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

Comparing Palliation Strategies for Single-ventricle Anatomy With Transposed Great Arteries and Systemic Outflow Obstruction

OBJECTIVE: Patients with complex single-ventricle anatomy with transposed great arteries and systemic outflow obstruction (SV-TGA-SOO) undergo varied initial palliation with ultimate goal of Fontan circulation. We examine a longitudinal experience with multiple techniques, including the largest published cohort following palliative arterial switch operation (pASO), to describe outcomes and decision-making factors. METHODS: Neonates with SV-TGA-SOO who underwent initial surgical palliation from 1995 to 2022 at a single institution were retrospectively reviewed. RESULTS: In total, 71 neonates with SV-TGA-SOO underwent index surgical palliation at a median age of 7 days (interquartile range, 6-10) by pASO (n = 23), pulmonary artery band (PAB) with or without arch repair (n = 25), or modified Norwood with Damus-Kaye-Stansel aortopulmonary amalgamation (n = 23). Single-ventricle pathology included double-inlet left ventricle (n = 37, 52%), tricuspid atresia (n = 27, 38%), and others (n = 7, 10%). All mortalities (n = 5, 7%) occurred in the first interstage period after PAB (n = 3) and Norwood (n = 2). Subaortic obstruction in the PAB group was addressed by operative resection (n = 10 total, 7 at index operation) and/or delayed aortopulmonary amalgamation (n = 13, 52%). Two patients with pASO (9%) had early postoperative coronary complications, 1 requiring operative revision. Median follow-up for survivors was 10.4 years (interquartile range, 4.5-16.6 years). Comparing patients by their initial palliation type, notable significant differences included size of bulboventricular foramen, weight at initial operation, operation duration, postoperative length of stay, time to second-stage palliation, multiple pulmonary artery reinterventions, and left pulmonary artery interventions. There were no significant differences in overall survival, Fontan completion, reintervention-free survival in the first interstage period, pulmonary artery reintervention-free survival, long-term systemic valve competency, or ventricular dysfunction. CONCLUSIONS: Excellent mid- to long-term outcomes are achievable following neonatal palliation for SV-TGA-SOO via pASO, PAB, and modified Norwood, with comparable survival and Fontan completion. Initial palliation strategy should be individualized to optimize anatomy and physiology for successful Fontan by ensuring an unobstructed subaortic pathway and accessible pulmonary arteries. pASO is a reasonable strategy to consider for these heterogeneous lesions

Prevalence of osteoporosis and incidence of hip fracture in women - secular trends over 30 years

<p>Abstract</p> <p>Background</p> <p>The number of hip fractures during recent decades has been reported to be increasing, partly because of an increasing proportion of elderly women in the society. However, whether changes in hip fracture annual incidence in women are attributable to secular changes in the prevalence of osteoporosis is unclear.</p> <p>Methods</p> <p>Bone mineral density was evaluated by single-photon absorptiometry at the distal radius in 456 women aged 50 years or above and living in the same city. The measurements were obtained by the same densitometer during three separate time periods: 1970-74 (n = 106), 1987-93 (n = 175) and 1998-1999 (n = 178), and the age-adjusted prevalence of osteoporosis in these three cohorts was calculated. Additionally, all hip fractures sustained in the target population of women aged 50 years or above between 1967 and 2001 were registered, whereupon the crude and the age-adjusted annual incidence of hip fractures were calculated.</p> <p>Results</p> <p>There was no significant difference in the age-adjusted prevalence of osteoporosis when the three cohorts were compared (P = 1.00). The crude annual incidence (per 10,000 women) of hip fracture in the target population increased by 110% from 40 in 1967 to 84 in 2001. The overall trend in the crude incidence between 1967 and 2001 was increasing (1.58 per 10,000 women per year; 95 percent confidence interval, 1.17 to 1.99), whereas the age-adjusted incidence was stable over the same period (0.22 per 10,000 women per year; 95 percent confidence interval, -0.16 to 0.60).</p> <p>Conclusions</p> <p>The increased number of hip fracture in elderly women is more likely to be attributable to demographic changes in the population than to secular increase in the prevalence of osteoporosis.</p

The ERI-6/7 Helicase Acts at the First Stage of an siRNA Amplification Pathway That Targets Recent Gene Duplications

