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Showing papers by "University of Groningen published in 2019"


Journal ArticleDOI
Kazunori Akiyama, Antxon Alberdi1, Walter Alef2, Keiichi Asada3  +403 moreInstitutions (82)
TL;DR: In this article, the Event Horizon Telescope was used to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87.
Abstract: When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 +/- 3 mu as, which is circular and encompasses a central depression in brightness with a flux ratio greater than or similar to 10: 1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M = (6.5 +/- 0.7) x 10(9) M-circle dot. Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.

2,589 citations


Journal ArticleDOI
TL;DR: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failureand an ejection fraction of 45% or higher, and among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit in patients with lower ejection fractions and in women.
Abstract: Background The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients ...

1,306 citations


Journal ArticleDOI
31 Oct 2019-Cell
TL;DR: A consensus from the International Cell Senescence Association (ICSA) is presented, defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers.

1,220 citations


Journal ArticleDOI
Pierre Friedlingstein1, Pierre Friedlingstein2, Matthew W. Jones3, Michael O'Sullivan1, Robbie M. Andrew, Judith Hauck4, Glen P. Peters, Wouter Peters5, Wouter Peters6, Julia Pongratz7, Julia Pongratz8, Stephen Sitch1, Corinne Le Quéré3, Dorothee C. E. Bakker3, Josep G. Canadell9, Philippe Ciais10, Robert B. Jackson11, Peter Anthoni12, Leticia Barbero13, Leticia Barbero14, Ana Bastos8, Vladislav Bastrikov10, Meike Becker15, Meike Becker16, Laurent Bopp2, Erik T. Buitenhuis3, Naveen Chandra17, Frédéric Chevallier10, Louise Chini18, Kim I. Currie19, Richard A. Feely20, Marion Gehlen10, Dennis Gilfillan21, Thanos Gkritzalis22, Daniel S. Goll23, Nicolas Gruber24, Sören B. Gutekunst25, Ian Harris26, Vanessa Haverd9, Richard A. Houghton27, George C. Hurtt18, Tatiana Ilyina7, Atul K. Jain28, Emilie Joetzjer10, Jed O. Kaplan29, Etsushi Kato, Kees Klein Goldewijk30, Kees Klein Goldewijk31, Jan Ivar Korsbakken, Peter Landschützer7, Siv K. Lauvset15, Nathalie Lefèvre32, Andrew Lenton33, Andrew Lenton34, Sebastian Lienert35, Danica Lombardozzi36, Gregg Marland21, Patrick C. McGuire37, Joe R. Melton, Nicolas Metzl32, David R. Munro38, Julia E. M. S. Nabel7, Shin-Ichiro Nakaoka39, Craig Neill34, Abdirahman M Omar15, Abdirahman M Omar34, Tsuneo Ono, Anna Peregon10, Anna Peregon40, Denis Pierrot13, Denis Pierrot14, Benjamin Poulter41, Gregor Rehder42, Laure Resplandy43, Eddy Robertson44, Christian Rödenbeck7, Roland Séférian10, Jörg Schwinger30, Jörg Schwinger15, Naomi E. Smith5, Naomi E. Smith45, Pieter P. Tans20, Hanqin Tian46, Bronte Tilbrook33, Bronte Tilbrook34, Francesco N. Tubiello47, Guido R. van der Werf48, Andy Wiltshire44, Sönke Zaehle7 
University of Exeter1, École Normale Supérieure2, Norwich Research Park3, Alfred Wegener Institute for Polar and Marine Research4, Wageningen University and Research Centre5, University of Groningen6, Max Planck Society7, Ludwig Maximilian University of Munich8, Commonwealth Scientific and Industrial Research Organisation9, Centre national de la recherche scientifique10, Stanford University11, Karlsruhe Institute of Technology12, Cooperative Institute for Marine and Atmospheric Studies13, Atlantic Oceanographic and Meteorological Laboratory14, Bjerknes Centre for Climate Research15, Geophysical Institute, University of Bergen16, Japan Agency for Marine-Earth Science and Technology17, University of Maryland, College Park18, National Institute of Water and Atmospheric Research19, National Oceanic and Atmospheric Administration20, Appalachian State University21, Flanders Marine Institute22, Augsburg College23, ETH Zurich24, Leibniz Institute