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  • Preventing type 1 diabetes in childhood
    Science (IF 47.728) Pub Date : 2021-07-30
    Colin M. Dayan, Rachel E. J. Besser, Richard A. Oram, William Hagopian, Manu Vatish, Owen Bendor-Samuel, Matthew D. Snape, John A. Todd

    Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells of the pancreas are destroyed by T lymphocytes. Recent studies have demonstrated that monitoring for pancreatic islet autoantibodies, combined with genetic risk assessment, can identify most children who will develop T1D when they still have sufficient β cell function to control glucose concentrations without the

  • Immunotherapy: Building a bridge to a cure for type 1 diabetes
    Science (IF 47.728) Pub Date : 2021-07-30
    Jeffrey A. Bluestone, Jane H. Buckner, Kevan C. Herold

    Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by compromising immune homeostasis. Although the discovery and use of insulin have transformed T1D treatment, insulin therapy does not change the underlying disease or fully prevent complications. Over the past

  • Strategies for durable β cell replacement in type 1 diabetes
    Science (IF 47.728) Pub Date : 2021-07-30
    Todd M. Brusko, Holger A. Russ, Cherie L. Stabler

    Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration

  • Type 1 diabetes glycemic management: Insulin therapy, glucose monitoring, and automation
    Science (IF 47.728) Pub Date : 2021-07-30
    Bruce A. Perkins, Jennifer L. Sherr, Chantal Mathieu

    Despite innovations in insulin therapy since its discovery, most patients living with type 1 diabetes do not achieve sufficient glycemic control to prevent complications, and they experience hypoglycemia, weight gain, and major self-care burden. Promising pharmacological advances in insulin therapy include the refinement of extremely rapid insulin analogs, alternate insulin-delivery routes, liver-selective

  • Horizontally transmitted parasitoid killing factor shapes insect defense to parasitoids
    Science (IF 47.728) Pub Date : 2021-07-30
    Laila Gasmi, Edyta Sieminska, Shohei Okuno, Rie Ohta, Cathy Coutu, Mohammad Vatanparast, Stephanie Harris, Doug Baldwin, Dwayne D. Hegedus, David A. Theilmann, Aki Kida, Mio Kawabata, Shiori Sagawa, Jun Takatsuka, Ken Tateishi, Kazuyo Watanabe, Maki N. Inoue, Yasuhisa Kunimi, Yonggyun Kim, Martin A. Erlandson, Salvador Herrero, Madoka Nakai

    Interkingdom competition occurs between hymenopteran parasitoids and insect viruses sharing the same insect hosts. It has been assumed that parasitoid larvae die with the death of the infected host or as result of competition for host resources. Here we describe a gene family, parasitoid killing factor (pkf), that encodes proteins toxic to parasitoids of the Microgastrinae group and determines parasitism

  • Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
    Science (IF 47.728) Pub Date : 2021-07-30
    Tia A. Tummino, Veronica V. Rezelj, Benoit Fischer, Audrey Fischer, Matthew J. O’Meara, Blandine Monel, Thomas Vallet, Kris M. White, Ziyang Zhang, Assaf Alon, Heiko Schadt, Henry R. O’Donnell, Jiankun Lyu, Romel Rosales, Briana L. McGovern, Raveen Rathnasinghe, Sonia Jangra, Michael Schotsaert, Jean-René Galarneau, Nevan J. Krogan, Laszlo Urban, Kevan M. Shokat, Andrew C. Kruse, Adolfo García-Sastre

    Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic

  • lncRNA SLERT controls phase separation of FC/DFCs to facilitate Pol I transcription
    Science (IF 47.728) Pub Date : 2021-07-30
    Man Wu, Guang Xu, Chong Han, Peng-Fei Luan, Yu-Hang Xing, Fang Nan, Liang-Zhong Yang, Youkui Huang, Zheng-Hu Yang, Lin Shan, Li Yang, Jiaquan Liu, Ling-Ling Chen

    RNA polymerase I (Pol I) transcription takes place at the border of the fibrillar center (FC) and the dense fibrillar component (DFC) in the nucleolus. Here, we report that individual spherical FC/DFC units are coated by the DEAD-box RNA helicase DDX21 in human cells. The long noncoding RNA (lncRNA) SLERT binds to DDX21 RecA domains to promote DDX21 to adopt a closed conformation at a substoichiometric

  • Power generation and thermoelectric cooling enabled by momentum and energy multiband alignments
    Science (IF 47.728) Pub Date : 2021-07-30
    Bingchao Qin, Dongyang Wang, Xixi Liu, Yongxin Qin, Jin-Feng Dong, Jiangfan Luo, Jing-Wei Li, Wei Liu, Gangjian Tan, Xinfeng Tang, Jing-Feng Li, Jiaqing He, Li-Dong Zhao

