Calreticulin is a secreted BMP antagonist, expressed in Hensen's node during neural induction

Hensen's node is the “organizer” of the avian and mammalian early embryo. It has many functions, including neural induction and patterning of the ectoderm and mesoderm. Some of the signals responsible for these activities are known but these do not explain the full complexity of organizer activity. Here we undertake a functional screen to discover new secreted factors expressed by the node at this time of development. Using a Signal Sequence Trap in yeast, we identify several candidates. Here we focus on Calreticulin. We show that in addition to its known functions in intracellular Calcium regulation and protein folding, Calreticulin is secreted, it can bind to BMP4 and act as a BMP antagonist in vivo and in vitro. Calreticulin is not sufficient to account for all organizer functions but may contribute to the complexity of its activity

Communication and Low Mood (CALM): a randomized controlled trial of behavioural therapy for stroke patients with aphasia

Objective: The aim was to evaluate behavioural therapy as a treatment for low mood in people with aphasia. Design: A randomized controlled trial comparing behavioural therapy plus usual care with a usual care control. Potential participants with aphasia after stroke were screened for the presence of low mood. Those who met the criteria and gave consent were randomly allocated. Setting: Participants were recruited from hospital wards, community rehabilitation, speech and language therapy services and stroke groups. Subjects: Of 511 people with aphasia identified, 105 had low mood and were recruited. Interventions: Behavioural therapy was offered for up to three months. Outcomes were assessed three and six months after random allocation. Main measures: Stroke Aphasic Depression Questionnaire, Visual Analog Mood Scales ‘sad’ item, and Visual Analogue Self-Esteem Scale. Results: Participants were aged 29 to 94 years (mean 67.0, SD 13.5) and 66 (63%) were men. Regression analysis showed that at three months, when baseline values and communication impairment were controlled for, group allocation was a significant predictor of the Stroke Aphasic Depression Questionnaire (P < 0.05), visual analogue ‘sad’ (P = 0.03), and Visual Analogue Self-Esteem Scale (P < 0.01). At six months, group alone was a significant predictor of the Stroke Aphasic Depression Questionnaire (P < 0.05), and remained significant when baseline values were controlled for (P = 0.02). Mean Stroke Aphasic Depression Questionnaire 10-item hospital version scores decreased from baseline to six months by six points in the intervention group as compared with an increase of 1.9 points in the control group. Conclusions: Behavioural therapy seemed to improve the mood of people with aphasia

Continuous heating of a giant X-ray flare on Algol

Giant flares can release large amounts of energy within a few days: X-ray emission alone can be up to ten percent of the star's bolometric luminosity. These flares exceed the luminosities of the largest solar flares by many orders of magnitude, which suggests that the underlying physical mechanisms supplying the energy are different from those on the Sun. Magnetic coupling between the components in a binary system or between a young star and an accretion disk has been proposed as a prerequisite for giant flares. Here we report X-ray observations of a giant flare on Algol B, a giant star in an eclipsing binary system. We observed a total X-ray eclipse of the flare, which demonstrates that the plasma was confined to Algol B, and reached a maximum height of 0.6 stellar radii above its surface. The flare occurred around the south pole of Algol B, and energy must have been released continously throughout its life. We conclude that a specific extrastellar environment is not required for the presence of a flare, and that the processes at work are therefore similar to those on the Sun.Comment: Nature, Sept. 2 199

Imaging Coulomb Islands in a Quantum Hall Interferometer

In the Quantum Hall regime, near integer filling factors, electrons should only be transmitted through spatially-separated edge states. However, in mesoscopic systems, electronic transmission turns out to be more complex, giving rise to a large spectrum of magnetoresistance oscillations. To explain these observations, recent models put forward that, as edge states come close to each other, electrons can hop between counterpropagating edge channels, or tunnel through Coulomb islands. Here, we use scanning gate microscopy to demonstrate the presence of quantum Hall Coulomb islands, and reveal the spatial structure of transport inside a quantum Hall interferometer. Electron islands locations are found by modulating the tunneling between edge states and confined electron orbits. Tuning the magnetic field, we unveil a continuous evolution of active electron islands. This allows to decrypt the complexity of high magnetic field magnetoresistance oscillations, and opens the way to further local scale manipulations of quantum Hall localized states

Searching for Exoplanets Using a Microresonator Astrocomb

Detection of weak radial velocity shifts of host stars induced by orbiting planets is an important technique for discovering and characterizing planets beyond our solar system. Optical frequency combs enable calibration of stellar radial velocity shifts at levels required for detection of Earth analogs. A new chip-based device, the Kerr soliton microcomb, has properties ideal for ubiquitous application outside the lab and even in future space-borne instruments. Moreover, microcomb spectra are ideally suited for astronomical spectrograph calibration and eliminate filtering steps required by conventional mode-locked-laser frequency combs. Here, for the calibration of astronomical spectrographs, we demonstrate an atomic/molecular line-referenced, near-infrared soliton microcomb. Efforts to search for the known exoplanet HD 187123b were conducted at the Keck-II telescope as a first in-the-field demonstration of microcombs

An 800-million-solar-mass black hole in a significantly neutral Universe at redshift 7.5

Quasars are the most luminous non-transient objects known and as a result they enable studies of the Universe at the earliest cosmic epochs. Despite extensive efforts, however, the quasar ULAS J1120+0641 at z=7.09 has remained the only one known at z>7 for more than half a decade. Here we report observations of the quasar ULAS J134208.10+092838.61 (hereafter J1342+0928) at redshift z=7.54. This quasar has a bolometric luminosity of 4e13 times the luminosity of the Sun and a black hole mass of 8e8 solar masses. The existence of this supermassive black hole when the Universe was only 690 million years old---just five percent of its current age---reinforces models of early black-hole growth that allow black holes with initial masses of more than about 1e4 solar masses or episodic hyper-Eddington accretion. We see strong evidence of absorption of the spectrum of the quasar redwards of the Lyman alpha emission line (the Gunn-Peterson damping wing), as would be expected if a significant amount (more than 10 per cent) of the hydrogen in the intergalactic medium surrounding J1342+0928 is neutral. We derive a significant fraction of neutral hydrogen, although the exact fraction depends on the modelling. However, even in our most conservative analysis we find a fraction of more than 0.33 (0.11) at 68 per cent (95 per cent) probability, indicating that we are probing well within the reionization epoch of the Universe.Comment: Updated to match the final journal versio

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care

Acknowledgements We thank Robin Taylor for his informative thinking and publications on FeNO, which have helped to influence and direct the thinking of the authors. Funding Extraction of the real-life dataset was funded by Research in Real Life Limited, the analysis of the dataset and the writing of this manuscript were co-funded (50:50) by Research in Real Life Limited and Aerocrine.Peer reviewedPublisher PD

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles

Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in ω (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low ω global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes