Genomic test ends a long diagnostic odyssey in a patient with resistance to thyroid hormones

Background: Resistance to thyroid hormones is a very rare condition, which is often misdiagnosed and mistreated. The cases where there is a concomitant autoimmune thyroid disorder are ultra-rare and particularly challenging to treat. Diagnostic and research-based genomic testing can sometimes identify pathogenic variants unrelated to the primary reason for testing (incidental findings)

SN 2017ein and the Possible First Identification of a Type Ic Supernova Progenitor

We have identified a progenitor candidate in archival Hubble Space Telescope (HST) images for the Type Ic SN 2017ein in NGC 3938, pinpointing the candidate's location via HST Target-of-Opportunity imaging of the SN itself. This would be the first identification of a stellar-like object as a progenitor candidate for any Type Ic supernova to date. We also present observations of SN 2017ein during the first ~49 days since explosion. We find that SN 2017ein most resembles the well-studied Type Ic SN 2007gr. We infer that SN 2017ein experienced a total visual extinction of A_V~1.0--1.9 mag, predominantly because of dust within the host galaxy. Although the distance is not well known, if this object is the progenitor, it was likely of high initial mass, ~47--48 M_sun if a single star, or ~60--80 M_sun if in a binary system. However, we also find that the progenitor candidate could be a very blue and young compact cluster, further implying a very massive (>65 M_sun) progenitor. Furthermore, the actual progenitor might not be associated with the candidate at all and could be far less massive. From the immediate stellar environment, we find possible evidence for three different populations; if the SN progenitor was a member of the youngest population, this would be consistent with an initial mass of ~57 M_sun. After it has faded, the SN should be reobserved at high spatial resolution and sensitivity, to determine whether the candidate is indeed the progenitor.Comment: Revised, following referee's comments, and accepted to ApJ; 21 pages, 10 figure

Heterogeneity of Human Neutrophil CD177 Expression Results from CD177P1 Pseudogene Conversion

Most humans harbor both CD177neg and CD177pos neutrophils but 1–10% of people are CD177null, placing them at risk for formation of anti-neutrophil antibodies that can cause transfusion-related acute lung injury and neonatal alloimmune neutropenia. By deep sequencing the CD177 locus, we catalogued CD177 single nucleotide variants and identified a novel stop codon in CD177null individuals arising from a single base substitution in exon 7. This is not a mutation in CD177 itself, rather the CD177null phenotype arises when exon 7 of CD177 is supplied entirely by the CD177 pseudogene (CD177P1), which appears to have resulted from allelic gene conversion. In CD177 expressing individuals the CD177 locus contains both CD177P1 and CD177 sequences. The proportion of CD177hi neutrophils in the blood is a heritable trait. Abundance of CD177hi neutrophils correlates with homozygosity for CD177 reference allele, while heterozygosity for ectopic CD177P1 gene conversion correlates with increased CD177neg neutrophils, in which both CD177P1 partially incorporated allele and paired intact CD177 allele are transcribed. Human neutrophil heterogeneity for CD177 expression arises by ectopic allelic conversion. Resolution of the genetic basis of CD177null phenotype identifies a method for screening for individuals at risk of CD177 isoimmunisation

DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project

The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine–guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

Self-tolerance by clonal anergy of B cells is marked by an increase in IgD and decrease in IgM antigen receptor surface expression, yet the function of IgD on anergic cells is obscure. Here we define the RNA landscape of the in vivo anergy response, comprising 220 induced sequences including a core set of 97. Failure to co-express IgD with IgM decreases overall expression of receptors for self-antigen, but paradoxically increases the core anergy response, exemplified by increased Sdc1 encoding the cell surface marker syndecan-1. IgD expressed on its own is nevertheless competent to induce calcium signalling and the core anergy mRNA response. Syndecan-1 induction correlates with reduction of surface IgM and is exaggerated without surface IgD in many transitional and mature B cells. These results show that IgD attenuates the response to self-antigen in anergic cells and promotes their accumulation. In this way, IgD minimizes tolerance-induced holes in the pre-immune antibody repertoire.This work was supported by NIH grant U19 AI100627 and NHMRC grants 585490, 1016953 and 1081858 to C.C.G., NHMRC CJ Martin Fellowship 595989 to J.H.R., an Endeavour Award from the Australian Government to Z.S. and the National Collaborative Research Infrastructure Scheme Australian Phenomics Facilit