of Marine Sciences25, University of East Anglia26, Woods Hole Research Center27, University of Illinois at Urbana–Champaign28, University of Hong Kong29, Netherlands Environmental Assessment Agency30, Utrecht University31, University of Paris32, University of Tasmania33, Hobart Corporation34, University of Bern35, National Center for Atmospheric Research36, University of Reading37, Cooperative Institute for Research in Environmental Sciences38, National Institute for Environmental Studies39, Russian Academy of Sciences40, Goddard Space Flight Center41, Leibniz Institute for Baltic Sea Research42, Princeton University43, Met Office44, Lund University45, Auburn University46, Food and Agriculture Organization47, VU University Amsterdam48
TL;DR: In this article, the authors describe data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties, including emissions from land use and land use change, and show that the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere is a measure of imperfect data and understanding of the contemporary carbon cycle.
Abstract: . Accurate assessment of anthropogenic carbon dioxide ( CO2 ) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere – the “global carbon budget” – is important to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions ( EFF ) are based on energy statistics and cement production data, while emissions from land use change ( ELUC ), mainly deforestation, are based on land use and land use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly and its growth rate ( GATM ) is computed from the annual changes in concentration. The ocean CO2 sink ( SOCEAN ) and terrestrial CO2 sink ( SLAND ) are estimated with global process models constrained by observations. The resulting carbon budget imbalance ( BIM ), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ . For the last decade available (2009–2018), EFF was 9.5±0.5 GtC yr −1 , ELUC 1.5±0.7 GtC yr −1 , GATM 4.9±0.02 GtC yr −1 ( 2.3±0.01 ppm yr −1 ), SOCEAN 2.5±0.6 GtC yr −1 , and SLAND 3.2±0.6 GtC yr −1 , with a budget imbalance BIM of 0.4 GtC yr −1 indicating overestimated emissions and/or underestimated sinks. For the year 2018 alone, the growth in EFF was about 2.1 % and fossil emissions increased to 10.0±0.5 GtC yr −1 , reaching 10 GtC yr −1 for the first time in history, ELUC was 1.5±0.7 GtC yr −1 , for total anthropogenic CO2 emissions of 11.5±0.9 GtC yr −1 ( 42.5±3.3 GtCO2 ). Also for 2018, GATM was 5.1±0.2 GtC yr −1 ( 2.4±0.1 ppm yr −1 ), SOCEAN was 2.6±0.6 GtC yr −1 , and SLAND was 3.5±0.7 GtC yr −1 , with a BIM of 0.3 GtC. The global atmospheric CO2 concentration reached 407.38±0.1 ppm averaged over 2018. For 2019, preliminary data for the first 6–10 months indicate a reduced growth in EFF of +0.6 % (range of −0.2 % to 1.5 %) based on national emissions projections for China, the USA, the EU, and India and projections of gross domestic product corrected for recent changes in the carbon intensity of the economy for the rest of the world. Overall, the mean and trend in the five components of the global carbon budget are consistently estimated over the period 1959–2018, but discrepancies of up to 1 GtC yr −1 persist for the representation of semi-decadal variability in CO2 fluxes. A detailed comparison among individual estimates and the introduction of a broad range of observations shows (1) no consensus in the mean and trend in land use change emissions over the last decade, (2) a persistent low agreement between the different methods on the magnitude of the land CO2 flux in the northern extra-tropics, and (3) an apparent underestimation of the CO2 variability by ocean models outside the tropics. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set (Le Quere et al., 2018a, b, 2016, 2015a, b, 2014, 2013). The data generated by this work are available at https://doi.org/10.18160/gcp-2019 (Friedlingstein et al., 2019).

