The amyloid precursor protein potentiates CHOP induction and cell death in response to ER Ca2+ depletion

Poster presentation: Here we investigated the role of the amyloid precursor protein (APP) in regulation of Ca2+ store depletion-induced neural cell death. Ca2+ store depletion from the endoplasmic reticulum (ER) was induced by the SERCA (Sarco/Endoplasmic Reticulum Calcium ATPase) inhibitor thapsigargin which led to a rapid induction of the unfolded protein response (UPR) and a delayed activation of executioner caspases in the cultures. Overexpression of APP potently enhanced cytosolic Ca2+ levels and cell death after ER Ca2+ store depletion in comparison to vector-transfected controls. GeneChipR and RT-PCR analysis revealed that the expression of classical UPR chaperone genes was not altered by overexpression of APP.Interestingly, the induction of the ER stress-responsive pro-apoptotic transcription factor CHOP was significantly upregulated in APP-overexpressing cells in comparison to vectortransfected controls. Chelation of intracellular Ca2+ with BAPTA-AM revealed that enhanced CHOP expression after store depletion occured in a Ca2+-dependent manner in APPoverexpressing cells. Prevention of CHOP induction by BAPTA-AM and by RNA interference was also able to abrogate the potentiating effect of APP on thapsigargin-induced apoptosis. Application of the store-operated channel (SOC)-inhibitors SK F96365 and 2-APB downmodulated APP-triggered potentiation of cytosolic Ca2+ levels and apoptosis after treatment with thapsigargin. Our data demonstrate that APP-mediated regulation of ER Ca2+ homeostasis significantly modulates Ca2+ store depletion-induced cell death in a SOC- and CHOP-dependent manner, but independent of the UPR

An All-Sky Search for Three Flavors of Neutrinos from Gamma-Ray Bursts with the IceCube Neutrino Observatory

We present the results and methodology of a search for neutrinos produced in the decay of charged pions created in interactions between protons and gamma-rays during the prompt emission of 807 gamma-ray bursts (GRBs) over the entire sky. This three-year search is the first in IceCube for shower-like Cherenkov light patterns from electron, muon, and tau neutrinos correlated with GRBs. We detect five low-significance events correlated with five GRBs. These events are consistent with the background expectation from atmospheric muons and neutrinos. The results of this search in combination with those of IceCube's four years of searches for track-like Cherenkov light patterns from muon neutrinos correlated with Northern-Hemisphere GRBs produce limits that tightly constrain current models of neutrino and ultra high energy cosmic ray production in GRB fireballs.Comment: 33 pages, 14 figures; minor changes made to match published version in the Astrophysical Journal, 2016 June 2

Improved limits on dark matter annihilation in the Sun with the 79-string IceCube detector and implications for supersymmetry

We present an improved event-level likelihood formalism for including neutrino telescope data in global fits to new physics. We derive limits on spin-dependent dark matter-proton scattering by employing the new formalism in a re-analysis of data from the 79-string IceCube search for dark matter annihilation in the Sun, including explicit energy information for each event. The new analysis excludes a number of models in the weak-scale minimal supersymmetric standard model (MSSM) for the first time. This work is accompanied by the public release of the 79-string IceCube data, as well as an associated computer code for applying the new likelihood to arbitrary dark matter models.Comment: 24 pages, 8 figs, 1 table. Contact authors: Pat Scott & Matthias Danninger. Likelihood tool available at http://nulike.hepforge.org. v2: small updates to address JCAP referee repor

Lowering IceCube’s energy threshold for point source searches in the southern sky

Observation of a point source of astrophysical neutrinos would be a "smoking gun" signature of a cosmic-ray accelerator. While IceCube has recently discovered a diffuse flux of astrophysical neutrinos, no localized point source has been observed. Previous IceCube searches for point sources in the southern sky were restricted by either an energy threshold above a few hundred TeV or poor neutrino angular resolution. Here we present a search for southern sky point sources with greatly improved sensitivities to neutrinos with energies below 100 TeV. By selecting charged-current nu(mu) interacting inside the detector, we reduce the atmospheric background while retaining efficiency for astrophysical neutrino-induced events reconstructed with sub-degree angular resolution. The new event sample covers three years of detector data and leads to a factor of 10 improvement in sensitivity to point sources emitting below 100 TeV in the southern sky. No statistically significant evidence of point sources was found, and upper limits are set on neutrino emission from individual sources. A posteriori analysis of the highest-energy (similar to 100 TeV) starting event in the sample found that this event alone represents a 2.8 sigma deviation from the hypothesis that the data consists only of atmospheric background

