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  • Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
    Science (IF 41.845) Pub Date : 2021-03-03
    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 novel SARS-CoV-2 variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in November 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modelling approaches, we estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows

  • Targeting a neoantigen derived from a common TP53 mutation
    Science (IF 41.845) Pub Date : 2021-03-01
    Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, Andrew D. Skora, P. Aitana Azurmendi, Michael B. Murphy, Qiang Liu, Evangeline Watson, Yana Li, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein

    TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen–A (HLA-A) allele

  • Shulin packages axonemal outer dynein arms for ciliary targeting
    Science (IF 41.845) Pub Date : 2021-02-26
    Girish R. Mali, Ferdos Abid Ali, Clinton K. Lau, Farida Begum, Jérôme Boulanger, Jonathan D. Howe, Zhuo A. Chen, Juri Rappsilber, Mark Skehel, Andrew P. Carter

    The main force generators in eukaryotic cilia and flagella are axonemal outer dynein arms (ODAs). During ciliogenesis, these ~1.8-megadalton complexes are assembled in the cytoplasm and targeted to cilia by an unknown mechanism. Here, we used the ciliate Tetrahymena to identify two factors (Q22YU3 and Q22MS1) that bind ODAs in the cytoplasm and are required for ODA delivery to cilia. Q22YU3, which

  • Model-informed COVID-19 vaccine prioritization strategies by age and serostatus
    Science (IF 41.845) Pub Date : 2021-02-26
    Kate M. Bubar, Kyle Reinholt, Stephen M. Kissler, Marc Lipsitch, Sarah Cobey, Yonatan H. Grad, Daniel B. Larremore

    Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were

  • Reactive uptake of N2O5 by atmospheric aerosol is dominated by interfacial processes
    Science (IF 41.845) Pub Date : 2021-02-26
    Mirza Galib, David T. Limmer

    Nitrogen oxides are removed from the troposphere through the reactive uptake of N2O5 into aqueous aerosol. This process is thought to occur within the bulk of an aerosol, through solvation and subsequent hydrolysis. However, this perspective is difficult to reconcile with field measurements and cannot be verified directly because of the fast reaction kinetics of N2O5. Here, we use molecular simulations

  • Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
    Science (IF 41.845) Pub Date : 2021-02-26
    Kris M. White, Romel Rosales, Soner Yildiz, Thomas Kehrer, Lisa Miorin, Elena Moreno, Sonia Jangra, Melissa B. Uccellini, Raveen Rathnasinghe, Lynda Coughlan, Carles Martinez-Romero, Jyoti Batra, Ajda Rojc, Mehdi Bouhaddou, Jacqueline M. Fabius, Kirsten Obernier, Marion Dejosez, María José Guillén, Alejandro Losada, Pablo Avilés, Michael Schotsaert, Thomas Zwaka, Marco Vignuzzi, Kevan M. Shokat, Nevan

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro

  • Optical polarization–based seismic and water wave sensing on transoceanic cables
    Science (IF 41.845) Pub Date : 2021-02-26
    Zhongwen Zhan, Mattia Cantono, Valey Kamalov, Antonio Mecozzi, Rafael Müller, Shuang Yin, Jorge C. Castellanos

    Seafloor geophysical instrumentation is challenging to deploy and maintain but critical for studying submarine earthquakes and Earth’s interior. Emerging fiber-optic sensing technologies that can leverage submarine telecommunication cables present an opportunity to fill the data gap. We successfully sensed seismic and water waves over a 10,000-kilometer-long submarine cable connecting Los Angeles,

  • Quantum interference between spin-orbit split partial waves in the F + HD → HF + D reaction
    Science (IF 41.845) Pub Date : 2021-02-26
    Wentao Chen, Ransheng Wang, Daofu Yuan, Hailin Zhao, Chang Luo, Yuxin Tan, Shihao Li, Dong H. Zhang, Xingan Wang, Zhigang Sun, Xueming Yang

    The effect of electron spin-orbit interactions on chemical reaction dynamics has been a topic of much research interest. Here we report a combined experimental and theoretical study on the effect of electron spin and orbital angular momentum in the F + HD → HF + D reaction. Using a high-resolution imaging technique, we observed a peculiar horseshoe-shaped pattern in the product rotational-state–resolved