981 citations


Journal ArticleDOI
Kazunori Akiyama, Antxon Alberdi1, Walter Alef2, Keiichi Asada3  +251 moreInstitutions (58)
TL;DR: In this article, the first Event Horizon Telescope (EHT) images of M87 were presented, using observations from April 2017 at 1.3 mm wavelength, showing a prominent ring with a diameter of ~40 μas, consistent with the size and shape of the lensed photon orbit encircling the "shadow" of a supermassive black hole.
Abstract: We present the first Event Horizon Telescope (EHT) images of M87, using observations from April 2017 at 1.3 mm wavelength. These images show a prominent ring with a diameter of ~40 μas, consistent with the size and shape of the lensed photon orbit encircling the "shadow" of a supermassive black hole. The ring is persistent across four observing nights and shows enhanced brightness in the south. To assess the reliability of these results, we implemented a two-stage imaging procedure. In the first stage, four teams, each blind to the others' work, produced images of M87 using both an established method (CLEAN) and a newer technique (regularized maximum likelihood). This stage allowed us to avoid shared human bias and to assess common features among independent reconstructions. In the second stage, we reconstructed synthetic data from a large survey of imaging parameters and then compared the results with the corresponding ground truth images. This stage allowed us to select parameters objectively to use when reconstructing images of M87. Across all tests in both stages, the ring diameter and asymmetry remained stable, insensitive to the choice of imaging technique. We describe the EHT imaging procedures, the primary image features in M87, and the dependence of these features on imaging assumptions.

952 citations


Journal ArticleDOI
TL;DR: A new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm', is recommended, which requires comprehensive echocardiography and requires comprehensive natriuretic peptide levels and is typically performed by a cardiologist.
Abstract: Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for heart failure symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular (LV) ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e'), LV filling pressure estimated using E/e', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1 : Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2 : Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

825 citations


Journal ArticleDOI
Kazunori Akiyama, Antxon Alberdi1, Walter Alef2, Keiichi Asada3  +259 moreInstitutions (62)
TL;DR: In this article, a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by GRS was constructed and compared with the observed visibilities.
Abstract: The Event Horizon Telescope (EHT) has mapped the central compact radio source of the elliptical galaxy M87 at 1.3 mm with unprecedented angular resolution. Here we consider the physical implications of the asymmetric ring seen in the 2017 EHT data. To this end, we construct a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by general relativistic ray tracing. We compare the observed visibilities with this library and confirm that the asymmetric ring is consistent with earlier predictions of strong gravitational lensing of synchrotron emission from a hot plasma orbiting near the black hole event horizon. The ring radius and ring asymmetry depend on black hole mass and spin, respectively, and both are therefore expected to be stable when observed in future EHT campaigns. Overall, the observed image is consistent with expectations for the shadow of a spinning Kerr black hole as predicted by general relativity. If the black hole spin and M87's large scale jet are aligned, then the black hole spin vector is pointed away from Earth. Models in our library of non-spinning black holes are inconsistent with the observations as they do not produce sufficiently powerful jets. At the same time, in those models that produce a sufficiently powerful jet, the latter is powered by extraction of black hole spin energy through mechanisms akin to the Blandford-Znajek process. We briefly consider alternatives to a black hole for the central compact object. Analysis of existing EHT polarization data and data taken simultaneously at other wavelengths will soon enable new tests of the GRMHD models, as will future EHT campaigns at 230 and 345 GHz.

