A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses

PPI-Delayed Diagnosis of Gastrinoma: Oncologic Victim of Pharmacologic Success

Functional neuroendocrine tumors are often low-grade malignant neoplasms that can be cured by surgery if detected early, and such detection may in turn be accelerated by the recognition of neuropeptide hypersecretion syndromes. Uniquely, however, relief of peptic symptoms induced by hypergastrinemia is now available from acid-suppressive drugs such as proton-pump inhibitors (PPIs). Here we describe a clinical case in which time to diagnosis from the onset of peptic symptoms was delayed more than 10 years, in part reflecting symptom masking by continuous prescription of the PPI omeprazole. We propose diagnostic criteria for this under-recognized new clinical syndrome, and recommend that physicians routinely measure serum gastrin levels in persistent cases of PPI-dependent dyspepsia unassociated with H. pylori

Seventeen Tidal Disruption Events from the First Half of ZTF Survey Observations: Entering a New Era of Population Studies

While tidal disruption events (TDEs) have long been heralded as laboratories for the study of quiescent black holes, the small number of known TDEs and uncertainties in their emission mechanism have hindered progress towards this promise. Here present 17 new TDEs that have been detected recently by the Zwicky Transient Facility along with Swift UV and X-ray follow-up observations. Our homogeneous analysis of the optical/UV light curves, including 22 previously known TDEs from the literature, reveals a clean separation of light curve properties with spectroscopic class. The TDEs with Bowen fluorescence features in their optical spectra have smaller blackbody radii, as well as longer rise times and higher disruption rates compared to the rest of the sample. The Bowen fluorescence mechanism requires a high density which can be reached at smaller radii, which in turn yields longer diffusion timescales. Thus, the difference in rise times suggests the pre-peak TDE light curves are governed not by the fallback timescale, but instead by the diffusion of photons through the tidal debris. The small subset of TDEs that show only helium emission lines in their spectra have the longest rise times, the highest luminosities and the lowest rates. We also report, for the first time, the detection of soft X-ray flares from a TDE on day timescales. Based on the fact the flares peak at a luminosity similar to the optical/UV blackbody luminosity, we attribute them to brief glimpses through a reprocessing layer that otherwise obscures the inner accretion flow

Evolutionary origins of the estrogen signaling system : insights from amphioxus

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Steroid Biochemistry and Molecular Biology 127 (2011): 176–188, doi:10.1016/j.jsbmb.2011.03.022.Classically, the estrogen signaling system has two core components: cytochrome P450 aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in estrogen biosynthesis; and estrogen receptors (ERs), ligand activated transcription factors that interact with the regulatory region of target genes to mediate the biological effects of estrogen. While the importance of estrogens for regulation of reproduction, development and physiology has been well-documented in gnathostome vertebrates, the evolutionary origins of estrogen as a hormone are still unclear. As invertebrates within the phylum Chordata, cephalochordates (e.g. the amphioxus of the genus Branchiostoma) are among the closest invertebrate relatives of the vertebrates and can provide critical insight into the evolution of vertebrate-specific molecules and pathways. To address this question, this paper briefly reviews relevant earlier studies that help to illuminate the history of the aromatase and ER genes, with a particular emphasis on insights from amphioxus and other invertebrates. We then present new analyses of amphioxus aromatase and ER sequence and function, including an in silico model of the amphioxus aromatase protein, and CYP19 gene analysis. CYP19 shares a conserved gene structure with vertebrates (9 coding exons) and moderate sequence conservation (40% amino acid identity with human CYP19). Modeling of the amphioxus aromatase substrate binding site and simulated docking of androstenedione in comparison to the human aromatase shows that the substrate binding site is conserved and predicts that androstenedione could be a substrate for amphioxus CYP19. The amphioxus ER is structurally similar to vertebrate ERs, but differs in sequence and key residues of the ligand binding domain. Consistent with results from other laboratories, amphioxus ER did not bind radiolabeled estradiol, nor did it modulate gene expression on an estrogen-responsive element (ERE) in the presence 59 of estradiol, 4-hydroxytamoxifen, diethylstilbestrol, bisphenol A or genistein. Interestingly, it has been shown that a related gene, the amphioxus “steroid receptor” (SR), can be activated by estrogens and that amphioxus ER can repress this activation. CYP19, ER and SR are all primarily expressed in gonadal tissue, suggesting an ancient paracrine/autocrinesignaling role, but it is not yet known how their expression is regulated and, if estrogen is actually synthesized in amphioxus, whether it has a role in mediating any biological effects . Functional studies are clearly needed to link emerging bioinformatics and in vitro molecular biology results with organismal physiology to develop an understanding of the evolution of estrogen signaling.Supported by grants from the NIEHS P42 ES07381 (GVC, SV) and EPA (STAR-RD831301) (GVC), a Ruth L Kirschstein National Research Service Award (AT, F32 ES013092-01), an NIH traineeship (SS, SG), a NATO Fellowship (AN) and the Boston University Undergraduate Research Program (LC)

