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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

Background In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to c...

Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20–49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases.

The Galactic Center (GC) region hosts a variety of powerful astronomical sources and rare astrophysical processes that emit a large flux of non-thermal radiation. The inner 375 pc x 600 pc region, called the Central Molecular Zone, is home to the supermassive black hole Sagittarius A*, massive cloud complexes, and particle accelerators such as supernova remnants. We present the results of our improved analysis of the very-high-energy (VHE) gamma-ray emission above 2 TeV from the GC using 125 hours of data taken with the VERITAS imaging-atmospheric Cherenkov telescope between 2010 and 2018. The central source VER J1745-290, consistent with the position of Sagittarius A*, is detected at a significance of 38 standard deviations above the background level $(38\sigma)$, and we report its spectrum and light curve. Its differential spectrum is consistent with a power law with exponential cutoff, with a spectral index of $2.12^{+0.22}_{-0.17}$, a flux normalization at 5.3 TeV of $1.27^{+0.22}_{-0.23}\times 10^{-13}$ TeV-1 cm-2 s-1, and cutoff energy of $10.0^{+4.0}_{-2.0}$ TeV. We also present results on the diffuse emission near the GC, obtained by combining data from multiple regions along the GC ridge which yield a cumulative significance of $9.5\sigma$. The diffuse GC ridge spectrum is best fit by a power law with a hard index of 2.19 $\pm$ 0.20, showing no evidence of a cutoff up to 40 TeV. This strengthens the evidence for a potential accelerator of PeV cosmic rays being present in the GC. We also provide spectra of the other sources in our field of view with significant detections, composite supernova remnant G0.9+0.1 and HESS J1746-285., Comment: 19 pages, 8 figures, Accepted for publication in Astrophysical Journal

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20–30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.

HESS J0632+057 is a gamma-ray binary composed of a compact object orbiting a Be star with a period of about $315$ days. Extensive X-ray and TeV gamma-ray observations have revealed a peculiar light curve containing two peaks, separated by a dip. We present the results of simultaneous observations in hard X-rays with NuSTAR and in TeV gamma-rays with VERITAS, performed in November and December 2017. These observations correspond to the orbital phases $\phi\approx0.22$ and $0.3$, where the fluxes are rising towards the first light-curve peak. A significant variation of the spectral index from 1.77$\pm$0.05 to 1.56$\pm$0.05 is observed in the X-ray data. The multi-wavelength spectral energy distributions (SED) derived from the observations are interpreted in terms of a leptonic model, in which the compact object is assumed to be a pulsar and non-thermal radiation is emitted by high-energy electrons accelerated at the shock formed by the collision between the stellar and pulsar wind. The results of the SED fitting show that our data can be consistently described within this scenario, and allow us to estimate the magnetization of the pulsar wind at the location of the shock formation. The constraints on the pulsar-wind magnetization provided by our results are shown to be consistent with those obtained from other systems., Comment: Accepted for publication in The Astrophysical Journal

The astrophysical journal 896(1), 41 - (2020). doi:10.3847/1538-4357/ab910e, The radio source 3C 264, hosted by the giant elliptical galaxy NGC 3862, was observed with VERITAS between February 2017 and May 2019. These deep observations resulted in the discovery of very-high-energy (VHE; E $>100$ GeV) $\gamma$-ray emission from this active galaxy. An analysis of $\sim$57 hours of quality-selected live time yields a detection at the position of the source, corresponding to a statistical significance of 7.8 standard deviations above background. The observed VHE flux is variable on monthly time scales, with an elevated flux seen in 2018 observations. The VHE emission during this elevated state is well-characterized by a power-law spectrum with a photon index $\Gamma = 2.20 \pm 0.27$ and flux F($>315$ GeV) = ($7.6\pm 1.2_{\mathrm stat} \pm 2.3_{\mathrm syst})\times 10^{-13}$ cm$^{-2}$ s$^{-1}$, or approximately 0.7% of the Crab Nebula flux above the same threshold. 3C 264 ($z = 0.0217$) is the most distant radio galaxy detected at VHE, and the elevated state is thought to be similar to that of the famously outbursting jet in M 87. Consequently, extensive contemporaneous multi-wavelength data were acquired in 2018 at the time of the VHE high state. An analysis of these data, including VLBA, VLA, HST, Chandra and Swift observations in addition to the VERITAS data, is presented, along with a discussion of the resulting spectral energy distribution., Published by Univ.8743, Chicago, Ill. [u.a.]

