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  • Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil
    Science (IF 41.845) Pub Date : 2021-04-14
    Nuno R. Faria, Thomas A. Mellan, Charles Whittaker, Ingra M. Claro, Darlan da S. Candido, Swapnil Mishra, Myuki A. E. Crispim, Flavia C. S. Sales, Iwona Hawryluk, John T. McCrone, Ruben J. G. Hulswit, Lucas A. M. Franco, Mariana S. Ramundo, Jaqueline G. de Jesus, Pamela S. Andrade, Thais M. Coletti, Giulia M. Ferreira, Camila A. M. Silva, Erika R. Manuli, Rafael H. M. Pereira, Pedro S. Peixoto, Moritz

    Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased

  • Spatiotemporal pattern of COVID-19 spread in Brazil
    Science (IF 41.845) Pub Date : 2021-04-14
    Marcia C. Castro, Sun Kim, Lorena Barberia, Ana Freitas Ribeiro, Susie Gurzenda, Karina Braga Ribeiro, Erin Abbott, Jeffrey Blossom, Beatriz Rache, Burton H. Singer

    Brazil has been severely hit by COVID-19, with rapid spatial spread of both cases and deaths. We use daily data on reported cases and deaths to understand, measure, and compare the spatiotemporal pattern of the spread across municipalities. Indicators of clustering, trajectories, speed, and intensity of the movement of COVID-19 to interior areas, combined with indices of policy measures show that while

  • Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes
    Science (IF 41.845) Pub Date : 2021-04-13
    Chadi M. Saad-Roy, Sinead E. Morris, C. Jessica E. Metcalf, Michael J. Mina, Rachel E. Baker, Jeremy Farrar, Edward C. Holmes, Oliver G. Pybus, Andrea L. Graham, Simon A. Levin, Bryan T. Grenfell, Caroline E. Wagner

    In the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to SARS-CoV-2. Two critical issues arise: how will the timing of delivery of the second dose affect both infection dynamics and prospects for the evolution of viral immune escape via a build-up of partially immune individuals. Both hinge on the robustness

  • Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues
    Science (IF 41.845) Pub Date : 2021-04-12
    Fan Yang, Sandra C. A. Nielsen, Ramona A. Hoh, Katharina Röltgen, Oliver Fabian Wirz, Emily Haraguchi, Grace H. Jean, Ji-Yeun Lee, Tho D. Pham, Katherine J. L. Jackson, Krishna M. Roskin, Yi Liu, Khoa Nguyen, Robert S. Ohgami, Eleanor M. Osborne, Kari C. Nadeau, Claus U. Niemann, Julie Parsonnet, Scott D. Boyd

    Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated convergent antigen-specific antibody genes of similar sequences shared between individuals in pediatric and adult blood, and deceased organ donor tissues. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not

  • Bilateral visual projections exist in non-teleost bony fish and predate the emergence of tetrapods
    Science (IF 41.845) Pub Date : 2021-04-09
    Robin J. Vigouroux, Karine Duroure, Juliette Vougny, Shahad Albadri, Peter Kozulin, Eloisa Herrera, Kim Nguyen-Ba-Charvet, Ingo Braasch, Rodrigo Suárez, Filippo Del Bene, Alain Chédotal

    In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here we show that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral

  • Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors
    Science (IF 41.845) Pub Date : 2021-04-09
    Kasper Fugger, Ilirjana Bajrami, Mariana Silva Dos Santos, Sarah Jane Young, Simone Kunzelmann, Geoff Kelly, Graeme Hewitt, Harshil Patel, Robert Goldstone, Thomas Carell, Simon J. Boulton, James MacRae, Ian A. Taylor, Stephen C. West

    Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP

  • The primitive brain of early Homo
    Science (IF 41.845) Pub Date : 2021-04-09
    Marcia S. Ponce de León, Thibault Bienvenu, Assaf Marom, Silvano Engel, Paul Tafforeau, José Luis Alatorre Warren, David Lordkipanidze, Iwan Kurniawan, Delta Bayu Murti, Rusyad Adi Suriyanto, Toetik Koesbardiati, Christoph P. E. Zollikofer

    The brains of modern humans differ from those of great apes in size, shape, and cortical organization, notably in frontal lobe areas involved in complex cognitive tasks, such as social cognition, tool use, and language. When these differences arose during human evolution is a question of ongoing debate. Here, we show that the brains of early Homo from Africa and Western Asia (Dmanisi) retained a primitive

  • Pollen PCP-B peptides unlock a stigma peptide–receptor kinase gating mechanism for pollination
    Science (IF 41.845) Pub Date : 2021-04-09
    Chen Liu, Lianping Shen, Yu Xiao, David Vyshedsky, Chao Peng, Xiang Sun, Zhiwen Liu, Lijun Cheng, Hua Zhang, Zhifu Han, Jijie Chai, Hen-Ming Wu, Alice Y. Cheung, Chao Li

    Sexual reproduction in angiosperms relies on precise communications between the pollen and pistil. The molecular mechanisms underlying these communications remain elusive. We established that in Arabidopsis, a stigmatic gatekeeper, the ANJEA–FERONIA (ANJ–FER) receptor kinase complex, perceives the RAPID ALKALINIZATION FACTOR peptides RALF23 and RALF33 to induce reactive oxygen species (ROS) production

  • Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis
    Science (IF 41.845) Pub Date : 2021-04-09
    Hairong Lyu, Ilia Kevlishvili, Xuan Yu, Peng Liu, Guangbin Dong

    Mild methods to cleave the carbon-oxygen (C−O) bond in alkyl ethers could simplify chemical syntheses through the elaboration of these robust, readily available precursors. Here we report that dibromoboranes react with alkyl ethers in the presence of a nickel catalyst and zinc reductant to insert boron into the C−O bond. Subsequent reactivity can effect oxygen-to-nitrogen substitution or one-carbon

  • High-throughput injection molding of transparent fused silica glass
    Science (IF 41.845) Pub Date : 2021-04-09
    Markus Mader, Oliver Schlatter, Barbara Heck, Andreas Warmbold, Alex Dorn, Hans Zappe, Patrick Risch, Dorothea Helmer, Frederik Kotz, Bastian E. Rapp

    Glass is one of the most relevant high-performance materials that has the benefit of a favorable environmental footprint compared with that of other commodity materials. Despite the advantageous properties of glasses, polymers are often favored because they can be processed using scalable industrial replication techniques like injection molding (IM). Glasses are generally processed through melting

  • Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar
    Science (IF 41.845) Pub Date : 2021-04-09
    Teruaki Enoto, Toshio Terasawa, Shota Kisaka, Chin-Ping Hu, Sebastien Guillot, Natalia Lewandowska, Christian Malacaria, Paul S. Ray, Wynn C.G. Ho, Alice K. Harding, Takashi Okajima, Zaven Arzoumanian, Keith C. Gendreau, Zorawar Wadiasingh, Craig B. Markwardt, Yang Soong, Steve Kenyon, Slavko Bogdanov, Walid A. Majid, Tolga Güver, Gaurava K. Jaisawal, Rick Foster, Yasuhiro Murata, Hiroshi Takeuchi

    Giant radio pulses (GRPs) are sporadic bursts emitted by some pulsars that last a few microseconds and are hundreds to thousands of times brighter than regular pulses from these sources. The only GRP-associated emission outside of radio wavelengths is from the Crab Pulsar, where optical emission is enhanced by a few percentage points during GRPs. We observed the Crab Pulsar simultaneously at x-ray

  • Gate-controlled BCS-BEC crossover in a two-dimensional superconductor
    Science (IF 41.845) Pub Date : 2021-04-09
    Yuji Nakagawa, Yuichi Kasahara, Takuya Nomoto, Ryotaro Arita, Tsutomu Nojima, Yoshihiro Iwasa

    Bardeen-Cooper-Schrieffer (BCS) superfluidity and Bose-Einstein condensation (BEC) are the two extreme limits of the ground state of the paired fermion systems. We report crossover behavior from the BCS limit to the BEC limit realized by varying carrier density in a two-dimensional superconductor, electron-doped zirconium nitride chloride. The phase diagram, established by simultaneous measurements

  • Seeded 2D epitaxy of large-area single-crystal films of the van der Waals semiconductor 2H MoTe2
    Science (IF 41.845) Pub Date : 2021-04-09
    Xiaolong Xu, Yu Pan, Shuai Liu, Bo Han, Pingfan Gu, Siheng Li, Wanjin Xu, Yuxuan Peng, Zheng Han, Ji Chen, Peng Gao, Yu Ye

    The integration of two-dimensional (2D) van der Waals semiconductors into silicon electronics technology will require the production of large-scale, uniform, and highly crystalline films. We report a route for synthesizing wafer-scale single-crystalline 2H molybdenum ditelluride (MoTe2) semiconductors on an amorphous insulating substrate. In-plane 2D-epitaxy growth by tellurizing was triggered from

  • Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish
    Science (IF 41.845) Pub Date : 2021-04-09
    Masahito Ogawa, Fan-Suo Geng, David T. Humphreys, Esther Kristianto, Delicia Z. Sheng, Subhra P. Hui, Yuxi Zhang, Kotaro Sugimoto, Maki Nakayama, Dawei Zheng, Daniel Hesselson, Mark P. Hodson, Ozren Bogdanovic, Kazu Kikuchi

    Cardiac regeneration requires dedifferentiation and proliferation of mature cardiomyocytes, but the mechanisms underlying this plasticity remain unclear. Here, we identify a potent cardiomyogenic role for Krüppel-like factor 1 (Klf1/Eklf), which is induced in adult zebrafish myocardium upon injury. Myocardial inhibition of Klf1 function does not affect heart development, but it severely impairs regeneration

  • QSER1 protects DNA methylation valleys from de novo methylation
    Science (IF 41.845) Pub Date : 2021-04-09
    Gary Dixon, Heng Pan, Dapeng Yang, Bess P. Rosen, Therande Jashari, Nipun Verma, Julian Pulecio, Inbal Caspi, Kihyun Lee, Stephanie Stransky, Abigail Glezer, Chang Liu, Marco Rivas, Ritu Kumar, Yahui Lan, Ingrid Torregroza, Chuan He, Simone Sidoli, Todd Evans, Olivier Elemento, Danwei Huangfu

    DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells

  • Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
    Science (IF 41.845) Pub Date : 2021-04-09
    Nicholas G. Davies, Sam Abbott, Rosanna C. Barnard, Christopher I. Jarvis, Adam J. Kucharski, James D. Munday, Carl A. B. Pearson, Timothy W. Russell, Damien C. Tully, Alex D. Washburne, Tom Wenseleers, Amy Gimma, William Waites, Kerry L. M. Wong, Kevin van Zandvoort, Justin D. Silverman, CMMID COVID-19 Working Group1‡, COVID-19 Genomics UK (COG-UK) Consortium‡, Karla Diaz-Ordaz, Ruth Keogh, Rosalind

    A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants

  • Imaging cell lineage with a synthetic digital recording system
    Science (IF 41.845) Pub Date : 2021-04-09
    Ke-Huan K. Chow, Mark W. Budde, Alejandro A. Granados, Maria Cabrera, Shinae Yoon, Soomin Cho, Ting-hao Huang, Noushin Koulena, Kirsten L. Frieda, Long Cai, Carlos Lois, Michael B. Elowitz

    During multicellular development, spatial position and lineage history play powerful roles in controlling cell fate decisions. Using a serine integrase–based recording system, we engineered cells to record lineage information in a format that can be read out in situ. The system, termed integrase-editable memory by engineered mutagenesis with optical in situ readout (intMEMOIR), allowed in situ reconstruction

  • Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies
    Science (IF 41.845) Pub Date : 2021-04-09
    Y. M. Dennis Lo, Diana S. C. Han, Peiyong Jiang, Rossa W. K. Chiu

    Liquid biopsies that analyze cell-free DNA in blood plasma are used for noninvasive prenatal testing, oncology, and monitoring of organ transplant recipients. DNA molecules are released into the plasma from various bodily tissues. Physical and molecular features of cell-free DNA fragments and their distribution over the genome bear information about their tissues of origin. Moreover, patterns of DNA

  • Mechanism and dynamics of fatty acid photodecarboxylase
    Science (IF 41.845) Pub Date : 2021-04-09
    D. Sorigué, K. Hadjidemetriou, S. Blangy, G. Gotthard, A. Bonvalet, N. Coquelle, P. Samire, A. Aleksandrov, L. Antonucci, A. Benachir, S. Boutet, M. Byrdin, M. Cammarata, S. Carbajo, S. Cuiné, R. B. Doak, L. Foucar, A. Gorel, M. Grünbein, E. Hartmann, R. Hienerwadel, M. Hilpert, M. Kloos, T. J. Lane, B. Légeret, P. Legrand, Y. Li-Beisson, S. L. Y. Moulin, D. Nurizzo, G. Peltier, G. Schirò, R. L. Shoeman

    Fatty acid photodecarboxylase (FAP) is a photoenzyme with potential green chemistry applications. By combining static, time-resolved, and cryotrapping spectroscopy and crystallography as well as computation, we characterized Chlorella variabilis FAP reaction intermediates on time scales from subpicoseconds to milliseconds. High-resolution crystal structures from synchrotron and free electron laser

  • Structure and dynamics of the CGRP receptor in apo and peptide-bound forms
    Science (IF 41.845) Pub Date : 2021-04-09
    Tracy M. Josephs, Matthew J. Belousoff, Yi-Lynn Liang, Sarah J. Piper, Jianjun Cao, Daniel J. Garama, Katie Leach, Karen J. Gregory, Arthur Christopoulos, Debbie L. Hay, Radostin Danev, Denise Wootten, Patrick M. Sexton

    G protein–coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene–related peptide (CGRP)

  • X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
    Science (IF 41.845) Pub Date : 2021-04-02
    Sebastian Günther, Patrick Y. A. Reinke, Yaiza Fernández-García, Julia Lieske, Thomas J. Lane, Helen M. Ginn, Faisal H. M. Koua, Christiane Ehrt, Wiebke Ewert, Dominik Oberthuer, Oleksandr Yefanov, Susanne Meier, Kristina Lorenzen, Boris Krichel, Janine-Denise Kopicki, Luca Gelisio, Wolfgang Brehm, Ilona Dunkel, Brandon Seychell, Henry Gieseler, Brenna Norton-Baker, Beatriz Escudero-Pérez, Martin Domaracky

    The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast

  • Structure of the human Mediator-bound transcription preinitiation complex
    Science (IF 41.845) Pub Date : 2021-04-02
    R. Abdella, A. Talyzina, S. Chen, C. J. Inouye, R. Tjian, Y. He

    Eukaryotic transcription requires the assembly of a multisubunit preinitiation complex (PIC) composed of RNA polymerase II (Pol II) and the general transcription factors. The coactivator Mediator is recruited by transcription factors, facilitates the assembly of the PIC, and stimulates phosphorylation of the Pol II C-terminal domain (CTD) by the TFIIH subunit CDK7. Here, we present the cryo–electron

  • Long-term drying of Mars by sequestration of ocean-scale volumes of water in the crust
    Science (IF 41.845) Pub Date : 2021-04-02
    E. L. Scheller, B. L. Ehlmann, Renyu Hu, D. J. Adams, Y. L. Yung

