COMRADES determines in vivo RNA structures and interactions.

The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs.This work was supported by Cancer Research UK (C13474/A18583, C6946/A14492) and the Wellcome Trust (104640/Z/14/Z, 092096/Z/10/Z) to E.A.M. O.Z. was supported by the Human Frontier Science Program (HFSP, LT000558/2015), the European Molecular Biology Organization (EMBO, ALTF1622-2014), and the Blavatnik Family Foundation postdoctoral fellowship. G.K. and M.G. were supported by Wellcome Trust grant 207507 and UK Medical Research Council. A.T.L.L. and J.C.M. were supported by core funding from Cancer Research UK (award no. 17197 to JCM). J.C.M was also supported by core funding from EMBL. I.G. and L.W.M. were supported by the Wellcome Trust Senior Fellowship in Basic Biomedical Science to I.G. (207498/Z/17/Z). I.J.M., L.F.G. and J.S.-G. were supported by grants R01GM104475 and R01GM115649 from NIGMS. C.K.K was supported by City University of Hong Kong Projects 9610363 and 7200520, Croucher Foundation Project 9500030 and Hong Kong RGC Projects 9048103 and 9054020. C.-F.Q. was supported by the NSFC Excellent Young Scientist Fund 81522025 and the Newton Advanced Fellowship from the Academy of Medical Sciences, UK

First M87 Event Horizon Telescope Results. II. Array and Instrumentation

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

First M87 Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole

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 μas, which is circular and encompasses a central depression in brightness with a flux ratio 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) × 109 Me. Our radiowave 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

Safety and cost analysis of selective histopathological examination following appendicectomy and cholecystectomy (FANCY study): protocol and statistical analysis plan of a prospective observational multicentre study

IntroductionRoutine histopathological examination following appendicectomy and cholecystectomy has significant financial implications and comprises a substantial portion of the pathologists’ workload, while the incidence of unexpected pathology is low. The aim of the selective histopathological examination Following AppeNdicectomy and CholecystectomY (FANCY) study is to investigate the oncological safety and potential cost savings of selective histopathological examination based on macroscopic assessment performed by the surgeon.Methods and analysisThis is a Dutch multicentre prospective observational study, in which removed appendices and gallbladders will be systematically assessed by the operating surgeon for macroscopic abnormalities suspicious for malignant neoplasms. After visual inspection and digital palpation of the removed specimen, the operating surgeon will report whether macroscopic abnormalities suspicious for a malignant neoplasm are present, and if he or she believes additional microscopic examination by the pathologist is indicated. Regardless of the surgeon’s assessment, all specimens will be sent for histopathological examination. In this way, routine histopathological examination can be compared with a hypothetical situation in which specimens are routinely examined by surgeons and only sent to the pathologist on indication. The two main outcomes are oncological safety and potential cost savings of a selective policy. Oncological safety of selective histopathological examination will be assessed by calculating the number of patients in whom a histopathological diagnosis of an appendiceal neoplasm or gallbladder cancer with clinical consequences benefitting the patient would have been missed. A cost analysis will be performed to quantify the potential cost savings.Ethics and disseminationThe study protocol was reviewed by the Institutional Review Board of the Amsterdam UMC, location AMC, which decided that the Dutch Medical Research Involving Human Subjects Act is not applicable. In all participating centres, approval for execution of the FANCY study has been obtained from the local Institutional Review Board before the start of inclusion of patients. The study results will be disseminated through peer-reviewed publications and conference presentations. Guidelines will be revised according to the findings of the study.Trial registration numberNCT03510923.</jats:sec