  • The influence of juvenile dinosaurs on community structure and diversity
    Science (IF 41.845) Pub Date : 2021-02-26
    Katlin Schroeder, S. Kathleen Lyons, Felisa A. Smith

    Despite dominating biodiversity in the Mesozoic, dinosaurs were not speciose. Oviparity constrained even gigantic dinosaurs to less than 15 kg at birth; growth through multiple morphologies led to the consumption of different resources at each stage. Such disparity between neonates and adults could have influenced the structure and diversity of dinosaur communities. Here, we quantified this effect

  • 129I and 247Cm in meteorites constrain the last astrophysical source of solar r-process elements
    Science (IF 41.845) Pub Date : 2021-02-26
    Benoit Côté, Marius Eichler, Andrés Yagüe López, Nicole Vassh, Matthew R. Mumpower, Blanka Világos, Benjámin Soós, Almudena Arcones, Trevor M. Sprouse, Rebecca Surman, Marco Pignatari, Mária K. Pető, Benjamin Wehmeyer, Thomas Rauscher, Maria Lugaro

    The composition of the early Solar System can be inferred from meteorites. Many elements heavier than iron were formed by the rapid neutron capture process (r-process), but the astrophysical sources where this occurred remain poorly understood. We demonstrate that the near-identical half-lives (≃15.6 million years) of the radioactive r-process nuclei iodine-129 and curium-247 preserve their ratio,

  • Massively parallel ultrafast random bit generation with a chip-scale laser
    Science (IF 41.845) Pub Date : 2021-02-26
    Kyungduk Kim, Stefan Bittner, Yongquan Zeng, Stefano Guazzotti, Ortwin Hess, Qi Jie Wang, Hui Cao

    Random numbers are widely used for information security, cryptography, stochastic modeling, and quantum simulations. Key technical challenges for physical random number generation are speed and scalability. We demonstrate a method for ultrafast generation of hundreds of random bit streams in parallel with a single laser diode. Spatiotemporal interference of many lasing modes in a specially designed

  • Liver homeostasis is maintained by midlobular zone 2 hepatocytes
    Science (IF 41.845) Pub Date : 2021-02-26
    Yonglong Wei, Yunguan G. Wang, Yuemeng Jia, Lin Li, Jung Yoon, Shuyuan Zhang, Zixi Wang, Yu Zhang, Min Zhu, Tripti Sharma, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Jeffrey H. Albrecht, Phuong T. Le, Clifford J. Rosen, Tao Wang, Hao Zhu

    The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal

  • Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts
    Science (IF 41.845) Pub Date : 2021-02-26
    Jeffrey J. Quinn, Matthew G. Jones, Ross A. Okimoto, Shigeki Nanjo, Michelle M. Chan, Nir Yosef, Trever G. Bivona, Jonathan S. Weissman

    Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months

  • In situ genome sequencing resolves DNA sequence and structure in intact biological samples
    Science (IF 41.845) Pub Date : 2021-02-26
    Andrew C. Payne, Zachary D. Chiang, Paul L. Reginato, Sarah M. Mangiameli, Evan M. Murray, Chun-Chen Yao, Styliani Markoulaki, Andrew S. Earl, Ajay S. Labade, Rudolf Jaenisch, George M. Church, Edward S. Boyden, Jason D. Buenrostro, Fei Chen

    Understanding genome organization requires integration of DNA sequence and three-dimensional spatial context; however, existing genome-wide methods lack either base pair sequence resolution or direct spatial localization. Here, we describe in situ genome sequencing (IGS), a method for simultaneously sequencing and imaging genomes within intact biological samples. We applied IGS to human fibroblasts

  • Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair
    Science (IF 41.845) Pub Date : 2021-02-26
    Lingjuan He, Wenjuan Pu, Xiuxiu Liu, Zhenqian Zhang, Maoying Han, Yi Li, Xiuzhen Huang, Ximeng Han, Yan Li, Kuo Liu, Mengyang Shi, Liang Lai, Ruilin Sun, Qing-Dong Wang, Yong Ji, Jan S. Tchorz, Bin Zhou

    Organ homeostasis is orchestrated by time- and spatially restricted cell proliferation. Studies identifying cells with superior proliferative capacities often rely on the lineage tracing of a subset of cell populations, which introduces a potential selective bias. In this work, we developed a genetic system [proliferation tracer (ProTracer)] by incorporating dual recombinases to seamlessly record the

  • Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies
    Science (IF 41.845) Pub Date : 2021-02-26
    Che-Wei Chang, Eric Shao, Lennart Mucke

    Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer’s disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological

  • Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity
    Science (IF 41.845) Pub Date : 2021-02-26
    Mads Delbo Larsen, Erik L. de Graaf, Myrthe E. Sonneveld, H. Rosina Plomp, Jan Nouta, Willianne Hoepel, Hung-Jen Chen, Federica Linty, Remco Visser, Maximilian Brinkhaus, Tonći Šuštić, Steven W. de Taeye, Arthur E. H. Bentlage, Suvi Toivonen, Carolien A. M. Koeleman, Susanna Sainio, Neeltje A. Kootstra, Philip J. M. Brouwer, Chiara Elisabeth Geyer, Ninotska I. L. Derksen, Gertjan Wolbink, Menno de

    Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG

  • Controlling quantum many-body dynamics in driven Rydberg atom arrays
    Science (IF 41.845) Pub Date : 2021-02-25
    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 non-equilibrium quantum dynamics in many-body systems is challenging as interactions typically lead to thermalization and a chaotic spreading throughout Hilbert space. We investigate non-equilibrium dynamics following 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

  • Haplotype-resolved diverse human genomes and integrated analysis of structural variation
    Science (IF 41.845) Pub Date : 2021-02-25
    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 contig N50: 26 Mbp) integrate all forms of genetic variation even across complex loci. We identify 107,590

  • Molecular mechanism of cytokinin-activated cell division in Arabidopsis
    Science (IF 41.845) Pub Date : 2021-02-25
    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. Here we show, in the Arabidopsis shoot apical meristem (SAM), that cytokinin regulates cell division by promoting nuclear shuttling

  • Enhanced optical asymmetry in supramolecular chiroplasmonic assemblies with long-range order
    Science (IF 41.845) Pub Date : 2021-02-25
    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 long-range organization of nanoparticles similar to liquid crystals found in helical assemblies of gold

  • T cell circuits that sense antigen density with an ultrasensitive threshold
    Science (IF 41.845) Pub Date : 2021-02-25
    Rogelio A. Hernandez-Lopez, Wei Yu, Katelyn A. Cabral, Olivia A. Creasey, Maria del Pilar Lopez Pazmino, Yurie Tonai, Arsenia De Guzman, Anna Mäkelä, Kalle Saksela, Zev J. Gartner, Wendell A. Lim

    Overexpressed tumor associated antigens (e.g., HER2 and epidermal growth factor receptor) are attractive targets for therapeutic T cells, but toxic “off-tumor” cross-reaction with normal tissues expressing low levels of target antigen can occur with Chimeric Antigen Receptor (CAR) T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive feedback circuit that

  • Photo-induced receptor confinement drives ligand-independent GPCR signaling
    Science (IF 41.845) Pub Date : 2021-02-25
    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 photo-instructive matrix with ultra-small lock-and-key interaction pairs to

  • Cygnus X-1 contains a 21–solar mass black hole—Implications for massive star winds
    Science (IF 41.845) Pub Date : 2021-02-23
    James C. A. Miller-Jones, Arash Bahramian, Jerome A. Orosz, Ilya Mandel, Lijun Gou, Thomas J. Maccarone, Coenraad J. Neijssel, Xueshan Zhao, Janusz Ziółkowski, Mark J. Reid, Phil Uttley, Xueying Zheng, Do-Young Byun, Richard Dodson, Victoria Grinberg, Taehyun Jung, Jeong-Sook Kim, Benito Marcote, Sera Markoff, María J. Rioja, Anthony P. Rushton, David M. Russell, Gregory R. Sivakoff, Alexandra J. Tetarenko

    The evolution of massive stars is influenced by the mass lost to stellar winds over their lifetimes. These winds limit the masses of the stellar remnants (such as black holes) that the stars ultimately produce. We use radio astrometry to refine the distance to the black hole X-ray binary Cygnus X-1, which we find to be 2.22−0.17+0.18 kiloparsecs. When combined with archival optical data, this implies

