X-rays across the galaxy population - II. The distribution of AGN accretion rates as a function of stellar mass and redshift

We use deep Chandra X-ray imaging to measure the distribution of specific black hole accretion rates ($L_X$ relative to the stellar mass of the galaxy) and thus trace AGN activity within star-forming and quiescent galaxies, as a function of stellar mass (from $10^{8.5}-10^{11.5} M_\odot$) and redshift (to $z \sim 4$). We adopt near-infrared selected samples of galaxies from the CANDELS and UltraVISTA surveys, extract X-ray data for every galaxy, and use a flexible Bayesian method to combine these data and to measure the probability distribution function of specific black hole accretion rates, $\lambda_{sBHAR}$. We identify a broad distribution of $\lambda_{sBHAR}$ in both star-forming and quiescent galaxies---likely reflecting the stochastic nature of AGN fuelling---with a roughly power-law shape that rises toward lower $\lambda_{sBHAR}$, a steep cutoff at $\lambda_{sBHAR} \gtrsim 0.1-1$ (in Eddington equivalent units), and a turnover or flattening at $\lambda_{sBHAR} \lesssim 10^{-3}-10^{-2}$. We find that the probability of a star-forming galaxy hosting a moderate $\lambda_{sBHAR}$ AGN depends on stellar mass and evolves with redshift, shifting toward higher $\lambda_{sBHAR}$ at higher redshifts. This evolution is truncated at a point corresponding to the Eddington limit, indicating black holes may self-regulate their growth at high redshifts when copious gas is available. The probability of a quiescent galaxy hosting an AGN is generally lower than that of a star-forming galaxy, shows signs of suppression at the highest stellar masses, and evolves strongly with redshift. The AGN duty cycle in high-redshift ($z\gtrsim2$) quiescent galaxies thus reaches $\sim$20 per cent, comparable to the duty cycle in star-forming galaxies of equivalent stellar mass and redshift

X-rays across the galaxy population – I. Tracing the main sequence of star formation

We use deep $\textit{Chandra}$ imaging to measure the distribution of X-ray luminosities (LX) for samples of star-forming galaxies as a function of stellar mass and redshift, using a Bayesian method to push below the nominal X-ray detection limits. Our luminosity distributions all show narrow peaks at LX ≲ 10$^{42}$ erg s$^{-1}$ that we associate with star formation, as opposed to AGN that are traced by a broad tail to higher LX. Tracking the luminosity of these peaks as a function of stellar mass reveals an ‘X-ray main sequence’ with a constant slope ≈0.63 ± 0.03 over 8.5≲logM∗/M⊙≲11.5 and 0.1 ≲ z ≲ 4, with a normalization that increases with redshift as (1 + z)$^{3.79 ± 0.12}$. We also compare the peak X-ray luminosities with UV-to-IR tracers of star formation rates (SFRs) to calibrate the scaling between LX and SFR. We find that LX ∝ SFR$^{0.83}$ × (1 + z)$^{1.3}$, where the redshift evolution and non-linearity likely reflect changes in high-mass X-ray binary populations of star-forming galaxies. Using galaxies with a broader range of SFR, we also constrain a stellar-mass-dependent contribution to LX, likely related to low-mass X-ray binaries. Using this calibration, we convert our X-ray main sequence to SFRs and measure a star-forming main sequence with a constant slope ≈0.76 ± 0.06 and a normalization that evolves with redshift as (1 + z)$^{2.95 ± 0.33}$. Based on the X-ray emission, there is no evidence for a break in the main sequence at high stellar masses, although we cannot rule out a turnover given the uncertainties in the scaling of LX to SFR.JA acknowledges support from ERC Advanced Grant FEEDBACK 340442. ALC acknowledges support from NSF CAREER award AST-1055081. AG acknowledges the THALES project 383549 that is jointly funded by the European Union and the Greek Government in the framework of the programme “Education and lifelong learning”. This work is based in part on observations taken by the 3D-HST Treasury Program (GO 12177 and 12328) with the NASA/ESA HST, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26555. Based in part on data obtained with the European Southern Observatory Very Large Telescope, Paranal, Chile , under Large Program 185.A-0791, and made available by the VUDS team at the CESAM data center, Laboratoire d’Astrophysique de Marseille, France. The scientific results reported in this article are based to a significant degree on observations made by the Chandra X-ray Observatory

The MOSDEF Survey: The Metallicity Dependence of X-Ray Binary Populations at z ∼ 2

Population synthesis models predict that high-mass X-ray binary (HMXB) populations produced in low-metallicity environments should be more X-ray luminous, a trend supported by studies of nearby galaxies. This trend may be responsible for the observed increase of the X-ray luminosity (L X) per star formation rate (SFR) with redshift due to the decrease of metallicity (Z) at fixed stellar mass as a function of redshift. To test this hypothesis, we use a sample of 79 z ∼ 2 star-forming galaxies with oxygen abundance measurements from the MOSDEF survey, which obtained rest-frame optical spectra for ∼1500 galaxies in the CANDELS fields at 1.37 < z < 3.80. Using Chandra data from the Chandra AEGIS-X Deep, Chandra Deep Field North, and Chandra Deep Field South surveys, we stack the X-ray data at the galaxy locations in bins of redshift and Z because the galaxies are too faint to be individually detected. In agreement with previous studies, the average L X/SFR of our z ∼ 2 galaxy sample is enhanced by ≈0.4-0.8 dex relative to local HMXB L X-SFR scaling relations. Splitting our sample by Z, we find that L X/SFR and Z are anticorrelated with 97% confidence. This observed Z dependence for HMXB-dominated galaxies is consistent with both the local L X-SFR-Z relation and a subset of population synthesis models. Although the statistical significance of the observed trends is weak owing to the low X-ray statistics, these results constitute the first direct evidence connecting the redshift evolution of L X/SFR and the Z dependence of HMXBs

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Breakdown of the Endothelial Barrier Function in Tumor Cell Transmigration

The ability of tumor cells to metastasize is associated with a poor prognosis for cancer. During the process of metastasis, tumor cells circulating in the blood or lymph vessels can adhere to, and potentially transmigrate through, the endothelium and invade the connective tissue. We studied the effectiveness of the endothelium as a barrier against the invasion of 51 tumor cell lines into a three-dimensional collagen matrix. Only nine tumor cell lines showed attenuated invasion in the presence of an endothelial cell monolayer, whereas 17 cell lines became invasive or showed a significantly increased invasion. Endothelial cells cocultured with invasive tumor cells increased chemokine gene expression of IL-8 and Gro-β. Expression of the IL-8 and Gro-β receptor, CXCR2, was upregulated in invasive tumor cells. Addition of IL-8 or Gro-β increased tumor cell invasiveness by more than twofold. Tumor cell variants selected for high CXCR2 expression were fourfold more invasive in the presence of an endothelial cell layer, whereas CXCR2 siRNA knock-down cells were fivefold less invasive. We demonstrate that Gro-β and IL-8 secreted by endothelial cells, together with CXCR2 receptor expression on invasive tumor cells, contribute to the breakdown of the endothelial barrier by enhancing tumor cell force generation and cytoskeletal remodeling dynamics

Dynamic Analysis of Vascular Morphogenesis Using Transgenic Quail Embryos

Background: One of the least understood and most central questions confronting biologists is how initially simple clusters or sheet-like cell collectives can assemble into highly complex three-dimensional functional tissues and organs. Due to the limits of oxygen diffusion, blood vessels are an essential and ubiquitous presence in all amniote tissues and organs. Vasculogenesis, the de novo self-assembly of endothelial cell (EC) precursors into endothelial tubes, is the first step in blood vessel formation [1]. Static imaging and in vitro models are wholly inadequate to capture many aspects of vascular pattern formation in vivo, because vasculogenesis involves dynamic changes of the endothelial cells and of the forming blood vessels, in an embryo that is changing size and shape. Methodology/Principal Findings: We have generated Tie1 transgenic quail lines Tg(tie1:H2B-eYFP) that express H2B-eYFP in all of their endothelial cells which permit investigations into early embryonic vascular morphogenesis with unprecedented clarity and insight. By combining the power of molecular genetics with the elegance of dynamic imaging, we follow the precise patterning of endothelial cells in space and time. We show that during vasculogenesis within the vascular plexus, ECs move independently to form the rudiments of blood vessels, all while collectively moving with gastrulating tissues that flow toward the embryo midline. The aortae are a composite of somatic derived ECs forming its dorsal regions and the splanchnic derived ECs forming its ventral region. The ECs in the dorsal regions of the forming aortae exhibit variable mediolateral motions as they move rostrally; those in more ventral regions show significant lateral-to-medial movement as they course rostrally. Conclusions/Significance: The present results offer a powerful approach to the major challenge of studying the relative role(s) of the mechanical, molecular, and cellular mechanisms of vascular development. In past studies, the advantages of the molecular genetic tools available in mouse were counterbalanced by the limited experimental accessibility needed for imaging and perturbation studies. Avian embryos provide the needed accessibility, but few genetic resources. The creation of transgenic quail with labeled endothelia builds upon the important roles that avian embryos have played in previous studies of vascular development

Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium

Divergent Responses of Different Endothelial Cell Types to Infection with Candida albicans and Staphylococcus aureus

Endothelial cells are important in the pathogenesis of bloodstream infections caused by Candida albicans and Staphylococcus aureus. Numerous investigations have used human umbilical vein endothelial cells (HUVECs) to study microbial-endothelial cell interactions in vitro. However, the use of HUVECs requires a constant supply of umbilical cords, and there are significant donor-to-donor variations in these endothelial cells. The use of an immortalized endothelial cell line would obviate such difficulties. One candidate in this regard is HMEC-1, an immortalized human dermal microvascular endothelial cell line. To determine if HMEC-1 cells are suitable for studying the interactions of C. albicans and S. aureus with endothelial cells in vitro, we compared the interactions of these organisms with HMEC-1 cells and HUVECs. We found that wild-type C. albicans had significantly reduced adherence to and invasion of HMEC-1 cells as compared to HUVECs. Although wild-type S. aureus adhered to and invaded HMEC-1 cells similarly to HUVECs, an agr mutant strain had significantly reduced invasion of HMEC-1 cells, but not HUVECs. Furthermore, HMEC-1 cells were less susceptible to damage induced by C. albicans, but more susceptible to damage caused by S. aureus. In addition, HMEC-1 cells secreted very little IL-8 in response to infection with either organism, whereas infection of HUVECs induced substantial IL-8 secretion. This weak IL-8 response was likely due to the anatomic site from which HMEC-1 cells were obtained because infection of primary human dermal microvascular endothelial cells with C. albicans and S. aureus also induced little increase in IL-8 production above basal levels. Thus, C. albicans and S. aureus interact with HMEC-1 cells in a substantially different manner than with HUVECs, and data obtained with one type of endothelial cell cannot necessarily be extrapolated to other types

Comparative analysis of RNA sequencing methods for degraded or low-input samples

available in PMC 2014 January 01RNA-seq is an effective method for studying the transcriptome, but it can be difficult to apply to scarce or degraded RNA from fixed clinical samples, rare cell populations or cadavers. Recent studies have proposed several methods for RNA-seq of low-quality and/or low-quantity samples, but the relative merits of these methods have not been systematically analyzed. Here we compare five such methods using metrics relevant to transcriptome annotation, transcript discovery and gene expression. Using a single human RNA sample, we constructed and sequenced ten libraries with these methods and compared them against two control libraries. We found that the RNase H method performed best for chemically fragmented, low-quality RNA, and we confirmed this through analysis of actual degraded samples. RNase H can even effectively replace oligo(dT)-based methods for standard RNA-seq. SMART and NuGEN had distinct strengths for measuring low-quantity RNA. Our analysis allows biologists to select the most suitable methods and provides a benchmark for future method development.National Institutes of Health (U.S.) (Pioneer Award DP1-OD003958-01)National Human Genome Research Institute (U.S.) (NHGRI) 1P01HG005062-01)National Human Genome Research Institute (U.S.) (NHGRI Center of Excellence in Genome Science Award 1P50HG006193-01)Howard Hughes Medical Institute (Investigator)Merkin Family Foundation for Stem Cell ResearchBroad Institute of MIT and Harvard (Klarman Cell Observatory)National Human Genome Research Institute (U.S.) (NHGRI grant HG03067)Fonds voor Wetenschappelijk Onderzoek--Vlaandere