The relation of metal-poor stars to nearby solar analogues

Sun-like dwarf stars in the solar neighborhood reflect ages, an ``average'' chemical evolution, and departures from that average. We show the chemical, and kinematic properties of four groups of Sunlike dwarfs form a continuum related to age. We plot [Fe/H] vs. age, as well as kinematical values for the four groups. The vertical (negative) scatter in [Fe/H] increases with age in a systematic way: as the age increases, [Fe/H] decreases. The sets of Solar and metal-poor stars in the solar neighborhood are related by distributions in [Fe/H] vs. age, as well as in Galactic position (XYZ) and velocity space (UVW). Among the samples there are no clusters of points that set one sample apart from the others. The distributions vary slowly from one set to the next, suggesting a mixture of stellar populations. A plot in Energy vs angular momentum phase space, with coordinate origin moved to the Galactic center, highlights different aspects of the kinematics of the four groups of stars. We finally compare the kinematic properties of these four groups with those of two sets of ultra metal-poor stars.Comment: 8 pages, 6 figure

Six supersoft X-ray binaries: system parameters and twin-jet outflows

A comparison is made between the properties of CAL 83, CAL 87, RX J0513.9-6951, 1E 0035.4-7230 (SMC 13), RX J0019.8+2156, and RX J0925.7-4758, all supersoft X-ray binaries. Spectra with the same resolution and wavelength coverage of these systems are compared and contrasted. Some new photometry is also presented. The equivalent widths of the principal emission lines of H and He II differ by more than an order of magnitude among these sources, although those of the highest ionization lines (e.g. O VI) are very similar. In individual systems, the velocity curves derived from various ions often differ in phasing and amplitude, but those whose phasing is consistent with the light curves (implying the lines are formed near the compact star) give masses of $\sim 1.2M_{\odot}$ and $\sim 0.5M_{\odot}$ for the degenerate and mass-losing stars, respectively. This finding is in conflict with currently prevailing theoretical models for supersoft binaries. The three highest luminosity sources show evidence of "jet" outflows, with velocities of $\sim 1-4 \times10^3 km/s$. In CAL 83 the shape of the He II 4686\AA profile continues to show evidence that these jets may precess with a period of $\sim 69$ days.Comment: 27 pages including 5 tables, plus 6 figures. To appear in Ap

Global optical/infrared - X-ray correlations in X-ray binaries: quantifying disc and jet contributions

The optical/near-infrared (OIR) region of the spectra of low-mass X-ray binaries appears to lie at the intersection of a variety of different emission processes. In this paper we present quasi-simultaneous OIR - X-ray observations of 33 XBs in an attempt to estimate the contributions of various emission processes in these sources, as a function of X-ray state and luminosity. A global correlation is found between OIR and X-ray luminosity for low-mass black hole candidate XBs (BHXBs) in the hard X-ray state, of the form L_OIR is proportional to Lx^0.6. This correlation holds over 8 orders of magnitude in Lx and includes data from BHXBs in quiescence and at large distances (LMC and M31). A similar correlation is found in low-mass neutron star XBs (NSXBs) in the hard state. For BHXBs in the soft state, all the near-infrared (NIR) and some of the optical emission is suppressed below the correlation, a behaviour indicative of the jet switching off/on in transition to/from the soft state. We compare these relations to theoretical models of a number of emission processes. We find that X-ray reprocessing in the disc and emission from the jets both predict a slope close to 0.6 for BHXBs, and both contribute to the OIR in BHXBs in the hard state, the jets producing ~90 percent of the NIR emission at high luminosities. X-ray reprocessing dominates the OIR in NSXBs in the hard state, with possible contributions from the jets (only at high luminosity) and the viscously heated disc. We also show that the optically thick jet spectrum of BHXBs extends to near the K-band. (abridged)Comment: Accepted for publication in MNRAS; 19 pages, 7 figure

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist