A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome

Funding J.A.B. acknowledges funding from iNOVA4Health-UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência through national funds and cofunded by Fundo Europeu de Desenvolvimento Regional (FEDER) under the PT2020 Partnership Agreement.The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in DAND5, a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a DAND5 biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in DAND5 (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the DAND5 c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in DAND5 causing an autosomal recessive heterotaxy syndrome.publishersversionpublishe

A Luminous and Isolated Gamma-Ray Flare from the Blazar B2 1215+30

B2 1215+30 is a BL-Lac-type blazar that was first detected at TeV energies by the MAGIC atmospheric Cherenkov telescopes and subsequently confirmed by the Very Energetic Radiation Imaging Telescope Array System (VERITAS) observatory with data collected between 2009 and 2012. In 2014 February 08, VERITAS detected a large-amplitude flare from B2 1215+30 during routine monitoring observations of the blazar 1ES 1218+304, located in the same field of view. The TeV flux reached 2.4 times the Crab Nebula flux with a variability timescale of . Multiwavelength observations with Fermi-LAT, Swift, and the Tuorla Observatory revealed a correlated high GeV flux state and no significant optical counterpart to the flare, with a spectral energy distribution where the gamma-ray luminosity exceeds the synchrotron luminosity. When interpreted in the framework of a one-zone leptonic model, the observed emission implies a high degree of beaming, with Doppler factor , and an electron population with spectral index

A Search for Spectral Hysteresis and Energy-dependent Time Lags from X-Ray and TeV Gamma-Ray Observations of Mrk 421

Abstract Blazars are variable emitters across all wavelengths over a wide range of timescales, from months down to minutes. It is therefore essential to observe blazars simultaneously at different wavelengths, especially in the X-ray and gamma-ray bands, where the broadband spectral energy distributions usually peak. In this work, we report on three target-of-opportunity observations of Mrk 421, one of the brightest TeV blazars, triggered by a strong flaring event at TeV energies in 2014. These observations feature long, continuous, and simultaneous exposures with XMM-Newton (covering the X-ray and optical/ultraviolet bands) and VERITAS (covering the TeV gamma-ray band), along with contemporaneous observations from other gamma-ray facilities (MAGIC and Fermi-Large Area Telescope) and a number of radio and optical facilities. Although neither rapid flares nor significant X-ray/TeV correlation are detected, these observations reveal subtle changes in the X-ray spectrum of the source over the course of a few days. We search the simultaneous X-ray and TeV data for spectral hysteresis patterns and time delays, which could provide insight into the emission mechanisms and the source properties (e.g., the radius of the emitting region, the strength of the magnetic field, and related timescales). The observed broadband spectra are consistent with a one-zone synchrotron self-Compton model. We find that the power spectral density distribution at 4 × 10−4 Hz from the X-ray data can be described by a power-law model with an index value between 1.2 and 1.8, and do not find evidence for a steepening of the power spectral index (often associated with a characteristic length scale) compared to the previously reported values at lower frequencies

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations

Evidence for proton acceleration up to TeV energies based on VERITAS and Fermi-LAT observations of the Cas A SNR

We present a study of $\gamma$-ray emission from the core-collapse supernova remnant Cas~A in the energy range from 0.1GeV to 10TeV. We used 65 hours of VERITAS data to cover 200 GeV - 10 TeV, and 10.8 years of \textit{Fermi}-LAT data to cover 0.1-500 GeV. The spectral analysis of \textit{Fermi}-LAT data shows a significant spectral curvature around $1.3 \pm 0.4_{stat}$ GeV that is consistent with the expected spectrum from pion decay. Above this energy, the joint spectrum from \textit{Fermi}-LAT and VERITAS deviates significantly from a simple power-law, and is best described by a power-law with spectral index of $2.17\pm 0.02_{stat}$ with a cut-off energy of $2.3 \pm 0.5_{stat}$ TeV. These results, along with radio, X-ray and $\gamma$-ray data, are interpreted in the context of leptonic and hadronic models. Assuming a one-zone model, we exclude a purely leptonic scenario and conclude that proton acceleration up to at least 6 TeV is required to explain the observed $\gamma$-ray spectrum. From modeling of the entire multi-wavelength spectrum, a minimum magnetic field inside the remnant of $B_{\mathrm{min}}\approx150\,\mathrm{\mu G}$ is deduced.Comment: 33 pages, 9 Figures, 6 Table

