Ageritin from pioppino mushroom: The prototype of ribotoxin-like proteins, a novel family of specific ribonucleases in edible mushrooms

Ageritin is a specific ribonuclease, extracted from the edible mushroom Cyclocybe aegerita (synonym Agrocybe aegerita), which cleaves a single phosphodiester bond located within the uni-versally conserved alpha-sarcin loop (SRL) of 23–28S rRNAs. This cleavage leads to the inhibition of protein biosynthesis, followed by cellular death through apoptosis. The structural and enzy-matic properties show that Ageritin is the prototype of a novel specific ribonucleases family named ‘ribotoxin-like proteins’, recently found in fruiting bodies of other edible basidiomycetes mushrooms (e.g., Ostreatin from Pleurotus ostreatus, Edulitins from Boletus edulis, and Gambositin from Calocybe gambosa). Although the putative role of this toxin, present in high amount in fruiting body (>2.5 mg per 100 g) of C. aegerita, is unknown, its antifungal and insecticidal actions strongly support a role in defense mechanisms. Thus, in this review, we focus on structural, biological, antipathogenic, and enzymatic characteristics of this ribotoxin-like protein. We also highlight its biological relevance and potential biotechnological applications in agriculture as a bio-pesticide and in biomedicine as a therapeutic and diagnostic agent

Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers

Identification of Milk Component in Ancient Food Residue by Proteomics

Proteomic approaches based on mass spectrometry have been recently used in archaeological and art researches, generating promising results for protein identification. Little information is known about eastward spread and eastern limits of prehistoric milking in eastern Eurasia.In this paper, an ancient visible food remain from Subeixi Cemeteries (cal. 500 to 300 years BC) of the Turpan Basin in Xinjiang, China, preliminarily determined containing 0.432 mg/kg cattle casein with ELISA, was analyzed by using an improved method based on liquid chromatography (LC) coupled with MALDI-TOF/TOF-MS to further identify protein origin. The specific sequence of bovine casein and the homology sequence of goat/sheep casein were identified.The existence of milk component in ancient food implies goat/sheep and cattle milking in ancient Subeixi region, the furthest eastern location of prehistoric milking in the Old World up to date. It is envisioned that this work provides a new approach for ancient residue analysis and other archaeometry field

HESS J1809−-193: a halo of escaped electrons around a pulsar wind nebula?

Context. HESS J1809$-$193 is an unassociated very-high-energy $\gamma$-ray source located on the Galactic plane. While it has been connected to the nebula of the energetic pulsar PSR J1809$-$1917, supernova remnants and molecular clouds present in the vicinity also constitute possible associations. Recently, the detection of $\gamma$-ray emission up to energies of $\sim$100 TeV with the HAWC observatory has led to renewed interest in HESS J1809$-$193. Aims. We aim to understand the origin of the $\gamma$-ray emission of HESS J1809$-$193. Methods. We analysed 93.2 h of data taken on HESS J1809$-$193 above 0.27 TeV with the High Energy Stereoscopic System (H.E.S.S.), using a multi-component, three-dimensional likelihood analysis. In addition, we provide a new analysis of 12.5 yr of Fermi-LAT data above 1 GeV within the region of HESS J1809$-$193. The obtained results are interpreted in a time-dependent modelling framework. Results. For the first time, we were able to resolve the emission detected with H.E.S.S. into two components: an extended component that exhibits a spectral cut-off at $\sim$13 TeV, and a compact component that is located close to PSR J1809$-$1917 and shows no clear spectral cut-off. The Fermi-LAT analysis also revealed extended $\gamma$-ray emission, on scales similar to that of the extended H.E.S.S. component. Conclusions. Our modelling indicates that based on its spectrum and spatial extent, the extended H.E.S.S. component is likely caused by inverse Compton emission from old electrons that form a halo around the pulsar wind nebula. The compact component could be connected to either the pulsar wind nebula or the supernova remnant and molecular clouds. Due to its comparatively steep spectrum, modelling the Fermi-LAT emission together with the H.E.S.S. components is not straightforward. (abridged)Comment: 14 pages, 10 figures. Accepted for publication in A&A. Corresponding authors: Vikas Joshi, Lars Mohrman