  • Evidence of superfluidity in a dipolar supersolid from nonclassical rotational inertia
    Science (IF 41.845) Pub Date : 2021-02-23
    L. Tanzi, J. G. Maloberti, G. Biagioni, A. Fioretti, C. Gabbanini, G. Modugno

    A key manifestation of superfluidity in liquids and gases is a reduction of the moment of inertia under slow rotations. Non-classical rotational effects have also been considered in the context of the elusive supersolid phase of matter, in which superfluidity coexists with a lattice structure. Here we show that the recently discovered supersolid phase in dipolar quantum gases features a reduced moment

  • Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity
    Science (IF 41.845) Pub Date : 2021-02-19
    Travis R. Blum, Hao Liu, Michael S. Packer, Xiaozhe Xiong, Pyung-Gang Lee, Sicai Zhang, Michelle Richter, George Minasov, Karla J. F. Satchell, Min Dong, David R. Liu

    Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease

  • A global environmental crisis 42,000 years ago
    Science (IF 41.845) Pub Date : 2021-02-19
    Alan Cooper, Chris S. M. Turney, Jonathan Palmer, Alan Hogg, Matt McGlone, Janet Wilmshurst, Andrew M. Lorrey, Timothy J. Heaton, James M. Russell, Ken McCracken, Julien G. Anet, Eugene Rozanov, Marina Friedel, Ivo Suter, Thomas Peter, Raimund Muscheler, Florian Adolphi, Anthony Dosseto, J. Tyler Faith, Pavla Fenwick, Christopher J. Fogwill, Konrad Hughen, Mathew Lipson, Jiabo Liu, Norbert Nowaczyk

    Geological archives record multiple reversals of Earth’s magnetic poles, but the global impacts of these events, if any, remain unclear. Uncertain radiocarbon calibration has limited investigation of the potential effects of the last major magnetic inversion, known as the Laschamps Excursion [41 to 42 thousand years ago (ka)]. We use ancient New Zealand kauri trees (Agathis australis) to develop a

  • Determining structural and chemical heterogeneities of surface species at the single-bond limit
    Science (IF 41.845) Pub Date : 2021-02-19
    Jiayu Xu, Xiang Zhu, Shijing Tan, Yao Zhang, Bin Li, Yunzhe Tian, Huan Shan, Xuefeng Cui, Aidi Zhao, Zhenchao Dong, Jinlong Yang, Yi Luo, Bing Wang, J. G. Hou

    The structure determination of surface species has long been a challenge because of their rich chemical heterogeneities. Modern tip-based microscopic techniques can resolve heterogeneities from their distinct electronic, geometric, and vibrational properties at the single-molecule level but with limited interpretation from each. Here, we combined scanning tunneling microscopy (STM), noncontact atomic

  • Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody
    Science (IF 41.845) Pub Date : 2021-02-19
    C. Garrett Rappazzo, Longping V. Tse, Chengzi I. Kaku, Daniel Wrapp, Mrunal Sakharkar, Deli Huang, Laura M. Deveau, Thomas J. Yockachonis, Andrew S. Herbert, Michael B. Battles, Cecilia M. O’Brien, Michael E. Brown, James C. Geoghegan, Jonathan Belk, Linghang Peng, Linlin Yang, Yixuan Hou, Trevor D. Scobey, Dennis R. Burton, David Nemazee, John M. Dye, James E. Voss, Bronwyn M. Gunn, Jason S. McLellan

    The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to

  • High-entropy-stabilized chalcogenides with high thermoelectric performance
    Science (IF 41.845) Pub Date : 2021-02-19
    Binbin Jiang, Yong Yu, Juan Cui, Xixi Liu, Lin Xie, Jincheng Liao, Qihao Zhang, Yi Huang, Shoucong Ning, Baohai Jia, Bin Zhu, Shengqiang Bai, Lidong Chen, Stephen J. Pennycook, Jiaqing He

    Thermoelectric technology generates electricity from waste heat, but one bottleneck for wider use is the performance of thermoelectric materials. Manipulating the configurational entropy of a material by introducing different atomic species can tune phase composition and extend the performance optimization space. We enhanced the figure of merit (zT) value to 1.8 at 900 kelvin in an n-type PbSe-based

