RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

Probing the interaction interface of the GADD45β/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry

GADD45β is selectively and constitutively expressed in Multiple Myeloma cells, and this expression correlates with an unfavourable clinical outcome. GADD45β physically interacts with the JNK kinase, MKK7, inhibiting its activity to enable the survival of cancer cells. DTP3 is a small peptide inhibitor of the GADD45β/MKK7 complex and is able to restore MKK7/JNK activation, thereby promoting selective cell death of GADD45β-overexpressing cancer cells. Enzymatic MS foot-printing and diazirine-based chemical cross-linking MS (CX-MS) strategies were applied to study the interactions between GADD45β and MKK7 kinase domain (MKK7_KD) and between DTP3 and MKK7_KD. Our data show that the binding between GADD45β and MKK7 largely occurs between GADD45β loop 2 (region 103–117) and the kinase enzymatic pocket. We also show that DTP3 interferes with this GADD45β/MKK7 interaction by contacting the MKK7 peptides, 113–136 and 259–274. Accordingly, an MKK7_KD Δ(101–136) variant lacking Trp135 did not produce a fluorescence quenching effect upon the binding of DTP3. The assessment of the interaction between GADD45β and MKK7 and the elucidation of the recognition surfaces between DTP3 and MKK7 significantly advance the understanding of the mechanism underlying the inhibition of the GADD45β/MKK7 interaction by DTP3 and pave the way to the design of small-molecule DTP3 analogues

Unveiling extended gamma-ray emission around HESS J1813-178

Context. HESS J1813-178 is a very-high-energy γ-ray source spatially coincident with the young and energetic pulsar PSR J1813-1749 and thought to be associated with its pulsar wind nebula (PWN). Recently, evidence for extended high-energy emission in the vicinity of the pulsar has been revealed in the Fermi Large Area Telescope (LAT) data. This motivates revisiting the HESS J1813-178 region, taking advantage of improved analysis methods and an extended dataset. Aims. Using data taken by the High Energy Stereoscopic System (H.E.S.S.) experiment and the Fermi-LAT, we aim to describe the γ-ray emission in the region with a consistent model, to provide insights into its origin. Methods. We performed a likelihood-based analysis on 32 hours of H.E.S.S. data and 12 yr of Fermi-LAT data and we fitted a spectro-morphological model to the combined datasets. These results allowed us to develop a physical model for the origin of the observed γ-ray emission in the region. Results. In addition to the compact very-high-energy γ-ray emission centred on the pulsar, we find a significant yet previously undetected component along the Galactic plane. With Fermi-LAT data, we confirm extended high-energy emission consistent with the position and elongation of the extended emission observed with H.E.S.S. These results establish a consistent description of the emission in the region from GeV energies to several tens of TeV. Conclusions. This study suggests that HESS J1813-178 is associated with a γ-ray PWN powered by PSR J1813-1749. A possible origin of the extended emission component is inverse Compton emission from electrons and positrons that have escaped the confines of the pulsar and form a halo around the PWN.</p

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

Science verification of the new FlashCam-based camera in the 28m telescope of H.E.S.S

In October 2019 the central 28m telescope of the H.E.S.S. experiment has been upgraded with a new camera. The camera is based on the FlashCam design which has been developed in view of a possible future implementation in the medium-sized telescopes of the Cherenkov Telescope Array (CTA). We report here on the results of the science verification program that has been performed after commissioning of the new camera, to show that the camera and software pipelines are working up to expectations

Revisiting the PeVatron candidate MGRO J1908+06 with an updated H.E.S.S. analysis

Detecting and studying galactic gamma-ray sources emitting very-high energy photons sheds light on the acceleration and propagation of cosmic rays presumably created in these sources. Currently, there are few sources emitting photons with energies exceeding 100 TeV. In this work we revisit the unidentified source MGRO J1908+06, initially detected by Milagro, using an updated H.E.S.S. dataset and analysis pipeline. The vicinity of the source contains a supernova remnant and pulsars as well as molecular clouds. This makes the identification of the primary source(s) of galactic cosmic rays as well as the nature of the gamma-ray emission challenging, especially in light of the recent HAWC and LHAASO detection of the high energy tail of its spectrum. Exploiting the better angular resolution as compared to particle detectors, we investigate the morphology of the source as well as its spectral properties

Science verification of the new FlashCam-based camera in the 28 m telescope of H.E.S.S.

In October 2019 the central 28 m telescope of the H.E.S.S. experiment has been upgraded with a new camera. The camera is based on the FlashCam design which has been developed in view of a possible future implementation in the medium-sized telescopes of the Cherenkov Telescope Array (CTA). We report here on the results of the science verification program that has been performed after commissioning of the new camera, to show that the camera and software pipelines are working up to expectations

Detection of extended TeV emission around the Geminga pulsar with H.E.S.S

Highly extended gamma-ray emission around the Geminga pulsar was discovered by Milagro and verified by HAWC. Despite many observations with Imaging Atmospheric Cherenkov Telescopes (IACTs), detection of gamma-ray emission on angular scales exceeding the IACT field-of-view has proven challenging. Recent developments in analysis techniques have enabled the detection of significant emission around Geminga in archival data with H.E.S.S.. In 2019, further data on the Geminga region were obtained with an adapted observation strategy. Following the announcement of the detection of significant TeV emission around Geminga in archival data, in this contribution we present the detection in an independent dataset. New analysis results will be presented, and emphasis given to the technical challenges involved in observations of highly extended gamma-ray emission with IACTs

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