Significance We adapted natural language processing to the biological literature and demonstrated end-to-end automated knowledge discovery by exploring subtle word connections. General text mining scanned 21 million publication abstracts and selected a reliable 130,000 from which hypothesis generation algorithms predicted kinases not known to phosphorylate p53, but likely to do so. Six of these p53 kinase candidates passed experimental validation. Among them NEK2 was examined in depth and shown to repress p53 and promote cell division. This work demonstrates the possibility of integrating a vast corpora of written knowledge to compute valuable hypotheses that will often test true and fuel discovery., Scientific progress depends on formulating testable hypotheses informed by the literature. In many domains, however, this model is strained because the number of research papers exceeds human readability. Here, we developed computational assistance to analyze the biomedical literature by reading PubMed abstracts to suggest new hypotheses. The approach was tested experimentally on the tumor suppressor p53 by ranking its most likely kinases, based on all available abstracts. Many of the best-ranked kinases were found to bind and phosphorylate p53 (P value = 0.005), suggesting six likely p53 kinases so far. One of these, NEK2, was studied in detail. A known mitosis promoter, NEK2 was shown to phosphorylate p53 at Ser315 in vitro and in vivo and to functionally inhibit p53. These bona fide validations of text-based predictions of p53 phosphorylation, and the discovery of an inhibitory p53 kinase of pharmaceutical interest, suggest that automated reasoning using a large body of literature can generate valuable molecular hypotheses and has the potential to accelerate scientific discovery.

The majority of X-linked retinitis pigmentosa (XLRP) is due to mutations in the retinitis pigmentosa GTPase regulator ( RPGR ) gene. Determining the pathogenicity of novel variants is important for enrollment of patients into gene therapy trials. Sequencing and analysis of RPGR variants in ORF15 is challenging, as it is highly repetitive and rich in purines. Overlapping reading frames and polymorphic insertions / deletions add further complexity to the detection of mutations. Identifying systemic manifestations in affected males and carrier phenotype in related females expedites confirmation of pathogenic variants. The authors present a 16-year-old boy with a history of primary ciliary dyskinesia presenting with complaints of nyctalopia and visual field constriction. Multimodal imaging found peripheral thinning of the retina and a characteristic foveal hyperautofluorescent ring in the proband, and a carrier phenotype in the asymptomatic mother. A novel c.1059_1059+2delGGT, p.(?) variant in RPGR was identified as hemizygous in the affected boy and heterozygous in his mother. This case study expands the genotypic spectrum of RPGR variants associated with systemic manifestations. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:548–552.]

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). We carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU), aiming to identify potential therapeutic entry points. Here we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3,177 Mecp2/Y genomes. Using exome sequencing, genetic crosses and association analysis, we identify 33 candidate genes in 30 of the suppressor lines. A network analysis shows that 61% of the candidate genes cluster into the functional categories of transcriptional repression, chromatin modification or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that are predicted to modulate synaptic signaling or lipid homeostasis. Surprisingly, mutations in genes that function in the DNA damage response (DDR) also improve symptoms in Mecp2/Y mice. The combinatorial effects of multiple loci can be resolved by employing association analysis. One line, which was previously reported to carry a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8 (Rbbp8 or CtIP), which regulates a DDR choice in double stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology directed repair and non-homologous end joining is important for neuronal cells. In this and other lines, the presence of two suppressor mutations confers better symptom improvement than one locus alone, suggesting that combination therapies could be effective in RTT.

