Development of a Testing Funnel for Identification of Small-Molecule Modulators Targeting Secretin Receptors

The secretin receptor (SCTR), a prototypical class B G protein-coupled receptor (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of its endogenous peptide ligand secretin. SCTRs can be found in a variety of tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, and brain. Beyond that, modulation of SCTR-mediated signaling has therapeutic potential for the treatment of multiple diseases, such as heart failure, obesity, and diabetes. However, no ligands other than secretin and its peptide analogs have been described to regulate SCTRs, probably due to inherent challenges in family B GPCR drug discovery. Here we report creation of a testing funnel that allowed targeted detection of SCTR small-molecule activators. Pursuing the strategy to identify positive allosteric modulators (PAMs), we established a unique primary screening assay employing a mixture of three orthosteric stimulators that was compared in a screening campaign testing 12,000 small-molecule compounds. Beyond that, we developed a comprehensive set of secondary assays, such as a radiolabel-free target engagement assay and a NanoBiT (NanoLuc Binary Technology)-based approach to detect β-arrestin-2 recruitment, all feasible in a high-throughput environment as well as capable of profiling ligands and hits regarding their effect on binding and receptor function. This combination of methods enabled the discovery of five promising scaffolds, four of which have been validated and further characterized with respect to their allosteric activities. We propose that our results may serve as starting points for developing the first in vivo active small molecules targeting SCTRs

Performance of SK-Gd's Upgraded Real-time Supernova Monitoring System

Among multi-messenger observations of the next galactic core-collapse supernova, Super-Kamiokande (SK) plays a critical role in detecting the emitted supernova neutrinos, determining the direction to the supernova (SN), and notifying the astronomical community of these observations in advance of the optical signal. On 2022, SK has increased the gadolinium dissolved in its water target (SK-Gd) and has achieved a Gd concentration of 0.033%, resulting in enhanced neutron detection capability, which in turn enables more accurate determination of the supernova direction. Accordingly, SK-Gd's real-time supernova monitoring system (Abe te al. 2016b) has been upgraded. SK_SN Notice, a warning system that works together with this monitoring system, was released on December 13, 2021, and is available through GCN Notices (Barthelmy et al. 2000). When the monitoring system detects an SN-like burst of events, SK_SN Notice will automatically distribute an alarm with the reconstructed direction to the supernova candidate within a few minutes. In this paper, we present a systematic study of SK-Gd's response to a simulated galactic SN. Assuming a supernova situated at 10 kpc, neutrino fluxes from six supernova models are used to characterize SK-Gd's pointing accuracy using the same tools as the online monitoring system. The pointing accuracy is found to vary from 3-7$^\circ$ depending on the models. However, if the supernova is closer than 10 kpc, SK_SN Notice can issue an alarm with three-degree accuracy, which will benefit follow-up observations by optical telescopes with large fields of view.Comment: 38 pages, 29 figures, 6 table

Search for Cosmic-ray Boosted Sub-GeV Dark Matter using Recoil Protons at Super-Kamiokande

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton$\times$years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross-section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross-section between $10^{-33}\text{ cm}^{-2}$ and $10^{-27}\text{ cm}^{-2}$ for dark matter mass from 10 MeV/$c^2$ to 1 GeV/$c^2$.Comment: With 1-page appendi

Supernova Model Discrimination with Hyper-Kamiokande

Core-collapse supernovae are among the most magnificent events in the observable universe. They produce many of the chemical elements necessary for life to exist and their remnants—neutron stars and black holes—are interesting astrophysical objects in their own right. However, despite millennia of observations and almost a century of astrophysical study, the explosion mechanism of core-collapse supernovae is not yet well understood. Hyper-Kamiokande is a next-generation neutrino detector that will be able to observe the neutrino flux from the next galactic core-collapse supernova in unprecedented detail. We focus on the first 500 ms of the neutrino burst, corresponding to the accretion phase, and use a newly-developed, high-precision supernova event generator to simulate Hyper-Kamiokande's response to five different supernova models. We show that Hyper-Kamiokande will be able to distinguish between these models with high accuracy for a supernova at a distance of up to 100 kpc. Once the next galactic supernova happens, this ability will be a powerful tool for guiding simulations toward a precise reproduction of the explosion mechanism observed in nature

Measurements of the charge ratio and polarization of cosmic-ray muons with the Super-Kamiokande detector

We present the results of the charge ratio ($R$) and polarization ($P^{\mu}_{0}$) measurements using the decay electron events collected from 2008 September to 2022 June by the Super-Kamiokande detector. Because of its underground location and long operation, we performed high precision measurements by accumulating cosmic-ray muons. We measured the muon charge ratio to be $R=1.32 \pm 0.02$ $(\mathrm{stat.}{+}\mathrm{syst.})$ at $E_{\mu}\cos \theta_{\mathrm{Zenith}}=0.7^{+0.3}_{-0.2}$ $\mathrm{TeV}$, where $E_{\mu}$ is the muon energy and $\theta_{\mathrm{Zenith}}$ is the zenith angle of incoming cosmic-ray muons. This result is consistent with the Honda flux model while this suggests a tension with the $\pi K$ model of $1.9\sigma$. We also measured the muon polarization at the production location to be $P^{\mu}_{0}=0.52 \pm 0.02$ $(\mathrm{stat.}{+}\mathrm{syst.})$ at the muon momentum of $0.9^{+0.6}_{-0.1}$ $\mathrm{TeV}/c$ at the surface of the mountain; this also suggests a tension with the Honda flux model of $1.5\sigma$. This is the most precise measurement ever to experimentally determine the cosmic-ray muon polarization near $1~\mathrm{TeV}/c$. These measurement results are useful to improve the atmospheric neutrino simulations.Comment: 29 pages, 45 figure

Measurement of the cosmogenic neutron yield in Super-Kamiokande with gadolinium loaded water

Cosmic-ray muons that enter the Super-Kamiokande detector cause hadronic showers due to spallation in water, producing neutrons and radioactive isotopes. Those are a major background source for studies of MeV-scale neutrinos and searches for rare events. Since 2020, gadolinium was introduced in the ultra-pure water in the Super-Kamiokande detector to improve the detection efficiency of neutrons. In this study, the cosmogenic neutron yield was measured using data acquired during the period after the gadolinium loading. The yield was found to be $(2.76 \pm 0.02\,\mathrm{(stat.) \pm 0.19\,\mathrm{(syst.)}}) \times 10^{-4}\,\mu^{-1} \mathrm{g^{-1} cm^{2}}$ at 259 GeV of average muon energy at the Super-Kamiokande detector.Comment: 10 pages, 10 figures, 3 table

Search for Periodic Time Variations of the Solar 8^8B Neutrino Flux Between 1996 and 2018 in Super-Kamiokande

We report a search for time variations of the solar $^8$B neutrino flux using 5,804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a data set comprised of five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this data set to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53$\pm$0.35)\,\%, and a perihelion shift is ($-$1.5$\pm$13.5)\,days.Comment: 8 pages, 5 figures, 2 tables, and data file: "sksolartimevariation5804d.txt

Solar neutrino measurements using the full data period of Super-Kamiokande-IV

An analysis of solar neutrino data from the fourth phase of Super-Kamiokande~(SK-IV) from October 2008 to May 2018 is performed and the results are presented. The observation time of the data set of SK-IV corresponds to $2970$~days and the total live time for all four phases is $5805$~days. For more precise solar neutrino measurements, several improvements are applied in this analysis: lowering the data acquisition threshold in May 2015, further reduction of the spallation background using neutron clustering events, precise energy reconstruction considering the time variation of the PMT gain. The observed number of solar neutrino events in $3.49$--$19.49$ MeV electron kinetic energy region during SK-IV is $65,443^{+390}_{-388}\,(\mathrm{stat.})\pm 925\,(\mathrm{syst.})$ events. Corresponding $\mathrm{^{8}B}$ solar neutrino flux is $(2.314 \pm 0.014\, \rm{(stat.)} \pm 0.040 \, \rm{(syst.)}) \times 10^{6}~\mathrm{cm^{-2}\,s^{-1}}$, assuming a pure electron-neutrino flavor component without neutrino oscillations. The flux combined with all SK phases up to SK-IV is $(2.336 \pm 0.011\, \rm{(stat.)} \pm 0.043 \, \rm{(syst.)}) \times 10^{6}~\mathrm{cm^{-2}\,s^{-1}}$. Based on the neutrino oscillation analysis from all solar experiments, including the SK $5805$~days data set, the best-fit neutrino oscillation parameters are $\rm{sin^{2} \theta_{12,\,solar}} = 0.306 \pm 0.013$ and $\Delta m^{2}_{21,\,\mathrm{solar}} = (6.10^{+ 0.95}_{-0.81}) \times 10^{-5}~\rm{eV}^{2}$, with a deviation of about 1.5$\sigma$ from the $\Delta m^{2}_{21}$ parameter obtained by KamLAND. The best-fit neutrino oscillation parameters obtained from all solar experiments and KamLAND are $\sin^{2} \theta_{12,\,\mathrm{global}} = 0.307 \pm 0.012$ and $\Delta m^{2}_{21,\,\mathrm{global}} = (7.50^{+ 0.19}_{-0.18}) \times 10^{-5}~\rm{eV}^{2}$.Comment: 47 pages, 61 figure