A magnetic massive star has experienced a stellar merger.

Massive stars (those ≥8 solar masses at formation) have radiative envelopes that cannot sustain a dynamo, the mechanism that produces magnetic fields in lower-mass stars. Despite this, approximately 7% of massive stars have observed magnetic fields, the origin of which is debated. We used multi-epoch interferometric and spectroscopic observations to characterize HD 148937, a binary system of two massive stars. We found that only one star is magnetic and that it appears younger than its companion. The system properties and a surrounding bipolar nebula can be reproduced with a model in which two stars merged (in a previous triple system) to produce the magnetic massive star. Our results provide observational evidence that magnetic fields form in at least some massive stars through stellar mergers.

Newly formed dust within the circumstellar environment of SN Ia-CSM 2018evt.

Dust associated with various stellar sources in galaxies at all cosmic epochs remains a controversial topic, particularly whether supernovae play an important role in dust production. We report evidence of dust formation in the cold, dense shell behind the ejecta-circumstellar medium (CSM) interaction in the Type Ia-CSM supernova (SN) 2018evt three years after the explosion, characterized by a rise in mid-infrared emission accompanied by an accelerated decline in the optical radiation of the SN. Such a dust-formation picture is also corroborated by the concurrent evolution of the profiles of the Hα emission line. Our model suggests enhanced CSM dust concentration at increasing distances from the SN as compared to what can be expected from the density profile of the mass loss from a steady stellar wind. By the time of the last mid-infrared observations at day +1,041, a total amount of 1.2 ± 0.2 × 10-2 M⊙ of new dust has been formed by SN 2018evt, making SN 2018evt one of the most prolific dust factories among supernovae with evidence of dust formation. The unprecedented witness of the intense production procedure of dust may shed light on the perceptions of dust formation in cosmic history.

[Genetic counselling and testing in pulmonary arterial hypertension - A consensus statement on behalf of the International Consortium for Genetic Studies in PAH - French version]. / Conseil génétique et dépistage de l'hypertension artérielle pulmonaire ­ consensus du Consortium international pour les études génétiques dans l'HTAP ­ version française.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder characterized by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, B-cell lymphoma X (Bcl-x) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs while inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor-like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target.

Electromagnetic evidence that SSS17a is the result of a binary neutron star merger.

Eleven hours after the detection of gravitational wave source GW170817 by the Laser Interferometer Gravitational-Wave Observatory and Virgo Interferometers, an associated optical transient, SSS17a, was identified in the galaxy NGC 4993. Although the gravitational wave data indicate that GW170817 is consistent with the merger of two compact objects, the electromagnetic observations provide independent constraints on the nature of that system. We synthesize the optical to near-infrared photometry and spectroscopy of SSS17a collected by the One-Meter Two-Hemisphere collaboration, finding that SSS17a is unlike other known transients. The source is best described by theoretical models of a kilonova consisting of radioactive elements produced by rapid neutron capture (the r-process). We conclude that SSS17a was the result of a binary neutron star merger, reinforcing the gravitational wave result.

Early spectra of the gravitational wave source GW170817: Evolution of a neutron star merger.

On 17 August 2017, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of SSS17a from 11.75 hours until 8.5 days after the merger. Over the first hour of observations, the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measured the photosphere cooling from [Formula: see text] to [Formula: see text] kelvin, and determined a photospheric velocity of roughly 30% of the speed of light. The spectra of SSS17a began displaying broad features after 1.46 days and evolved qualitatively over each subsequent day, with distinct blue (early-time) and red (late-time) components. The late-time component is consistent with theoretical models of r-process-enriched neutron star ejecta, whereas the blue component requires high-velocity, lanthanide-free material.

Light curves of the neutron star merger GW170817/SSS17a: Implications for r-process nucleosynthesis.

On 17 August 2017, gravitational waves (GWs) were detected from a binary neutron star merger, GW170817, along with a coincident short gamma-ray burst, GRB 170817A. An optical transient source, Swope Supernova Survey 17a (SSS17a), was subsequently identified as the counterpart of this event. We present ultraviolet, optical, and infrared light curves of SSS17a extending from 10.9 hours to 18 days postmerger. We constrain the radioactively powered transient resulting from the ejection of neutron-rich material. The fast rise of the light curves, subsequent decay, and rapid color evolution are consistent with multiple ejecta components of differing lanthanide abundance. The late-time light curve indicates that SSS17a produced at least ~0.05 solar masses of heavy elements, demonstrating that neutron star mergers play a role in rapid neutron capture (r-process) nucleosynthesis in the universe.