The extragalactic background light (EBL), a diffuse photon field in the optical and infrared range, is a record of radiative processes over the Universe's history. Spectral measurements of blazars at very high energies ($>$100 GeV) enable the reconstruction of the spectral energy distribution (SED) of the EBL, as the blazar spectra are modified by redshift- and energy-dependent interactions of the gamma-ray photons with the EBL. The spectra of 14 VERITAS-detected blazars are included in a new measurement of the EBL SED that is independent of EBL SED models. The resulting SED covers an EBL wavelength range of 0.56--56 $��$m, and is in good agreement with lower limits obtained by assuming that the EBL is entirely due to radiation from cataloged galaxies., Accepted for publication in The Astrophysical Journal

The astrophysical journal / 1 876(2), 95 (2019). doi:10.3847/1538-4357/ab14f4, We conduct a search for periodic emission in the very high-energy (VHE) gamma-ray band (E > 100 GeV) from a total of 13 pulsars in an archival VERITAS data set with a total exposure of over 450 hr. The set of pulsars includes many of the brightest young gamma-ray pulsars visible in the Northern Hemisphere. The data analysis resulted in nondetections of pulsed VHE gamma-rays from each pulsar. Upper limits on a potential VHE gamma-ray flux are derived at the 95% confidence level above three energy thresholds using two methods. These are the first such searches for pulsed VHE emission from each of the pulsars, and the obtained limits constrain a possible flux component manifesting at VHEs as is seen for the Crab pulsar., Published by Institute of Physics Publ., London

When biopsying a fetal tissue like chorionic villi or amniotic fluid, there is a chance of getting some maternal material that could contaminate the fetal specimen and might lead to a misdiagnosis. Thus, all prenatal samples should be subjected to testing for maternal cell contamination. This is done using quantitative fluorescent PCR (QF-PCR) of short tandem repeat (STR) markers.

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 Tables

Blazars are known for their variability on a wide range of timescales at all wavelengths. Most studies of TeV gamma-ray blazars focus on short timescales, especially during flares. With a decade of observations from the Fermi-LAT and VERITAS, we present an extensive study of the long-term multi-wavelength radio-to-gamma-ray flux-density variability, with the addition of a couple of short-time radio-structure and optical polarization observations of the blazar 1ES 1215+303 (z=0.130), with a focus on its gamma-ray emission from 100 MeV to 30 TeV. Multiple strong GeV gamma-ray flares, a long-term increase in the gamma-ray and optical flux baseline and a linear correlation between these two bands are observed over the ten-year period. Typical HBL behaviors are identified in the radio morphology and broadband spectrum of the source. Three stationary features in the innermost jet are resolved by VLBA at 43.1, 22.2, and 15.3 GHz. We employ a two-component synchrotron self-Compton model to describe different flux states of the source, including the epoch during which an extreme shift in energy of the synchrotron peak frequency from infrared to soft X-rays is observed., Comment: Accepted for publication in the Astrophysical Journal

We present results from deep observations towards the Cygnus region using 300 hours of very-high-energy (VHE) $\gamma$-ray data taken with the VERITAS Cherenkov telescope array and over seven years of high-energy $\gamma$-ray data taken with the Fermi satellite at an energy above 1 GeV. As the brightest region of diffuse $\gamma$-ray emission in the northern sky, the Cygnus region provides a promising area to probe the origins of cosmic rays. We report the identification of a potential Fermi-LAT counterpart to VER J2031+415 (TeV J2032+4130), and resolve the extended VHE source VER J2019+368 into two source candidates (VER J2018+367* and VER J2020+368*) and characterize their energy spectra. The Fermi-LAT morphology of 3FGL 2021.0+4031e (the Gamma-Cygni supernova remnant) was examined and a region of enhanced emission coincident with VER J2019+407 was identified and jointly fit with the VERITAS data. By modeling 3FGL J2015.6+3709 as two sources, one located at the location of the pulsar wind nebula CTB 87 and one at the quasar QSO J2015+371, a continuous spectrum from 1 GeV to 10 TeV was extracted for VER J2016+371 (CTB 87). An additional 71 locations coincident with Fermi-LAT sources and other potential objects of interest were tested for VHE $\gamma$-ray emission, with no emission detected and upper limits on the differential flux placed at an average of 2.3% of the Crab Nebula ux. We interpret these observations in a multiwavelength context and present the most detailed $\gamma$-ray view of the region to date., Comment: 49 Pages, 22 Figures, 13 Tables, Accepted to ApJ

HESS J1943+213 is a very-high-energy (VHE; $>$100 GeV) $\gamma$-ray source in the direction of the Galactic Plane. Studies exploring the classification of the source are converging towards its identification as an extreme synchrotron BL Lac object. Here we present 38 hours of VERITAS observations of HESS J1943+213 taken over two years. The source is detected with $\sim$20 standard deviations significance, showing a remarkably stable flux and spectrum in VHE $\gamma$-rays. Multi-frequency very-long-baseline array (VLBA) observations of the source confirm the extended, jet-like structure previously found in the 1.6 GHz band with European VLBI Network and detect this component in the 4.6 GHz and the 7.3 GHz bands. The radio spectral indices of the core and the jet and the level of polarization derived from the VLBA observations are in a range typical for blazars. Data from VERITAS, $Fermi$-LAT, $Swift$-XRT, FLWO 48$''$ telescope, and archival infrared and hard X-ray observations are used to construct and model the spectral energy distribution (SED) of the source with a synchrotron-self-Compton model. The well-measured $\gamma$-ray peak of the SED with VERITAS and $Fermi$-LAT provides constraining upper limits on the source redshift. Possible contribution of secondary $\gamma$-rays from ultra-high-energy cosmic ray-initiated electromagnetic cascades to the $\gamma$-ray emission is explored, finding that only a segment of the VHE spectrum can be accommodated with this process. A variability search is performed across X-ray and $\gamma$-ray bands. No statistically significant flux or spectral variability is detected., Comment: Accepted for publication in The Astrophysical Journal

Combined with measurements made by very-long-baseline interferometry, the observations of fast TeV gamma-ray flares probe the structure and emission mechanism of blazar jets. However, only a handful of such flares have been detected to date, and only within the last few years have these flares been observed from lower-frequency-peaked BL Lac objects and flat-spectrum radio quasars. We report on a fast TeV gamma-ray flare from the blazar BL Lacertae observed by the Very Energetic Radiation Imaging Telescope Array System (VERITAS). with a rise time of ∼2.3 hr and a decay time of ∼36 min. The peak flux above 200 GeV is (4.2 ± 0.6) ×10 photon m s measured with a 4-minute-binned light curve, corresponding to ∼180% of the flux that is observed from the Crab Nebula above the same energy threshold. Variability contemporaneous with the TeV gamma-ray flare was observed in GeV gamma-ray, X-ray, and optical flux, as well as in optical and radio polarization. Additionally, a possible moving emission feature with superluminal apparent velocity was identified in Very Long Baseline Array observations at 43 GHz, potentially passing the radio core of the jet around the time of the gamma-ray flare. We discuss the constraints on the size, Lorentz factor, and location of the emitting region of the flare, and the interpretations with several theoretical models that invoke relativistic plasma passing stationary shocks.© 2018. The American Astronomical Society. All rights reserved., VERITAS is supported by grants from the U.S. Department of Energy Office of Science, the U.S. National Science Foundation and the Smithsonian Institution, and by NSERC in Canada. We acknowledge the excellent work of the technical support staff at the Fred Lawrence Whipple Observatory and at the collaborating institutions in the construction and operation of the instrument. The research at Boston University was supported in part by NASA Fermi Guest Investigator Program grant 80NSSC17K 0694. The VLBA is an instrument of the Long Baseline Observatory (LBO). The LBO is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. This research has made use of data from the MOJAVE database that is maintained by the MOJAVE team (Lister et al. 2009) and supported by NASA Fermi grant NNX15AU76G. This work made use of the Swinburne University of Technology software correlator (Deller et al. 2011), developed as part of the Australian Major National Research Facilities Programme and operated under licence. Y.Y.K. and A.B.P. are partly supported by the Russian Foundation for Basic Research (project 17-02-00197), the government of the Russian Federation (agreement 05.Y09.21.0018), and the Alexander von Humboldt Foundation. T.S. was funded by the Academy of Finland projects 274477 and 284495. This research has made use of data from the OVRO 40 m monitoring program (Richards et al. 2011) which is supported in part by NASA grants NNX08AW31G, NNX11A043G, and NNX14AQ89G and NSF grants AST-0808050 and AST-1109911. The monitoring of BL. Lacertae and other blazars at the Steward Observatory is supported through NASA Fermi Guest Investigator grant NNX15AU81G. I.A. acknowledges support by a Ramon y Cajal grant of the Ministerio de Economia y Competitividad (MINECO) of Spain. Acquisition and reduction of the MAPCAT data was supported in part by MINECO through grants AYA2010-14844, AYA2013-40825-P, and AYA2016-80889-P, and by the Regional Government of Andalucia through grant P09-FQM-4784. The MAPCAT observations were carried out at the German-Spanish Calar Alto Observatory, which is jointly operated by the Max-Planck-Institut fur Astronomie and the Instituto de Astrofisica de Andalucia-CSIC. The St. Petersburg University team acknowledges support from Russian Science Foundation grant 17-12-01029.

We present very-high-energy $\gamma$-ray observations of the BL Lac object 1ES 2344+514 taken by the Very Energetic Radiation Imaging Telescope Array System (VERITAS) between 2007 and 2015. 1ES 2344+514 is detected with a statistical significance above background of $20.8\sigma$ in $47.2$ hours (livetime) of observations, making this the most comprehensive very-high-energy study of 1ES 2344+514 to date. Using these observations the temporal properties of 1ES 2344+514 are studied on short and long times scales. We fit a constant flux model to nightly- and seasonally-binned light curves and apply a fractional variability test, to determine the stability of the source on different timescales. We reject the constant-flux model for the 2007-2008 and 2014-2015 nightly-binned light curves and for the long-term seasonally-binned light curve at the $> 3\sigma$ level. The spectra of the time-averaged emission before and after correction for attenuation by the extragalactic background light are obtained. The observed time-averaged spectrum above 200 GeV is satisfactorily fitted (${\chi^2/NDF = 7.89/6}$) by a power-law function with index $\Gamma = 2.46 \pm 0.06_{stat} \pm 0.20_{sys} $ and extends to at least 8 TeV. The extragalactic-background-light-deabsorbed spectrum is adequately fit (${\chi^2/NDF = 6.73/6}$) by a power-law function with index $\Gamma = 2.15 \pm 0.06_{stat} \pm 0.20_{sys} $ while an F-test indicates that the power-law with exponential cutoff function provides a marginally-better fit ($\chi^2/NDF $ = $2.56 / 5 $) at the 2.1$\sigma$ level. The source location is found to be consistent with the published radio location and its spatial extent is consistent with a point source., Comment: 7 pages, 2 figures. Published in Monthly Notices of the Royal Astronomical Society

The pathogenicity of individual de novo missense mutations in autism spectrum disorder remains difficult to validate. Here we asked in 2,384 probands whether these variants exhibited collective functional impact biases across pathways. As measured with Evolutionary Action (EA) in 368 gene groupings, we found significant biases in axonogenesis, synaptic transmission, and other neurodevelopmental pathways. Strikingly, both de novo and inherited missense variants in prioritized genes correlated with patient IQ. This general integrative approach thus detects missense variants most likely to contribute to autism pathogenesis and is the first, to our knowledge, to link missense variant impact to autism phenotypic severity.

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 limits

The astrophysical journal 836(1), 23 (2017). doi:10.3847/1538-4357/836/1/23, 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 has been 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 hr of VERITAS and 84 months of Fermi-LAT observations, which represent 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 ± 0.42$_{stat}$ ± 0.20$_{sys}$. It is also softer than the spectral index in the GeV energy range, 2.14 ± 0.09$_{stat}$ ± 0.02$_{sys}$, measured in 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., Published by IOP Publ., Chicago, Ill. [u.a.]

Astroparticle physics 91, 34 - 43 (2017). doi:10.1016/j.astropartphys.2017.03.001, 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., Published by Elsevier, Amsterdam [u.a.]

Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2-null male mice has provided insight into pathogenesis of the disorder-most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity, and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2-mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements, and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of techniques described in several different Current Protocols in Mouse Biology articles to carry out testing in a preclinical model. Curr. Protoc. Mouse Biol. 3:187-204 © 2013 by John Wiley & Sons, Inc.