The Zwicky Transient Facility: System Overview, Performance, and First Results

The Zwicky Transient Facility (ZTF) is a new optical time-domain survey that uses the Palomar 48 inch Schmidt telescope. A custom-built wide-field camera provides a 47 deg 2 field of view and 8 s readout time, yielding more than an order of magnitude improvement in survey speed relative to its predecessor survey, the Palomar Transient Factory. We describe the design and implementation of the camera and observing system. The ZTF data system at the Infrared Processing and Analysis Center provides near-real-time reduction to identify moving and varying objects. We outline the analysis pipelines, data products, and associated archive. Finally, we present on-sky performance analysis and first scientific results from commissioning and the early survey. ZTF’s public alert stream will serve as a useful precursor for that of the Large Synoptic Survey Telescope

Studies of systematic uncertainty effects on IceCube’s real-time angular uncertainty

Sources of astrophysical neutrinos can potentially be discovered through the detection of neutrinos in coincidence with electromagnetic or gravitational waves. Real-time alerts generated by IceCube play an important role in this search, acting as triggers for follow-up observations with instruments sensitive to other wavelengths. Once a high-energy event is detected by the IceCube real-time program, a complex and time consuming direction reconstruction method is run in order to calculate an accurate localisation. To investigate the effect of systematic uncertainties on the uncertainty estimate of the location, we simulate a set of high-energy events with a wide range of directions for different ice model realisations, the dominant systematic error in our localization uncertainty. This makes use of a novel simulation tool, which allows the treatment of systematic uncertainties with multiple continuously varied nuisance parameters. These events will be reconstructed using various reconstruction methods. This study will enable us to include systematic uncertainties in a robust manner in the real-time direction and error estimates

The Zwicky Transient Facility: Science Objectives

The Zwicky Transient Facility (ZTF), a public–private enterprise, is a new time-domain survey employing a dedicated camera on the Palomar 48-inch Schmidt telescope with a 47 deg2 field of view and an 8 second readout time. It is well positioned in the development of time-domain astronomy, offering operations at 10% of the scale and style of the Large Synoptic Survey Telescope (LSST) with a single 1-m class survey telescope. The public surveys will cover the observable northern sky every three nights in g and r filters and the visible Galactic plane every night in g and r. Alerts generated by these surveys are sent in real time to brokers. A consortium of universities that provided funding (“partnership”) are undertaking several boutique surveys. The combination of these surveys producing one million alerts per night allows for exploration of transient and variable astrophysical phenomena brighter than r∼20.5 on timescales of minutes to years. We describe the primary science objectives driving ZTF, including the physics of supernovae and relativistic explosions, multi-messenger astrophysics, supernova cosmology, active galactic nuclei, and tidal disruption events, stellar variability, and solar system objects. © 2019. The Astronomical Society of the Pacific

Multimessenger Gamma-Ray and Neutrino Coincidence Alerts using HAWC and IceCube sub-threshold Data

The High Altitude Water Cherenkov (HAWC) and IceCube observatories, through the Astrophysical Multimessenger Observatory Network (AMON) framework, have developed a multimessenger joint search for extragalactic astrophysical sources. This analysis looks for sources that emit both cosmic neutrinos and gamma rays that are produced in photo-hadronic or hadronic interactions. The AMON system is running continuously, receiving sub-threshold data (i.e. data that is not suited on its own to do astrophysical searches) from HAWC and IceCube, and combining them in real-time. We present here the analysis algorithm, as well as results from archival data collected between June 2015 and August 2018, with a total live-time of 3.0 years. During this period we found two coincident events that have a false alarm rate (FAR) of $<1$ coincidence per year, consistent with the background expectations. The real-time implementation of the analysis in the AMON system began on November 20th, 2019, and issues alerts to the community through the Gamma-ray Coordinates Network with a FAR threshold of $<4$ coincidences per year.Comment: 14 pages, 5 figures, 3 table