Bactericidal activities of the cationic steroid CSA-13 and the cathelicidin peptide LL-37 against Helicobacter pylori in simulated gastric juice

BACKGROUND: The worldwide appearance of drug-resistant strains of H. pylori motivates a search for new agents with therapeutic potential against this family of bacteria that colonizes the stomach, and is associated with adenocarcinoma development. This study was designed to assess in vitro the anti-H. pylori potential of cathelicidin LL-37 peptide, which is naturally present in gastric juice, its optimized synthetic analog WLBU2, and the non-peptide antibacterial agent ceragenin CSA-13. RESULTS: In agreement with previous studies, increased expression of hCAP-18/LL-37 was observed in gastric mucosa obtained from H. pylori infected subjects. MBC (minimum bactericidal concentration) values determined in nutrient-containing media range from 100-800 μg/ml for LL-37, 17.8-142 μg/ml for WLBU2 and 0.275-8.9 μg/ml for ceragenin CSA-13. These data indicate substantial, but widely differing antibacterial activities against clinical isolates of H. pylori. After incubation in simulated gastric juice (low pH with presence of pepsin) CSA-13, but not LL-37 or WLBU2, retained antibacterial activity. Compared to LL-37 and WLBU2 peptides, CSA-13 activity was also more resistant to inhibition by isolated host gastric mucins. CONCLUSION: These data indicate that cholic acid-based antimicrobial agents such as CSA-13 resist proteolytic degradation and inhibition by mucin and have potential for treatment of H. pylori infections, including those caused by the clarithromycin and/or metronidazole-resistant strains

Searches for Neutrinos from Gamma-Ray Bursts Using the IceCube Neutrino Observatory

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma-rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between 2011 May and 2018 October to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to ≲1% of the observed diffuse neutrino flux, and emission on timescales up to 104 s is constrained to 24% of the total diffuse flux.Peer Reviewe

A search for time-dependent astrophysical neutrino emission with IceCube data from 2012 to 2017

High-energy neutrinos are unique messengers of the high-energy universe, tracing the processes of cosmic-ray acceleration. This paper presents analyses focusing on time-dependent neutrino point-source searches. A scan of the whole sky, making no prior assumption about source candidates, is performed, looking for a space and time clustering of high-energy neutrinos in data collected by the IceCube Neutrino Observatory between 2012 and 2017. No statistically significant evidence for a time-dependent neutrino signal is found with this search during this period since all results are consistent with the background expectation. Within this study period, the blazar 3C 279, showed strong variability, inducing a very prominent gamma-ray flare observed in 2015 June. This event motivated a dedicated study of the blazar, which consists of searching for a time-dependent neutrino signal correlated with the gamma-ray emission. No evidence for a time-dependent signal is found. Hence, an upper limit on the neutrino fluence is derived, allowing us to constrain a hadronic emission model

LeptonInjector and LeptonWeighter: A neutrino event generator and weighter for neutrino observatories

We present a high-energy neutrino event generator, called LeptonInjector, alongside an event weighter, called LeptonWeighter. Both are designed for large-volume Cherenkov neutrino telescopes such as IceCube. The neutrino event generator allows for quick and flexible simulation of neutrino events within and around the detector volume, and implements the leading Standard Model neutrino interaction processes relevant for neutrino observatories: neutrino-nucleon deep-inelastic scattering and neutrino-electron annihilation. In this paper, we discuss the event generation algorithm, the weighting algorithm, and the main functions of the publicly available code, with examples.Comment: 28 pages, 10 figures, 3 table

Improved Characterization of the Astrophysical Muon–neutrino Flux with 9.5 Years of IceCube Data

We present a measurement of the high-energy astrophysical muon–neutrino flux with the IceCube Neutrino Observatory. The measurement uses a high-purity selection of 650k neutrino-induced muon tracks from the northern celestial hemisphere, corresponding to 9.5 yr of experimental data. With respect to previous publications, the measurement is improved by the increased size of the event sample and the extended model testing beyond simple power-law hypotheses. An updated treatment of systematic uncertainties and atmospheric background fluxes has been implemented based on recent models. The best-fit single power-law parameterization for the astrophysical energy spectrum results in a normalization of ${\phi }_{@100\mathrm{TeV}}^{{\nu }_{\mu }+{\bar{\nu }}_{\mu }}={1.44}_{-0.26}^{+0.25}\times {10}^{-18}\,{\mathrm{GeV}}^{-1}{\mathrm{cm}}^{-2}{{\rm{s}}}^{-1}{\mathrm{sr}}^{-1}$ and a spectral index ${\gamma }_{\mathrm{SPL}}={2.37}_{-0.09}^{+0.09}$, constrained in the energy range from 15 TeV to 5 PeV. The model tests include a single power law with a spectral cutoff at high energies, a log-parabola model, several source-class-specific flux predictions from the literature, and a model-independent spectral unfolding. The data are consistent with a single power-law hypothesis, however, spectra with softening above one PeV are statistically more favorable at a two-sigma level

Improved Characterization of the Astrophysical Muon–neutrino Flux with 9.5 Years of IceCube Data

We present a measurement of the high-energy astrophysical muon–neutrino flux with the IceCube Neutrino Observatory. The measurement uses a high-purity selection of 650k neutrino-induced muon tracks from the northern celestial hemisphere, corresponding to 9.5 yr of experimental data. With respect to previous publications, the measurement is improved by the increased size of the event sample and the extended model testing beyond simple power-law hypotheses. An updated treatment of systematic uncertainties and atmospheric background fluxes has been implemented based on recent models. The best-fit single power-law parameterization for the astrophysical energy spectrum results in a normalization of ${\phi }_{@100\mathrm{TeV}}^{{\nu }_{\mu }+{\bar{\nu }}_{\mu }}={1.44}_{-0.26}^{+0.25}\times {10}^{-18}\,{\mathrm{GeV}}^{-1}{\mathrm{cm}}^{-2}{{\rm{s}}}^{-1}{\mathrm{sr}}^{-1}$ and a spectral index ${\gamma }_{\mathrm{SPL}}={2.37}_{-0.09}^{+0.09}$, constrained in the energy range from 15 TeV to 5 PeV. The model tests include a single power law with a spectral cutoff at high energies, a log-parabola model, several source-class-specific flux predictions from the literature, and a model-independent spectral unfolding. The data are consistent with a single power-law hypothesis, however, spectra with softening above one PeV are statistically more favorable at a two-sigma level

A muon-track reconstruction exploiting stochastic losses for large-scale Cherenkov detectors

IceCube is a cubic-kilometer Cherenkov telescope operating at the South Pole. The main goal of IceCube is the detection of astrophysical neutrinos and the identification of their sources. High-energy muon neutrinos are observed via the secondary muons produced in charge current interactions with nuclei in the ice. Currently, the best performing muon track directional reconstruction is based on a maximum likelihood method using the arrival time distribution of Cherenkov photons registered by the experiment's photomultipliers. A known systematic shortcoming of the prevailing method is to assume a continuous energy loss along the muon track. However at energies $>1$ TeV the light yield from muons is dominated by stochastic showers. This paper discusses a generalized ansatz where the expected arrival time distribution is parametrized by a stochastic muon energy loss pattern. This more realistic parametrization of the loss profile leads to an improvement of the muon angular resolution of up to $20\%$ for through-going tracks and up to a factor 2 for starting tracks over existing algorithms. Additionally, the procedure to estimate the directional reconstruction uncertainty has been improved to be more robust against numerical errors

Search for High-energy Neutrino Emission from Galactic X-Ray Binaries with IceCube

We present the first comprehensive search for high-energy neutrino emission from high- and low-mass X-ray binaries conducted by IceCube. Galactic X-ray binaries are long-standing candidates for the source of Galactic hadronic cosmic rays and neutrinos. The compact object in these systems can be the site of cosmic-ray acceleration, and neutrinos can be produced by interactions of cosmic rays with radiation or gas, in the jet of a microquasar, in the stellar wind, or in the atmosphere of the companion star. We study X-ray binaries using 7.5 yr of IceCube data with three separate analyses. In the first, we search for periodic neutrino emission from 55 binaries in the Northern Sky with known orbital periods. In the second, the X-ray light curves of 102 binaries across the entire sky are used as templates to search for time-dependent neutrino emission. Finally, we search for time-integrated emission of neutrinos for a list of 4 notable binaries identified as microquasars. In the absence of a significant excess, we place upper limits on the neutrino flux for each hypothesis and compare our results with theoretical predictions for several binaries. In addition, we evaluate the sensitivity of the next generation neutrino telescope at the South Pole, IceCube-Gen2, and demonstrate its power to identify potential neutrino emission from these binary sources in the Galaxy