Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategie

The X-ray nebula around the Seyfert 2 galaxy NGC4388

We report on X-ray emission from the Seyfert 2 galaxy NGC4388 observed with the Chandra X-ray Observatory. A hard X-ray peak is found at the position of the active nucleus suggested by optical and radio observations. Extended soft X-ray emission correlates well with the ionization cone found in optical line emission. A large soft X-ray extension is found up to 16 kpc to the north of the galaxy. Photoionized gas with low ionization parameters (xi<3) appears to be the likely explanation of this emission. The same ionized gas clouds could be responsible for the optical [OIII] emission. Fe K line emission from cold material is found to be extended by a few kpc.Comment: 12 pages, one colour figure included, MNRAS in pres

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 hospitalization2,3,4 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

Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of PAI-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEArray analyses aiming to detect molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by RT-PCR and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis, and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined anti-tumor strategies

A tomographic map of the large-scale matter distribution using the eBOSS—Stripe 82 Lyα\alpha forest

International audienceThe Lyman-α (hereafter Lyα) forest is a probe of large-scale matter density fluctuations at high redshift, z > 2.1. It consists of H I absorption spectra along individual lines-of-sight. If the line-of-sight density is large enough, 3D maps of H I absorption can be inferred by tomographic reconstruction. In this article, we investigate the Lyα forest available in the Stripe 82 field (220 deg2), based on the quasar spectra from SDSS Data Release DR16. The density of observed quasar spectra is 37 deg−2 with a mean pixel signal-to-noise ratio of two per angstrom. This study provides an intermediate case between the average SDSS density and that of the much denser but smaller CLAMATO survey. We derive a 3D map of large-scale matter fluctuations from these data, using a Wiener filter technique. The total volume of the map is 0.94 h−3 Gpc3. Its resolution is 13 h−1 Mpc, which is related to the mean transverse distance between nearest lines-of-sight. From this map, we provide a catalog of voids and protocluster candidates in the cosmic web. The map-making and void catalog are compared to simulated eBOSS Stripe 82 observations. A stack over quasar positions provides a visualization of the Lyα forest-quasar cross-correlation. This tomographic reconstruction constitutes the largest-volume high-redshift 3D map of matter fluctuations

The Lyman-α forest in three dimensions: measurements of large scale flux correlations from BOSS 1st-year data

Using a sample of approximately 14,000 z>2.1 quasars observed in the first year of the Baryon Oscillation Spectroscopic Survey (BOSS), we measure the three-dimensional correlation function of absorption in the Lyman-alpha forest. The angle-averaged correlation function of transmitted flux (F = exp(-tau)) is securely detected out to comoving separations of 60 Mpc/h, the first detection of flux correlations across widely separated sightlines. A quadrupole distortion of the redshift-space correlation function by peculiar velocities, the signature of the gravitational instability origin of structure in the Lyman-alpha forest, is also detected at high significance. We obtain a good fit to the data assuming linear theory redshift-space distortion and linear bias of the transmitted flux, relative to the matter fluctuations of a standard LCDM cosmological model (inflationary cold dark matter with a cosmological constant). At 95% confidence, we find a linear bias parameter 0.16<b<0.24 and redshift-distortion parameter 0.44<beta<1.20, at central redshift z=2.25, with a well constrained combination b(1+\beta)=0.336 +/- 0.012. The errors on beta are asymmetric, with beta=0 excluded at over 5 sigma confidence level. The value of beta is somewhat low compared to theoretical predictions, and our tests on synthetic data suggest that it is depressed (relative to expectations for the Lyman-alpha forest alone) by the presence of high column density systems and metal line absorption. These results set the stage for cosmological parameter determinations from three-dimensional structure in the Lyman-alpha forest, including anticipated constraints on dark energy from baryon acoustic oscillations

Measurement of baryon acoustic oscillations in the Lyman-α forest fluctuations in BOSS data release 9

We use the Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 9 (DR9) to detect and measure the position of the Baryonic Acoustic Oscillation (BAO) feature in the three-dimensional correlation function in the Lyman-α flux fluctuations at a redshift zeff = 2.4. The feature is clearly detected at significance between 3 and 5 sigma (depending on the broadband model and method of error covariance matrix estimation) and is consistent with predictions of the standard ΛCDM model. We assess the biases in our method, stability of the error covariance matrix and possible systematic effects. We fit the resulting correlation function with several models that decouple the broadband and acoustic scale information. For an isotropic dilation factor, we measure 100 × (αiso - 1) = -1.6+2.0 +4.3 +7.4-2.0 -4.1 -6.8 (stat.) ±1.0 (syst.) (multiple statistical errors denote 1,2 and 3 sigma confidence limits) with respect to the acoustic scale in the fiducial cosmological model (flat ΛCDM with Ωm = 0.27, h = 0.7). When fitting separately for the radial and transversal dilation factors we find marginalised constraints 100 × (α|| - 1) = -1.3+3.5 +7.6 +12.3-3.3 -6.7 -10.2 (stat.) ±2.0 (syst.) and 100 × (α⊥ - 1) = -2.2+7.4 +17-7.1 -15 (stat.) ±3.0 (syst.). The dilation factor measurements are significantly correlated with cross-correlation coefficient of ~ -0.55. Errors become significantly non-Gaussian for deviations over 3 standard deviations from best fit value. Because of the data cuts and analysis method, these measurements give tighter constraints than a previous BAO analysis of the BOSS DR9 Lyman-α sample, providing an important consistency test of the standard cosmological model in a new redshift regime