    Thermoelectric materials transfer heat and electrical energy, hence they are useful for power generation or cooling applications. Many of these materials have narrow bandgaps, especially for cooling applications. We developed SnSe crystals with a wide bandgap (Eg ≈ 33 kBT) with attractive thermoelectric properties through Pb alloying. The momentum and energy multiband alignments promoted by Pb alloying

  • Liquid medium annealing for fabricating durable perovskite solar cells with improved reproducibility
    Science (IF 47.728) Pub Date : 2021-07-30
    Nengxu Li, Xiuxiu Niu, Liang Li, Hao Wang, Zijian Huang, Yu Zhang, Yihua Chen, Xiao Zhang, Cheng Zhu, Huachao Zai, Yang Bai, Sai Ma, Huifen Liu, Xixia Liu, Zhenyu Guo, Guilin Liu, Rundong Fan, Hong Chen, Jianpu Wang, Yingzhuo Lun, Xueyun Wang, Jiawang Hong, Haipeng Xie, Devon S. Jakob, Xiaoji G. Xu, Qi Chen, Huanping Zhou

    Solution processing of semiconductors is highly promising for the high-throughput production of cost-effective electronics and optoelectronics. Although hybrid perovskites have potential in various device applications, challenges remain in the development of high-quality materials with simultaneously improved processing reproducibility and scalability. Here, we report a liquid medium annealing (LMA)

  • Half-integer quantized anomalous thermal Hall effect in the Kitaev material candidate α-RuCl3
    Science (IF 47.728) Pub Date : 2021-07-30
    T. Yokoi, S. Ma, Y. Kasahara, S. Kasahara, T. Shibauchi, N. Kurita, H. Tanaka, J. Nasu, Y. Motome, C. Hickey, S. Trebst, Y. Matsuda

    Half-integer thermal quantum Hall conductance has recently been reported for the two-dimensional honeycomb material α-RuCl3. We found that the half-integer thermal Hall plateau appears even for a magnetic field with no out-of-plane components. The measured field-angular variation of the quantized thermal Hall conductance has the same sign structure as the topological Chern number of the pure Kitaev

  • Linked Weyl surfaces and Weyl arcs in photonic metamaterials
    Science (IF 47.728) Pub Date : 2021-07-30
    Shaojie Ma, Yangang Bi, Qinghua Guo, Biao Yang, Oubo You, Jing Feng, Hong-Bo Sun, Shuang Zhang

    Generalization of the concept of band topology from lower-dimensional to higher-dimensional (n > 3) physical systems is expected to introduce new bulk and boundary topological effects. However, theoretically predicted topological singularities in five-dimensional systems—Weyl surfaces and Yang monopoles—have either not been demonstrated in realistic physical systems or are limited to purely synthetic

  • Qubit spin ice
    Science (IF 47.728) Pub Date : 2021-07-30
    Andrew D. King, Cristiano Nisoli, Edward D. Dahl, Gabriel Poulin-Lamarre, Alejandro Lopez-Bezanilla

    Artificial spin ices are frustrated spin systems that can be engineered, in which fine tuning of geometry and topology has allowed the design and characterization of exotic emergent phenomena at the constituent level. Here, we report a realization of spin ice in a lattice of superconducting qubits. Unlike conventional artificial spin ice, our system is disordered by both quantum and thermal fluctuations

  • A fast link between face perception and memory in the temporal pole
    Science (IF 47.728) Pub Date : 2021-07-30
    Sofia M. Landi, Pooja Viswanathan, Stephen Serene, Winrich A. Freiwald

    The question of how the brain recognizes the faces of familiar individuals has been important throughout the history of neuroscience. Cells linking visual processing to person memory have been proposed but not found. Here, we report the discovery of such cells through recordings from an area in the macaque temporal pole identified with functional magnetic resonance imaging. These cells responded to

  • Plant PIEZO homologs modulate vacuole morphology during tip growth
    Science (IF 47.728) Pub Date : 2021-07-30
    Ivan Radin, Ryan A. Richardson, Joshua H. Coomey, Ethan R. Weiner, Carlisle S. Bascom, Ting Li, Magdalena Bezanilla, Elizabeth S. Haswell

    In animals, PIEZOs are plasma membrane–localized cation channels involved in diverse mechanosensory processes. We investigated PIEZO function in tip-growing cells in the moss Physcomitrium patens and the flowering plant Arabidopsis thaliana. PpPIEZO1 and PpPIEZO2 redundantly contribute to the normal growth, size, and cytoplasmic calcium oscillations of caulonemal cells. Both PpPIEZO1 and PpPIEZO2 localized

