Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding.

Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent β-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

FMR1 premutation and full mutation molecular mechanisms related to autism

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism

Identification and mitigation of narrow spectral artifacts that degrade searches for persistent gravitational waves in the first two observing runs of Advanced LIGO

Searches are under way in Advanced LIGO and Virgo data for persistent gravitational waves from continuous sources, e.g. rapidly rotating galactic neutron stars, and stochastic sources, e.g. relic gravitational waves from the Big Bang or superposition of distant astrophysical events such as mergers of black holes or neutron stars. These searches can be degraded by the presence of narrow spectral artifacts (lines) due to instrumental or environmental disturbances. We describe a variety of methods used for finding, identifying and mitigating these artifacts, illustrated with particular examples. Results are provided in the form of lists of line artifacts that can safely be treated as non-astrophysical. Such lists are used to improve the efficiencies and sensitivities of continuous and stochastic gravitational wave searches by allowing vetoes of false outliers and permitting data cleaning

Identification and mitigation of narrow spectral artifacts that degrade searches for persistent gravitational waves in the first two observing runs of Advanced LIGO

Searches are under way in Advanced LIGO and Virgo data for persistent gravitational waves from continuous sources, e.g. rapidly rotating galactic neutron stars, and stochastic sources, e.g. relic gravitational waves from the Big Bang or superposition of distant astrophysical events such as mergers of black holes or neutron stars. These searches can be degraded by the presence of narrow spectral artifacts (lines) due to instrumental or environmental disturbances. We describe a variety of methods used for finding, identifying and mitigating these artifacts, illustrated with particular examples. Results are provided in the form of lists of line artifacts that can safely be treated as non-astrophysical. Such lists are used to improve the efficiencies and sensitivities of continuous and stochastic gravitational wave searches by allowing vetoes of false outliers and permitting data cleaning.Comment: 21 page

First measurement of the Hubble Constant from a Dark Standard Siren using the Dark Energy Survey Galaxies and the LIGO/Virgo Binary–Black-hole Merger GW170814

International audienceWe present a multi-messenger measurement of the Hubble constant H 0 using the binary–black-hole merger GW170814 as a standard siren, combined with a photometric redshift catalog from the Dark Energy Survey (DES). The luminosity distance is obtained from the gravitational wave signal detected by the Laser Interferometer Gravitational-Wave Observatory (LIGO)/Virgo Collaboration (LVC) on 2017 August 14, and the redshift information is provided by the DES Year 3 data. Black hole mergers such as GW170814 are expected to lack bright electromagnetic emission to uniquely identify their host galaxies and build an object-by-object Hubble diagram. However, they are suitable for a statistical measurement, provided that a galaxy catalog of adequate depth and redshift completion is available. Here we present the first Hubble parameter measurement using a black hole merger. Our analysis results in , which is consistent with both SN Ia and cosmic microwave background measurements of the Hubble constant. The quoted 68% credible region comprises 60% of the uniform prior range [20, 140] km s−1 Mpc−1, and it depends on the assumed prior range. If we take a broader prior of [10, 220] km s−1 Mpc−1, we find (57% of the prior range). Although a weak constraint on the Hubble constant from a single event is expected using the dark siren method, a multifold increase in the LVC event rate is anticipated in the coming years and combinations of many sirens will lead to improved constraints on H 0

A gravitational-wave standard siren measurement of the Hubble constant

On 17 August 2017, the Advanced LIGO 1 and Virgo 2 detectors observed the gravitational-wave event GW170817-a strong signal from the merger of a binary neutron-star system 3 . Less than two seconds after the merger, a γ-ray burst (GRB 170817A) was detected within a region of the sky consistent with the LIGO-Virgo-derived location of the gravitational-wave source 4-6 . This sky region was subsequently observed by optical astronomy facilities 7 , resulting in the identification 8-13 of an optical transient signal within about ten arcseconds of the galaxy NGC 4993. This detection of GW170817 in both gravitational waves and electromagnetic waves represents the first 'multi-messenger' astronomical observation. Such observations enable GW170817 to be used as a 'standard siren' 14-18 (meaning that the absolute distance to the source can be determined directly from the gravitational-wave measurements) to measure the Hubble constant. This quantity represents the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Here we report a measurement of the Hubble constant that combines the distance to the source inferred purely from the gravitational-wave signal with the recession velocity inferred from measurements of the redshift using the electromagnetic data. In contrast to previous measurements, ours does not require the use of a cosmic 'distance ladder' 19 : the gravitational-wave analysis can be used to estimate the luminosity distance out to cosmological scales directly, without the use of intermediate astronomical distance measurements. We determine the Hubble constant to be about 70 kilometres per second per megaparsec. This value is consistent with existing measurements 20,21 , while being completely independent of them. Additional standard siren measurements from future gravitationalwave sources will enable the Hubble constant to be constrained to high precision

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

GW170104: Observation of a 50-Solar-Mass Binary Black Hole Coalescence at Redshift 0.2

We describe the observation of GW170104, a gravitational-wave signal produced by the coalescence of a pair of stellar-mass black holes. The signal was measured on January 4, 2017 at 10: 11: 58.6 UTC by the twin advanced detectors of the Laser Interferometer Gravitational-Wave Observatory during their second observing run, with a network signal-to-noise ratio of 13 and a false alarm rate less than 1 in 70 000 years. The inferred component black hole masses are 31.2(-6.0)(+8.4)M-circle dot and 19.4(-5.9)(+5.3)M(circle dot) (at the 90% credible level). The black hole spins are best constrained through measurement of the effective inspiral spin parameter, a mass-weighted combination of the spin components perpendicular to the orbital plane, chi(eff) = -0.12(-0.30)(+0.21) . This result implies that spin configurations with both component spins positively aligned with the orbital angular momentum are disfavored. The source luminosity distance is 880(-390)(+450) Mpc corresponding to a redshift of z = 0.18(-0.07)(+0.08) . We constrain the magnitude of modifications to the gravitational-wave dispersion relation and perform null tests of general relativity. Assuming that gravitons are dispersed in vacuum like massive particles, we bound the graviton mass to m(g) <= 7.7 x 10(-23) eV/c(2). In all cases, we find that GW170104 is consistent with general relativity