The IceCube Neutrino Observatory - Contributions to ICRC 2015 Part II: Atmospheric and Astrophysical Diffuse Neutrino Searches of All Flavors

Papers on atmospheric and astrophysical diffuse neutrino searches of all flavors submitted to the 34th International Cosmic Ray Conference (ICRC 2015, The Hague) by the IceCube Collaboration.Comment: 66 pages, 36 figures, Papers submitted to the 34th International Cosmic Ray Conference, The Hague 2015, v2 has a corrected author lis

Search for Dark Matter Annihilation in the Galactic Center with IceCube-79

The Milky Way is expected to be embedded in a halo of dark matter particles, with the highest density in the central region, and decreasing density with the halo-centric radius. Dark matter might be indirectly detectable at Earth through a flux of stable particles generated in dark matter annihilations and peaked in the direction of the Galactic Center. We present a search for an excess flux of muon (anti-) neutrinos from dark matter annihilation in the Galactic Center using the cubic-kilometer-sized IceCube neutrino detector at the South Pole. There, the Galactic Center is always seen above the horizon. Thus, new and dedicated veto techniques against atmospheric muons are required to make the southern hemisphere accessible for IceCube. We used 319.7 live-days of data from IceCube operating in its 79-string configuration during 2010 and 2011. No neutrino excess was found and the final result is compatible with the background. We present upper limits on the self-annihilation cross-section, \left, for WIMP masses ranging from 30 GeV up to 10 TeV, assuming cuspy (NFW) and flat-cored (Burkert) dark matter halo profiles, reaching down to $\simeq 4 \cdot 10^{-24}$ cm$^3$ s$^{-1}$, and $\simeq 2.6 \cdot 10^{-23}$ cm$^3$ s$^{-1}$ for the $\nu\overline{\nu}$ channel, respectively.Comment: 14 pages, 9 figures, Submitted to EPJ-C, added references, extended limit overvie

Characterization of the Atmospheric Muon Flux in IceCube

Muons produced in atmospheric cosmic ray showers account for the by far dominant part of the event yield in large-volume underground particle detectors. The IceCube detector, with an instrumented volume of about a cubic kilometer, has the potential to conduct unique investigations on atmospheric muons by exploiting the large collection area and the possibility to track particles over a long distance. Through detailed reconstruction of energy deposition along the tracks, the characteristics of muon bundles can be quantified, and individual particles of exceptionally high energy identified. The data can then be used to constrain the cosmic ray primary flux and the contribution to atmospheric lepton fluxes from prompt decays of short-lived hadrons. In this paper, techniques for the extraction of physical measurements from atmospheric muon events are described and first results are presented. The multiplicity spectrum of TeV muons in cosmic ray air showers for primaries in the energy range from the knee to the ankle is derived and found to be consistent with recent results from surface detectors. The single muon energy spectrum is determined up to PeV energies and shows a clear indication for the emergence of a distinct spectral component from prompt decays of short-lived hadrons. The magnitude of the prompt flux, which should include a substantial contribution from light vector meson di-muon decays, is consistent with current theoretical predictions.Comment: 36 pages, 39 figure

A combined maximum-likelihood analysis of the high-energy astrophysical neutrino flux measured with IceCube

Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies $\gtrsim30$ TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, $\nu_\mu$-induced tracks from the Northern hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index $-2.50\pm0.09$ and a flux at 100 TeV of $\left(6.7_{-1.2}^{+1.1}\right)\cdot10^{-18}\,\mathrm{GeV}^{-1}\mathrm{s}^{-1}\mathrm{sr}^{-1}\mathrm{cm}^{-2}$. Under the same assumptions, an unbroken power law with index $-2$ is disfavored with a significance of 3.8 $\sigma$ ($p=0.0066\%$) with respect to the best fit. This significance is reduced to 2.1 $\sigma$ ($p=1.7\%$) if instead we compare the best fit to a spectrum with index $-2$ that has an exponential cut-off at high energies. Allowing the electron neutrino flux to deviate from the other two flavors, we find a $\nu_e$ fraction of $0.18\pm0.11$ at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay dominated sources, is rejected with a significance of 3.6 $\sigma$ ($p=0.014\%$).Comment: 16 pages, 10 figures; accepted for publication in The Astrophysical Journal; updated one referenc