Endogenous small interfering RNAs (siRNAs) are a class of naturally occuring regulatory RNAs found in fungi, plants, and animals. Some endogenous siRNAs are required to silence transposons or function in chromosome segregation; however, the specific roles of most endogenous siRNAs are unclear. The helicase gene eri-6/7 was identified in the nematode Caenorhabditis elegans by the enhanced response to exogenous double-stranded RNAs (dsRNAs) of the null mutant. eri-6/7 encodes a helicase homologous to small RNA factors Armitage in Drosophila, SDE3 in Arabidopsis, and Mov10 in humans. Here we show that eri-6/7 mutations cause the loss of 26-nucleotide (nt) endogenous siRNAs derived from genes and pseudogenes in oocytes and embryos, as well as deficiencies in somatic 22-nucleotide secondary siRNAs corresponding to the same loci. About 80 genes are eri-6/7 targets that generate the embryonic endogenous siRNAs that silence the corresponding mRNAs. These 80 genes share extensive nucleotide sequence homology and are poorly conserved, suggesting a role for these endogenous siRNAs in silencing of and thereby directing the fate of recently acquired, duplicated genes. Unlike most endogenous siRNAs in C. elegans, eri-6/7–dependent siRNAs require Dicer. We identify that the eri-6/7–dependent siRNAs have a passenger strand that is ∼19 nt and is inset by ∼3–4 nts from both ends of the 26 nt guide siRNA, suggesting non-canonical Dicer processing. Mutations in the Argonaute ERGO-1, which associates with eri-6/7–dependent 26 nt siRNAs, cause passenger strand stabilization, indicating that ERGO-1 is required to separate the siRNA duplex, presumably through endonucleolytic cleavage of the passenger strand. Thus, like several other siRNA–associated Argonautes with a conserved RNaseH motif, ERGO-1 appears to be required for siRNA maturation

Comparative Genomics Reveals Two Novel RNAi Factors in Trypanosoma brucei and Provides Insight into the Core Machinery

The introduction ten years ago of RNA interference (RNAi) as a tool for molecular exploration in Trypanosoma brucei has led to a surge in our understanding of the pathogenesis and biology of this human parasite. In particular, a genome-wide RNAi screen has recently been combined with next-generation Illumina sequencing to expose catalogues of genes associated with loss of fitness in distinct developmental stages. At present, this technology is restricted to RNAi-positive protozoan parasites, which excludes T. cruzi, Leishmania major, and Plasmodium falciparum. Therefore, elucidating the mechanism of RNAi and identifying the essential components of the pathway is fundamental for improving RNAi efficiency in T. brucei and for transferring the RNAi tool to RNAi-deficient pathogens. Here we used comparative genomics of RNAi-positive and -negative trypanosomatid protozoans to identify the repertoire of factors in T. brucei. In addition to the previously characterized Argonaute 1 (AGO1) protein and the cytoplasmic and nuclear Dicers, TbDCL1 and TbDCL2, respectively, we identified the RNA Interference Factors 4 and 5 (TbRIF4 and TbRIF5). TbRIF4 is a 3′-5′ exonuclease of the DnaQ superfamily and plays a critical role in the conversion of duplex siRNAs to the single-stranded form, thus generating a TbAGO1-siRNA complex required for target-specific cleavage. TbRIF5 is essential for cytoplasmic RNAi and appears to act as a TbDCL1 cofactor. The availability of the core RNAi machinery in T. brucei provides a platform to gain mechanistic insights in this ancient eukaryote and to identify the minimal set of components required to reconstitute RNAi in RNAi-deficient parasites

Plant ARGONAUTEs: Features, Functions and Unknowns

ARGONAUTEs (AGOs) are the effector proteins in eukaryotic small RNA(sRNA)– based gene silencing pathways controlling gene expression and transposon activity. In plants, AGOs regulate key biological processes such as development, response to stress, genome structure and integrity, and pathogen defense. Canonical functions of plant AGO–sRNA complexes include the endonucleolytic cleavage or translational inhibition of target RNAs, and the methylation of target DNAs. Here, I provide a brief update on the major features, molecular functions and biological roles of plant AGOs. A special focus is given to the more recent discoveries related to emerging molecular or biological functions of plant AGOs, as well as to the major unknowns in the plant AGO field.This work was supported by an Individual Fellowship from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 655841 to A.C.Carbonell Olivares, A. (2017). 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Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity