The Giant Radio Array for Neutrino Detection (GRAND) 1 is a planned large-scale observatory of ultra-highenergy (UHE) cosmic particles -cosmic rays, gamma rays, and neutrinos with energies exceeding 10 8 GeV. Its ultimate goal is to solve the long-standing mystery of the origin of UHE cosmic rays. It will do so by detecting an unprecedented number of UHECRs and by looking with unmatched sensitivity for the undiscovered UHE neutrinos and gamma rays associated to them. Three key features of GRAND will make this possible: its large exposure at ultra-high energies, sub-degree angular resolution, and sensitivity to the unique signals made by UHE neutrinos.The strategy of GRAND is to detect the radio emission coming from large particle showers that develop in the terrestrial atmosphereextensive air showers -as a result of the interaction of UHE cosmic rays, gamma, rays, and neutrinos. To achieve this, GRAND will be the largest array of radio antennas ever built. The relative affordability of radio antennas makes the scale of construction possible. GRAND will build on years of progress in the field of radio-detection and apply the large body of technological, theoretical, and numerical advances, for the first time, to the radio-detection of air showers initiated by UHE neutrinos.The design of GRAND will be modular, consisting of several independent sub-arrays, each of 10 000 radio antennas deployed over 10 000 km 2 in radio-quiet locations. A staged construction plan ensures that key techniques are progressively validated, while simultaneously achieving important science goals in UHECR physics, radioastronomy, and cosmology early during construction.Already by 2025, using the first sub-array of 10 000 antennas, GRAND could discover the long-sought cosmogenic neutrinos -produced by interactions of ultra-high-energy cosmic-rays with cosmic photon fields -if their flux is as high as presently allowed, by reaching a sensitivity comparable to planned upgraded versions of existing experiments. By the 2030s, in its final configuration of 20 sub-arrays, GRAND will reach an unparalleled sensitivity to cosmogenic neutrino fluxes of 4 • 10 −10 GeV cm −2 s −1 sr −1 within 3 years of operation, which will guarantee their detection even if their flux is tiny. Because of its sub-degree angular resolution, GRAND will also search for point sources of UHE neutrinos, steady and transient, potentially starting UHE neutrino astronomy. Because of its access to ultra-high energies, GRAND will chart fundamental neutrino physics at these energies for the first time.GRAND will also be the largest detector of UHE cosmic rays and gamma rays. It will improve UHECR statistics at the highest energies ten-fold within a few years, and either discover UHE gamma rays or improve their limits ten-fold. Further, it will be a valuable tool in radioastronomy and cosmology, allowing for the discovery and follow-up of large numbers of radio transients -fast radio bursts, giant radio pulses -and for precise studies of the epoch of reionization.Following the disc...

Highlights d Intracellular PD-L1 binds RNA and regulates the RNA stability of DNA damage genes d PD-L1 competes with the RNA exosome to regulate RNA stability globally d PD-L1 is important for proper DNA damage response and repair d The PD-L1 antibody H1A sensitizes tumors to DNA-damaging therapy

DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.

The ataxia-telangiectasia mutated (ATM) kinase, an upstream kinase of the DNA damage response (DDR), is rapidly activated following DNA damage, and phosphorylates its downstream targets to launch DDR signaling. However, the mechanism of ATM activation is still not completely understood. Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 is important for Suv39h1 and Tip60 recruitment. Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. These findings reveal that ufmylation of histone H4 by UFL1 is an important step for amplification of ATM activation and maintenance of genomic integrity.