Detection of extended gamma-ray emission around the Geminga pulsar with H.E.S.S

Geminga is an enigmatic radio-quiet gamma-ray pulsar located at a mere 250 pc distance from Earth. Extended very-high-energy gamma-ray emission around the pulsar was discovered by Milagro and later confirmed by HAWC, which are both water Cherenkov detector-based experiments. However, evidence for the Geminga pulsar wind nebula in gamma rays has long evaded detection by imaging atmospheric Cherenkov telescopes (IACTs) despite targeted observations. The detection of gamma-ray emission on angular scales > 2 deg poses a considerable challenge for the background estimation in IACT data analysis. With recent developments in understanding the complementary background estimation techniques of water Cherenkov and atmospheric Cherenkov instruments, the H.E.S.S. IACT array can now confirm the detection of highly extended gamma-ray emission around the Geminga pulsar with a radius of at least 3 deg in the energy range 0.5-40 TeV. We find no indications for statistically significant asymmetries or energy-dependent morphology. A flux normalisation of $(2.8\pm0.7)\times10^{-12}$ cm$^{-2}$s$^{-1}$TeV$^{-1}$ at 1 TeV is obtained within a 1 deg radius region around the pulsar. To investigate the particle transport within the halo of energetic leptons around the pulsar, we fitted an electron diffusion model to the data. The normalisation of the diffusion coefficient obtained of $D_0 = 7.6^{+1.5}_{-1.2} \times 10^{27}$ cm$^2$s$^{-1}$, at an electron energy of 100 TeV, is compatible with values previously reported for the pulsar halo around Geminga, which is considerably below the Galactic average.Comment: 16 pages, 15 figures, 7 tables. Accepted for publication in Astronomy & Astrophysic

H.E.S.S. ToO program on nearby core-collapse Supernovae : search for very-high energy γ-ray emission towards the SN candidate AT2019krl in M74

While the youngest known supernova remnants (SNRs), such as Cassiopeia A (Cas A), have been proven to be able to accelerate cosmic rays (CRs) only up to ∼ 10$^{14}$ eV at their present evolutionary stages, recent studies have shown that particle energies larger than a few PeV (10$^{15}$ eV) could be reached during the early stages of a core-collapse Supernova (cc-SN), when the high-velocity forward shock expands into the dense circumstellar medium (CSM) shaped by the stellar progenitor wind. Such environments, in particular the type IIn SNe whose progenitors may exhibit mass loss rates as high as 10$^{-2}$ M$_{\bigodot}$ yr$^{-1}$, could thus lead to γ-ray emission from $\pi ^{0}$ decay in hadronic interactions, potentially detectable with current Cherenkov telescopes at very-high energies. Such a detection would provide direct evidence for efficient acceleration of CR protons/nuclei in supernovae, and hence new insights on the long-standing issue of the origin of Galactic Cosmic Rays. In that context, the High Energy Stereoscopic System (H.E.S.S.) has been carrying out a Target of Opportunity program since 2016 to search for such an early very-high-energy γ-ray emission towards nearby core-collapse supernovae and supernova candidates (up to ∼ 10 Mpc), within a few weeks after discovery. After giving an overview of this H.E.S.S. Target of Opportunity program, we present the results obtained from the July 2019 observations towards the transient AT2019krl, originally classified as a type IIn supernova, which occurred in the galaxy M74 at ∼ 9.8 Mpc. Although its nature still remains unclear, the derived H.E.S.S. constraints on this transient are placed in the general context of the expected VHE γ-ray emission from core-collapse supernovae

Evidence of 100 TeV γ-ray emission from HESS J1702-420 : a new PeVatron candidate

The identification of active PeVatrons, hadronic particle accelerators reaching the knee of the cosmic-ray spectrum (at the energy of few PeV), is crucial to understand the origin of cosmic rays in the Galaxy. In this context, we report on new H.E.S.S. observations of the PeVatron candidate HESS J1702-420, which bring evidence for the presence of γ-rays up to 100 TeV. This is the first time in the history of H.E.S.S. that photons with such high energy are observed. Remarkably, the new deep observations allowed the discovery of a new γ-ray source component, called HESS J1702-420A, that was previously hidden under the bulk emission traditionally associated with HESS J1702-420. This new object has a power-law spectral slope < 2 and a γ-ray spectrum that, extending with no sign of curvature up to 100 TeV, makes it an excellent candidate site for the presence of PeV-energy cosmic rays. This discovery brings new information to the ongoing debate on the nature of the unidentified source HESSJ1702-420, and on the origin of Galactic cosmic rays

Search for dark matter annihilation signals from unidentified Fermi-LAT objects with H.E.S.S.

