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Overexpression of CD24, a glycosyl phosphatidylinositol-linked sialoglycoprotein, is associated with poor outcome in urothelial carcinoma and contributes to experimental tumor growth and metastasis. However, the requirement for CD24 (Cd24a in mice) in tumorigenesis and spontaneous metastasis from the orthotopic site remains uncharacterized. Using N -butyl- N -(4-hydroxybutyl) nitrosamine induction of invasive and metastatic bladder cancer, we show that Cd24a -deficient male mice developed fewer bladder tumors than C57BL/6 control male mice. Evaluating only mice with evidence of primary tumors, we observed that Cd24a- deficient male mice also had fewer metastases than wild-type counterparts. In parallel observations, stratification of patients based on CD24 immunohistochemical expression in their tumors revealed that high levels of CD24 are associated with poor prognosis in males. In female patients and mice the above observations were not present. Given the significant role of CD24 in males, we sought to assess the relationship between androgen and CD24 regulation. We discovered that androgen receptor knockdown in UM-UC-3 and TCCSUP human urothelial carcinoma cell lines resulted in suppression of CD24 expression and cell proliferation. Androgen treatment also led to increased CD24 promoter activity, dependent on the presence of androgen receptor. In vivo, androgen deprivation resulted in reduced growth and CD24 expression of UM-UC-3 xenografts, and the latter was rescued by exogenous CD24 overexpression. These findings demonstrate an important role for CD24 in urothelial tumorigenesis and metastasis in male mice and indicate that CD24 is androgen regulated, providing the foundation for urothelial bladder cancer therapy with antiandrogens.

Using a structure-based approach, small molecule inhibitors that selectively target the GTPase Ral are identified and characterized; these first-generation inhibitors will be valuable tools for elucidating the Ral signalling pathway and constitute a step towards developing Ral-specific agents for cancer therapy. Small molecule inhibitors against Ral GTPase Signalling through the Ras GTPase pathway is often hyperactive in cancer, and Ras pathway components are being extensively studied as targets for potential cancer therapies. Here, in a structure-based approach, Dan Theodorescu and colleagues discover small molecule inhibitors that selectively target the Ral GTPase, an important downstream mediator of Ras signalling. The inhibitors bind Ral in its inactive state and are characterised biochemically, in cellular assays and in mice. These first-generation inhibitors will be valuable tools for elucidating Ral signalling and a step towards developing Ral-specific agents for cancer therapy. The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis 1 . Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and 1 H– 15 N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.

A promising energy range to look for angular correlations between cosmic rays of extragalactic origin and their sources is at the highest energies, above a few tens of EeV (1 EeV ≡ 1018 eV). Despite the flux of these particles being extremely low, the area of ∼3000 km2 covered at the Pierre Auger Observatory, and the 17 yr data-taking period of the Phase 1 of its operations, have enabled us to measure the arrival directions of more than 2600 ultra-high-energy cosmic rays above 32 EeV. We publish this data set, the largest available at such energies from an integrated exposure of 122,000 km2 sr yr, and search it for anisotropies over the 3.4π steradians covered with the Observatory. Evidence for a deviation in excess of isotropy at intermediate angular scales, with ∼15° Gaussian spread or ∼25° top-hat radius, is obtained at the 4σ significance level for cosmic-ray energies above ∼40 EeV.

We present a measurement of the cosmic-ray spectrum above 100 PeV using the part of the surface detector of the Pierre Auger Observatory that has a spacing of 750 m. An inflection of the spectrum is observed, confirming the presence of the so-called second-knee feature. The spectrum is then combined with that of the 1500 m array to produce a single measurement of the flux, linking this spectral feature with the three additional breaks at the highest energies. The combined spectrum, with an energy scale set calorimetrically via fluorescence telescopes and using a single detector type, results in the most statistically and systematically precise measurement of spectral breaks yet obtained. These measurements are critical for furthering our understanding of the highest energy cosmic rays.

Results are presented for the measurement of large-scale anisotropies in the arrival directions of ultra–high-energy cosmic rays detected at the Pierre Auger Observatory during 19 yr of operation, prior to AugerPrime, the upgrade of the observatory. The 3D dipole amplitude and direction are reconstructed above 4 EeV in four energy bins. Besides the established dipolar anisotropy in R.A. above 8 EeV, the Fourier amplitude of the 8–16 EeV energy bin is now also above the 5σ discovery level. No time variation of the dipole moment above 8 EeV is found, setting an upper limit to the rate of change of such variations of 0.3% yr−1 at the 95% confidence level. Additionally, the results for the angular power spectrum are shown, demonstrating no other statistically significant multipoles. The results for the equatorial dipole component down to 0.03 EeV are presented, using for the first time a data set obtained with a trigger that has been optimized for lower energies. Finally, model predictions are discussed and compared with observations, based on two source emission scenarios obtained in the combined fit of spectrum and composition above 0.6 EeV.