  • Temporal shifts in antibiotic resistance elements govern phage-pathogen conflicts
    Science (IF 47.728) Pub Date : 2021-07-30
    Kristen N. LeGault, Stephanie G. Hays, Angus Angermeyer, Amelia C. McKitterick, Fatema-tuz Johura, Marzia Sultana, Tahmeed Ahmed, Munirul Alam, Kimberley D. Seed

    Bacteriophage predation selects for diverse antiphage systems that frequently cluster on mobilizable defense islands in bacterial genomes. However, molecular insight into the reciprocal dynamics of phage-bacterial adaptations in nature is lacking, particularly in clinical contexts where there is need to inform phage therapy efforts and to understand how phages drive pathogen evolution. Using time-shift

  • Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion
    Science (IF 47.728) Pub Date : 2021-07-30
    Ruth Choa, Junichiro Tohyama, Shogo Wada, Hu Meng, Jian Hu, Mariko Okumura, Rebecca M. May, Tanner F. Robertson, Ruth-Anne Langan Pai, Arben Nace, Christian Hopkins, Elizabeth A. Jacobsen, Malay Haldar, Garret A. FitzGerald, Edward M. Behrens, Andy J. Minn, Patrick Seale, George Cotsarelis, Brian Kim, John T. Seykora, Mingyao Li, Zoltan Arany, Taku Kambayashi

    Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure

  • Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span
    Science (IF 47.728) Pub Date : 2021-07-30
    M. Grunewald, S. Kumar, H. Sharife, E. Volinsky, A. Gileles-Hillel, T. Licht, A. Permyakova, L. Hinden, S. Azar, Y. Friedmann, P. Kupetz, R. Tzuberi, A. Anisimov, K. Alitalo, M. Horwitz, S. Leebhoff, O. Z. Khoma, R. Hlushchuk, V. Djonov, R. Abramovitch, J. Tam, E. Keshet

    Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented

  • Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates
    Science (IF 47.728) Pub Date : 2021-07-29
    Kizzmekia S. Corbett, Martha C. Nason, Britta Flach, Matthew Gagne, Sarah O’Connell, Timothy S. Johnston, Shruti N. Shah, Venkata Viswanadh Edara, Katharine Floyd, Lilin Lai, Charlene McDanal, Joseph R. Francica, Barbara Flynn, Kai Wu, Angela Choi, Matthew Koch, Olubukola M. Abiona, Anne P. Werner, Juan I. Moliva, Shayne F. Andrew, Mitzi M. Donaldson, Jonathan Fintzi, Dillon R. Flebbe, Evan Lamb, Amy

    Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of SARS-CoV-2 vaccine, mRNA-1273. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and

  • Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells
    Science (IF 47.728) Pub Date : 2021-07-29
    Ioannis Sarropoulos, Mari Sepp, Robert Frömel, Kevin Leiss, Nils Trost, Evgeny Leushkin, Konstantin Okonechnikov, Piyush Joshi, Peter Giere, Lena M. Kutscher, Margarida Cardoso-Moreira, Stefan M. Pfister, Henrik Kaessmann

    Organ development is orchestrated by cell- and time-specific gene regulatory networks. In this study, we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring snATAC-seq profiles for ~90,000 cells spanning eleven stages, we mapped cerebellar cell types and identified candidate cis-regulatory elements (CREs). We detected extensive spatiotemporal

  • Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme
    Science (IF 47.728) Pub Date : 2021-07-27
    Chang Liu, Wei Shi, Scott T. Becker, David G. Schatz, Bin Liu, Yang Yang

    Coronavirus 3′–5′ exoribonuclease (ExoN), residing in the nonstructural protein (nsp) 10-nsp14 complex, boosts replication fidelity by proofreading RNA synthesis and is critical for the virus life cycle. ExoN also recognizes and excises nucleotide analog inhibitors incorporated into the nascent RNA, undermining the effectiveness of nucleotide analog-based antivirals. Here, we present cryo-electron

  • Structure of an AMPK complex in an inactive, ATP-bound state
    Science (IF 47.728) Pub Date : 2021-07-23
    Yan Yan, Somnath Mukherjee, Kaleeckal G. Harikumar, Timothy S. Strutzenberg, X. Edward Zhou, Kelly Suino-Powell, Ting-Hai Xu, Ryan D. Sheldon, Jared Lamp, Joseph S. Brunzelle, Katarzyna Radziwon, Abigail Ellis, Scott J. Novick, Irving E. Vega, Russell G. Jones, Laurence J. Miller, H. Eric Xu, Patrick R. Griffin, Anthony A. Kossiakoff, Karsten Melcher

    Adenosine monophosphate (AMP)–activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing

  • Plant “helper” immune receptors are Ca2+-permeable nonselective cation channels
    Science (IF 47.728) Pub Date : 2021-07-23
    Pierre Jacob, Nak Hyun Kim, Feihua Wu, Farid El-Kasmi, Yuan Chi, William G. Walton, Oliver J. Furzer, Adam D. Lietzan, Sruthi Sunil, Korina Kempthorn, Matthew R. Redinbo, Zhen-Ming Pei, Li Wan, Jeffery L. Dangl

    Plant nucleotide-binding leucine-rich repeat receptors (NLRs) regulate immunity and cell death. In Arabidopsis, a subfamily of “helper” NLRs is required by many “sensor” NLRs. Active NRG1.1 oligomerized, was enriched in plasma membrane puncta, and conferred cytoplasmic calcium ion (Ca2+) influx in plant and human cells. NRG1.1-dependent Ca2+ influx and cell death were sensitive to Ca2+ channel blockers

  • Peta–electron volt gamma-ray emission from the Crab Nebula
    Science (IF 47.728) Pub Date : 2021-07-23
    The LHAASO Collaboration*†, Zhen Cao, F. Aharonian, Q. An, Axikegu, L. X. Bai, Y. X. Bai, Y. W. Bao, D. Bastieri, X. J. Bi, Y. J. Bi, H. Cai, J. T. Cai, Zhe Cao, J. Chang, J. F. Chang, B. M. Chen, E. S. Chen, J. Chen, Liang Chen, Liang Chen, Long Chen, M. J. Chen, M. L. Chen, Q. H. Chen, S. H. Chen, S. Z. Chen, T. L. Chen, X. L. Chen, Y. Chen, N. Cheng, Y. D. Cheng, S. W. Cui, X. H. Cui, Y. D. Cui

    The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10−4 to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence

  • Coherent manipulation of an Andreev spin qubit
    Science (IF 47.728) Pub Date : 2021-07-23
    M. Hays, V. Fatemi, D. Bouman, J. Cerrillo, S. Diamond, K. Serniak, T. Connolly, P. Krogstrup, J. Nygård, A. Levy Yeyati, A. Geresdi, M. H. Devoret

    Two promising architectures for solid-state quantum information processing are based on electron spins electrostatically confined in semiconductor quantum dots and the collective electrodynamic modes of superconducting circuits. Superconducting electrodynamic qubits involve macroscopic numbers of electrons and offer the advantage of larger coupling, whereas semiconductor spin qubits involve individual

  • Upper mantle structure of Mars from InSight seismic data
    Science (IF 47.728) Pub Date : 2021-07-23
    Amir Khan, Savas Ceylan, Martin van Driel, Domenico Giardini, Philippe Lognonné, Henri Samuel, Nicholas C. Schmerr, Simon C. Stähler, Andrea C. Duran, Quancheng Huang, Doyeon Kim, Adrien Broquet, Constantinos Charalambous, John F. Clinton, Paul M. Davis, Mélanie Drilleau, Foivos Karakostas, Vedran Lekic, Scott M. McLennan, Ross R. Maguire, Chloé Michaut, Mark P. Panning, William T. Pike, Baptiste Pinot

    For 2 years, the InSight lander has been recording seismic data on Mars that are vital to constrain the structure and thermochemical state of the planet. We used observations of direct (P and S) and surface-reflected (PP, PPP, SS, and SSS) body-wave phases from eight low-frequency marsquakes to constrain the interior structure to a depth of 800 kilometers. We found a structure compatible with a low-velocity

  • Thickness and structure of the martian crust from InSight seismic data
    Science (IF 47.728) Pub Date : 2021-07-23
    Brigitte Knapmeyer-Endrun, Mark P. Panning, Felix Bissig, Rakshit Joshi, Amir Khan, Doyeon Kim, Vedran Lekić, Benoit Tauzin, Saikiran Tharimena, Matthieu Plasman, Nicolas Compaire, Raphael F. Garcia, Ludovic Margerin, Martin Schimmel, Éléonore Stutzmann, Nicholas Schmerr, Ebru Bozdağ, Ana-Catalina Plesa, Mark A. Wieczorek, Adrien Broquet, Daniele Antonangeli, Scott M. McLennan, Henri Samuel, Chloé

    A planet’s crust bears witness to the history of planetary formation and evolution, but for Mars, no absolute measurement of crustal thickness has been available. Here, we determine the structure of the crust beneath the InSight landing site on Mars using both marsquake recordings and the ambient wavefield. By analyzing seismic phases that are reflected and converted at subsurface interfaces, we find

  • Seismic detection of the martian core
    Science (IF 47.728) Pub Date : 2021-07-23
    Simon C. Stähler, Amir Khan, W. Bruce Banerdt, Philippe Lognonné, Domenico Giardini, Savas Ceylan, Mélanie Drilleau, A. Cecilia Duran, Raphaël F. Garcia, Quancheng Huang, Doyeon Kim, Vedran Lekic, Henri Samuel, Martin Schimmel, Nicholas Schmerr, David Sollberger, Éléonore Stutzmann, Zongbo Xu, Daniele Antonangeli, Constantinos Charalambous, Paul M. Davis, Jessica C. E. Irving, Taichi Kawamura, Martin

    Clues to a planet’s geologic history are contained in its interior structure, particularly its core. We detected reflections of seismic waves from the core-mantle boundary of Mars using InSight seismic data and inverted these together with geodetic data to constrain the radius of the liquid metal core to 1830 ± 40 kilometers. The large core implies a martian mantle mineralogically similar to the terrestrial

  • Inhibited nonradiative decay at all exciton densities in monolayer semiconductors
    Science (IF 47.728) Pub Date : 2021-07-23
    Hyungjin Kim, Shiekh Zia Uddin, Naoki Higashitarumizu, Eran Rabani, Ali Javey

    Most optoelectronic devices operate at high photocarrier densities, where all semiconductors suffer from enhanced nonradiative recombination. Nonradiative processes proportionately reduce photoluminescence (PL) quantum yield (QY), a performance metric that directly dictates the maximum device efficiency. Although transition metal dichalcogenide (TMDC) monolayers exhibit near-unity PL QY at low exciton

  • Atomically resolved single-molecule triplet quenching
    Science (IF 47.728) Pub Date : 2021-07-23
    Jinbo Peng, Sophia Sokolov, Daniel Hernangómez-Pérez, Ferdinand Evers, Leo Gross, John M. Lupton, Jascha Repp

    The nonequilibrium triplet state of molecules plays an important role in photocatalysis, organic photovoltaics, and photodynamic therapy. We report the direct measurement of the triplet lifetime of an individual pentacene molecule on an insulating surface with atomic resolution by introducing an electronic pump-probe method in atomic force microscopy. Strong quenching of the triplet lifetime is observed

  • Innovation and geographic spread of a complex foraging culture in an urban parrot
    Science (IF 47.728) Pub Date : 2021-07-23
    Barbara C. Klump, John M. Martin, Sonja Wild, Jana K. Hörsch, Richard E. Major, Lucy M. Aplin

    The emergence, spread, and establishment of innovations within cultures can promote adaptive responses to anthropogenic change. We describe a putative case of the development of a cultural adaptation to urban environments: opening of household waste bins by wild sulphur-crested cockatoos. A spatial network analysis of community science reports revealed the geographic spread of bin opening from three

  • Retinal waves prime visual motion detection by simulating future optic flow
    Science (IF 47.728) Pub Date : 2021-07-23
    Xinxin Ge, Kathy Zhang, Alexandra Gribizis, Ali S. Hamodi, Aude Martinez Sabino, Michael C. Crair

    The ability to perceive and respond to environmental stimuli emerges in the absence of sensory experience. Spontaneous retinal activity prior to eye opening guides the refinement of retinotopy and eye-specific segregation in mammals, but its role in the development of higher-order visual response properties remains unclear. Here, we describe a transient window in neonatal mouse development during which

  • Enterically derived high-density lipoprotein restrains liver injury through the portal vein
    Science (IF 47.728) Pub Date : 2021-07-23
    Yong-Hyun Han, Emily J. Onufer, Li-Hao Huang, Robert W. Sprung, W. Sean Davidson, Rafael S. Czepielewski, Mary Wohltmann, Mary G. Sorci-Thomas, Brad W. Warner, Gwendalyn J. Randolph

    The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)–binding protein (LBP). HDL3, but not HDL2 or low-density

  • Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma
    Science (IF 47.728) Pub Date : 2021-07-23
    Andrea Cugurra, Tornike Mamuladze, Justin Rustenhoven, Taitea Dykstra, Giorgi Beroshvili, Zev J. Greenberg, Wendy Baker, Zach Papadopoulos, Antoine Drieu, Susan Blackburn, Mitsuhiro Kanamori, Simone Brioschi, Jasmin Herz, Laura G. Schuettpelz, Marco Colonna, Igor Smirnov, Jonathan Kipnis