Cosmological N-body simulations show that Milky-Way-sized galaxies harbor a population of unmerged dark matter subhalos. These subhalos could shine in gamma rays and be eventually detected in gamma-ray surveys as unidentified sources. We search for very-high-energy (VHE, E $\geq$ 100~GeV) gamma-ray emission using H.E.S.S. observations carried out from a thorough selection of unidentified Fermi-LAT Objects (UFOs) as dark matter subhalo candidates. Provided that the dark matter mass is higher than a few hundred GeV, the emission of the UFOs can be well described by dark matter annihilation models. No significant VHE gamma-ray emission is detected in any UFO dataset nor in their combination. We, therefore, derive constraints on the product of the velocity-weighted annihilation cross-section \left by the J-factor on dark matter models describing the UFO emissions. Upper limits at 95% confidence level are derived on \left J in W$^{+}$W$^{-}$ and τ$^{+}$τ$^{-}$ annihilation channels for the TeV dark matter particles. Focusing on thermal WIMPs, strong constraints on the J-factors are obtained from H.E.S.S. observations. Adopting model-dependent predictions from cosmological N-body simulations on the J-factor distribution function for Milky Way (MW)-sized galaxies, only $\lesssim$ 0.3 ~TeV mass dark matter models marginally allow to explain observed UFO emission

Search for enhanced TeV gamma ray emission from Giant Molecular Clouds using H.E.S.S.

Cosmic Ray (CR) interactions with the dense gas inside Giant Molecular Clouds (GMCs) produce neutral pions, which in turn decay into gamma rays. Thus, the gamma ray emission from GMCs is a direct tracer of the cosmic ray density and the matter density inside the clouds. Detection of enhanced TeV emission from GMCs, i.e., an emission significantly larger than what is expected from the average Galactic cosmic rays illuminating the cloud, can imply a variation in the local cosmic ray density, due to, for example, the presence of a recent accelerator in proximity to the cloud. Such gamma-ray observations can be crucial in probing the cosmic ray distribution across our Galaxy, but are complicated to perform with present generation Imaging Atmospheric Cherenkov Telescopes (IACTs). These studies require differentiating between the strong cosmic-ray induced background, the large scale diffuse emission, and the emission from the clouds, which is difficult to the small field of view of present generation IACTs. In this contribution, we use H.E.S.S. data collected over 16 years to search for TeV emission from GMCs in the inner molecular galacto-centric ring of our Galaxy. We implement a 3D FoV likelihood technique, and simultaneously model the hadronic background, the galactic diffuse emission and the emission expected from known VHE sources to probe for excess TeV gamma ray emission from GMCs

Is PKS 0625-354 another variable TeV active galactic nucleus?

The majority of the active galactic nuclei (AGN) detected at very-high-energies above 100 GeV belong to the class of blazars with a small angle between the jet-axis and the line-of-sight. Only about 10 percent of the gamma-ray AGN are objects with a larger viewing angle resulting in a smaller Doppler boosting of the emission. Originally, it was believed that gamma-ray emission can only be observed from blazars and those are variable in its brightness. Instead, the last years have shown that non-blazar active galaxies also show a fascinating variability behaviour which provide important new insights into the physical processes responsible for the gamma-ray production and especially for flaring events. Here, we report on the observation of gamma-ray variability of the active galaxy PKS 0625−354 detected with the H.E.S.S. telescopes in November 2018. The classification of PKS 0625−354 is a still matter of debate. The H.E.S.S. measurements were performed as part of a flux observing program and showed in the first night of the observation a detection of the object with > 5σ. A denser observation campaign followed for the next nine nights resulting in a decrease of the gamma-ray flux. Those observations were accompanied with Swift in the X-ray and UV/optical band allowing for the reconstruction of a multi-band broad-band spectral energy distribution. We will discuss the implications of the gamma-ray variability of the object