IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sj\uf6gren\u2019s syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions

On the progenitor of binary neutron star merger GW170817

On 2017 August 17 the merger of two compact objects with masses consistent with two neutron stars was discovered through gravitational-wave (GW170817), gamma-ray (GRB 170817A), and optical (SSS17a/AT 2017gfo) observations. The optical source was associated with the early-type galaxy NGC 4993 at a distance of just ∼40 Mpc, consistent with the gravitational-wave measurement, and the merger was localized to be at a projected distance of ∼2 kpc away from the galaxy's center. We use this minimal set of facts and the mass posteriors of the two neutron stars to derive the first constraints on the progenitor of GW170817 at the time of the second supernova (SN). We generate simulated progenitor populations and follow the three-dimensional kinematic evolution from binary neutron star (BNS) birth to the merger time, accounting for pre-SN galactic motion, for considerably different input distributions of the progenitor mass, pre-SN semimajor axis, and SN-kick velocity. Though not considerably tight, we find these constraints to be comparable to those for Galactic BNS progenitors. The derived constraints are very strongly influenced by the requirement of keeping the binary bound after the second SN and having the merger occur relatively close to the center of the galaxy. These constraints are insensitive to the galaxy's star formation history, provided the stellar populations are older than 1 Gyr

THE RATE OF BINARY BLACK HOLE MERGERS INFERRED FROM ADVANCED LIGO OBSERVATIONS SURROUNDING GW150914

A transient gravitational-wave signal, GW150914, was identi fi ed in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To asse ss the implications of this discovery, the detectors remained in operation with unchanged con fi gurations over a period of 39 days around the time of t he signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate ( FAR ) of < ́ -- 4.9 10 yr 61 , yielding a p -value for GW150914 of < ́ - 210 7 . Parameter estimation follo w-up on this trigger identi fi es its source as a binary black hole ( BBH ) merger with component masses ( )( ) = - + - + mm M ,36,29 12 4 5 4 4 at redshift = - + z 0.09 0.04 0.03 ( median and 90% credible range ) . Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between – -- 2 53 Gpc yr 31 ( comoving frame ) . Incorporating all search triggers that pass a much lower threshold while accounting for the uncerta inty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from – -- 13 600 Gpc yr 31 depending on assumptions about the BBH mass distribution. All together, our various rate estimat es fall in the conservative range – -- 2 600 Gpc yr 31

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS

Integrative epigenomics in Sjögren's syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune populati

Estimating the contribution of dynamical ejecta in the kilonova associated with GW170817

The source of the gravitational-wave (GW) signal GW170817, very likely a binary neutron star merger, was also observed electromagnetically, providing the first multi-messenger observations of this type. The two-week-long electromagnetic (EM) counterpart had a signature indicative of an r-process-induced optical transient known as a kilonova. This Letter examines how the mass of the dynamical ejecta can be estimated without a direct electromagnetic observation of the kilonova, using GW measurements and a phenomenological model calibrated to numerical simulations of mergers with dynamical ejecta. Specifically, we apply the model to the binary masses inferred from the GW measurements, and use the resulting mass of the dynamical ejecta to estimate its contribution (without the effects of wind ejecta) to the corresponding kilonova light curves from various models. The distributions of dynamical ejecta mass range between Mej = 10 -³ - 10-² M⊙ for various equations of state, assuming that the neutron stars are rotating slowly. In addition, we use our estimates of the dynamical ejecta mass and the neutron star merger rates inferred from GW170817 to constrain the contribution of events like this to the r-process element abundance in the Galaxy when ejecta mass from post-merger winds is neglected. We find that if 10% of the matter dynamically ejected from binary neutron star (BNS) mergers is converted to r-process elements, GW170817-like BNS mergers could fully account for the amount of r-process material observed in the Milky Way

First targeted search for gravitational-wave bursts from core-collapse supernovae in data of first-generation laser interferometer detectors

We present results from a search for gravitational-wave bursts coincident with two core-collapse supernovae observed optically in 2007 and 2011. We employ data from the Laser Interferometer Gravitational-wave Observatory (LIGO), the Virgo gravitational-wave observatory, and the GEO 600 gravitational-wave observatory. The targeted core-collapse supernovae were selected on the basis of (1) proximity (within approximately 15 Mpc), (2) tightness of observational constraints on the time of core collapse that defines the gravitational-wave search window, and (3) coincident operation of at least two interferometers at the time of core collapse. We find no plausible gravitational-wave candidates. We present the probability of detecting signals from both astrophysically well-motivated and more speculative gravitational-wave emission mechanisms as a function of distance from Earth, and discuss the implications for the detection of gravitational waves from core-collapse supernovae by the upgraded Advanced LIGO and Virgo detectors

Low-latency gravitational-wave alerts for multimessenger astronomy during the second Advanced LIGO and Virgo observing run

Advanced LIGO's second observing run (O2), conducted from 2016 November 30 to 2017 August 25, combined with Advanced Virgo's first observations in 2017 August, witnessed the birth of gravitational-wave multimessenger astronomy. The first ever gravitational-wave detection from the coalescence of two neutron stars, GW170817, and its gamma-ray counterpart, GRB 170817A, led to an electromagnetic follow-up of the event at an unprecedented scale. Several teams from across the world searched for EM/neutrino counterparts to GW170817, paving the way for the discovery of optical, X-ray, and radio counterparts. In this article, we describe the online identification of gravitational-wave transients and the distribution of gravitational-wave alerts by the LIGO and Virgo collaborations during O2. We also describe the gravitational-wave observables that were sent in the alerts to enable searches for their counterparts. Finally, we give an overview of the online candidate alerts shared with observing partners during O2. Alerts were issued for 14 candidates, 6 of which have been confirmed as gravitational-wave events associated with the merger of black holes or neutron stars. Of the 14 alerts, 8 were issued less than an hour after data acquisition

Observation of gravitational waves from a binary black hole merger

Albert Einstein's general theory of relativity, first published a century ago, was described by physicist Max Born as "the greatest feat of human thinking about nature."We report on two major scientific breakthroughs involving key predictions of Einstein's theory: the first direct detection of gravitational waves and the first observation of the collision and merger of a pair of black holes. This cataclysmic event, producing the gravitational-wave signal GW150914, took place in a distant galaxy more than one billion light years from the Earth. It was observed on September 14, 2015 by the two detectors of the Laser Interferometer Gravitational-Wave Observatory (LIGO), arguably the most sensitive scientific instruments ever constructed. LIGO estimated that the peak gravitational-wave power radiated during the final moments of the black hole merger was more than ten times greater than the combined light power from all the stars and galaxies in the observable Universe. This remarkable discovery marks the beginning of an exciting new era of astronomy as we open an entirely new, gravitational-wave window on the Universe