A catalog containing details of the highest-energy cosmic rays recorded through the detection of extensive air showers at the Pierre Auger Observatory is presented with the aim of opening the data to detailed examination. Descriptions of the 100 showers created by the highest-energy particles recorded between 2004 January 1 and 2020 December 31 are given for cosmic rays that have energies in the range 78–166 EeV. Details are also given on a further nine very energetic events that have been used in the calibration procedure adopted to determine the energy of each primary. A sky plot of the arrival directions of the most energetic particles is shown. No interpretations of the data are offered.

Ultrahigh-energy cosmic rays are known to be mainly of extragalactic origin, and their propagation is limited by energy losses, so their arrival directions are expected to correlate with the large-scale structure of the local Universe. In this work, we investigate the possible presence of intermediate-scale excesses in the flux of the most energetic cosmic rays from the direction of the supergalactic plane region using events with energies above 20 EeV recorded with the surface detector array of the Pierre Auger Observatory up to 2022 December 31, with a total exposure of 135,000 km2 sr yr. The strongest indication for an excess that we find, with a posttrial significance of 3.1σ, is in the Centaurus region, as in our previous reports, and it extends down to lower energies than previously studied. We do not find any strong hints of excesses from any other region of the supergalactic plane at the same angular scale. In particular, our results do not confirm the reports by the Telescope Array Collaboration of excesses from two regions in the Northern Hemisphere at the edge of the field of view of the Pierre Auger Observatory. With a comparable integrated exposure over these regions, our results there are in good agreement with the expectations from an isotropic distribution.

For several decades, the origin of ultra-high-energy cosmic rays (UHECRs) has been an unsolved question of high-energy astrophysics. One approach for solving this puzzle is to correlate UHECRs with high-energy neutrinos, since neutrinos are a direct probe of hadronic interactions of cosmic rays and are not deflected by magnetic fields. In this paper, we present three different approaches for correlating the arrival directions of neutrinos with the arrival directions of UHECRs. The neutrino data are provided by the IceCube Neutrino Observatory and ANTARES, while the UHECR data with energies above ∼50 EeV are provided by the Pierre Auger Observatory and the Telescope Array. All experiments provide increased statistics and improved reconstructions with respect to our previous results reported in 2015. The first analysis uses a high-statistics neutrino sample optimized for point-source searches to search for excesses of neutrino clustering in the vicinity of UHECR directions. The second analysis searches for an excess of UHECRs in the direction of the highest-energy neutrinos. The third analysis searches for an excess of pairs of UHECRs and highest-energy neutrinos on different angular scales. None of the analyses have found a significant excess, and previously reported overfluctuations are reduced in significance. Based on these results, we further constrain the neutrino flux spatially correlated with UHECRs.

Using data collected at the Pierre Auger Observatory during the past 3.7 years, we demonstrated a correlation between the arrival directions of cosmic rays with energy above 6 × 10 19 electron volts and the positions of active galactic nuclei (AGN) lying within ∼75 megaparsecs. We rejected the hypothesis of an isotropic distribution of these cosmic rays with at least a 99% confidence level from a prescribed a priori test. The correlation we observed is compatible with the hypothesis that the highest-energy particles originate from nearby extragalactic sources whose flux has not been substantially reduced by interaction with the cosmic background radiation. AGN or objects having a similar spatial distribution are possible sources.

The Pierre Auger Collaboration has embraced the concept of open access to their research data since its foundation, with the aim of giving access to the widest possible community. A gradual process of release began as early as 2007 when 1% of the cosmic-ray data was made public, along with 100% of the space-weather information. In February 2021, a portal was released containing 10% of cosmic-ray data collected by the Pierre Auger Observatory from 2004 to 2018, during the first phase of operation of the Observatory. The Open Data Portal includes detailed documentation about the detection and reconstruction procedures, analysis codes that can be easily used and modified and, additionally, visualization tools. Since then, the Portal has been updated and extended. In 2023, a catalog of the highest-energy cosmic-ray events examined in depth has been included. A specific section dedicated to educational use has been developed with the expectation that these data will be explored by a wide and diverse community, including professional and citizen scientists, and used for educational and outreach initiatives. This paper describes the context, the spirit, and the technical implementation of the release of data by the largest cosmic-ray detector ever built and anticipates its future developments.