808 citations


Journal ArticleDOI
Kazunori Akiyama, Antxon Alberdi1, Walter Alef2, Keiichi Asada3  +394 moreInstitutions (78)
TL;DR: The Event Horizon Telescope (EHT) as mentioned in this paper is a very long baseline interferometry (VLBI) array that comprises millimeter and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth.
Abstract: The Event Horizon Telescope (EHT) is a very long baseline interferometry (VLBI) array that comprises millimeter- and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth. At a nominal operating wavelength of ~1.3 mm, EHT angular resolution (λ/D) is ~25 μas, which is sufficient to resolve nearby supermassive black hole candidates on spatial and temporal scales that correspond to their event horizons. With this capability, the EHT scientific goals are to probe general relativistic effects in the strong-field regime and to study accretion and relativistic jet formation near the black hole boundary. In this Letter we describe the system design of the EHT, detail the technology and instrumentation that enable observations, and provide measures of its performance. Meeting the EHT science objectives has required several key developments that have facilitated the robust extension of the VLBI technique to EHT observing wavelengths and the production of instrumentation that can be deployed on a heterogeneous array of existing telescopes and facilities. To meet sensitivity requirements, high-bandwidth digital systems were developed that process data at rates of 64 gigabit s^(−1), exceeding those of currently operating cm-wavelength VLBI arrays by more than an order of magnitude. Associated improvements include the development of phasing systems at array facilities, new receiver installation at several sites, and the deployment of hydrogen maser frequency standards to ensure coherent data capture across the array. These efforts led to the coordination and execution of the first Global EHT observations in 2017 April, and to event-horizon-scale imaging of the supermassive black hole candidate in M87.

756 citations


Journal ArticleDOI
TL;DR: Scientists working on the response of bacteria to antibiotics define antibiotic persistence and provide practical guidance on how to study bacterial persister cells, and provide a guide to measuring persistence.
Abstract: Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.

659 citations


Journal ArticleDOI
Kazunori Akiyama, Antxon Alberdi1, Walter Alef2, Keiichi Asada3  +243 moreInstitutions (60)
TL;DR: In this paper, the Event Horizon Telescope (EHT) 1.3 mm radio wavelength observations of the supermassive black hole candidate at the center of the radio galaxy M87 and the quasar 3C 279, taken during the 2017 April 5-11 observing campaign are presented.
Abstract: We present the calibration and reduction of Event Horizon Telescope (EHT) 1.3 mm radio wavelength observations of the supermassive black hole candidate at the center of the radio galaxy M87 and the quasar 3C 279, taken during the 2017 April 5–11 observing campaign. These global very long baseline interferometric observations include for the first time the highly sensitive Atacama Large Millimeter/submillimeter Array (ALMA); reaching an angular resolution of 25 μas, with characteristic sensitivity limits of ~1 mJy on baselines to ALMA and ~10 mJy on other baselines. The observations present challenges for existing data processing tools, arising from the rapid atmospheric phase fluctuations, wide recording bandwidth, and highly heterogeneous array. In response, we developed three independent pipelines for phase calibration and fringe detection, each tailored to the specific needs of the EHT. The final data products include calibrated total intensity amplitude and phase information. They are validated through a series of quality assurance tests that show consistency across pipelines and set limits on baseline systematic errors of 2% in amplitude and 1° in phase. The M87 data reveal the presence of two nulls in correlated flux density at ~3.4 and ~8.3 Gλ and temporal evolution in closure quantities, indicating intrinsic variability of compact structure on a timescale of days, or several light-crossing times for a few billion solar-mass black hole. These measurements provide the first opportunity to image horizon-scale structure in M87.

