Galaxy mergers can initiate quenching by unlocking an AGN-driven transformation of the baryon cycle

We use zoom simulations to show how merger-driven disruption of the gas disc in a galaxy provides its central active galactic nucleus (AGN) with fuel to drive outflows that entrain and expel a significant fraction of the circumgalactic medium (CGM). This in turn suppresses replenishment of the interstellar medium, causing the galaxy to quench up to several Gyr after the merger. We start by performing a zoom simulation of a present-day star-forming disc galaxy with the EAGLE galaxy formation model. Then, we re-simulate the galaxy with controlled changes to its initial conditions, using the genetic modification technique. These modifications either increase or decrease the stellar mass ratio of the galaxy’s last significant merger, which occurs at z ≈ 0.74. The halo reaches the same present-day mass in all cases, but changing the mass ratio of the merger yields markedly different galaxy and CGM properties. We find that a merger can unlock rapid growth of the central supermassive black hole if it disrupts the co-rotational motion of gas in the black hole’s vicinity. Conversely, if a less disruptive merger occurs and gas close to the black hole is not disturbed, the AGN does not strongly affect the CGM, and consequently the galaxy continues to form stars. Our result illustrates how a unified view of AGN feedback, the baryon cycle and the interstellar medium is required to understand how mergers and quenching are connected over long timescales

An EAGLE’s View of Ex-situ Galaxy Growth

Modern observational and analytic techniques now enable the direct measurement of star formation histories and the inference of galaxy assembly histories. However, current theoretical predictions of assembly are not ideally suited for direct comparison with such observational data. We therefore extend the work of prior examinations of the contribution of ex-situ stars to the stellar mass budget of simulated galaxies. Our predictions are specifically tailored for direct testing with a new generation of observational techniques by calculating ex-situ fractions as functions of galaxy mass and morphological type, for a range of surface brightnesses. These enable comparison with results from large FoV IFU spectrographs, and increasingly accurate spectral fitting, providing a look-up method for the estimated accreted fraction. We furthermore provide predictions of ex-situ mass fractions as functions of galaxy mass, galactocentric radius and environment. Using z = 0 snapshots from the 100cMpc3 and 25cMpc3 EAGLE simulations we corroborate the findings of prior studies, finding that ex-situ fraction increases with stellar mass for central and satellite galaxies in a stellar mass range of 2× 107 - 1.9× 1012 M⊙. For those galaxies of mass M*>5× 108M⊙, we find that the total ex-situ mass fraction is greater for more extended galaxies at fixed mass. When categorising satellite galaxies by their parent group/cluster halo mass we find that the ex-situ fraction decreases with increasing parent halo mass at fixed galaxy mass. This apparently counter-intuitive result may be due to high passing velocities within large cluster halos inhibiting efficient accretion onto individual galaxies

The gas fractions of dark matter haloes hosting simulated similar to L-star galaxies are governed by the feedback history of their black holes

We examine the origin of scatter in the relationship between the gas fraction and mass of dark matter haloes hosting present-day similar to L-star central galaxies in the EAGLE simulations. The scatter is uncorrelated with the accretion rate of the central galaxy's black hole (BH), but correlates strongly and negatively with the BH's mass, implicating differences in the expulsion of gas by active galactic nucleus feedback, throughout the assembly of the halo, as the main cause of scatter. Haloes whose central galaxies host undermassive BHs also tend to retain a higher gas fraction, and exhibit elevated star formation rates (SFRs). Diversity in the mass of central BHs stems primarily from diversity in the dark matter halo binding energy, as these quantities are strongly and positively correlated at fixed halo mass, such that similar to L-star galaxies hosted by haloes that are more (less) tightly bound develop central BHs that are more (less) massive than is typical for their halo mass. Variations in the halo gas fraction at fixed halo mass are reflected in both the soft X-ray luminosity and thermal Sunyaev-Zel'dovich flux, suggesting that the prediction of a strong coupling between the properties of galaxies and their halo gas fractions can be tested with measurements of these diagnostics for galaxies with diverse SFRs but similar halo masses.Peer reviewe

Predictions for the X-ray circumgalactic medium of edge-on discs and spheroids

We investigate how the X-ray circumgalactic medium (CGM) of present-day galaxies depends on galaxy morphology and azimuthal angle using mock observations generated from the EAGLE cosmological hydrodynamic simulation. By creating mock stacks of {\it eROSITA}-observed galaxies oriented to be edge-on, we make several observationally-testable predictions for galaxies in the stellar mass range $M_\star=10^{10.7-11.2}\;$M$_{\odot}$. The soft X-ray CGM of disc galaxies is between 60 and 100\% brighter along the semi-major axis compared to the semi-minor axis, between 10-30 kpc. This azimuthal dependence is a consequence of the hot ($T>10^6$ K) CGM being non-spherical: specifically it is flattened along the minor axis such that denser and more luminous gas resides in the disc plane and co-rotates with the galaxy. Outflows enrich and heat the CGM preferentially perpendicular to the disc, but we do not find an observationally-detectable signature along the semi-minor axis. Spheroidal galaxies have hotter CGMs than disc galaxies related to spheroids residing at higher halos masses, which may be measurable through hardness ratios spanning the $0.2-1.5$ keV band. While spheroids appear to have brighter CGMs than discs for the selected fixed $M_\star$ bin, this owes to spheroids having higher stellar and halo masses within that $M_\star$ bin, and obscures the fact that both simulated populations have similar total CGM luminosities at the exact same $M_\star$. Discs have brighter emission inside 20 kpc and more steeply declining profiles with radius than spheroids. We predict that the {\it eROSITA} 4-year all-sky survey should detect many of the signatures we predict here, although targeted follow-up observations of highly inclined nearby discs after the survey may be necessary to observe some of our azimuthally-dependent predictions.Comment: 12 pages, 11 figures, 1 table. Submitted to MNRAS. Comments welcom

A DNA nanoswitch incorporating the fluorescent base analogue 2-aminopurine detects single nucleotide mismatches in unlabelled targets

DNA nanoswitches can be designed to detect unlabelled nucleic acid targets and have been shown to discriminate between targets which differ in the identity of only one base. This paper demonstrates that the fluorescent base analogue 2-aminopurine (AP) can be used to discriminate between nanoswitches with and without targets and to discriminate between matched and mismatched targets. In particular, we have used both steady-state and time-resolved fluorescence spectroscopy to determine differences in AP environment at the branchpoint of nanoswitches assembled using complementary targets and targets which incorporate single base mismatches

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

Background: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids.  Methods: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994.  Findings: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060–2810] in the metformin group vs 1770 mg [1020–2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI −0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (−3835 mm 2, 95% CI −6781 to −888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima–media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01).  Interpretation: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation.  Funding: Barts Charity and Merck Serono

Changes in arginase isoforms in a murine model of neonatal brain hypoxia-ischemia.

BackgroundArginases (ARG isoforms, ARG-1/ARG-2) are key regulatory enzymes of inflammation and tissue repair; however, their role after neonatal brain hypoxia (H) and hypoxia-ischemia (HI) remains unknown.MethodsC57BL/6 mice subjected to the Vannucci procedure on postnatal day (P9) were sacrificed at different timepoints. The degree of brain damage was assessed histologically. ARG spatiotemporal localization was determined via immunohistochemistry. ARG expression was measured by Western blot and activity spectrophotometrically.ResultsARG isoform expression increased during neurodevelopment (P9-P17) in the cortex and hippocampus. This was suppressed with H and HI only in the hippocampus. In the cortex, both isoforms increased with H alone and only ARG-2 increased with HI at 3 days. ARG activity during neurodevelopment remained unchanged, but increased at 1 day with H and not HI. ARG-1 localized with microglia at the injury site as early as 4 h after injury, while ARG-2 localized with neurons.ConclusionsARG isoform expression increases with age from P9 to P17, but is suppressed by injury specifically in the hippocampus and not in the cortex. Both levels and activity of ARG isoforms increase with H, while ARG-1 immunolabelling is upregulated in the HI cortex. Evidently, ARG isoforms in the brain differ in spatiotemporal localization, expression, and activity during neurodevelopment and after injury.ImpactArginase isoforms change during neurodevelopment and after neonatal brain HI. This is the first study investigating the key enzymes of inflammation and tissue repair called arginases following murine neonatal brain HI. The highly region- and cell-specific expression suggests the possibility of specific functions of arginases. ARG-1 in microglia at the injury site may regulate neuroinflammation, while ARG-2 in neurons of developmental structures may impact neurodevelopment. While further studies are needed to describe the exact role of ARGs after neonatal brain HI, our study adds valuable data on anatomical localization and expression of ARGs in brain during development and after stroke

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts