Galactic cosmic rays reach energies of at least a few Peta-electronvolts (1 PeV =1015 electron volts)1 . This implies our Galaxy contains PeV accelerators (PeVatrons), but all proposed models of Galactic cosmic-ray accelerators encounter non-trivial difficulties at exactly these energies 2 . Tens of Galactic accelerators capable of accelerating particle to tens of TeV (1 TeV =10 12 electron volts) energies were inferred from recent gamma-ray observations 3 . None of the currently known accelerators, however, not even the handful of shell-type supernova remnants commonly believed to supply most Galactic cosmic rays, have shown the characteristic tracers of PeV particles: power-law spectra of gamma rays extending without a cutoff or a spectral break to tens of TeV 4 . Here we report deep gamma-ray observations with arcminute angular resolution of the Galactic Centre regions, which show the expected tracer of the presence of PeV particles within the central 10 parsec of the Galaxy. We argue 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 outbursts 5 and an outflow from the Galactic Center 6 . 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 10 6−7 years, and therefore should be considered as a viable alternative to supernova remnants as a source of PeV Galactic cosmic rays.The large photon statistics accumulated over the last 10 years of observations with the High Energy Stereoscopic System (H.E.S.S.), together with improvements in the methods of data analysis, allow for a deep study of the properties of the diffuse very-high-energy (VHE; more than 100 GeV) emission of the central molecular zone. This region surrounding the Galactic Centre contains predominantly molecular gas and extends (in projection) out to r∼250 pc at positive galactic longitudes and r∼150 pc at negative longitudes. The map of the central molecular zone as seen in VHE γ-rays (Fig. 1) shows a strong (although not linear; see below) correlation between the brightness distribution of VHE γ-rays and the locations of massive gas-rich complexes. This points towards a hadronic origin of the diffuse emission 7 , where the γ-rays result from the interactions of relativistic protons with the ambient gas. The second important mechanism of production of VHE γ-rays 3 is the inverse Compton scattering of electrons. However, the severe radiative losses suffered by multi-TeV electrons in the Galactic Centre region prevent them from propagating over scales comparable to the size of the central molecular zone, thus disfavouring a leptonic origin of the γ-rays (see discussion in Methods and Extended Data Figures 1 and 2). The location and the particle injection rate history of the cosmic-ray accelerator(s), responsible for the relativistic protons, determine the spatial distribution of these cosmic rays which...

No abstract

Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5 %. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products.

In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E2 synthase-1 and nuclear factor kappa B revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. As conceivable source for novel anti-inflammatory compounds. Phytochemical investigation of the ethanolic crude extract resulted in the isolation and identification of 11 constituents, belonging to depsides and derivatives of orsellinic acid, olivetolic acid and olivetol. The two depsides imbricaric acid (4) and perlatolic acid (5) approved dual inhibitory activities on microsomal prostaglandin E2 synthase-1 (IC50 = 1.9 and 0.4 µM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC50 = 5.3 and 1.8 µM, resp.) and on purified enzyme (IC50 = 3.5 and 0.4 µM, resp.). Additionally, these two main constituents quantified in the extract with 15.22% (4) and 9.10% (5) showed significant inhibition of tumor necrosis factor alpha-induced nuclear factor kappa B activation in luciferase reporter cells with IC50 values of 2.0 and 7.0 µM, respectively. In a murine in vivo model of inflammation, 5 impaired the inflammatory, thioglycollate-induced recruitment of leukocytes to the peritoneum. The potent inhibitory effects on the three identified targets attest 4 and 5 a pronounced multi-target anti-inflammatory profile which warrants further investigation on their pharmacokinetics and in vivo efficacy.

Context. Polycyclic aromatic hydrocarbons (PAHs) are known today to be one of the carriers of the ubiquitous aromatic infrared (IR) bands. The IR spectra of many astrophysical objects show IR emission features derived from PAH molecules of different size. Space-based observations have shown that these IR emission features are omnipresent and can be found in most objects. However, some of the characteristics of the emitting population remain unclear. The emission bands show details that cannot be explained so far. These unidentified IR features require more laboratory and observational investigations. Aims. We present a theoretical study of the IR spectra of PAHs containing (5, 7)-member ring defects, focusing on pyrene (C 16 H 10 ) and coronene (C 24 H 12 ). Methods. Using density functional theory, we investigated the effects of these defects on the IR spectra of pyrene and coronene and their cations and anions. In addition, we explored parts of the potential energy surface of the neutral species and discuss alternative formation pathways.Results. The addition of (5, 7)-membered ring defects in pyrene and coronene results in a change of the IR spectra: both molecules lose their typical spectroscopic signature. We find shifts in the positions of the band as well as different intensities and an increase in the number of features. The boundaries in terms of the size of the PAHs exhibiting a (5, 7)-membered ring defect are studied and shown. Investigating the minimum energy pathway leads to a result of 8.21 eV for pyrene and 8.41 eV for coronene as the minimum activation barriers for the transformation from ground to defected state. Whereas pyrene retains some of its symmetry because of the symmetry exhibited by the Stone-Wales defect itself, coronene loses much more of its symmetry. The formation of these (5, 7)-ring defects in PAHs may be well supported in asymptotic giant branch stars or planetary nebulae. These environments strongly enable the transition from the ground to the defected state. Therefore the knowledge of the IR spectra of these molecules will support future investigations aiming for a thorough understanding of the unidentified IR emission bands.