Investigating the Relationship between Environment and Active Galactic Nuclei activity at High Redshift

This thesis presents an investigation into the relationship between large-scale structure environment and Active Galactic Nuclei (AGN) activity at high redshift. To accomplish this, the environments of AGN are studied from two complementary perspectives. Firstly, various observations of a specific large-scale structure at z = 2.3 are used to assess the level of AGN activity in relation to the field. The main result of this study is that both the emission-line and X-ray selected AGN populations are significantly enhanced; X-ray detected Lyman Alpha Emitters (LAEs), however, are not found to be significantly enhanced. The host galaxy properties of z ~ 1 X-ray sources are then derived and studied in detail. Confirming previous results, X-ray sources are found in optically luminous (MB ~< −20.5mag), massive (log(M∗/ M⊙) ≥ 10.5) red and blue hosts. A larger fraction of red/green hosts harbour obscured (log(NH) ≥ 22) AGN than blue, with the most obscured sources (log(NH) ≥ 23.5) also being more frequently found in red/green host galaxies than blue. The second approach used the 3rd-nearest neighbour measure to study the environment of X-ray hosts at z ~ 1, accounting for their optical colour, luminosity and stellar mass. A main new and important result is that X-ray hosts are found in regions of enhanced density compared to optical galaxies of equivalent mass, which is not due to the observed colour-density relation at z ~ 1. The enhancement is found to be most significant at the reddest colours, brightest luminosities, and highest stellar masses. The results from this thesis show that the dense environments probed in this work generally promote AGN activity. This is probably not due to major mergers, but could be due to an increased probability of minor mergers/interactions and/or milder environmental processes triggering nuclear activity. Alternatively, perhaps there is some other galaxy property (e.g., residing in higher mass haloes) which is conducive to AGN activity

Contribution of the region Glu181 to Val200 of the extracellular loop of the human P2X1 receptor to agonist binding and gating revealed using cysteine scanning mutagenesis1

At the majority of mutants in the region Glu181-Val200 incorporating a conserved AsnPheThrΦΦxLys motif cysteine substitution had no effect on sensitivity to ATP, partial agonists, or methanethiosulfonate (MTS) compounds. For the F185C mutant the efficacy of partial agonists was reduced by ∼ 90% but there was no effect on ATP potency or the actions of MTS reagents. At T186C, F188C and K190C mutants ATP potency and partial agonists responses were reduced. The ATP sensitivity of the K190C mutant was rescued towards WT levels by positively charged (2-aminoethyl)methanethiosulfonate hydrobromide and reduced by negatively charged sodium (2-sulfonatoethyl) methanethiosulfonate. Both MTS reagents decreased ATP potency at the T186C mutant, and abolished responses at the F195C mutant. 32P-2-azido ATP binding to the mutants T186C and K190C was sensitive to MTS reagents consistent with an effect on binding, however binding at F195C was unaffected indicating an effect on gating. The accessibility of the introduced cysteines was probed with (2-aminoethyl)methanethiosulfonate hydrobromide-biotin, this showed that the region Thr186-Ser192 is likely to form a beta sheet and that accessibility is blocked by ATP. Taken together these results suggest that Thr186, Phe188 and Lys190 are involved in ATP binding to the receptor and Phe185 and Phe195 contribute to agonist evoked conformational changes

HS 1700+6416: the first high redshift non lensed NAL-QSO showing variable high velocity outflows