Astronomy. ASASSN-15lh: A highly super-luminous supernova.

We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± 0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.

Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.

Global analysis of the haematopoietic and endothelial transcriptome during zebrafish development.

In this paper, we use zebrafish embryos to characterise the transcriptome of the developing blood and endothelium, two cell types that are closely associated during development. High-throughput sequencing identified 754 genes whose transcripts are enriched threefold or more in blood and/or vascular endothelial cells compared with the rest of the embryo at 26-28 h post fertilisation. Of these genes, 388 were classified as novel to these cell types after cross-reference with PubMed and the zebrafish information network (ZFIN). Analysis by quantitative PCR and in situ hybridisation showed that 83% (n=41) of these novel genes are expressed in blood or vascular endothelium. Of 10 novel genes selected for knockdown by antisense morpholino oligonucleotides, we confirmed that two, tmem88a and trim2a, are required for primitive erythropoiesis and myelopoiesis. Our results provide a catalogue of genes whose expression is enriched in the developing blood and endothelium in zebrafish, many of which will be required for the development of those cell types, both in fish and in mammals.

Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema.

We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.

The course of the distal saphenous nerve: a cadaveric investigation and clinical implications.

INTRODUCTION: Injury to the saphenous nerve at the ankle has been described as a complication resulting from incision and dissection over the distal tibia and medial malleolus. However, the exact course and location of the distal saphenous nerve is not well described in the literature. The purpose of this study was to determine the distal limit of the saphenous nerve and its anatomic relationship to commonly identified orthopaedic landmarks and surgical incisions. METHODS: Sixteen cadaveric ankles were examined at the level of the distal tibia medial malleolus. An incision was made along the medial aspect of the lower extremity from the knee to the hallux to follow the course and branches of the saphenous nerve under direct visualization. We recorded the shortest distance from the most distal visualized portion of the saphenous nerve to the tip of the medial malleolus, to the antero-medial arthroscopic portal site, and to the tibialis anterior tendon. RESULTS: The saphenous nerve runs posterior to the greater saphenous vein in the leg and divides into an anterior and posterior branch approximately 3 cm proximal to the tip of the medial malleolus. These branches terminate in the integument proximal to the tip of the medial malleolus, while the vein continues into the foot. The anterior branch ends at the anterior aspect of the medial malleolus near the posterior edge of the greater saphenous vein. The posterior branch ends near the posterior aspect of the medial malleolus. The average distance from the distal-most visualized aspect of the saphenous nerve to the tip of the medial malleolus measured 8mm +/-; 5mm; from the nerve to the medial arthroscopic portal measured 14mm +/-2mm; and from the nerve to the tibialis anterior measured 16mm +/-3mm. In only one case (of 16) was there an identifiable branch of the saphenous nerve extending to the foot and in this specimen it extended to the first metatarsophalangeal joint. The first metatarsophalangeal joint was innervated by the superficial peroneal nerve in all cases. Small variations were also noted. DISCUSSION AND CONCLUSIONS: This study highlights the proximity of the distal saphenous nerve to common landmarks in orthopaedic surgery. This has important clinical implications in ankle arthroscopy, tarsal tunnel syndrome, fixation of distal tibia medial malleolar fractures, and other procedures centered about the medial malleolus. While the distal course of the saphenous nerve is generally predictable, variations exist and thus the orthopaedic surgeon must operate cautiously to prevent iatrogenic injury. To avoid saphenous nerve injury, incisions should stay distal to the tip of the medial malleolus. The medial arthroscopic portal should be more than one centimeter from the anterior aspect of the medial malleolus which will also avoid the greater saphenous vein. Incision over the anterior tibialis tendon should stay within one centimeter of the medial edge of the tendon.

Circumstellar material in type Ia supernovae via sodium absorption features.

Type Ia supernovae are key tools for measuring distances on a cosmic scale. They are generally thought to be the thermonuclear explosion of an accreting white dwarf in a close binary system. The nature of the mass donor is still uncertain. In the single-degenerate model it is a main-sequence star or an evolved star, whereas in the double-degenerate model it is another white dwarf. We show that the velocity structure of absorbing material along the line of sight to 35 type Ia supernovae tends to be blueshifted. These structures are likely signatures of gas outflows from the supernova progenitor systems. Thus, many type Ia supernovae in nearby spiral galaxies may originate in single-degenerate systems.