625 citations


Journal ArticleDOI
Mark Chaisson1, Mark Chaisson2, Ashley D. Sanders, Xuefang Zhao3, Xuefang Zhao4, Ankit Malhotra, David Porubsky5, David Porubsky6, Tobias Rausch, Eugene J. Gardner7, Oscar L. Rodriguez8, Li Guo9, Ryan L. Collins4, Xian Fan10, Jia Wen11, Robert E. Handsaker4, Robert E. Handsaker12, Susan Fairley13, Zev N. Kronenberg2, Xiangmeng Kong14, Fereydoun Hormozdiari15, Dillon Lee16, Aaron M. Wenger17, Alex Hastie, Danny Antaki18, Thomas Anantharaman, Peter A. Audano2, Harrison Brand4, Stuart Cantsilieris2, Han Cao, Eliza Cerveira, Chong Chen10, Xintong Chen7, Chen-Shan Chin17, Zechen Chong10, Nelson T. Chuang7, Christine C. Lambert17, Deanna M. Church, Laura Clarke13, Andrew Farrell16, Joey Flores19, Timur R. Galeev14, David U. Gorkin20, David U. Gorkin18, Madhusudan Gujral18, Victor Guryev6, William Haynes Heaton, Jonas Korlach17, Sushant Kumar14, Jee Young Kwon21, Ernest T. Lam, Jong Eun Lee, Joyce V. Lee, Wan-Ping Lee, Sau Peng Lee, Shantao Li14, Patrick Marks, Karine A. Viaud-Martinez19, Sascha Meiers, Katherine M. Munson2, Fabio C. P. Navarro14, Bradley J. Nelson2, Conor Nodzak11, Amina Noor18, Sofia Kyriazopoulou-Panagiotopoulou, Andy Wing Chun Pang, Yunjiang Qiu20, Yunjiang Qiu18, Gabriel Rosanio18, Mallory Ryan, Adrian M. Stütz, Diana C.J. Spierings6, Alistair Ward16, Anne Marie E. Welch2, Ming Xiao22, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley13, Ernesto Lowy13, Sergei Yakneen, Steven A. McCarroll12, Steven A. McCarroll4, Goo Jun23, Li Ding24, Chong-Lek Koh25, Bing Ren18, Bing Ren20, Paul Flicek13, Ken Chen10, Mark Gerstein, Pui-Yan Kwok26, Peter M. Lansdorp27, Peter M. Lansdorp6, Peter M. Lansdorp28, Gabor T. Marth16, Jonathan Sebat18, Xinghua Shi11, Ali Bashir8, Kai Ye9, Scott E. Devine7, Michael E. Talkowski12, Michael E. Talkowski4, Ryan E. Mills3, Tobias Marschall5, Jan O. Korbel13, Evan E. Eichler2, Charles Lee21 
TL;DR: A suite of long-read, short- read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms are applied to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner.
Abstract: The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.

Journal ArticleDOI
TL;DR: Evidence is provided that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function and there was clear, separate evidence of benefit for all eG FR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m2.

Journal ArticleDOI
Hunna J. Watson1, Hunna J. Watson2, Hunna J. Watson3, Zeynep Yilmaz2  +255 moreInstitutions (99)
TL;DR: The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index.
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Journal ArticleDOI
Heather Orpana1, Heather Orpana2, Laurie B. Marczak3, Megha Arora3  +338 moreInstitutions (173)
06 Feb 2019-BMJ
TL;DR: Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide and can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Abstract: Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.

Journal ArticleDOI
TL;DR: In this paper, a review of the advancements made within this field is critically discussed with special attention to the potential of these two classes of compounds as green chemical products: cyclic and polymeric carbonates.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Sheelu Abraham3  +1215 moreInstitutions (134)
TL;DR: In this paper, the mass, spin, and redshift distributions of binary black hole (BBH) mergers with LIGO and Advanced Virgo observations were analyzed using phenomenological population models.
Abstract: We present results on the mass, spin, and redshift distributions with phenomenological population models using the 10 binary black hole (BBH) mergers detected in the first and second observing runs completed by Advanced LIGO and Advanced Virgo. We constrain properties of the BBH mass spectrum using models with a range of parameterizations of the BBH mass and spin distributions. We find that the mass distribution of the more massive BH in such binaries is well approximated by models with no more than 1% of BHs more massive than 45 M and a power-law index of (90% credibility). We also show that BBHs are unlikely to be composed of BHs with large spins aligned to the orbital angular momentum. Modeling the evolution of the BBH merger rate with redshift, we show that it is flat or increasing with redshift with 93% probability. Marginalizing over uncertainties in the BBH population, we find robust estimates of the BBH merger rate density of R= (90% credibility). As the BBH catalog grows in future observing runs, we expect that uncertainties in the population model parameters will shrink, potentially providing insights into the formation of BHs via supernovae, binary interactions of massive stars, stellar cluster dynamics, and the formation history of BHs across cosmic time.