    The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation

  • Revealing enzyme functional architecture via high-throughput microfluidic enzyme kinetics
    Science (IF 47.728) Pub Date : 2021-07-23
    C. J. Markin, D. A. Mokhtari, F. Sunden, M. J. Appel, E. Akiva, S. A. Longwell, C. Sabatti, D. Herschlag, P. M. Fordyce

    Systematic and extensive investigation of enzymes is needed to understand their extraordinary efficiency and meet current challenges in medicine and engineering. We present HT-MEK (High-Throughput Microfluidic Enzyme Kinetics), a microfluidic platform for high-throughput expression, purification, and characterization of more than 1500 enzyme variants per experiment. For 1036 mutants of the alkaline

  • Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders
    Science (IF 47.728) Pub Date : 2021-07-23
    Simone Brioschi, Wei-Le Wang, Vincent Peng, Meng Wang, Irina Shchukina, Zev J. Greenberg, Jennifer K. Bando, Natalia Jaeger, Rafael S. Czepielewski, Amanda Swain, Denis A. Mogilenko, Wandy L. Beatty, Peter Bayguinov, James A. J. Fitzpatrick, Laura G. Schuettpelz, Catrina C. Fronick, Igor Smirnov, Jonathan Kipnis, Virginia S. Shapiro, Gregory F. Wu, Susan Gilfillan, Marina Cella, Maxim N. Artyomov,

    The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells

  • Spatiotemporal invasion dynamics of SARS-CoV-2 lineage B.1.1.7 emergence
    Science (IF 47.728) Pub Date : 2021-07-22
    Moritz U.G. Kraemer, Verity Hill, Christopher Ruis, Simon Dellicour, Sumali Bajaj, John T. McCrone, Guy Baele, Kris V. Parag, Anya Lindström Battle, Bernardo Gutierrez, Ben Jackson, Rachel Colquhoun, Áine O’Toole, Brennan Klein, Alessandro Vespignani, The COVID-19 Genomics UK (CoG-UK) consortium‡, Erik Volz, Nuno R. Faria, David Aanensen, Nicholas J. Loman, Louis du Plessis, Simon Cauchemez, Andrew

    Understanding the causes and consequences of the emergence of SARS-CoV-2 variants of concern is crucial to pandemic control yet difficult to achieve, as they arise in the context of variable human behavior and immunity. We investigate the spatial invasion dynamics of lineage B.1.1.7 by jointly analyzing UK human mobility, virus genomes, and community-based PCR data. We identify a multi-stage spatial

  • Spatiotemporal characterization of the field-induced insulator-to-metal transition
    Science (IF 47.728) Pub Date : 2021-07-22
    Javier del Valle, Nicolas M. Vargas, Rodolfo Rocco, Pavel Salev, Yoav Kalcheim, Pavel N. Lapa, Coline Adda, Min-Han Lee, Paul Y. Wang, Lorenzo Fratino, Marcelo J. Rozenberg, Ivan K. Schuller

    Many correlated systems feature an insulator-to-metal transition that can be triggered by an electric field. Although it is known that metallization takes place through filament formation, the details of how this process initiates and evolves remain elusive. We use in-operando optical reflectivity to capture the growth dynamics of the metallic phase with space and time resolution. We demonstrate that

  • A DNA-repair pathway can affect transcriptional noise to promote cell fate transitions
    Science (IF 47.728) Pub Date : 2021-07-22
    Ravi V. Desai, Xinyue Chen, Benjamin Martin, Sonali Chaturvedi, Dong Woo Hwang, Weihan Li, Chen Yu, Sheng Ding, Matt Thomson, Robert H. Singer, Robert A. Coleman, Maike M.K. Hansen, Leor S. Weinberger

    Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base-excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA-repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression

  • Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2
    Science (IF 47.728) Pub Date : 2021-07-20
    Nir Drayman, Jennifer K. DeMarco, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel Á. Muñoz-Alía, Brooke Schuster, Vishnu Nair, Kyu-yeon Han, Amornrat O’Brien, Anastasia Tomatsidou

    There is an urgent need for antiviral agents that treat SARS-CoV-2 infection. We screened a library of 1,900 clinically safe drugs against OC43, a human beta-coronavirus that causes the common cold and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in vitro. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro

  • Accurate prediction of protein structures and interactions using a three-track neural network
    Science (IF 47.728) Pub Date : 2021-07-19
    Minkyung Baek, Frank DiMaio, Ivan Anishchenko, Justas Dauparas, Sergey Ovchinnikov, Gyu Rie Lee, Jue Wang, Qian Cong, Lisa N. Kinch, R. Dustin Schaeffer, Claudia Millán, Hahnbeom Park, Carson Adams, Caleb R. Glassman, Andy DeGiovanni, Jose H. Pereira, Andria V. Rodrigues, Alberdina A. van Dijk, Ana C. Ebrecht, Diederik J. Opperman, Theo Sagmeister, Christoph Buhlheller, Tea Pavkov-Keller, Manoj K.