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%., Accepted for publication in the Astrophysical Journal

The astrophysical journal / 2 818(2), L33(2016). doi:10.3847/2041-8205/818/2/L33, The F-type star KIC 8462852 has recently been identified as an exceptional target for search for extraterrestrial intelligence (SETI) observations. We describe an analysis methodology for optical SETI, which we have used to analyze nine hours of serendipitous archival observations of KIC 8462852 made with the VERITAS gamma-ray observatory between 2009 and 2015. No evidence of pulsed optical beacons, above a pulse intensity at the Earth of approximately $1\;\mathrm{photon}\;{{\rm{m}}}^{-2}$, is found. We also discuss the potential use of imaging atmospheric Cherenkov telescope arrays in searching for extremely short duration optical transients in general., Published by Institute of Physics Publ., London

The binary millisecond radio pulsar PSR J1023+0038 exhibits many characteristics similar to the gamma-ray binary system PSR B1259--63/LS 2883, making it an ideal candidate for the study of high-energy non-thermal emission. It has been the subject of multi-wavelength campaigns following the disappearance of the pulsed radio emission in 2013 June, which revealed the appearance of an accretion disk around the neutron star. We present the results of very high-energy gamma-ray observations carried out by VERITAS before and after this change of state. Searches for steady and pulsed emission of both data sets yield no significant gamma-ray signal above 100 GeV, and upper limits are given for both a steady and pulsed gamma-ray flux. These upper limits are used to constrain the magnetic field strength in the shock region of the PSR J1023+0038 system. Assuming that very high-energy gamma rays are produced via an inverse-Compton mechanism in the shock region, we constrain the shock magnetic field to be greater than $\sim$2 G before the disappearance of the radio pulsar and greater than $\sim$10 G afterwards., 7 pages, 3 figures, accepted for publication in ApJ

Astronomy and astrophysics 603, A31 (2017). doi:10.1051/0004-6361/201629540, We present an extensive study of the BL Lac object Mrk 501 based on a data set collected during the multi-instrument campaign spanning from 2009 March 15 to 2009 August 1, which includes, among other instruments, MAGIC, VERITAS, Whipple 10 m, and Fermi-LAT to cover the γ-ray range from 0.1 GeV to 20 TeV; RXTE and Swift to cover wavelengths from UV tohard X-rays; and GASP-WEBT, which provides coverage of radio and optical wavelengths. Optical polarization measurements were provided for a fraction of the campaign by the Steward and St. Petersburg observatories. We evaluate the variability of the source and interband correlations, the γ-ray flaring activity occurring in May 2009, and interpret the results within two synchrotron self-Compton (SSC) scenarios. Aims. The multiband variability observed during the full campaign is addressed in terms of the fractional variability, and the possible correlations are studied by calculating the discrete correlation function for each pair of energy bands where the significance was evaluated with dedicated Monte Carlo simulations. The space of SSC model parameters is probed following a dedicated grid-scan strategy, allowing for a wide range of models to be tested and offering a study of the degeneracy of model-to-data agreement in the individual model parameters, hence providing a less biased interpretation than the “single-curve SSC model adjustment” typically reported in the literature. Methods. We find an increase in the fractional variability with energy, while no significant interband correlations of flux changes are found on the basis of the acquired data set. The SSC model grid-scan shows that the flaring activity around May 22 cannot be modeled adequately with a one-zone SSC scenario (using an electron energy distribution with two breaks), while it can be suitably described within a two (independent) zone SSC scenario. Here, one zone is responsible for the quiescent emission from the averaged 4.5-month observing period, while the other one, which is spatially separated from the first, dominates the flaring emission occurring at X-rays and very-high-energy (>100 GeV, VHE) γ rays. The flaring activity from May 1, which coincides with a rotation of the electric vector polarization angle (EVPA), cannot be satisfactorily reproduced by either a one-zone or a two-independent-zone SSC model, yet this is partially affected by the lack of strictly simultaneous observations and the presence of large flux changes on sub-hour timescales (detected at VHE γ rays). Results. The higher variability in the VHE emission and lack of correlation with the X-ray emission indicate that, at least during the 4.5-month observing campaign in 2009, the highest energy (and most variable) electrons that are responsible for the VHE γ rays do not make a dominant contribution to the ~1 keV emission. Alternatively, there could be a very variable component contributing to the VHE γ-ray emission in addition to that coming from the SSC scenario. The studies with our dedicated SSC grid-scan show that there is some degeneracy in both the one-zone and the two-zone SSC scenarios probed, with several combinations of model parameters yielding a similar model-to-data agreement, and some parameters better constrained than others. The observed γ-ray flaring activity, with the EVPA rotation coincident with the first γ-ray flare, resembles those reported previously for low frequency peaked blazars, hence suggesting that there are many similarities in the flaring mechanisms of blazars with different jet properties., Published by EDP Sciences, Les Ulis

