BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells

The embryonic formation of midbrain dopaminergic (mDA) neurons in vivo provides critical guidelines for the in vitro differentiation of mDA neurons from stem cells, which are currently being developed for Parkinson’s disease cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for in vivo specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (Bmp5 -/- ; Bmp7 -/- ) lackmDAneurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in Bmp5 -/- ; Bmp7 -/- mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog). Conditionally inactivatingSMAD1in neural stem cells of mice in vivo (Smad1 Nes ) hampered the differentiation of progenitor cells intomDAneurons by preventing cell cycle exit, especially of TH + SOX6 + (tyrosine hydroxylase, SRY-box 6) and TH + GIRK2 + (potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the in vitro differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis in vivo that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons in vitro, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process

Large-scale Cosmic-Ray Anisotropies above 4 EeV Measured by the Pierre Auger Observatory

We present a detailed study of the large-scale anisotropies of cosmic rays with energies above 4 EeV measured using the Pierre Auger Observatory. For the energy bins [4, 8] EeV and E ≥ 8 EeV, the most significant signal is a dipolar modulation in R.A. at energies above 8 EeV, as previously reported. In this paper we further scrutinize the highest-energy bin by splitting it into three energy ranges. We find that the amplitude of the dipole increases with energy above 4 EeV. The growth can be fitted with a power law with index β = 0.79 ± 0.19. The directions of the dipoles are consistent with an extragalactic origin of these anisotropies at all the energies considered. Additionally, we have estimated the quadrupolar components of the anisotropy: they are not statistically significant. We discuss the results in the context of the predictions from different models for the distribution of ultrahigh-energy sources and cosmic magnetic fields

Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, $(\sec \theta)_\mathrm{max}$, sensitive to the mass composition of cosmic rays above $3 \times 10^{18}$ eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modelling that must be resolved before the mass composition can be inferred from $(\sec \theta)_\mathrm{max}$.Comment: Replaced with published version. Added journal reference and DO

An Indication of Anisotropy in Arrival Directions of Ultra-high-energy Cosmic Rays through Comparison to the Flux Pattern of Extragalactic Gamma-Ray Sources

A new analysis of the data set from the Pierre Auger Observatory provides evidence for anisotropy in the arrival directions of ultra-high-energy cosmic rays on an intermediate angular scale, which is indicative of excess arrivals from strong, nearby sources. The data consist of 5514 events above 20 EeV with zenith angles up to 80 recorded before 2017 April 30. Sky models have been created for two distinct populations of extragalactic gamma-ray emitters: active galactic nuclei from the second catalog of hard Fermi-LAT sources (2FHL) and starburst galaxies from a sample that was examined with Fermi-LAT. Flux-limited samples, which include all types of galaxies from the Swift-BAT and 2MASS surveys, have been investigated for comparison. The sky model of cosmic-ray density constructed using each catalog has two free parameters, the fraction of events correlating with astrophysical objects, and an angular scale characterizing the clustering of cosmic rays around extragalactic sources. A maximum-likelihood ratio test is used to evaluate the best values of these parameters and to quantify the strength of each model by contrast with isotropy. It is found that the starburst model fits the data better than the hypothesis of isotropy with a statistical significance of 4.0σ, the highest value of the test statistic being for energies above 39 EeV. The three alternative models are favored against isotropy with 2.7σ-3.2σ significance. The origin of the indicated deviation from isotropy is examined and prospects for more sensitive future studies are discussed

Ultrahigh-energy neutrino follow-up of Gravitational Wave events GW150914 and GW151226 with the Pierre Auger Observatory

On September 14, 2015 the Advanced LIGO detectors observed their first gravitational-wave (GW) transient GW150914. This was followed by a second GW event observed on December 26, 2015. Both events were inferred to have arisen from the merger of black holes in binary systems. Such a system may emit neutrinos if there are magnetic fields and disk debris remaining from the formation of the two black holes. With the surface detector array of the Pierre Auger Observatory we can search for neutrinos with energy above 100 PeV from point-like sources across the sky with equatorial declination from about -65 deg. to +60 deg., and in particular from a fraction of the 90% confidence-level (CL) inferred positions in the sky of GW150914 and GW151226. A targeted search for highly-inclined extensive air showers, produced either by interactions of downward-going neutrinos of all flavors in the atmosphere or by the decays of tau leptons originating from tau-neutrino interactions in the Earth's crust (Earth-skimming neutrinos), yielded no candidates in the Auger data collected within $\pm 500$ s around or 1 day after the coordinated universal time (UTC) of GW150914 and GW151226, as well as in the same search periods relative to the UTC time of the GW candidate event LVT151012. From the non-observation we constrain the amount of energy radiated in ultrahigh-energy neutrinos from such remarkable events.Comment: Published version. Added journal reference and DOI. Added Report Numbe

