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A search for new supernova remnants (SNRs) has been conducted using TeV gamma-ray data from the H.E.S.S. Galactic plane survey. As an identification criterion, shell morphologies that are characteristic for known resolved TeV SNRs have been used. Three new SNR candidates were identified in the H.E.S.S. data set with this method. Extensive multiwavelength searches for counterparts were conducted. A radio SNR candidate has been identified to be a counterpart to HESS J1534-571. The TeV source is therefore classified as a SNR. For the other two sources, HESS J1614-518 and HESS J1912 + 101, no identifying counterparts have been found, thus they remain SNR candidates for the time being. TeV-emitting SNRs are key objects in the context of identifying the accelerators of Galactic cosmic rays. The TeV emission of the relativistic particles in the new sources is examined in view of possible leptonic and hadronic emission scenarios, taking the current multiwavelength knowledge into account.
Context. Microquasars are potential gamma-ray emitters. Indications of transient episodes of gamma-ray emission were recently reported in at least two systems: Cyg X-1 and Cyg X-3. The identification of additional gamma-ray-emitting microquasars is required to better understand how gamma-ray emission can be produced in these systems. Aims. Theoretical models have predicted very high-energy (VHE) gamma-ray emission from microquasars during periods of transient outburst. Observations reported herein were undertaken with the objective of observing a broadband flaring event in the gamma-ray and X-ray bands. Methods. Contemporaneous observations of three microquasars, GRS 1915+105, Circinus X-1, and V4641 Sgr, were obtained using the High Energy Spectroscopic System (H.E.S.S.) telescope array and the Rossi X-ray Timing Explorer (RXTE) satellite. X-ray analyses for each microquasar were performed and VHE gamma-ray upper limits from contemporaneous H.E.S.S. observations were derived. Results. No significant gamma-ray signal has been detected in any of the three systems. The integral gamma-ray photon flux at the observational epochs is constrained to be I(>560 GeV) < 7.3 x 10(-13) cm(-2) S-1, I(>560 GeV) < 1.2 x 10-(12) cm s(-1), and I(>240 GeV) < 4.5 x 10(-12) cm(-2) s(-1) for GRS 1915+105, Circinus X-1, and V4641 Sgr, respectively. Conclusions. The gamma-ray upper limits obtained using H.E.S.S. are examined in the context of previous Cherenkov telescope observations of microquasars. The effect of intrinsic absorption is modelled for each target and found to have negligible impact on the flux of escaping gamma-rays. When combined with the X-ray behaviour observed using RXTE, the derived results indicate that if detectable VHE gamma-ray emission from microquasars is commonplace, then it is likely to be highly transient.
Galactic cosmic rays reach energies of at least a few petaelectronvolts (of the order of 1015 electronvolts). This implies that our Galaxy contains petaelectronvolt accelerators (‘PeVatrons’), but all proposed models of Galactic cosmic-ray accelerators encounter difficulties at exactly these energies. Dozens of Galactic accelerators capable of accelerating particles to energies of tens of teraelectronvolts (of the order of 1013 electronvolts) were inferred from recent γ-ray observations3. However, none of the currently known accelerators—not even the handful of shell-type supernova remnants commonly believed to supply most Galactic cosmic rays—has shown the characteristic tracers of petaelectronvolt particles, namely, power-law spectra of γ-rays extending without a cut-off or a spectral break to tens of teraelectronvolts4. Here we report deep γ-ray observations with arcminute angular resolution of the region surrounding the Galactic Centre, which show the expected tracer of the presence of petaelectronvolt protons within the central 10 parsecs of the Galaxy. We propose that the supermassive black hole Sagittarius A* is linked to this PeVatron. Sagittarius A* went through active phases in the past, as demonstrated by X-ray outbursts5and an outflow from the Galactic Centre6. Although its current rate of particle acceleration is not sufficient to provide a substantial contribution to Galactic cosmic rays, Sagittarius A* could have plausibly been more active over the last 106–107 years, and therefore should be considered as a viable alternative to supernova remnants as a source of petaelectronvolt Galactic cosmic rays.
Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
The diffuse very high-energy (VHE; > 100 GeV) gamma-ray emission observed in the central 200 pc of the Milky Way by H.E.S.S. was found to follow dense matter distribution in the central molecular zone (CMZ) up to a longitudinal distance of about 130 pc to the Galactic centre (GC), where the flux rapidly decreases. This was initially interpreted as the result of a burst-like injection of energetic particles 104 yr ago, but a recent more sensitive H.E.S.S. analysis revealed that the cosmic-ray (CR) density profile drops with the distance to the centre, making data compatible with a steady cosmic PeVatron at the GC. In this paper, we extend this analysis to obtain, for the first time, a detailed characterisation of the correlation with matter and to search for additional features and individual gamma-ray sources in the inner 200 pc. Taking advantage of 250 h of H.E.S.S. data and improved analysis techniques, we perform a detailed morphology study of the diffuse VHE emission observed from the GC ridge and reconstruct its total spectrum. To test the various contributions to the total gamma-ray emission, we used an iterative 2D maximum-likelihood approach that allows us to build a phenomenological model of the emission by summing a number of different spatial components. We show that the emission correlated with dense matter covers the full CMZ and that its flux is about half the total diffuse emission flux. We also detect some emission at higher latitude that is likely produced by hadronic collisions of CRs in less dense regions of the GC interstellar medium. We detect an additional emission component centred on the GC and extending over about 15 pc that is consistent with the existence of a strong CR density gradient and confirms the presence of a CR accelerator at the very centre of our Galaxy. We show that the spectrum of full ridge diffuse emission is compatible with that previously derived from the central regions, suggesting that a single population of particles fills the entire CMZ. Finally, we report the discovery of a VHE gamma-ray source near the GC radio arc and argue that it is produced by the pulsar wind nebula candidate G0.13-0.11.
Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
Studying the temporal variability of BL Lac objects at the highest energies provides unique insights into the extreme physical processes occurring in relativistic jets and in the vicinity of super-massive black holes. To this end, the long-term variability of the BL Lac object PKS 2155 304 is analyzed in the high (HE, 100MeV < E < 300 GeV) and very high energy (VHE, E > 200 GeV) gamma-ray domain. Over the course of similar to 9 yr of H. E. S. S. observations the VHE light curve in the quiescent state is consistent with a log-normal behavior. The VHE variability in this state is well described by flicker noise (power-spectral-density index beta(VHE) = 1 .10(+ 0 : 10) (0 : 13)) on timescales larger than one day. An analysis of similar to 5.5 yr of HE Fermi-LAT data gives consistent results (beta(HE) = 1 : 20(+ 0 : 21) (0 : 23), on timescales larger than 10 days) compatible with the VHE findings. The HE and VHE power spectral densities show a scale invariance across the probed time ranges. A direct linear correlation between the VHE and HE fluxes could neither be excluded nor firmly established. These long-term-variability properties are discussed and compared to the red noise behavior (beta similar to 2) seen on shorter timescales during VHE-flaring states. The difference in power spectral noise behavior at VHE energies during quiescent and flaring states provides evidence that these states are influenced by different physical processes, while the compatibility of the HE and VHE long-term results is suggestive of a common physical link as it might be introduced by an underlying jet-disk connection.
We construct new concrete examples of relative differential characters, which we call Cheeger-Chern-Simons characters. They combine the well-known Cheeger-Simons characters with Chern-Simons forms. In the same way as Cheeger-Simons characters generalize Chern-Simons invariants of oriented closed manifolds, Cheeger-Chern-Simons characters generalize Chern-Simons invariants of oriented manifolds with boundary. We study the differential cohomology of compact Lie groups G and their classifying spaces BG. We show that the even degree differential cohomology of BG canonically splits into Cheeger-Simons characters and topologically trivial characters. We discuss the transgression in principal G-bundles and in the universal bundle. We introduce two methods to lift the universal transgression to a differential cohomology valued map. They generalize the Dijkgraaf-Witten correspondence between 3-dimensional Chern-Simons theories and Wess-Zumino-Witten terms to fully extended higher-order Chern-Simons theories. Using these lifts, we also prove two versions of a differential Hopf theorem. Using Cheeger-Chern-Simons characters and transgression, we introduce the notion of differential trivializations of universal characteristic classes. It generalizes well-established notions of differential String classes to arbitrary degree. Specializing to the class , we recover isomorphism classes of geometric string structures on Spin (n) -bundles with connection and the corresponding spin structures on the free loop space. The Cheeger-Chern-Simons character associated with the class together with its transgressions to loop space and higher mapping spaces defines a Chern-Simons theory, extended down to points. Differential String classes provide trivializations of this extended Chern-Simons theory. This setting immediately generalizes to arbitrary degree: for any universal characteristic class of principal G-bundles, we have an associated Cheeger-Chern-Simons character and extended Chern-Simons theory. Differential trivialization classes yield trivializations of this extended Chern-Simons theory.