  • Human impacts on global freshwater fish biodiversity
    Science (IF 41.845) Pub Date : 2021-02-19
    Guohuan Su, Maxime Logez, Jun Xu, Shengli Tao, Sébastien Villéger, Sébastien Brosse

    Freshwater fish represent one-fourth of the world’s vertebrates and provide irreplaceable goods and services but are increasingly affected by human activities. A new index, Cumulative Change in Biodiversity Facets, revealed marked changes in biodiversity in >50% of the world’s rivers covering >40% of the world’s continental surface and >37% of the world’s river length, whereas <14% of the world’s surface

  • Cholangiocyte organoids can repair bile ducts after transplantation in the human liver
    Science (IF 41.845) Pub Date : 2021-02-19
    Fotios Sampaziotis, Daniele Muraro, Olivia C. Tysoe, Stephen Sawiak, Timothy E. Beach, Edmund M. Godfrey, Sara S. Upponi, Teresa Brevini, Brandon T. Wesley, Jose Garcia-Bernardo, Krishnaa Mahbubani, Giovanni Canu, Richard Gieseck, Natalie L. Berntsen, Victoria L. Mulcahy, Keziah Crick, Corrina Fear, Sharayne Robinson, Lisa Swift, Laure Gambardella, Johannes Bargehr, Daniel Ortmann, Stephanie E. Brown

    Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However

  • Mechanism of membrane-tethered mitochondrial protein synthesis
    Science (IF 41.845) Pub Date : 2021-02-19
    Yuzuru Itoh, Juni Andréll, Austin Choi, Uwe Richter, Priyanka Maiti, Robert B. Best, Antoni Barrientos, Brendan J. Battersby, Alexey Amunts

    Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo–electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1–like (OXA1L) through three distinct contact sites. OXA1L binding is correlated with a series

  • Prospective mapping of viral mutations that escape antibodies used to treat COVID-19
    Science (IF 41.845) Pub Date : 2021-02-19
    Tyler N. Starr, Allison J. Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary, Adam S. Dingens, Jonathan Z. Li, Jesse D. Bloom

    Antibodies are a potential therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the risk of the virus evolving to escape them remains unclear. Here we map how all mutations to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. These complete maps uncover a single amino acid mutation that fully

  • Clinically relevant mutations in core metabolic genes confer antibiotic resistance
    Science (IF 41.845) Pub Date : 2021-02-19
    Allison J. Lopatkin, Sarah C. Bening, Abigail L. Manson, Jonathan M. Stokes, Michael A. Kohanski, Ahmed H. Badran, Ashlee M. Earl, Nicole J. Cheney, Jason H. Yang, James J. Collins

    Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli

  • Microbial single-cell RNA sequencing by split-pool barcoding
    Science (IF 41.845) Pub Date : 2021-02-19
    Anna Kuchina, Leandra M. Brettner, Luana Paleologu, Charles M. Roco, Alexander B. Rosenberg, Alberto Carignano, Ryan Kibler, Matthew Hirano, R. William DePaolo, Georg Seelig

    Single-cell RNA sequencing (scRNA-seq) has become an essential tool for characterizing gene expression in eukaryotes, but current methods are incompatible with bacteria. Here, we introduce microSPLiT (microbial split-pool ligation transcriptomics), a high-throughput scRNA-seq method for Gram-negative and Gram-positive bacteria that can resolve heterogeneous transcriptional states. We applied microSPLiT

  • Absolute and arbitrary orientation of single-molecule shapes
    Science (IF 41.845) Pub Date : 2021-02-19
    Ashwin Gopinath, Chris Thachuk, Anya Mitskovets, Harry A. Atwater, David Kirkpatrick, Paul W. K. Rothemund

    DNA origami is a modular platform for the combination of molecular and colloidal components to create optical, electronic, and biological devices. Integration of such nanoscale devices with microfabricated connectors and circuits is challenging: Large numbers of freely diffusing devices must be fixed at desired locations with desired alignment. We present a DNA origami molecule whose energy landscape

  • Recurrent evolution of vertebrate transcription factors by transposase capture
    Science (IF 41.845) Pub Date : 2021-02-19
    Rachel L. Cosby, Julius Judd, Ruiling Zhang, Alan Zhong, Nathaniel Garry, Ellen J. Pritham, Cédric Feschotte