    Geological evidence shows that ancient Mars had large volumes of liquid water. Models of past hydrogen escape to space, calibrated with observations of the current escape rate, cannot explain the present-day deuterium-to-hydrogen isotope ratio (D/H). We simulated volcanic degassing, atmospheric escape, and crustal hydration on Mars, incorporating observational constraints from spacecraft, rovers, and

  • Extinction at the end-Cretaceous and the origin of modern Neotropical rainforests
    Science (IF 41.845) Pub Date : 2021-04-02
    Mónica R. Carvalho, Carlos Jaramillo, Felipe de la Parra, Dayenari Caballero-Rodríguez, Fabiany Herrera, Scott Wing, Benjamin L. Turner, Carlos D’Apolito, Millerlandy Romero-Báez, Paula Narváez, Camila Martínez, Mauricio Gutierrez, Conrad Labandeira, German Bayona, Milton Rueda, Manuel Paez-Reyes, Dairon Cárdenas, Álvaro Duque, James L. Crowley, Carlos Santos, Daniele Silvestro

    The end-Cretaceous event was catastrophic for terrestrial communities worldwide, yet its long-lasting effect on tropical forests remains largely unknown. We quantified plant extinction and ecological change in tropical forests resulting from the end-Cretaceous event using fossil pollen (>50,000 occurrences) and leaves (>6000 specimens) from localities in Colombia. Late Cretaceous (Maastrichtian) rainforests

  • A van der Waals interface that creates in-plane polarization and a spontaneous photovoltaic effect
    Science (IF 41.845) Pub Date : 2021-04-02
    Takatoshi Akamatsu, Toshiya Ideue, Ling Zhou, Yu Dong, Sota Kitamura, Mao Yoshii, Dongyang Yang, Masaru Onga, Yuji Nakagawa, Kenji Watanabe, Takashi Taniguchi, Joseph Laurienzo, Junwei Huang, Ziliang Ye, Takahiro Morimoto, Hongtao Yuan, Yoshihiro Iwasa

    Van der Waals interfaces can be formed by layer stacking without regard to lattice constants or symmetries of individual building blocks. We engineered the symmetry of a van der Waals interface of tungsten selenide and black phosphorus and realized in-plane electronic polarization that led to the emergence of a spontaneous photovoltaic effect. Spontaneous photocurrent was observed along the polar direction

  • Nonlinear tuning of PT symmetry and non-Hermitian topological states
    Science (IF 41.845) Pub Date : 2021-04-02
    Shiqi Xia, Dimitrios Kaltsas, Daohong Song, Ioannis Komis, Jingjun Xu, Alexander Szameit, Hrvoje Buljan, Konstantinos G. Makris, Zhigang Chen

    Topology, parity-time (PT) symmetry, and nonlinearity are at the origin of many fundamental phenomena in complex systems across the natural sciences, but their mutual interplay remains unexplored. We established a nonlinear non-Hermitian topological platform for active tuning of PT symmetry and topological states. We found that the loss in a topological defect potential in a non-Hermitian photonic

  • Isolated boron in zeolite for oxidative dehydrogenation of propane
    Science (IF 41.845) Pub Date : 2021-04-02
    Hang Zhou, Xianfeng Yi, Yu Hui, Liang Wang, Wei Chen, Yucai Qin, Ming Wang, Jiabi Ma, Xuefeng Chu, Yeqing Wang, Xin Hong, Zifeng Chen, Xiangju Meng, Hai Wang, Qiuyan Zhu, Lijuan Song, Anmin Zheng, Feng-Shou Xiao

    Oxidative dehydrogenation of propane (ODHP) is a key technology for producing propene from shale gas, but conventional metal oxide catalysts are prone to overoxidation to form valueless COx. Boron-based catalysts were recently found to be selective for this reaction, and B–O–B oligomers are generally regarded as active centers. We show here that the isolated boron in a zeolite framework without such

  • Applied pesticide toxicity shifts toward plants and invertebrates, even in GM crops
    Science (IF 41.845) Pub Date : 2021-04-02
    Ralf Schulz, Sascha Bub, Lara L. Petschick, Sebastian Stehle, Jakob Wolfram

    Pesticide impacts are usually discussed in the context of applied amounts while disregarding the large but environmentally relevant variations in substance-specific toxicity. Here, we systemically interpret changes in the use of 381 pesticides over 25 years by considering 1591 substance-specific acute toxicity threshold values for eight nontarget species groups. We find that the toxicity of applied

  • At-risk marine biodiversity faces extensive, expanding, and intensifying human impacts
    Science (IF 41.845) Pub Date : 2021-04-02
    Casey C. O’Hara, Melanie Frazier, Benjamin S. Halpern

    Human activities and climate change threaten marine biodiversity worldwide, though sensitivity to these stressors varies considerably by species and taxonomic group. Mapping the spatial distribution of 14 anthropogenic stressors from 2003 to 2013 onto the ranges of 1271 at-risk marine species sensitive to them, we found that, on average, species faced potential impacts across 57% of their ranges, that