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(2A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(2B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.

Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists.

BACKGROUND AND PURPOSE: Bone morphogenetic proteins (BMPs) were first identified through their role in inducing bone and cartilage formation, but many other important functions have since been ascribed to BMPs, including dorsoventral patterning, angiogenesis and tissue homeostasis. Using dorsomorphin and LDN193189, selective small molecule inhibitors of BMP signalling, we investigated the role of BMP signalling in early vascular patterning in zebrafish. EXPERIMENTAL APPROACH: The effects of dorsomorphin and LDN193189 on vascular endothelial growth factor-a (VEGF) and BMP signalling in developing zebrafish and in human pulmonary artery endothelial cells were determined using confocal microscopy, Western blotting and quantitative PCR. KEY RESULTS: We showed that dorsomorphin, similar to the VEGF inhibitor SU5416, strongly inhibits intersegmental vessel formation in zebrafish and that this is due to inhibition of VEGF activation of VEGF receptor 2 (VEGFR2), leading to reduced VEGF-induced phospho-ERK (extracellular regulated kinase) 1/2 and VEGF target gene transcription. These effects occurred at concentrations of dorsomorphin that block BMP signalling. We also showed that LDN193189, an analogue of dorsomorphin, more potently blocks BMP signalling but has no effect on VEGF signalling in zebrafish and does not disrupt early vascular patterning. CONCLUSIONS AND IMPLICATIONS: Dorsomorphin inhibits both BMP and VEGF signalling, whereas LDN193189 is a more selective BMP antagonist. Results obtained in cardiovascular studies using dorsomorphin need to be interpreted with caution, and use of LDN193189 would be preferable due to its selectivity. Our data also suggest that BMP signalling is dispensable for early patterning of intersegmental vessels in zebrafish.

Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension.

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

Pulmonary hypertension: advances in pathogenesis and treatment.

Pulmonary hypertension is an orphan disease that until recently has received limited attention within the wider medical community. This has changed distinctly in the last 10 years with the advent of new classes of therapy and a renewed interest in mechanisms of pathogenesis. This review utilized information gathered from recent conferences, and a review of the literature was conducted using MedLine and Pubmed. Accepted mechanisms of pathogenesis and currently available treatments are presented. We will discuss interesting new concepts in pathogenesis, including the importance of genetic forms of the disease and in particular the transforming growth factor receptor superfamily and the evolving evidence of the contribution of dysregulated immunity. Areas of research may yield therapeutic benefits in the not-too-distant future, including anti-proliferative therapies and stem cell therapy.

Endothelial progenitor cells in pulmonary hypertension - dawn of cell-based therapy?

There is mounting interest in the concept of endothelial progenitor cell (EPC) therapy for the treatment of pulmonary arterial hypertension (PAH). Recent successful pilot studies in idiopathic PAH have raised questions about the contribution of progenitor cells circulating in the peripheral blood to pulmonary vascular homeostasis and to the process of vascular remodelling. This review will summarise the work performed to date in animal and human therapeutic trials and clarify what is known about the potential contribution of EPCs to the pathophysiology of PAH.

Controlling the in vivo activity of Wnt liposomes.

Liposomes offer a method of delivering small molecules, nucleic acids, and proteins to sites within the body. Typically, bioactive materials are encapsulated within the liposomal aqueous core and liposomal phase transition is elicited by pH or temperature changes. We developed a new class of liposomes for the in vivo delivery of lipid-modified proteins. First, we show that the inclusion of a chromophore into the liposomal or vesosomal membrane renders these lipid vesicles extremely sensitive to very small (muJ) changes in energy. Next, we demonstrate that the lipid-modified Wnt protein is not encapsulated within a liposome but rather is tethered to the exoliposomal surface in an active configuration. When applied to intact skin, chromophore-modified liposomes do not penetrate past the corneal layer of the epidermis, but remain localized to the site of application. Injury to the epidermis allows rapid penetration of liposomes into the dermis, which suggests that mild forms of dermabrasion will greatly enhance transdermal delivery of liposome-packaged molecules. Finally, we demonstrate that topical application of Wnt3a liposomes rapidly stimulates proliferation of cells in the corneal layer, resulting in a thicker, more fibrillous epidermis.