Calibration of the Logarithmic-Periodic Dipole Antenna (LPDA) Radio Stations at the Pierre Auger Observatory using an Octocopter

An in-situ calibration of a logarithmic periodic dipole antenna with a frequency coverage of 30 MHz to 80 MHz is performed. Such antennas are part of a radio station system used for detection of cosmic ray induced air showers at the Engineering Radio Array of the Pierre Auger Observatory, the so-called Auger Engineering Radio Array (AERA). The directional and frequency characteristics of the broadband antenna are investigated using a remotely piloted aircraft (RPA) carrying a small transmitting antenna. The antenna sensitivity is described by the vector effective length relating the measured voltage with the electric-field components perpendicular to the incoming signal direction. The horizontal and meridional components are determined with an overall uncertainty of 7.4^{+0.9}_{-0.3} % and 10.3^{+2.8}_{-1.7} % respectively. The measurement is used to correct a simulated response of the frequency and directional response of the antenna. In addition, the influence of the ground conductivity and permittivity on the antenna response is simulated. Both have a negligible influence given the ground conditions measured at the detector site. The overall uncertainties of the vector effective length components result in an uncertainty of 8.8^{+2.1}_{-1.3} % in the square root of the energy fluence for incoming signal directions with zenith angles smaller than 60{\deg}.Comment: Published version. Updated online abstract only. Manuscript is unchanged with respect to v2. 39 pages, 15 figures, 2 table

Multi-resolution anisotropy studies of ultrahigh-energy cosmic rays detected at the Pierre Auger Observatory

We report a multi-resolution search for anisotropies in the arrival directions of cosmic rays detected at the Pierre Auger Observatory with local zenith angles up to $80^\circ$ and energies in excess of 4 EeV ($4 \times 10^{18}$ eV). This search is conducted by measuring the angular power spectrum and performing a needlet wavelet analysis in two independent energy ranges. Both analyses are complementary since the angular power spectrum achieves a better performance in identifying large-scale patterns while the needlet wavelet analysis, considering the parameters used in this work, presents a higher efficiency in detecting smaller-scale anisotropies, potentially providing directional information on any observed anisotropies. No deviation from isotropy is observed on any angular scale in the energy range between 4 and 8 EeV. Above 8 EeV, an indication for a dipole moment is captured; while no other deviation from isotropy is observed for moments beyond the dipole one. The corresponding $p$-values obtained after accounting for searches blindly performed at several angular scales, are $1.3 \times 10^{-5}$ in the case of the angular power spectrum, and $2.5 \times 10^{-3}$ in the case of the needlet analysis. While these results are consistent with previous reports making use of the same data set, they provide extensions of the previous works through the thorough scans of the angular scales.Comment: Published version. Added journal reference and DOI. Added Report Numbe

Observation of inclined EeV air showers with the radio detector of the Pierre Auger Observatory

With the Auger Engineering Radio Array (AERA) of the Pierre Auger Observatory, we have observed the radio emission from 561 extensive air showers with zenith angles between 60 and 84. In contrast to air showers with more vertical incidence, these inclined air showers illuminate large ground areas of several km2 with radio signals detectable in the 30 to 80 MHz band. A comparison of the measured radio-signal amplitudes with Monte Carlo simulations of a subset of 50 events for which we reconstruct the energy using the Auger surface detector shows agreement within the uncertainties of the current analysis. As expected for forward-beamed radio emission undergoing no significant absorption or scattering in the atmosphere, the area illuminated by radio signals grows with the zenith angle of the air shower. Inclined air showers with EeV energies are thus measurable with sparse radio-antenna arrays with grid sizes of a km or more. This is particularly attractive as radio detection provides direct access to the energy in the electromagnetic cascade of an air shower, which in case of inclined air showers is not accessible by arrays of particle detectors on the ground