Identifying the SN 2022acko progenitor with JWST

We report on analysis using the James Webb Space Telescope (JWST) to identify a candidate progenitor star of the Type II-plateau supernova SN 2022acko in the nearby, barred spiral galaxy NGC 1300. To our knowledge, our discovery represents the first time JWST has been used to localize a progenitor system in pre-explosion archival Hubble Space Telescope (HST) images. We astrometrically registered a JWST NIRCam image from 2023 January, in which the SN was serendipitously captured, to pre-SN HST F160W and F814W images from 2017 and 2004, respectively. An object corresponding precisely to the SN position has been isolated with reasonable confidence. That object has a spectral energy distribution (SED) and overall luminosity consistent with a single-star model having an initial mass possibly somewhat less than the canonical 8 Msun theoretical threshold for core collapse (although masses as high as 9 Msun for the star are also possible); however, the star's SED and luminosity are inconsistent with that of a super-asymptotic giant branch star which might be a forerunner of an electron-capture SN. The properties of the progenitor alone imply that SN 2022acko is a relatively normal SN II-P, albeit most likely a low-luminosity one. The progenitor candidate should be confirmed with follow-up HST imaging at late times, when the SN has sufficiently faded. This potential use of JWST opens a new era of identifying SN progenitor candidates at high spatial resolution.Comment: 8 pages, substantial changes from v1, to appear in MNRA

The blue supergiant progenitor of the Supernova Imposter at 2019krl

Extensive archival Hubble Space Telescope, Spitzer Space Telescope, and Large Binocular Telescope imaging of the recent intermediate-luminosity transient, AT 2019krl in M74, reveal a bright optical and mid-infrared progenitor star. While the optical peak of the event was missed, a peak was detected in the infrared with an absolute magnitude of M 4.5 μm = -18.4 mag, leading us to infer a visual-wavelength peak absolute magnitude of -13.5 to -14.5. The pre-discovery light curve indicated no outbursts over the previous 16 yr. The colors, magnitudes, and inferred temperatures of the progenitor best match a 13-14 M o˙ yellow or blue supergiant (BSG) if only foreground extinction is taken into account, or a hotter and more massive star if any additional local extinction is included. A pre-eruption spectrum of the star reveals strong Hα and [N ii] emission with wings extending to 2000 km s-1. The post-eruption spectrum is fairly flat and featureless with only Hα, Na i D, [Ca ii], and the Ca ii triplet in emission. As in many previous intermediate-luminosity transients, AT 2019krl shows remarkable observational similarities to luminous blue variable (LBV) giant eruptions, SN 2008S-like events, and massive-star mergers. However, the information about the pre-eruption star favors either a relatively unobscured BSG or a more extinguished LBV with M > 20 Mo˙ likely viewed pole-on.Fil: Andrews, Jennifer E.. University of Arizona; Estados UnidosFil: Jencson, Jacob E.. University of Arizona; Estados UnidosFil: Van Dyk, Schuyler D.. Spitzer Science Center; Estados UnidosFil: Smith, Nathan. University of Arizona; Estados UnidosFil: Neustadt, Jack M. M.. Ohio State University; Estados UnidosFil: Sand, David J.. University of Arizona; Estados UnidosFil: Kreckel, K.. Astronomisches Rechen-institut Heidelberg; AlemaniaFil: Kochanek, C.S.. Ohio State University; Estados UnidosFil: Valenti, S.. University of California at Davis; Estados UnidosFil: Strader, Jay. Michigan State University; Estados UnidosFil: Bersten, Melina Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Blanc, Guillermo A.. Universidad de Chile; ChileFil: Bostroem, K. Azalee. University of California at Davis; Estados UnidosFil: Brink, Thomas G.. University of California at Berkeley; Estados UnidosFil: Emsellem, Eric. European Southern Observatory; AlemaniaFil: Filippenko, Alexei V.. University of California at Berkeley; Estados UnidosFil: Folatelli, Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Kasliwal, Mansi. California Institute of Technology; Estados UnidosFil: Masci, Frank J.. Spitzer Science Center; Estados UnidosFil: McElroy, Rebecca. The University Of Sydney; AustraliaFil: Milisavljevic, Dan. Purdue University; Estados UnidosFil: Santoro, Francesco. Max Planck Institut für Astronomie; AlemaniaFil: Szalai, Tamás. University of Szeged; Hungrí

SN 2017ein and the Possible First Identification of a Type Ic Supernova Progenitor

We have identified a progenitor candidate in archival Hubble Space Telescope (HST) images for the Type Ic supernova (SN Ic) SN 2017ein in NGC 3938, pinpointing the candidate's location via HSTTarget of Opportunity imaging of the SN itself. This would be the first identification of a stellar-like object as a progenitor candidate for any SN Ic to date. We also present observations of SN 2017ein during the first ~49 days since explosion. We find that SN 2017ein most resembles the well-studied SN Ic SN 2007gr. We infer that SN 2017ein experienced a total visual extinction of A_V ≈ 1.0–1.9 mag, predominantly because of dust within the host galaxy. Although the distance is not well known, if this object is the progenitor, it was likely of high initial mass, ~47–48 M⊙ if a single star, or ~60–80 M⊙ if in a binary system. However, we also find that the progenitor candidate could be a very blue and young compact cluster, further implying a very massive (>65 M⊙) progenitor. Furthermore, the actual progenitor might not be associated with the candidate at all and could be far less massive. From the immediate stellar environment, we find possible evidence for three different populations; if the SN progenitor was a member of the youngest population, this would be consistent with an initial mass of ~57 M⊙. After it has faded, the SN should be reobserved at high spatial resolution and sensitivity, to determine whether the candidate is indeed the progenitor