Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging

A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans

In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles. In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. The longevity response to dietary restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation. In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins

Ultra-luminous quasars at redshift z>4.5z>4.5 from SkyMapper

The most luminous quasars at high redshift harbour the fastest-growing and most massive black holes in the early Universe. They are exceedingly rare and hard to find. Here, we present our search for the most luminous quasars in the redshift range from $z=4.5$ to $5$ using data from SkyMapper, Gaia and WISE. We use colours to select likely high-redshift quasars and reduce the stellar contamination of the candidate set with parallax and proper motion data. In $\sim$12,500~deg$^2$ of Southern sky, we find 92 candidates brighter than $R_p=18.2$. Spectroscopic follow-up has revealed 21 quasars at $z\ge 4$ (16 of which are within $z=[4.5,5]$), as well as several red quasars, BAL quasars and objects with unusual spectra, which we tentatively label OFeLoBALQSOs at redshifts of $z\approx 1$ to $2$. This work lifts the number of known bright $z\ge 4.5$ quasars in the Southern hemisphere from 10 to 26 and brings the total number of quasars known at $R_p<18.2$ and $z\ge 4.5$ to 42.Comment: Submitted to MNRAS, 10 page

SkyMapper Southern Survey: First Data Release (DR1)

We present the first data release (DR1) of the SkyMapper Southern Survey, a hemispheric survey carried out with the SkyMapper Telescope at Siding Spring Observatory in Australia. Here, we present the survey strategy, data processing, catalogue construction and database schema. The DR1 dataset includes over 66,000 images from the Shallow Survey component, covering an area of 17,200 deg$^2$ in all six SkyMapper passbands $uvgriz$, while the full area covered by any passband exceeds 20,000 deg$^2$. The catalogues contain over 285 million unique astrophysical objects, complete to roughly 18 mag in all bands. We compare our $griz$ point-source photometry with PanSTARRS1 DR1 and note an RMS scatter of 2%. The internal reproducibility of SkyMapper photometry is on the order of 1%. Astrometric precision is better than 0.2 arcsec based on comparison with Gaia DR1. We describe the end-user database, through which data are presented to the world community, and provide some illustrative science queries.Comment: 31 pages, 19 figures, 10 tables, PASA, accepte

SkyMapper Southern Survey: Second Data Release (DR2)

We present the second data release (DR2) of the SkyMapper Southern Survey, a hemispheric survey carried out with the SkyMapper Telescope at Siding Spring Observatory in Australia, using six optical filters: $u,v,g,r,i,z$. DR2 is the first release to go beyond the $\sim$18mag (10${\sigma}$) limit of the Shallow Survey released in DR1, and includes portions of the sky at full survey depth that reach >21mag in $g$ and $r$ filters. The DR2 photometry has a precision as measured by internal reproducibility of 1% in $u$ and $v$, and 0.7% in $griz$. More than 21 000 deg$^2$ have data in some filters (at either Shallow or Main Survey depth) and over 7 000 deg$^2$ have deep Main Survey coverage in all six filters. Finally, about 18 000 deg$^2$ have Main Survey data in $i$ and $z$ filters, albeit not yet at full depth. The release contains over 120 000 images, as well as catalogues with over 500 million unique astrophysical objects and nearly 5 billion individual detections. It also contains cross-matches with a range of external catalogues such as Gaia DR2, Pan-STARRS1 DR1, GALEX GUVcat, 2MASS, and AllWISE, as well as spectroscopic surveys such as 2MRS, GALAH, 6dFGS, and 2dFLenS.Comment: 21 pages, 17 figures. As of 25 Aug 2020, DR2 is available to the world at http://skymapper.anu.edu.a

Ultra-luminous quasars at redshift z > 4.5 from SkyMapper

The most luminous quasars at high-redshift harbour the fastest growing and most massive black holes in the early Universe. They are exceedingly rare and hard to find. Here, we present our search for the most luminous quasars in the redshift range from z = 4.5 to 5 using data from SkyMapper, Gaia, and WISE. We use colours to select likely high-redshift quasars and reduce the stellar contamination of the candidate set with parallax and proper motion data. In ∼12 500 deg2 of Southern sky, we find 92 candidates brighter than Rp = 18.2. Spectroscopic follow-up has revealed 21 quasars at z ≥ 4 (16 of which are within z = [4.5, 5]), as well as several red quasars, Broad-Absorption-Line (BAL) quasars and objects with unusual spectra, which we tentatively label OFeLoBALQSOs at redshifts of z ≈ 1 to 2. This work lifts the number of known bright z ≥ 4.5 quasars in the Southern hemisphere from 10 to 26 and brings the total number of quasars known at Rp < 18.2 and z ≥ 4.5 to 42

Testing the gravitational lensing explanation for the MgII problem in GRBs

Sixty percent of gamma-ray bursts (GRBs) reveal strong MgII absorbing systems, which is a factor of ~2 times the rate seen along lines-of-sight to quasars. The discrepancy in the covering factor is most likely to be the result of either quasars being obscured due to dust, or the consequence of many GRBs being strongly gravitationally lensed. We analyze observations of GRBs that show strong foreground MgII absorption. We Monte-Carlo the distances between foreground galaxies in the HUDF and lines of sight distributed randomly within a radius derived from the covering factor, and find that galaxies are located systematically closer to the position of the observed GRBs than expected for random lines of sight. This over-density at small impact parameters is statistically more robust than the well known excess of MgII absorbers among GRB afterglow spectra, and presents a new puzzle for MgII absorption studies. The over-density cannot be explained by obscuration in the GRB sample, but is a natural consequence of gravitational lensing. Upon examining the particular configurations of galaxies near a sample of GRBs with strong MgII absorption, we find several intriguing lensing candidates. Our results suggest that lensing provides a viable contribution to the observed enhancement of strong MgII absorption along lines of sight to GRBs, and we outline the future observations required to test this hypothesis conclusively.Comment: v2 includes major updates in response to referee's comments. 15 pages, 10 figures, accepted for publication in Ap

Nationwide, population-based observational study of the molecular epidemiology and temporal trend of carbapenemase-producing Enterobacterales in Norway, 2015 to 2021

National and regional carbapenemaseproducing Enterobacterales (CPE) surveillance is essential to understand the burden of antimicrobial resistance, elucidate outbreaks, and develop infection-control or antimicrobial-treatment recommendations. Aim: This study aimed to describe CPE and their epidemiology in Norway from 2015 to 2021. Methods: A nationwide, population-based observational study of all verified clinical and carriage CPE isolates submitted to the national reference laboratory was conducted. Isolates were characterised by antimicrobial susceptibility testing, whole genome sequencing (WGS) and basic metadata. Annual CPE incidences were also estimated. Results: A total of 389 CPE isolates were identified from 332 patients of 63years median age (range:0–98). These corresponded to 341 cases, 184 (54%) being male. Between 2015 and 2021, the annual incidence of CPE cases increased from 0.6 to 1.1per 100,000person-years. For CPEisolates with available data on colonisation/infection, 58% (226/389)were associated with colonisation and 38% (149/389) with clinical infections. WGS revealed a predominance of OXA-48-like (51%; 198/389) and NDM (34%; 134/389) carbapenemases in a diversified population of Escherichia coli and Klebsiella pneumoniae, including high-risk clones also detected globally. Most CPE isolates were travel-related (63%;245/389). Although local outbreaks and healthcare-associated transmission occurred, no interregional spread was detected. Nevertheless, 18% (70/389) of isolates not directly related to import points towards potentially unidentified transmission routes. A decline in travelassociated cases was observed during the COVID-19 pandemic. Conclusions: The close-to-doubling of CPE case incidence between 2015 and 2021 was associated with foreign travel and genomic diversity. To limit further transmission and outbreaks, continued screening and monitoring is essential

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}⊙ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient's position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.The AST3 project is supported by the National Basic Research Program (973 Program) of China (Grant Nos. 2013CB834901, 2013CB834900, 2013CB834903), and the Chinese Polar Environment Comprehensive Investigation & Assessment Program (grant No. CHINARE2016-02-03-05). The construction of the AST3 telescopes has received fundings from Tsinghua University, Nanjing University, Beijing Normal University, University of New South Wales, and Texas A&M University, the Australian Antarctic Division, and the National Collaborative Research Infrastructure Strategy (NCRIS) of Australia. It has also received funding from Chinese Academy of Sciences through the Center for Astronomical Mega-Science and National Astronomical Observatory of China (NAOC).The collaboration between LIGO/Virgo and EVN/e-MERLIN is part of a project that has received funding from the European Unions Horizon 2020 research and innovation programme under grant agreement No. 653477.B.C., V.C., A.G., and W.S.P. gratefully acknowledge NASA funding through contract NNM13AA43C. M.S.B., R.H., P.J., C.A.M., S.P., R.D.P., M.S., and P.V. gratefully acknowledge NASA funding from cooperative agreement NNM11AA01A. E.B. is supported by an appointment to the NASA Postdoctoral Program at the Goddard Space Flight Center, administered by Universities Space Research Association under contract with NASA. D.K., C.A.W.H., C.M. H., and J.R. gratefully acknowledge NASA funding through the Fermi-GBM project. Support for the German contribution to GBM was provided by the Bundesministerium für Bildung und Forschung (BMBF) via the Deutsches Zentrum für Luft und Raumfahrt (DLR) under contract number 50 QV 0301. A. v.K. was supported by the Bundesministeriums für Wirtschaft und Technologie (BMWi) through DLR grant 50 OG 1101. S. M.B. acknowledges support from Science Foundation Ireland under grant 12/IP/1288.Part of the funding for GROND was generously granted from the Leibniz-Prize to Prof. G. Hasinger (DFG grant HA 1850/28-1). “We acknowledge the excellent help in obtaining GROND data from Angela Hempel, Markus Rabus and Régis Lachaume on La Silla.