index of and a flux above the 165 GeV threshold of m -2 s -1. The measured flux and spectrum differ substantially from recent results reported in particular by the CANGAROO collaboration

Discovery of the Binary Pulsar PSR B1259-63 in Very-High-Energy Gamma Rays around Periastron with H.E.S.S

We report the discovery of very-high-energy (VHE) gamma-ray emission of the binary system PSR B1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the H.E.S.S. experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a gamma-ray signal from the binary system was detected with a total significance above 13 sigma. The flux was found to vary significantly on timescales of days which makes PSR B1259-63 the first variable galactic source of VHE gamma-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F_0(E/1 TeV)^-Gamma with a photon index Gamma = 2.7+-0.2_stat+-0.2_sys and flux normalisation F_0 = (1.3+-0.1_stat+-0.3_sys) 10^-12 TeV^-1 cm^-2 s^-1. This detection of VHE gamma-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE gamma-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.Comment: 10 pages, 8 figures, accepted in Astronomy and Astrophysics on 2 June 2005, replace: document unchanged, replaced author field in astro-ph entry - authors are all members of the H.E.S.S. collaboration and three additional authors (99+3, see document

A possible association of the new VHE gamma-ray source HESS J1825--137 with the pulsar wind nebula G18.0--0.7

We report on a possible association of the recently discovered very high-energy $\gamma$-ray source HESS J1825--137 with the pulsar wind nebula (commonly referred to as G 18.0--0.7) of the $2.1\times 10^{4}$ year old Vela-like pulsar PSR B1823--13. HESS J1825--137 was detected with a significance of 8.1 $\sigma$ in the Galactic Plane survey conducted with the H.E.S.S. instrument in 2004. The centroid position of HESS J1825--137 is offset by 11\arcmin south of the pulsar position. \emph{XMM-Newton} observations have revealed X-ray synchrotron emission of an asymmetric pulsar wind nebula extending to the south of the pulsar. We argue that the observed morphology and TeV spectral index suggest that HESS J1825--137 and G 18.0--0.7 may be associated: the lifetime of TeV emitting electrons is expected to be longer compared to the {\it XMM-Newton} X-ray emitting electrons, resulting in electrons from earlier epochs (when the spin-down power was larger) contributing to the present TeV flux. These electrons are expected to be synchrotron cooled, which explains the observed photon index of $\sim 2.4$, and the longer lifetime of TeV emitting electrons naturally explains why the TeV nebula is larger than the X-ray size. Finally, supernova remnant expansion into an inhomogeneous medium is expected to create reverse shocks interacting at different times with the pulsar wind nebula, resulting in the offset X-ray and TeV $\gamma$-ray morphology.Comment: 5 pages, 3 figures, to appear in Astronomy and Astrophysics Letter

3.9 day orbital modulation in the TeV gamma-ray flux and spectrum from the X-ray binary LS 5039

New observations of LS 5039, a High Mass X-ray Binary comprising a massive star and compact object, were carried out with the High Energy Stereoscopic System of Cherenkov Telescopes (H.E.S.S.) in 2005 at very high energy (VHE) gamma-ray energies. These observations reveal that its flux and energy spectrum are modulated with the 3.9 day orbital period of the binary system. This is the first time in gamma-ray astronomy that orbital modulation has been observed, and periodicity clearly established using ground-based gamma-ray detectors. The VHE gamma-ray emission is largely confined to half of the orbit, peaking around the inferior conjunction epoch of the compact object. For this epoch, there is also a hardening of the energy spectrum in the energy range between 0.2 TeV and a few TeV. The flux vs. orbital phase profile provides the first clear indication of gamma-ray absorption via pair production within an astrophysical source, a process which is expected to occur if the gamma-ray production site is situated within ~1 AU of the compact object. Moreover the production region size must be not significantly greater than the binary separation (~0.15 AU). Notably, these constraints are also considerably smaller than the collimated outflows or jets (extending out to ~1000 AU) observed in LS 5039. The spectral hardening could arise from variations with phase in the maximum electron energies, and/or the dominant VHE gamma-ray production mechanism.Comment: 8 pages, 8 figures, accepted for publication in Astronomy & Astrophysic

Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer : final results of a randomised phase 2 clinical trial

The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). Vx-001 could induce specific CD8 immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. Clinical trial registration: NCT0193515

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD

Background: Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.              Methods: Adult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD. Results: Compared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases (Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC. Conclusions: This study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level

Fasting and High-Fat Diet Alter Histone Deacetylase Expression in the Medial Hypothalamus

Increasing attention is now being given to the epigenetic regulation of animal and human behaviors including the stress response and drug addiction. Epigenetic factors also influence feeding behavior and metabolic phenotypes, such as obesity and insulin sensitivity. In response to fasting and high-fat diets, the medial hypothalamus changes the expression of neuropeptides regulating feeding, metabolism, and reproductive behaviors. Histone deacetylases (HDACs) are involved in the epigenetic control of gene expression and alter behavior in response to a variety of environmental factors. Here, we examined the expression of HDAC family members in the medial hypothalamus of mice in response to either fasting or a high-fat diet. In response to fasting, HDAC3 and −4 expression levels increased while HDAC10 and −11 levels decreased. Four weeks on a high-fat diet resulted in the increased expression of HDAC5 and −8. Moreover, fasting decreased the number of acetylated histone H3- and acetylated histone H4-positive cells in the ventrolateral subdivision of the ventromedial hypothalamus. Therefore, HDACs may be implicated in altered gene expression profiles in the medial hypothalamus under different metabolic states