We present a detailed analysis of the X-ray emission of HS 1700+6416, a high redshift (z=2.7348), luminous quasar, classified as a Narrow Absorption Line (NAL) quasar on the basis of its SDSS spectrum. The source has been observed 9 times by Chandra and once by XMM from 2000 to 2007. Long term variability is clearly detected, between the observations, in the 2-10 keV flux varying by a factor of three (~3-9x10^-14 erg s^-1 cm^-2) and in the amount of neutral absorption (Nh < 10^22 cm^-2 in 2000 and 2002 and Nh=4.4+-1.2x10^22 cm^-2 in 2007). Most interestingly, one broad absorption feature is clearly detected at 10.3+-0.7 keV (rest frame) in the 2000 Chandra observation, while two similar features, at 8.9+-0.4 and at 12.5+-0.7 keV, are visible when the 8 contiguous Chandra observations of 2007 are stacked together. In the XMM observation of 2002, strongly affected by background flares, there is a hint for a similar feature at 8.0+-0.3 keV. We interpreted these features as absorption lines from a high velocity, highly ionized (i.e. Fe XXV, FeXXVI) outflowing gas. In this scenario, the outflow velocities inferred are in the range v=0.12-0.59c. To reproduce the observed features, the gas must have high column density (Nh>3x10^23 cm^-2), high ionization parameter (log(xi)>3.3 erg cm s^-1) and a large range of velocities (Delta V~10^4 km s^-1). This Absorption Line QSO is the fourth high-z quasar displaying X-ray signatures of variable, high velocity outflows, and among these, is the only one non-lensed. A rough estimate of the minimum kinetic energy carried by the wind of up to 18% L(bol), based on a biconical geometry of the wind, implies that the amount of energy injected in the outflow environment is large enough to produce effective mechanical feedback.Comment: 10 pages, 6 figures. Accepted for publication in Astronomy and Astrophysic

Excess AGN Activity in the z=2.30 Protocluster in HS 1700+64

We present the results of spectroscopic, narrow-band and X-ray observations of a z=2.30 protocluster in the field of the QSO HS 1700+643. Using a sample of BX/MD galaxies, which are selected to be at z~2.2-2.7 by their rest-frame ultraviolet colours, we find that there are 5 protocluster AGN which have been identified by characteristic emission-lines in their optical/near-IR spectra; this represents an enhancement over the field significant at ~98.5 per cent confidence. Using a ~200 ks Chandra/ACIS-I observation of this field we detect a total of 161 X-ray point sources to a Poissonian false-probability limit of 4x10^{-6} and identify 8 of these with BX/MD galaxies. Two of these are spectroscopically confirmed protocluster members and are also classified as emission-line AGN. When compared to a similarly selected field sample the analysis indicates this is also evidence for an enhancement of X-ray selected BX/MD AGN over the field, significant at ~99 per cent confidence. Deep Lya narrow-band imaging reveals that a total of 4/123 Lya emitters (LAEs) are found to be associated with X-ray sources, with two of these confirmed protocluster members and one highly likely member. We do not find a significant enhancement of AGN activity in this LAE sample over that of the field (result significant at only 87 per cent confidence). The X-ray emitting AGN fractions for the BX/MD and LAE samples are found to be 6.9_{-4.4}^{+9.2} and 2.9_{-1.6}^{+2.9} per cent, respectively, for protocluster AGN with L_{2-10 keV}>4.6x10^{43} erg s^{-1} at z=2.30. These findings are similar to results from the z=3.09 protocluster in the SSA 22 field found by Lehmer et al. (2009), in that both suggest AGN activity is favoured in dense environments at z>2.Comment: 8 pages, 2 figures. Accepted for publication in MNRAS

The clustering of X-ray selected AGN at z=0.1

The clustering properties of moderate luminosity ($L_X = \rm 10^{41} - 10^{44} \, erg \,s^{-1}$) X-ray selected AGN at $z\approx0.1$ are explored. X-ray sources in the redshift interval $0.03<z<0.2$ are selected from a serendipitous XMM survey of the SDSS footprint (XMM/SDSS) and are cross-correlated with the SDSS Main galaxy sample. The inferred X-ray AGN auto-correlation function is described by a power law with amplitude $r_0\approx5\,$h$^{-1}$Mpc and slope $\gamma\approx2.0$. The corresponding mass of the dark matter haloes that host X-ray AGN at $z\approx0.1$ is \approx 10^{13} \,h ^{-1} \, M_{\sun}. Comparison with studies at higher redshift shows that this mass scale is characteristic of moderate luminosity X-ray AGN out to $z\approx 1$. Splitting the AGN sample by rest-frame color shows that X-ray sources in red hosts are more clustered than those associated with blue galaxies, in agreement with results at $z\approx1$. We also find that the host galaxies of X-ray AGN have lower stellar masses compared to the typical central galaxy of a \approx 10^{13} \,h ^{-1} \, M_{\sun} dark matter halo. AGN hosts either have experienced less stellar mass growth compared to the average central galaxy of a \approx 10^{13} \,h ^{-1} \, M_{\sun} halo or a fraction of them are associated with satellite galaxies.Comment: MNRAS accepted 14 pages, 8 figures, 5 table

Infrared Excess Sources: Compton Thick QSOs, low luminosity Seyferts or starbursts?

We explore the nature of Infrared Excess sources (IRX), which are proposed as candidates for luminous L_X(2-10keV)>1e43erg/s Compton Thick (N_H>2e24cm^{-2}$) QSOs at z~2. Lower redshift, z~1, analogues of the distant IRX population are identified by firstly redshifting to z=2 the SEDs of all sources with secure spectroscopic redshifts in the AEGIS (6488) and the GOODS-North (1784) surveys and then selecting those that qualify as IRX sources at that redshift. A total of 19 galaxies are selected. The mean redshift of the sample is$z\approx1$. We do not find strong evidence for Compton Thick QSOs in the sample. For 9 sources with X-ray counterparts, the X-ray spectra are consistent with Compton Thin AGN. Only 3 of them show tentative evidence for Compton Thick obscuration. The SEDs of the X-ray undetected population are consistent with starburst activity. There is no evidence for a hot dust component at the mid-infrared associated with AGN heated dust. If the X-ray undetected sources host AGN, an upper limit of L_X(2-10keV) =1e43erg/s is estimated for their intrinsic luminosity. We propose that a large fraction of the$z\approx2$ IRX population are not Compton Thick QSOs but low luminosity [L_X(2-10keV)<1e43erg/s], possibly Compton Thin, AGN or dusty starbursts. It is shown that the decomposition of the AGN and starburst contribution to the mid-IR is essential for interpreting the nature of this population, as star-formation may dominate this wavelength regime.Comment: Accepted by MNRA

Averaging the AGN X-ray spectra from deep Chandra fields

The X-ray spectra of Active Galactic Nuclei (AGN) carry the signatures of the emission from the central region, close to the Super Massive Black Hole (SMBH). For this reason, the study of deep X-ray spectra is a powerful instrument to investigate the origin of their emission. The emission line most often observed in the X-ray spectra of AGN is Fe K. It is known that it can be broadened and deformed by relativistic effects if emitted close enough to the central SMBH. In recent statistical studies of the X-ray spectra of AGN samples, it is found that a narrow Fe line is ubiquitous, while whether the broad features are as common is still uncertain. We present here the results of an investigation on the characteristics of the Fe line in the average X-ray spectra of AGN in deep Chandra fields. The average spectrum of the AGN is computed using Chandra spectra with more than 200 net counts from the AEGIS, Chandra Deep Field North and Chandra Deep Field South surveys. The sample spans a broader range of X-ray luminosities than other samples studied with stacking methods up to z=3.5. We analyze the average spectra of this sample using our own averaging method, checking the results against extensive simulations. Subsamples defined in terms of column density of the local absorber, luminosity and z are also investigated. We found a very significant Fe line with a narrow profile in all our samples and in almost all the subsamples that we constructed. The equivalent width (EW) of the narrow line estimated in the average spectrum of the full sample is 74 eV. The broad line component is significantly detected in the subsample of AGN with L<1.43 1E44 cgs and z<0.76, with EW=108 eV. We concluded that the narrow Fe line is an ubiquitous feature of the X-ray spectra of the AGN up to z=3.5.The broad line component is significant in the X-ray spectra of the AGN with low luminosity and low z.Comment: 17 pages, 23 figures, accepted for publication in Astronomy & Astrophysics. Replacements in the bibliography: Iwasawa K., Mainieri V., Brusa M., et al., 2011, arXiv:1111.2447v1 (previously: Iwasawa et al 2011, in preparation); Mateos S., Carrera F.J., Page M.J., et al., 2010, \aap, 510, A35 (previously: Mateos S., Warwick R.S., Carrera F.J., et al., 2008, \aap, 492, 51

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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