    Genes with novel cellular functions may evolve through exon shuffling, which can assemble novel protein architectures. Here, we show that DNA transposons provide a recurrent supply of materials to assemble protein-coding genes through exon shuffling. We find that transposase domains have been captured—primarily via alternative splicing—to form fusion proteins at least 94 times independently over the

  • Plant evolution driven by interactions with symbiotic and pathogenic microbes
    Science (IF 41.845) Pub Date : 2021-02-19
    Pierre-Marc Delaux, Sebastian Schornack

    During 450 million years of diversification on land, plants and microbes have evolved together. This is reflected in today’s continuum of associations, ranging from parasitism to mutualism. Through phylogenetics, cell biology, and reverse genetics extending beyond flowering plants into bryophytes, scientists have started to unravel the genetic basis and evolutionary trajectories of plant-microbe associations

  • De novo design of transmembrane β barrels
    Science (IF 41.845) Pub Date : 2021-02-19
    Anastassia A. Vorobieva, Paul White, Binyong Liang, Jim E. Horne, Asim K. Bera, Cameron M. Chow, Stacey Gerben, Sinduja Marx, Alex Kang, Alyssa Q. Stiving, Sophie R. Harvey, Dagan C. Marx, G. Nasir Khan, Karen G. Fleming, Vicki H. Wysocki, David J. Brockwell, Lukas K. Tamm, Sheena E. Radford, David Baker

    Transmembrane β-barrel proteins (TMBs) are of great interest for single-molecule analytical technologies because they can spontaneously fold and insert into membranes and form stable pores, but the range of pore properties that can be achieved by repurposing natural TMBs is limited. We leverage the power of de novo computational design coupled with a “hypothesis, design, and test” approach to determine

  • Inferring the effectiveness of government interventions against COVID-19
    Science (IF 41.845) Pub Date : 2021-02-19
    Jan M. Brauner, Sören Mindermann, Mrinank Sharma, David Johnston, John Salvatier, Tomáš Gavenčiak, Anna B. Stephenson, Gavin Leech, George Altman, Vladimir Mikulik, Alexander John Norman, Joshua Teperowski Monrad, Tamay Besiroglu, Hong Ge, Meghan A. Hartwick, Yee Whye Teh, Leonid Chindelevitch, Yarin Gal, Jan Kulveit

    Governments are attempting to control the COVID-19 pandemic with nonpharmaceutical interventions (NPIs). However, the effectiveness of different NPIs at reducing transmission is poorly understood. We gathered chronological data on the implementation of NPIs for several European and non-European countries between January and the end of May 2020. We estimated the effectiveness of these NPIs, which range

  • Structure and dynamics of the CGRP receptor in apo and peptide-bound forms
    Science (IF 41.845) Pub Date : 2021-02-18
    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 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)

  • Tracing orbital images on ultrafast time scales
    Science (IF 41.845) Pub Date : 2021-02-18
    R. Wallauer, M. Raths, K. Stallberg, L. Münster, D. Brandstetter, X. Yang, J. Güdde, P. Puschnig, S. Soubatch, C. Kumpf, F. C. Bocquet, F. S. Tautz, U. Höfer

    Frontier orbitals determine fundamental molecular properties such as chemical reactivities. Although electron distributions of occupied orbitals can be imaged in momentum space by photoemission tomography, it has so far been impossible to follow the momentum-space dynamics of a molecular orbital in time, for example through an excitation or a chemical reaction. Here, we combined time-resolved photoemission

  • SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model
    Science (IF 41.845) Pub Date : 2021-02-18
    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 the SARS-CoV-2 virus 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 inhibited SARS-CoV-2 Mpro activity

  • Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets
    Science (IF 41.845) Pub Date : 2021-02-17
    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. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection, and based on in vitro efficacy and in vivo biodistribution selected a dimeric form for evaluation

  • The role of officer race and gender in police-civilian interactions in Chicago
    Science (IF 41.845) Pub Date : 2021-02-12
    Bocar A. Ba, Dean Knox, Jonathan Mummolo, Roman Rivera

    Diversification is a widely proposed policing reform, but its impact is difficult to assess. We used records of millions of daily patrol assignments, determined through fixed rules and preassigned rotations that mitigate self-selection, to compare the average behavior of officers of different demographic profiles working in comparable conditions. Relative to white officers, Black and Hispanic officers