Gamma-ray observations of Tycho's SNR with VERITAS and Fermi

High-energy gamma-ray emission from supernova remnants (SNRs) has provided a unique perspective for studies of Galactic cosmic-ray acceleration. Tycho's SNR is a particularly good target because it is a young, type Ia SNR that is well-studied over a wide range of energies and located in a relatively clean environment. Since the detection of gamma-ray emission from Tycho's SNR by VERITAS and Fermi-LAT, there have been several theoretical models proposed to explain its broadband emission and high-energy morphology. We report on an update to the gamma-ray measurements of Tycho's SNR with 147 hours of VERITAS and 84 months of Fermi-LAT observations, which represents about a factor of two increase in exposure over previously published data. About half of the VERITAS data benefited from a camera upgrade, which has made it possible to extend the TeV measurements toward lower energies. The TeV spectral index measured by VERITAS is consistent with previous results, but the expanded energy range softens a straight power-law fit. At energies higher than 400 GeV, the power-law index is $2.92 \pm 0.42_{\mathrm{stat}} \pm 0.20_{\mathrm{sys}}$. It is also softer than the spectral index in the GeV energy range, $2.14 \pm 0.09_{\mathrm{stat}} \pm 0.02_{\mathrm{sys}}$, measured by this study using Fermi--LAT data. The centroid position of the gamma-ray emission is coincident with the center of the remnant, as well as with the centroid measurement of Fermi--LAT above 1 GeV. The results are consistent with an SNR shell origin of the emission, as many models assume. The updated spectrum points to a lower maximum particle energy than has been suggested previously.Comment: Accepted for publication in The Astrophysical Journa

Very-high-energy observations of the binaries V 404 Cyg and 4U 0115+634 during giant X-ray outbursts

Transient X-ray binaries produce major outbursts in which the X-ray flux can increase over the quiescent level by factors as large as $10^7$. The low-mass X-ray binary V 404 Cyg and the high-mass system 4U 0115+634 underwent such major outbursts in June and October 2015, respectively. We present here observations at energies above hundreds of GeV with the VERITAS observatory taken during some of the brightest X-ray activity ever observed from these systems. No gamma-ray emission has been detected by VERITAS in 2.5 hours of observations of the microquasar V 404 Cyg from 2015, June 20-21. The upper flux limits derived from these observations on the gamma-ray flux above 200 GeV of F $< 4.4\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ correspond to a tiny fraction (about $10^{-6}$) of the Eddington luminosity of the system, in stark contrast to that seen in the X-ray band. No gamma rays have been detected during observations of 4U 0115+634 in the period of major X-ray activity in October 2015. The flux upper limit derived from our observations is F $< 2.1\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ for gamma rays above 300 GeV, setting an upper limit on the ratio of gamma-ray to X-ray luminosity of less than 4%.Comment: Accepted for publication in the Astrophysical Journa

Discovery of very-high-energy emission from RGB J2243+203 and derivation of its redshift upper limit

Very-high-energy (VHE; $>$ 100 GeV) gamma-ray emission from the blazar RGB J2243+203 was discovered with the VERITAS Cherenkov telescope array, during the period between 21 and 24 December 2014. The VERITAS energy spectrum from this source can be fit by a power law with a photon index of $4.6 \pm 0.5$, and a flux normalization at 0.15 TeV of $(6.3 \pm 1.1) \times 10^{-10} ~ \textrm{cm}^{-2} \textrm{s}^{-1} \textrm{TeV}^{-1}$. The integrated \textit{Fermi}-LAT flux from 1 GeV to 100 GeV during the VERITAS detection is $(4.1 \pm 0.8) \times 10^{\textrm{-8}} ~\textrm{cm}^{\textrm{-2}}\textrm{s}^{\textrm{-1}}$, which is an order of magnitude larger than the four-year-averaged flux in the same energy range reported in the 3FGL catalog, ($4.0 \pm 0.1 \times 10^{\textrm{-9}} ~ \textrm{cm}^{\textrm{-2}}\textrm{s}^{\textrm{-1}}$). The detection with VERITAS triggered observations in the X-ray band with the \textit{Swift}-XRT. However, due to scheduling constraints \textit{Swift}-XRT observations were performed 67 hours after the VERITAS detection, not simultaneous with the VERITAS observations. The observed X-ray energy spectrum between 2 keV and 10 keV can be fitted with a power-law with a spectral index of $2.7 \pm 0.2$, and the integrated photon flux in the same energy band is $(3.6 \pm 0.6) \times 10^{-13} ~\textrm{cm}^{-2} \textrm{s}^{-1}$. EBL model-dependent upper limits of the blazar redshift have been derived. Depending on the EBL model used, the upper limit varies in the range from z $<~0.9$ to z $<~1.1$

Measurement of Cosmic-ray Electrons at TeV Energies by VERITAS

Cosmic-ray electrons and positrons (CREs) at GeV-TeV energies are a unique probe of our local Galactic neighborhood. CREs lose energy rapidly via synchrotron radiation and inverse-Compton scattering processes while propagating within the Galaxy and these losses limit their propagation distance. For electrons with TeV energies, the limit is on the order of a kiloparsec. Within that distance there are only a few known astrophysical objects capable of accelerating electrons to such high energies. It is also possible that the CREs are the products of the annihilation or decay of heavy dark matter (DM) particles. VERITAS, an array of imaging air Cherenkov telescopes in southern Arizona, USA, is primarily utilized for gamma-ray astronomy, but also simultaneously collects CREs during all observations. We describe our methods of identifying CREs in VERITAS data and present an energy spectrum, extending from 300 GeV to 5 TeV, obtained from approximately 300 hours of observations. A single power-law fit is ruled out in VERITAS data. We find that the spectrum of CREs is consistent with a broken power law, with a break energy at 710 $\pm$ 40$_{stat}$ $\pm$ 140$_{syst}$ GeV.Comment: 17 pages, 2 figures, accepted for publication in PR

Dark Matter Constraints from a Joint Analysis of Dwarf Spheroidal Galaxy Observations with VERITAS

We present constraints on the annihilation cross section of WIMP dark matter based on the joint statistical analysis of four dwarf galaxies with VERITAS. These results are derived from an optimized photon weighting statistical technique that improves on standard imaging atmospheric Cherenkov telescope (IACT) analyses by utilizing the spectral and spatial properties of individual photon events. We report on the results of $\sim$230 hours of observations of five dwarf galaxies and the joint statistical analysis of four of the dwarf galaxies. We find no evidence of gamma-ray emission from any individual dwarf nor in the joint analysis. The derived upper limit on the dark matter annihilation cross section from the joint analysis is $1.35\times 10^{-23} {\mathrm{ cm^3s^{-1}}}$ at 1 TeV for the bottom quark ($b\bar{b}$) final state, $2.85\times 10^{-24}{\mathrm{ cm^3s^{-1}}}$ at 1 TeV for the tau lepton ($\tau^{+}\tau^{-}$) final state and $1.32\times 10^{-25}{\mathrm{ cm^3s^{-1}}}$ at 1 TeV for the gauge boson ($\gamma\gamma$) final state.Comment: 14 pages, 9 figures, published in PRD, Ascii tables containing annihilation cross sections limits are available for download as ancillary files with readme.txt file description of limit