Monthly notices of the Royal Astronomical Society 459(3), 2550 - 2557 (2016). doi:10.1093/mnras/stw664, We present results from multiwavelength observations of the BL Lacertae object 1ES 1741 + 196, including results in the very high energy γ-ray regime using the Very Energetic Radiation Imaging Telescope Array System (VERITAS). The VERITAS time-averaged spectrum, measured above 180 GeV, is well modelled by a power law with a spectral index of 2.7 ± 0.7$_{stat}$ ± 0.2syst. The integral flux above 180 GeV is (3.9 ± 0.8$_{stat}$ ± 1.0$_{syst}$) × 10$^{−8}$ m$^{−2}$ s$^{−1}$, corresponding to 1.6 per cent of the Crab nebula flux on average. The multiwavelength spectral energy distribution of the source suggests that 1ES 1741+196 is an extreme-high-frequency-peaked BL Lacertae object. The observations analysed in this paper extend over a period of six years, during which time no strong flares were observed in any band. This analysis is therefore one of the few characterizations of a blazar in a non-flaring state., Published by Oxford Univ. Press, Oxford

The astrophysical journal 821(2), 129 (2016). doi:10.3847/0004-637X/821/2/129, The Galactic Center ridge has been observed extensively in the past by both GeV and TeV gamma-ray instrumentsrevealing a wealth of structure, including a diffuse component and the point sources G0.9+0.1 (a compositesupernova remnant) and Sgr A*(believed to be associated with the supermassive black hole located at the center of our Galaxy). Previous very high energy (VHE) gamma-ray observations with the H.E.S.S. experiment have also detected an extended TeV gamma-ray component along the Galactic plane in the > 300 GeV gamma-ray regime. Here we report on observations of the Galactic Center ridge from 2010 to 2014 by the VERITAS telescope array in the > 2 TeV energy range. From these observations we (1) provide improved measurements of the differential energy spectrum for Sgr A* in the > 2 TeV gamma-ray regime, (2) provide a detection in the > 2 TeV gamma-ray emission from the composite SNR G0.9+0.1 and an improved determination of its multi-TeV gamma-ray energy spectrum, and (3) report on the detection of VER J1746-289, a localized enhancement of > 2 TeV gamma-rayemission along the Galactic plane., Published by Univ.11032, Chicago, Ill. [u.a.]

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer’s, Parkinson’s, Huntington’s, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer’s disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background, and recurred on re-introduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.

We present KnIT, the Knowledge Integration Toolkit, a system for accelerating scientific discovery and predicting previously unknown protein-protein interactions. Such predictions enrich biological research and are pertinent to drug discovery and the understanding of disease. Unlike a prior study, KnIT is now fully automated and demonstrably scalable. It extracts information from the scientific literature, automatically identifying direct and indirect references to protein interactions, which is knowledge that can be represented in network form. It then reasons over this network with techniques such as matrix factorization and graph diffusion to predict new, previously unknown interactions. The accuracy and scope of KnIT's knowledge extractions are validated using comparisons to structured, manually curated data sources as well as by performing retrospective studies that predict subsequent literature discoveries using literature available prior to a given date. The KnIT methodology is a step towards automated hypothesis generation from text, with potential application to other scientific domains.

Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2-null male mice has provided insight into pathogenesis of the disorder-most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity, and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2-mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements, and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of techniques described in several different Current Protocols in Mouse Biology articles to carry out testing in a preclinical model. Curr. Protoc. Mouse Biol. 3:187-204 © 2013 by John WileySons, Inc.

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 $

Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss. We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line. Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.

Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism.

Physical review / D 98(6), 062004 (2018). doi:10.1103/PhysRevD.98.062004, 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, 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±40$_{stat}$±140$_{syst}$ GeV., Published by APS, Woodbury, NY