Journal ArticleDOI
Roel Aaij, C. Abellán Beteta1, Bernardo Adeva2, Marco Adinolfi3  +858 moreInstitutions (57)
TL;DR: This is the most precise measurement of R_{K} to date and is compatible with the standard model at the level of 2.5 standard deviations.
Abstract: A measurement of the ratio of branching fractions of the decays B + → K + μ + μ − and B + → K + e + e − is presented. The proton-proton collision data used correspond to an integrated luminosity of 5.0 fb − 1 recorded with the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. For the dilepton mass-squared range 1.1 < q 2 < 6.0 GeV 2 / c 4 the ratio of branching fractions is measured to be R K = 0.84 6 + 0.060 − 0.054 + 0.016 − 0.014 , where the first uncertainty is statistical and the second systematic. This is the most precise measurement of R K to date and is compatible with the standard model at the level of 2.5 standard deviations.

Journal ArticleDOI
TL;DR: Critically examine several issues with the use of the most popular centrality indices in psychological networks: degree, betweenness, and closeness centrality, and conclude that betweenness and closness centrality seem especially unsuitable as measures of node importance.
Abstract: Centrality indices are a popular tool to analyze structural aspects of psychological networks. As centrality indices were originally developed in the context of social networks, it is unclear to what extent these indices are suitable in a psychological network context. In this article we critically examine several issues with the use of the most popular centrality indices in psychological networks: degree, betweenness, and closeness centrality. We show that problems with centrality indices discussed in the social network literature also apply to the psychological networks. Assumptions underlying centrality indices, such as presence of a flow and shortest paths, may not correspond with a general theory of how psychological variables relate to one another. Furthermore, the assumptions of node distinctiveness and node exchangeability may not hold in psychological networks. We conclude that, for psychological networks, betweenness and closeness centrality seem especially unsuitable as measures of node importance. We therefore suggest three ways forward: (a) using centrality measures that are tailored to the psychological network context, (b) reconsidering existing measures of importance used in statistical models underlying psychological networks, and (c) discarding the concept of node centrality entirely. Foremost, we argue that one has to make explicit what one means when one states that a node is central, and what assumptions the centrality measure of choice entails, to make sure that there is a match between the process under study and the centrality measure that is used. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Journal ArticleDOI
15 Mar 2019-Science
TL;DR: The oceanic sink for anthropogenic carbon dioxide (CO2) over the period 1994 to 2007 is estimated to be 31 ± 4% of the global anthropogenic CO2 emissions over this period, consistent with the expectation of the ocean uptake having increased in proportion to the rise in atmospheric CO2.
Abstract: We quantify the oceanic sink for anthropogenic carbon dioxide (CO 2 ) over the period 1994 to 2007 by using observations from the global repeat hydrography program and contrasting them to observations from the 1990s. Using a linear regression–based method, we find a global increase in the anthropogenic CO 2 inventory of 34 ± 4 petagrams of carbon (Pg C) between 1994 and 2007. This is equivalent to an average uptake rate of 2.6 ± 0.3 Pg C year −1 and represents 31 ± 4% of the global anthropogenic CO 2 emissions over this period. Although this global ocean sink estimate is consistent with the expectation of the ocean uptake having increased in proportion to the rise in atmospheric CO 2 , substantial regional differences in storage rate are found, likely owing to climate variability–driven changes in ocean circulation.

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B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1237 moreInstitutions (131)
TL;DR: In this paper, the authors place constraints on the dipole radiation and possible deviations from GR in the post-Newtonian coefficients that govern the inspiral regime of a binary neutron star inspiral.
Abstract: The recent discovery by Advanced LIGO and Advanced Virgo of a gravitational wave signal from a binary neutron star inspiral has enabled tests of general relativity (GR) with this new type of source. This source, for the first time, permits tests of strong-field dynamics of compact binaries in the presence of matter. In this Letter, we place constraints on the dipole radiation and possible deviations from GR in the post-Newtonian coefficients that govern the inspiral regime. Bounds on modified dispersion of gravitational waves are obtained; in combination with information from the observed electromagnetic counterpart we can also constrain effects due to large extra dimensions. Finally, the polarization content of the gravitational wave signal is studied. The results of all tests performed here show good agreement with GR.

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Roel Aaij, C. Abellán Beteta1, Bernardo Adeva2, Marco Adinolfi3  +877 moreInstitutions (60)
TL;DR: In this paper, a new pentaquark state, P_{c}(4312)+, was discovered with a statistical significance of 7.3σ in a data sample of Λ_{b}^{0}→J/ψpK^{-} decays, which is an order of magnitude larger than that previously analyzed by the LHCb Collaboration.
Abstract: A narrow pentaquark state, P_{c}(4312)^{+}, decaying to J/ψp, is discovered with a statistical significance of 7.3σ in a data sample of Λ_{b}^{0}→J/ψpK^{-} decays, which is an order of magnitude larger than that previously analyzed by the LHCb Collaboration. The P_{c}(4450)^{+} pentaquark structure formerly reported by LHCb is confirmed and observed to consist of two narrow overlapping peaks, P_{c}(4440)^{+} and P_{c}(4457)^{+}, where the statistical significance of this two-peak interpretation is 5.4σ. The proximity of the Σ_{c}^{+}D[over ¯]^{0} and Σ_{c}^{+}D[over ¯]^{*0} thresholds to the observed narrow peaks suggests that they play an important role in the dynamics of these states.

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TL;DR: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding.
Abstract: Background It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. Methods We conducted ...

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01 Jan 2019
TL;DR: The potential of combining AFM with complementary techniques, including optical microscopy and spectroscopy of mechanosensitive fluorescent constructs, super-resolution microscopy, the patch clamp technique and the use of microstructured and fluidic devices to characterize the 3D distribution of mechanical responses within biological systems and to track their morphology and functional state as discussed by the authors.
Abstract: Mechanobiology emerges at the crossroads of medicine, biology, biophysics and engineering and describes how the responses of proteins, cells, tissues and organs to mechanical cues contribute to development, differentiation, physiology and disease. The grand challenge in mechanobiology is to quantify how biological systems sense, transduce, respond and apply mechanical signals. Over the past three decades, atomic force microscopy (AFM) has emerged as a key platform enabling the simultaneous morphological and mechanical characterization of living biological systems. In this Review, we survey the basic principles, advantages and limitations of the most common AFM modalities used to map the dynamic mechanical properties of complex biological samples to their morphology. We discuss how mechanical properties can be directly linked to function, which has remained a poorly addressed issue. We outline the potential of combining AFM with complementary techniques, including optical microscopy and spectroscopy of mechanosensitive fluorescent constructs, super-resolution microscopy, the patch clamp technique and the use of microstructured and fluidic devices to characterize the 3D distribution of mechanical responses within biological systems and to track their morphology and functional state. Mechanobiology describes how biological systems respond to mechanical stimuli. This Review surveys basic principles, advantages and limitations of applying and combining atomic force microscopy-based modalities with complementary techniques to characterize the morphology, mechanical properties and functional response of complex biological systems to mechanical cues.

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TL;DR: The requirements and merits of nanotechnology-based antimicrobials for the control of biofilm-infection form the focus of this Tutorial Review.
Abstract: Bacterial-infections are mostly due to bacteria in an adhering, biofilm-mode of growth and not due to planktonically growing, suspended-bacteria. Biofilm-bacteria are much more recalcitrant to conventional antimicrobials than planktonic-bacteria due to (1) emergence of new properties of biofilm-bacteria that cannot be predicted on the basis of planktonic properties, (2) low penetration and accumulation of antimicrobials in a biofilm, (3) disabling of antimicrobials due to acidic and anaerobic conditions prevailing in a biofilm, and (4) enzymatic modification or inactivation of antimicrobials by biofilm inhabitants. In recent years, new nanotechnology-based antimicrobials have been designed to kill planktonic, antibiotic-resistant bacteria, but additional requirements rather than the mere killing of suspended bacteria must be met to combat biofilm-infections. The requirements and merits of nanotechnology-based antimicrobials for the control of biofilm-infection form the focus of this Tutorial Review.

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TL;DR: A comprehensive study of comorbidity within mental disorders is undertaken, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice.
Abstract: Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5940778 persons were included in this study (2958293 men and 2982485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility..

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TL;DR: The use of multicomponent reactions for the preparation of substituted tetrazole derivatives is reviewed and synthetic approaches and their value are discussed by analyzing scope and limitations, and also enlighten their receptor binding mode.
Abstract: Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1 H- or 2 H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

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TL;DR: An overview of their rich history is provided and the contemporary relevance of the spiropyrans is highlighted.
Abstract: Spiropyrans have played a pivotal role in the emergence of the field of chromism following their discovery in the early 20th century, with almost ubiquitous use in materials applications especially since their photochromism was discovered in 1952. Their versatility continues to lend them to application in increasingly diverse fields not least due to recent discoveries of properties that have expanded their utility extensively. This review provides an overview of their rich history and highlights the contemporary relevance of the spiropyrans.

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TL;DR: The increase in the methane burden began in 2007, with the mean global mole fraction in remote surface background air rising from about 1775 ppb in 2006 to 1850 ppb by 2017, at rates not observed since the 1980s as discussed by the authors.
Abstract: Atmospheric methane grew very rapidly in 2014 (12.7±0.5 ppb/yr), 2015 (10.1±0.7 ppb/yr), 2016 (7.0± 0.7 ppb/yr) and 2017 (7.7±0.7 ppb/yr), at rates not observed since the 1980s. The increase in the methane burden began in 2007, with the mean global mole fraction in remote surface background air rising from about 1775 ppb in 2006 to 1850 ppb in 2017. Simultaneously the 13C/12C isotopic ratio (expressed as δ13CCH4) has shifted, in a new trend to more negative values that have been observed worldwide for over a decade. The causes of methane's recent mole fraction increase are therefore either a change in the relative proportions (and totals) of emissions from biogenic and thermogenic and pyrogenic sources, especially in the tropics and sub-tropics, or a decline in the atmospheric sink of methane, or both. Unfortunately, with limited measurement data sets, it is not currently possible to be more definitive. The climate warming impact of the observed methane increase over the past decade, if continued at >5 ppb/yr in the coming decades, is sufficient to challenge the Paris Agreement, which requires sharp cuts in the atmospheric methane burden. However, anthropogenic methane emissions are relatively very large and thus offer attractive targets for rapid reduction, which are essential if the Paris Agreement aims are to be attained.

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Leor Barack1, Vitor Cardoso2, Vitor Cardoso3, Samaya Nissanke4  +228 moreInstitutions (101)
TL;DR: A comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress can be found in this article, which is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
Abstract: The grand challenges of contemporary fundamental physics-dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem-all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'. © 2019 IOP Publishing Ltd.

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TL;DR: This Minireview summarizes the evolution of this cross-coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well-established methodology.
Abstract: The Pd-catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp(2))-N bonds. The pioneering reports from Migita and subsequently Buchwald and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin-free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald-Hartwig amination. This Minireview summarizes the evolution of this cross-coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well-established methodology.