  • Observation of a non-Hermitian phase transition in an optical quantum gas
    Science (IF 41.845) Pub Date : 2021-04-02
    Fahri Emre Öztürk, Tim Lappe, Göran Hellmann, Julian Schmitt, Jan Klaers, Frank Vewinger, Johann Kroha, Martin Weitz

    Quantum gases of light, such as photon or polariton condensates in optical microcavities, are collective quantum systems enabling a tailoring of dissipation from, for example, cavity loss. This characteristic makes them a tool to study dissipative phases, an emerging subject in quantum many-body physics. We experimentally demonstrate a non-Hermitian phase transition of a photon Bose-Einstein condensate

  • Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons
    Science (IF 41.845) Pub Date : 2021-04-02
    Dylan A. Reid, Patrick J. Reed, Johannes C. M. Schlachetzki, Ioana I. Nitulescu, Grace Chou, Enoch C. Tsui, Jeffrey R. Jones, Sahaana Chandran, Ake T. Lu, Claire A. McClain, Jean H. Ooi, Tzu-Wen Wang, Addison J. Lana, Sara B. Linker, Anthony S. Ricciardulli, Shong Lau, Simon T. Schafer, Steve Horvath, Jesse R. Dixon, Nasun Hah, Christopher K. Glass, Fred H. Gage

    Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life

  • Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
    Science (IF 41.845) Pub Date : 2021-04-02
    Evan W. Weber, Kevin R. Parker, Elena Sotillo, Rachel C. Lynn, Hima Anbunathan, John Lattin, Zinaida Good, Julia A. Belk, Bence Daniel, Dorota Klysz, Meena Malipatlolla, Peng Xu, Malek Bashti, Sabine Heitzeneder, Louai Labanieh, Panayiotis Vandris, Robbie G. Majzner, Yanyan Qi, Katalin Sandor, Ling-Chun Chen, Snehit Prabhu, Andrew J. Gentles, Thomas J. Wandless, Ansuman T. Satpathy, Howard Y. Chang

    T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)–T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction

  • Gamma rhythm communication between entorhinal cortex and dentate gyrus neuronal assemblies
    Science (IF 41.845) Pub Date : 2021-04-02
    Antonio Fernández-Ruiz, Azahara Oliva, Marisol Soula, Florbela Rocha-Almeida, Gergo A. Nagy, Gonzalo Martin-Vazquez, György Buzsáki

    Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus

  • Striatal dopamine mediates hallucination-like perception in mice
    Science (IF 41.845) Pub Date : 2021-04-02
    K. Schmack, M. Bosc, T. Ott, J. F. Sturgill, A. Kepecs

    Hallucinations, a central symptom of psychotic disorders, are attributed to excessive dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, largely because hallucinations have been challenging to study in model organisms. We developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high-confidence

  • The burgeoning reach of animal culture
    Science (IF 41.845) Pub Date : 2021-04-02
    Andrew Whiten

    Culture can be defined as all that is learned from others and is repeatedly transmitted in this way, forming traditions that may be inherited by successive generations. This cultural form of inheritance was once thought specific to humans, but research over the past 70 years has instead revealed it to be widespread in nature, permeating the lives of a diversity of animals, including all major classes

  • Haplotype-resolved diverse human genomes and integrated analysis of structural variation
    Science (IF 41.845) Pub Date : 2021-04-02
    Peter Ebert, Peter A. Audano, Qihui Zhu, Bernardo Rodriguez-Martin, David Porubsky, Marc Jan Bonder, Arvis Sulovari, Jana Ebler, Weichen Zhou, Rebecca Serra Mari, Feyza Yilmaz, Xuefang Zhao, PingHsun Hsieh, Joyce Lee, Sushant Kumar, Jiadong Lin, Tobias Rausch, Yu Chen, Jingwen Ren, Martin Santamarina, Wolfram Höps, Hufsah Ashraf, Nelson T. Chuang, Xiaofei Yang, Katherine M. Munson, Alexandra P. Lewis

    Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic

  • Designed proteins assemble antibodies into modular nanocages
    Science (IF 41.845) Pub Date : 2021-04-02
    Robby Divine, Ha V. Dang, George Ueda, Jorge A. Fallas, Ivan Vulovic, William Sheffler, Shally Saini, Yan Ting Zhao, Infencia Xavier Raj, Peter A. Morawski, Madeleine F. Jennewein, Leah J. Homad, Yu-Hsin Wan, Marti R. Tooley, Franziska Seeger, Ali Etemadi, Mitchell L. Fahning, James Lazarovits, Alex Roederer, Alexandra C. Walls, Lance Stewart, Mohammadali Mazloomi, Neil P. King, Daniel J. Campbell

    Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures

  • Structural insights into preinitiation complex assembly on core promoters
    Science (IF 41.845) Pub Date : 2021-04-01
    Xizi Chen, Yilun Qi, Zihan Wu, Xinxin Wang, Jiabei Li, Dan Zhao, Haifeng Hou, Yan Li, Zishuo Yu, Weida Liu, Mo Wang, Yulei Ren, Ze Li, Huirong Yang, Yanhui Xu