  • Catalytic asymmetric and stereodivergent oligonucleotide synthesis
    Science (IF 41.845) Pub Date : 2021-02-12
    Aaron L. Featherston, Yongseok Kwon, Matthew M. Pompeo, Oliver D. Engl, David K. Leahy, Scott J. Miller

    We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA

  • Establishment and lineage dynamics of the SARS-CoV-2 epidemic in the UK
    Science (IF 41.845) Pub Date : 2021-02-12
    Louis du Plessis, John T. McCrone, Alexander E. Zarebski, Verity Hill, Christopher Ruis, Bernardo Gutierrez, Jayna Raghwani, Jordan Ashworth, Rachel Colquhoun, Thomas R. Connor, Nuno R. Faria, Ben Jackson, Nicholas J. Loman, Áine O’Toole, Samuel M. Nicholls, Kris V. Parag, Emily Scher, Tetyana I. Vasylyeva, Erik M. Volz, Alexander Watts, Isaac I. Bogoch, Kamran Khan, COVID-19 Genomics UK (COG-UK) Consortium†

    The United Kingdom’s COVID-19 epidemic during early 2020 was one of world’s largest and was unusually well represented by virus genomic sampling. We determined the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes, including 26,181 from the UK sampled throughout the country’s first wave of infection

  • A massive stellar bulge in a regularly rotating galaxy 1.2 billion years after the Big Bang
    Science (IF 41.845) Pub Date : 2021-02-12
    Federico Lelli, Enrico M. Di Teodoro, Filippo Fraternali, Allison W. S. Man, Zhi-Yu Zhang, Carlos De Breuck, Timothy A. Davis, Roberto Maiolino

    Cosmological models predict that galaxies forming in the early Universe experience a chaotic phase of gas accretion and star formation, followed by gas ejection due to feedback processes. Galaxy bulges may assemble later via mergers or internal evolution. Here we present submillimeter observations (with spatial resolution of 700 parsecs) of ALESS 073.1, a starburst galaxy at redshift z≃5 when the Universe

  • Two-dimensional superconductivity and anisotropic transport at KTaO3 (111) interfaces
    Science (IF 41.845) Pub Date : 2021-02-12
    Changjiang Liu, Xi Yan, Dafei Jin, Yang Ma, Haw-Wen Hsiao, Yulin Lin, Terence M. Bretz-Sullivan, Xianjing Zhou, John Pearson, Brandon Fisher, J. Samuel Jiang, Wei Han, Jian-Min Zuo, Jianguo Wen, Dillon D. Fong, Jirong Sun, Hua Zhou, Anand Bhattacharya

    The distinctive electronic structure found at interfaces between materials can allow unconventional quantum states to emerge. Here we report on the discovery of superconductivity in electron gases formed at interfaces between (111)-oriented KTaO3 and insulating overlayers of either EuO or LaAlO3. The superconducting transition temperature, as high as 2.2 kelvin, is about one order of magnitude higher

  • Enhanced atomic ordering leads to high thermoelectric performance in AgSbTe2
    Science (IF 41.845) Pub Date : 2021-02-12
    Subhajit Roychowdhury, Tanmoy Ghosh, Raagya Arora, Manisha Samanta, Lin Xie, Niraj Kumar Singh, Ajay Soni, Jiaqing He, Umesh V. Waghmare, Kanishka Biswas

    High thermoelectric performance is generally achieved through either electronic structure modulations or phonon scattering enhancements, which often counteract each other. A leap in performance requires innovative strategies that simultaneously optimize electronic and phonon transports. We demonstrate high thermoelectric performance with a near room-temperature figure of merit, ZT ~ 1.5, and a maximum

  • Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease
    Science (IF 41.845) Pub Date : 2021-02-12
    Christina V. Theodoris, Ping Zhou, Lei Liu, Yu Zhang, Tomohiro Nishino, Yu Huang, Aleksandra Kostina, Sanjeev S. Ranade, Casey A. Gifford, Vladimir Uspenskiy, Anna Malashicheva, Sheng Ding, Deepak Srivastava

    Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach

  • Orogenic quiescence in Earth’s middle age
    Science (IF 41.845) Pub Date : 2021-02-12
    Ming Tang, Xu Chu, Jihua Hao, Bing Shen

