Maximum Entropy Estimation of the Galactic Bulge Morphology via the VVV Red Clump

The abundance and narrow magnitude dispersion of Red Clump (RC) stars make them a popular candidate for mapping the morphology of the bulge region of the Milky Way. Using an estimate of the RC's intrinsic luminosity function, we extracted the three-dimensional density distribution of the RC from deep photometric catalogues of the VISTA Variables in the Via Lactea (VVV) survey. We used maximum entropy based deconvolution to extract the spatial distribution of the bulge from Ks-band star counts. We obtained our extrapolated non-parametric model of the bulge over the inner 40 by 40 degrees squared region of the Galactic centre. Our reconstruction also naturally matches onto a parametric fit to the bulge outside the VVV region and inpaints overcrowded and high extinction regions. We found a range of bulge properties consistent with other recent investigations based on the VVV data. In particular, we estimated the bulge mass to be in the range 13 to 17 billion solar masses, the X-component to be between 18% and 25% of the bulge mass, and the bulge angle with respect to the Sun-Galactic centre line to be between 18 and 32 degrees. Studies of the Fermi Large Area Telescope (LAT) gamma-ray Galactic centre excess suggests that the excess may be traced by Galactic bulge distributed sources. We applied our deconvolved density in a template fitting analysis of this Fermi-LAT GeV excess and found an improvement in the fit compared to previous parametric based templates.Comment: 25 pages, 27 figures, minor typo correcte

Non-Parametric Density Reconstruction of the Galactic Bulge Area using Red Clump Stars in the VVV Survey

Studies of the red clump giant population in the inner Milky Way suggest the Galactic bulge/bar has a boxy/peanut/X-shaped structure as predicted by its formation via a disc buckling instability. We used a non-parametric method of estimating the Galactic bulge morphology that is based on maximum entropy regularisation. This enabled us to extract the three-dimensional distribution of the red giant stars in the bulge from deep photometric catalogues of the VISTA Variables in the Via Lactea (VVV) survey. Our high-resolution reconstruction confirms the well-known boxy/peanut/X-shaped structure of the bulge. We also find spiral arm structures that extend to around three kpc in front of and behind the bulge and are on different sides of the bulge major axis. We show that the detection of these structures is robust to the uncertainties in the luminosity function.Comment: 12 pages, 8 figures, V4: MNRAS accepted versio

A New Mechanism for Generation of Langmuir Circulations

A new mechanism has been identified that explains the generation of Langmuir circulations. A wind-driven current in the presence of surface waves gives rise to an instability where the emerging circulations redistribute the turbulence in the cross-wind direction. The non-uniform eddy-viscosity locally changes the rate of momentum transfer from the wind to the shear current, producing a non-uniform velocity field. The interaction of this non-uniform velocity field with the surface waves, due to the Craik-Leibovich vortex force, amplifies the circulations and creates a feedback mechanism. The currently accepted CL2 model of instability assumes a constant eddy-viscosity. This paper presents a model which explains the generation of Langmuir circulations and its predictions of both spatial and time scales are in good agreement with experimental results. The modeling approach combines a perturbation method with a RANS turbulence model. Through parametric variation of the perturbation, the growth rate and spatial scales of the circulations are extracted from the simulations

A new species of Magelona (Polychaeta: Magelonidae) from southern Namibia

A new species of Magelonidae, Magelona debeerei sp. nov., is described and illustrated from grab-samples collected at <100moff the southwest coast of Africa. Magelona debeerei sp. nov. has previously been identified from the region as M. papillicornis (Müller, 1858) by Day (1955, 1961, 1967) but differs from M. papillicornis sensu stricto by possessing dorsal medial lobes on chaetigers 4–8 and lateral pouches (Σ configuration) between chaetigers 10 and 11. Three species of Magelona have now been recorded from southern Africa (M. capensis Day, 1961, M. cincta Ehlers, 1908 and M. debeerei sp. nov.), and a key to Magelona from this region is provided

Both Geography and Ecology Contribute to Mating Isolation in Guppies

Local adaptation to different environments can promote mating isolation – either as an incidental by-product of trait divergence, or as a result of selection to avoid maladaptive mating. Numerous recent empirical examples point to the common influence of divergent natural selection on speciation based largely on evidence of strong pre-mating isolation between populations from different habitat types. Accumulating evidence for natural selection's influence on speciation is therefore no longer a challenge. The difficulty, rather, is in determining the mechanisms involved in the progress of adaptive divergence to speciation once barriers to gene flow are already present. Here, we present results of both laboratory and field experiments with Trinidadian guppies (Poecilia reticulata) from different environments, who do not show complete reproductive isolation despite adaptive divergence. We investigate patterns of mating isolation between populations that do and do not exchange migrants and show evidence for both by-product and reinforcement mechanisms depending on female ecology. Specifically, low-predation females discriminate against all high-predation males thus implying a by-product mechanism, whereas high-predation females only discriminate against low-predation males from further upstream in the same river, implying selection to avoid maladaptive mating. Our study thus confirms that mechanisms of adaptive speciation are not necessarily mutually exclusive and uncovers the complex ecology-geography interactions that underlie the evolution of mating isolation in nature

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570