    Transcription factor IID (TFIID) recognizes core promoters and supports preinitiation complex (PIC) assembly for RNA polymerase (Pol) II-mediated eukaryotic transcription. Here, we determined the structures of human TFIID-based PIC in three stepwise assembly states and revealed two-track PIC assembly: stepwise promoter deposition to Pol II and extensive modular reorganization on track I (on TATA-DBE

  • The impact of population-wide rapid antigen testing on SARS-CoV-2 prevalence in Slovakia
    Science (IF 41.845) Pub Date : 2021-03-26
    Martin Pavelka, Kevin Van-Zandvoort, Sam Abbott, Katharine Sherratt, Marek Majdan, CMMID COVID-19 working group5, Inštitút Zdravotných Analýz, Pavol Jarčuška, Marek Krajčí, Stefan Flasche, Sebastian Funk

    Slovakia conducted multiple rounds of population-wide rapid antigen testing for SARS-CoV-2 in late 2020, combined with a period of additional contact restrictions. Observed prevalence decreased by 58% (95% CI: 57-58%) within one week in the 45 counties that were subject to two rounds of mass testing, an estimate that remained robust when adjusting for multiple potential confounders. Adjusting for epidemic

  • Rapid speciation via the evolution of pre-mating isolation in the Iberá Seedeater
    Science (IF 41.845) Pub Date : 2021-03-26
    Sheela P. Turbek, Melanie Browne, Adrián S. Di Giacomo, Cecilia Kopuchian, Wesley M. Hochachka, Cecilia Estalles, Darío A. Lijtmaer, Pablo L. Tubaro, Luís Fábio Silveira, Irby J. Lovette, Rebecca J. Safran, Scott A. Taylor, Leonardo Campagna

    Behavioral isolation can catalyze speciation and permit the slow accumulation of additional reproductive barriers between co-occurring organisms. We illustrate how this process occurs by examining the genomic and behavioral bases of pre-mating isolation between two bird species (Sporophila hypoxantha and the recently discovered S. iberaensis) that belong to the southern capuchino seedeaters, a recent

  • Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes
    Science (IF 41.845) Pub Date : 2021-03-26
    Jiajia Ma, Shuming Chen, Peter Bellotti, Renyu Guo, Felix Schäfer, Arne Heusler, Xiaolong Zhang, Constantin Daniliuc, M. Kevin Brown, Kendall N. Houk, Frank Glorius

    Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges

  • A 35-million-year record of seawater stable Sr isotopes reveals a fluctuating global carbon cycle
    Science (IF 41.845) Pub Date : 2021-03-26
    Adina Paytan, Elizabeth M. Griffith, Anton Eisenhauer, Mathis P. Hain, Klaus Wallmann, Andrew Ridgwell

    Changes in the concentration and isotopic composition of the major constituents in seawater reflect changes in their sources and sinks. Because many of the processes controlling these sources and sinks are tied to the cycling of carbon, such records can provide insights into what drives past changes in atmospheric carbon dioxide and climate. Here, we present a stable strontium (Sr) isotope record derived

  • Molecular mechanism of cytokinin-activated cell division in Arabidopsis
    Science (IF 41.845) Pub Date : 2021-03-26
    Weibing Yang, Sandra Cortijo, Niklas Korsbo, Pawel Roszak, Katharina Schiessl, Aram Gurzadyan, Raymond Wightman, Henrik Jönsson, Elliot Meyerowitz

    Mitogens trigger cell division in animals. In plants, cytokinins, a group of phytohormones derived from adenine, stimulate cell proliferation. Cytokinin signaling is initiated by membrane-associated histidine kinase receptors and transduced through a phosphorelay system. We show that in the Arabidopsis shoot apical meristem (SAM), cytokinin regulates cell division by promoting nuclear shuttling of

  • Controlling quantum many-body dynamics in driven Rydberg atom arrays
    Science (IF 41.845) Pub Date : 2021-03-26
    D. Bluvstein, A. Omran, H. Levine, A. Keesling, G. Semeghini, S. Ebadi, T. T. Wang, A. A. Michailidis, N. Maskara, W. W. Ho, S. Choi, M. Serbyn, M. Greiner, V. Vuletić, M. D. Lukin

    The control of nonequilibrium quantum dynamics in many-body systems is challenging because interactions typically lead to thermalization and a chaotic spreading throughout Hilbert space. We investigate nonequilibrium dynamics after rapid quenches in a many-body system composed of 3 to 200 strongly interacting qubits in one and two spatial dimensions. Using a programmable quantum simulator based on

  • Stabilizing black-phase formamidinium perovskite formation at room temperature and high humidity
    Science (IF 41.845) Pub Date : 2021-03-26
    Wei Hui, Lingfeng Chao, Hui Lu, Fei Xia, Qi Wei, Zhenhuang Su, Tingting Niu, Lei Tao, Bin Du, Deli Li, Yue Wang, He Dong, Shouwei Zuo, Bixin Li, Wei Shi, Xueqin Ran, Ping Li, Hui Zhang, Zhongbin Wu, Chenxin Ran, Lin Song, Guichuan Xing, Xingyu Gao, Jing Zhang, Yingdong Xia, Yonghua Chen, Wei Huang

    The stabilization of black-phase formamidinium lead iodide (α-FAPbI3) perovskite under various environmental conditions is considered necessary for solar cells. However, challenges remain regarding the temperature sensitivity of α-FAPbI3 and the requirements for strict humidity control in its processing. Here we report the synthesis of stable α-FAPbI3, regardless of humidity and temperature, based

  • Three-dimensional vectorial imaging of surface phonon polaritons
    Science (IF 41.845) Pub Date : 2021-03-26
    Xiaoyan Li, Georg Haberfehlner, Ulrich Hohenester, Odile Stéphan, Gerald Kothleitner, Mathieu Kociak

    Surface phonon polaritons (SPhPs) are coupled photon-phonon excitations that emerge at the surfaces of nanostructured materials. Although they strongly influence the optical and thermal behavior of nanomaterials, no technique has been able to reveal the complete three-dimensional (3D) vectorial picture of their electromagnetic density of states. Using a highly monochromated electron beam in a scanning

  • Enhanced optical asymmetry in supramolecular chiroplasmonic assemblies with long-range order
    Science (IF 41.845) Pub Date : 2021-03-26
    Jun Lu, Yao Xue, Kalil Bernardino, Ning-Ning Zhang, Weverson R. Gomes, Naomi S. Ramesar, Shuhan Liu, Zheng Hu, Tianmeng Sun, Andre Farias de Moura, Nicholas A. Kotov, Kun Liu

    Chiral assemblies of plasmonic nanoparticles are known for strong circular dichroism but not for high optical asymmetry, which is limited by the unfavorable combination of electrical and magnetic field components compounded by strong scattering. Here, we show that these limitations can be overcome by the long-range organization of nanoparticles in a manner similar to the liquid crystals and found in

  • SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model
    Science (IF 41.845) Pub Date : 2021-03-26
    Jingxin Qiao, Yue-Shan Li, Rui Zeng, Feng-Liang Liu, Rong-Hua Luo, Chong Huang, Yi-Fei Wang, Jie Zhang, Baoxue Quan, Chenjian Shen, Xin Mao, Xinlei Liu, Weining Sun, Wei Yang, Xincheng Ni, Kai Wang, Ling Xu, Zi-Lei Duan, Qing-Cui Zou, Hai-Lin Zhang, Wang Qu, Yang-Hao-Peng Long, Ming-Hua Li, Rui-Cheng Yang, Xiaolong Liu, Jing You, Yangli Zhou, Rui Yao, Wen-Pei Li, Jing-Ming Liu, Pei Chen, Yang Liu,

    The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds

  • Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets
    Science (IF 41.845) Pub Date : 2021-03-26
    Rory D. de Vries, Katharina S. Schmitz, Francesca T. Bovier, Camilla Predella, Jonathan Khao, Danny Noack, Bart L. Haagmans, Sander Herfst, Kyle N. Stearns, Jennifer Drew-Bear, Sudipta Biswas, Barry Rockx, Gaël McGill, N. Valerio Dorrello, Samuel H. Gellman, Christopher A. Alabi, Rik L. de Swart, Anne Moscona, Matteo Porotto

    Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy

  • The molecular assembly of the marsupial γμ T cell receptor defines a third T cell lineage
    Science (IF 41.845) Pub Date : 2021-03-26
    Kimberly A. Morrissey, Marcin Wegrecki, T. Praveena, Victoria L. Hansen, Lijing Bu, Komagal Kannan Sivaraman, Samuel Darko, Daniel C. Douek, Jamie Rossjohn, Robert D. Miller, Jérôme Le Nours

    αβ and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γμTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vμ-Vμj-Cμ) μ-chain. γμTCRs were characterized by restricted diversity in the Vγ and Vμj domains and a highly diverse unpaired

  • Liver type 1 innate lymphoid cells develop locally via an interferon-γ–dependent loop
    Science (IF 41.845) Pub Date : 2021-03-26
    Lu Bai, Margaux Vienne, Ling Tang, Yann Kerdiles, Marion Etiennot, Bertrand Escalière, Justine Galluso, Haiming Wei, Rui Sun, Eric Vivier, Hui Peng, Zhigang Tian

    The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains Lin−Sca-1+Mac-1+ hematopoietic stem cells derived from the fetal liver. This population includes Lin−CD122+CD49a+ progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ

  • WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity
    Science (IF 41.845) Pub Date : 2021-03-26
    Ming Liu, Jinyi Zhang, Benjamin D. Pinder, Qingquan Liu, Dingyan Wang, Hao Yao, Yubo Gao, Aras Toker, Jimin Gao, Alan Peterson, Jia Qu, Katherine A. Siminovitch

    Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional Wave2 ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender

  • The microbiome and human cancer
    Science (IF 41.845) Pub Date : 2021-03-26
    Gregory D. Sepich-Poore, Laurence Zitvogel, Ravid Straussman, Jeff Hasty, Jennifer A. Wargo, Rob Knight

    Microbial roles in cancer formation, diagnosis, prognosis, and treatment have been disputed for centuries. Recent studies have provocatively claimed that bacteria, viruses, and/or fungi are pervasive among cancers, key actors in cancer immunotherapy, and engineerable to treat metastases. Despite these findings, the number of microbes known to directly cause carcinogenesis remains small. Critically

  • Photoinduced receptor confinement drives ligand-independent GPCR signaling
    Science (IF 41.845) Pub Date : 2021-03-26
    M. Florencia Sánchez, Sylvia Els-Heindl, Annette G. Beck-Sickinger, Ralph Wieneke, Robert Tampé

    Cell-cell communication relies on the assembly of receptor-ligand complexes at the plasma membrane. The spatiotemporal receptor organization has a pivotal role in evoking cellular responses. We studied the clustering of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) and established a photoinstructive matrix with ultrasmall lock-and-key interaction pairs to control

  • Age groups that sustain resurging COVID-19 epidemics in the United States
    Science (IF 41.845) Pub Date : 2021-03-26
    Mélodie Monod, Alexandra Blenkinsop, Xiaoyue Xi, Daniel Hebert, Sivan Bershan, Simon Tietze, Marc Baguelin, Valerie C. Bradley, Yu Chen, Helen Coupland, Sarah Filippi, Jonathan Ish-Horowicz, Martin McManus, Thomas Mellan, Axel Gandy, Michael Hutchinson, H. Juliette T. Unwin, Sabine L. van Elsland, Michaela A. C. Vollmer, Sebastian Weber, Harrison Zhu, Anne Bezancon, Neil M. Ferguson, Swapnil Mishra

    After initial declines, in mid-2020 a resurgence in transmission of novel coronavirus disease (COVID-19) occurred in the United States and Europe. As efforts to control COVID-19 disease are reintensified, understanding the age demographics driving transmission and how these affect the loosening of interventions is crucial. We analyze aggregated, age-specific mobility trends from more than 10 million

  • Hunting the eagle killer: A cyanobacterial neurotoxin causes vacuolar myelinopathy
    Science (IF 41.845) Pub Date : 2021-03-26
    Steffen Breinlinger, Tabitha J. Phillips, Brigette N. Haram, Jan Mareš, José A. Martínez Yerena, Pavel Hrouzek, Roman Sobotka, W. Matthew Henderson, Peter Schmieder, Susan M. Williams, James D. Lauderdale, H. Dayton Wilde, Wesley Gerrin, Andreja Kust, John W. Washington, Christoph Wagner, Benedikt Geier, Manuel Liebeke, Heike Enke, Timo H. J. Niedermeyer, Susan B. Wilde

    Vacuolar myelinopathy is a fatal neurological disease that was initially discovered during a mysterious mass mortality of bald eagles in Arkansas in the United States. The cause of this wildlife disease has eluded scientists for decades while its occurrence has continued to spread throughout freshwater reservoirs in the southeastern United States. Recent studies have demonstrated that vacuolar myelinopathy

  • Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy
    Science (IF 41.845) Pub Date : 2021-03-25
    Marieke Verweij, Scott G. Hansen, Ravi Iyer, Nessy John, Daniel Malouli, David Morrow, Isabel Scholz, Jennie Womack, Shaheed Abdulhaqq, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Julia C. Ford, Andrea N. Selseth, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jason Shao, Jonah B. Sacha, Michael K. Axthelm, Paul T. Edlefsen, Jeffrey D. Lifson, Louis

    Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex (MHC)-II and MHC-E, not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular

  • Diversity and functional landscapes in the microbiota of animals in the wild
    Science (IF 41.845) Pub Date : 2021-03-25
    Doron Levin, Neta Raab, Yishay Pinto, Daphna Rothschild, Gal Zanir, Anastasia Godneva, Nadav Mellul, David Futorian, Doran Gal, Sigal Leviatan, David Zeevi, Ido Bachelet, Eran Segal

    Animals in the wild are able to subsist on pathogen-infected and poisonous food and show immunity to various diseases. These may be due to their microbiota, yet we have a poor understanding of animal microbial diversity and function. We used metagenomics to analyze the gut microbiota of over 180 species in the wild, covering diverse classes, feeding behaviors, geographies, and traits. Using de novo

  • Structure of the activated human minor spliceosome
    Science (IF 41.845) Pub Date : 2021-03-19
    Rui Bai, Ruixue Wan, Lin Wang, Kui Xu, Qiangfeng Zhang, Jianlin Lei, Yigong Shi

    The minor spliceosome mediates splicing of the rare but essential U12-type precursor messenger RNA. Here, we report the atomic features of the activated human minor spliceosome determined by cryo–electron microscopy at 2.9-angstrom resolution. The 5′ splice site and branch point sequence of the U12-type intron are recognized by the U6atac and U12 small nuclear RNAs (snRNAs), respectively. Five newly

  • Processive RNA polymerization and promoter recognition in an RNA World
    Science (IF 41.845) Pub Date : 2021-03-19
    Razvan Cojocaru, Peter J. Unrau

    Early life is thought to have required the self-replication of RNA by RNA replicases. However, how such replicases evolved and subsequently enabled gene expression remains largely unexplored. We engineered and selected a holopolymerase ribozyme that uses a sigma factor–like specificity primer to first recognize an RNA promoter sequence and then, in a second step, rearrange to a processive elongation

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