    Mountain belts modulate denudation flux and hydrologic processes and are thus fundamental to nutrient cycling on Earth’s surface. We used europium anomalies in detrital zircons to track mountain-building processes over Earth’s history. We show that the average thickness of active continental crust varied on billion-year time scales, with the thickest crust formed in the Archean and Phanerozoic. By

  • Seismic crustal imaging using fin whale songs
    Science (IF 41.845) Pub Date : 2021-02-12
    Václav M. Kuna, John L. Nábělek

    Fin whale calls are among the strongest animal vocalizations that are detectable over great distances in the oceans. We analyze fin whale songs recorded at ocean-bottom seismometers in the northeast Pacific Ocean and show that in addition to the waterborne signal, the song recordings also contain signals reflected and refracted from crustal interfaces beneath the stations. With these data, we constrain

  • Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice
    Science (IF 41.845) Pub Date : 2021-02-12
    Alexander A. Cohen, Priyanthi N. P. Gnanapragasam, Yu E. Lee, Pauline R. Hoffman, Susan Ou, Leesa M. Kakutani, Jennifer R. Keeffe, Hung-Jen Wu, Mark Howarth, Anthony P. West, Christopher O. Barnes, Michel C. Nussenzweig, Pamela J. Bjorkman

    Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles with four to eight distinct

  • Immunological characteristics govern the transition of COVID-19 to endemicity
    Science (IF 41.845) Pub Date : 2021-02-12
    Jennie S. Lavine, Ottar N. Bjornstad, Rustom Antia

    We are currently faced with the question of how the severity of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may change in the years ahead. Our analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that infection-blocking immunity wanes rapidly but that disease-reducing immunity is long-lived. Our model, incorporating these components

  • Communicating clocks shape circadian homeostasis
    Science (IF 41.845) Pub Date : 2021-02-12
    Kevin B. Koronowski, Paolo Sassone-Corsi

    Circadian clocks temporally coordinate physiology and align it with geophysical time, which enables diverse life-forms to anticipate daily environmental cycles. In complex organisms, clock function originates from the molecular oscillator within each cell and builds upward anatomically into an organism-wide system. Recent advances have transformed our understanding of how clocks are connected to achieve

  • Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment
    Science (IF 41.845) Pub Date : 2021-02-12
    Cleber A. Trujillo, Edward S. Rice, Nathan K. Schaefer, Isaac A. Chaim, Emily C. Wheeler, Assael A. Madrigal, Justin Buchanan, Sebastian Preissl, Allen Wang, Priscilla D. Negraes, Ryan A. Szeto, Roberto H. Herai, Alik Huseynov, Mariana S. A. Ferraz, Fernando S. Borges, Alexandre H. Kihara, Ashley Byrne, Maximillian Marin, Christopher Vollmers, Angela N. Brooks, Jonathan D. Lautz, Katerina Semendeferi

    The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent

  • Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape
    Science (IF 41.845) Pub Date : 2021-02-12
    Paul-Albert Koenig, Hrishikesh Das, Hejun Liu, Beate M. Kümmerer, Florian N. Gohr, Lea-Marie Jenster, Lisa D. J. Schiffelers, Yonas M. Tesfamariam, Miki Uchima, Jennifer D. Wuerth, Karl Gatterdam, Natalia Ruetalo, Maria H. Christensen, Caroline I. Fandrey, Sabine Normann, Jan M. P. Tödtmann, Steffen Pritzl, Leo Hanke, Jannik Boos, Meng Yuan, Xueyong Zhu, Jonathan L. Schmid-Burgk, Hiroki Kato, Michael

    The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography

  • Cellular transcriptomics reveals evolutionary identities of songbird vocal circuits
    Science (IF 41.845) Pub Date : 2021-02-12
    Bradley M. Colquitt, Devin P. Merullo, Genevieve Konopka, Todd F. Roberts, Michael S. Brainard

    Birds display advanced behaviors, including vocal learning and problem-solving, yet lack a layered neocortex, a structure associated with complex behavior in mammals. To determine whether these behavioral similarities result from shared or distinct neural circuits, we used single-cell RNA sequencing to characterize the neuronal repertoire of the songbird song motor pathway. Glutamatergic vocal neurons

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