    DeepMind presented remarkably accurate predictions at the recent CASP14 protein structure prediction assessment conference. We explored network architectures incorporating related ideas and obtained the best performance with a three-track network in which information at the 1D sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track

  • Generation of ovarian follicles from mouse pluripotent stem cells
    Science (IF 47.728) Pub Date : 2021-07-16
    Takashi Yoshino, Takahiro Suzuki, Go Nagamatsu, Haruka Yabukami, Mika Ikegaya, Mami Kishima, Haruka Kita, Takuya Imamura, Kinichi Nakashima, Ryuichi Nishinakamura, Makoto Tachibana, Miki Inoue, Yuichi Shima, Ken-ichirou Morohashi, Katsuhiko Hayashi

    Oocytes mature in a specialized fluid-filled sac, the ovarian follicle, which provides signals needed for meiosis and germ cell growth. Methods have been developed to generate functional oocytes from pluripotent stem cell–derived primordial germ cell–like cells (PGCLCs) when placed in culture with embryonic ovarian somatic cells. In this study, we developed culture conditions to recreate the stepwise

  • A massive rock and ice avalanche caused the 2021 disaster at Chamoli, Indian Himalaya
    Science (IF 47.728) Pub Date : 2021-07-16
    D. H. Shugar, M. Jacquemart, D. Shean, S. Bhushan, K. Upadhyay, A. Sattar, W. Schwanghart, S. McBride, M. Van Wyk de Vries, M. Mergili, A. Emmer, C. Deschamps-Berger, M. McDonnell, R. Bhambri, S. Allen, E. Berthier, J. L. Carrivick, J. J. Clague, M. Dokukin, S. A. Dunning, H. Frey, S. Gascoin, U. K. Haritashya, C. Huggel, A. Kääb, J. S. Kargel, J. L. Kavanaugh, P. Lacroix, D. Petley, S. Rupper, M.

    On 7 February 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. More than 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27 × 106 cubic meters of

  • Chromatin landscape signals differentially dictate the activities of mSWI/SNF family complexes
    Science (IF 47.728) Pub Date : 2021-07-16
    Nazar Mashtalir, Hai T. Dao, Akshay Sankar, Hengyuan Liu, Aaron J. Corin, John D. Bagert, Eva J. Ge, Andrew R. D’Avino, Martin Filipovski, Brittany C. Michel, Geoffrey P. Dann, Tom W. Muir, Cigall Kadoch

    Mammalian SWI/SNF (mSWI/SNF) adenosine triphosphate–dependent chromatin remodelers modulate genomic architecture and gene expression and are frequently mutated in disease. However, the specific chromatin features that govern their nucleosome binding and remodeling activities remain unknown. We subjected endogenously purified mSWI/SNF complexes and their constituent assembly modules to a diverse library

  • Self-assembled iron-containing mordenite monolith for carbon dioxide sieving
    Science (IF 47.728) Pub Date : 2021-07-16
    Yu Zhou, Jianlin Zhang, Lei Wang, Xili Cui, Xiaoling Liu, Sie Shing Wong, Hua An, Ning Yan, Jingyan Xie, Cong Yu, Peixin Zhang, Yonghua Du, Shibo Xi, Lirong Zheng, Xingzhong Cao, Yajing Wu, Yingxia Wang, Chongqing Wang, Haimeng Wen, Lei Chen, Huabin Xing, Jun Wang

    The development of low-cost, efficient physisorbents is essential for gas adsorption and separation; however, the intrinsic tradeoff between capacity and selectivity, as well as the unavoidable shaping procedures of conventional powder sorbents, greatly limits their practical separation efficiency. Herein, an exceedingly stable iron-containing mordenite zeolite monolith with a pore system of precisely

  • Autonomous self-repair in piezoelectric molecular crystals
    Science (IF 47.728) Pub Date : 2021-07-16
    Surojit Bhunia, Shubham Chandel, Sumanta Kumar Karan, Somnath Dey, Akash Tiwari, Susobhan Das, Nishkarsh Kumar, Rituparno Chowdhury, Saikat Mondal, Ishita Ghosh, Amit Mondal, Bhanu Bhusan Khatua, Nirmalya Ghosh, C. Malla Reddy

    Living tissue uses stress-accumulated electrical charge to close wounds. Self-repairing synthetic materials, which are typically soft and amorphous, usually require external stimuli, prolonged physical contact, and long healing times. We overcome many of these limitations in piezoelectric bipyrazole organic crystals, which recombine following mechanical fracture without any external direction, autonomously

  • Cage effects control the mechanism of methane hydroxylation in zeolites
    Science (IF 47.728) Pub Date : 2021-07-16
    Benjamin E. R. Snyder, Max L. Bols, Hannah M. Rhoda, Dieter Plessers, Robert A. Schoonheydt, Bert F. Sels, Edward I. Solomon

    Catalytic conversion of methane to methanol remains an economically tantalizing but fundamentally challenging goal. Current technologies based on zeolites deactivate too rapidly for practical application. We found that similar active sites hosted in different zeolite lattices can exhibit markedly different reactivity with methane, depending on the size of the zeolite pore apertures. Whereas zeolite

  • Determinants of crystal structure transformation of ionic nanocrystals in cation exchange reactions
    Science (IF 47.728) Pub Date : 2021-07-16
    Zhanzhao Li, Masaki Saruyama, Toru Asaka, Yasutomi Tatetsu, Toshiharu Teranishi

    Changes in the crystal system of an ionic nanocrystal during a cation exchange reaction are unusual yet remain to be systematically investigated. In this study, chemical synthesis and computational modeling demonstrated that the height of hexagonal-prism roxbyite (Cu1.8S) nanocrystals with a distorted hexagonal close-packed sulfide anion (S2−) sublattice determines the final crystal phase of the cation-exchanged

  • Wafer-scale heterostructured piezoelectric bio-organic thin films
    Science (IF 47.728) Pub Date : 2021-07-16
    Fan Yang, Jun Li, Yin Long, Ziyi Zhang, Linfeng Wang, Jiajie Sui, Yutao Dong, Yizhan Wang, Rachel Taylor, Dalong Ni, Weibo Cai, Ping Wang, Timothy Hacker, Xudong Wang

    Piezoelectric biomaterials are intrinsically suitable for coupling mechanical and electrical energy in biological systems to achieve in vivo real-time sensing, actuation, and electricity generation. However, the inability to synthesize and align the piezoelectric phase at a large scale remains a roadblock toward practical applications. We present a wafer-scale approach to creating piezoelectric biomaterial

  • Neural representations of space in the hippocampus of a food-caching bird
    Science (IF 47.728) Pub Date : 2021-07-16
    H. L. Payne, G. F. Lynch, D. Aronov

    Spatial memory in vertebrates requires brain regions homologous to the mammalian hippocampus. Between vertebrate clades, however, these regions are anatomically distinct and appear to produce different spatial patterns of neural activity. We asked whether hippocampal activity is fundamentally different even between distant vertebrates that share a strong dependence on spatial memory. We studied tufted

  • Rank-dependent social inheritance determines social network structure in spotted hyenas
    Science (IF 47.728) Pub Date : 2021-07-16
    Amiyaal Ilany, Kay E. Holekamp, Erol Akçay

    The structure of animal social networks influences survival and reproductive success, as well as pathogen and information transmission. However, the general mechanisms determining social structure remain unclear. Using data from 73,767 social interactions among wild spotted hyenas collected over 27 years, we show that the process of social inheritance determines how offspring relationships are formed

  • Universal phase dynamics in VO2 switches revealed by ultrafast operando diffraction
    Science (IF 47.728) Pub Date : 2021-07-16
    Aditya Sood, Xiaozhe Shen, Yin Shi, Suhas Kumar, Su Ji Park, Marc Zajac, Yifei Sun, Long-Qing Chen, Shriram Ramanathan, Xijie Wang, William C. Chueh, Aaron M. Lindenberg

    Understanding the pathways and time scales underlying electrically driven insulator-metal transitions is crucial for uncovering the fundamental limits of device operation. Using stroboscopic electron diffraction, we perform synchronized time-resolved measurements of atomic motions and electronic transport in operating vanadium dioxide (VO2) switches. We discover an electrically triggered, isostructural

  • Estimating epidemiologic dynamics from cross-sectional viral load distributions
    Science (IF 47.728) Pub Date : 2021-07-16
    James A. Hay, Lee Kennedy-Shaffer, Sanjat Kanjilal, Niall J. Lennon, Stacey B. Gabriel, Marc Lipsitch, Michael J. Mina

    Estimating an epidemic’s trajectory is crucial for developing public health responses to infectious diseases, but case data used for such estimation are confounded by variable testing practices. We show that the population distribution of viral loads observed under random or symptom-based surveillance—in the form of cycle threshold (Ct) values obtained from reverse transcription quantitative polymerase

  • Senolytics reduce coronavirus-related mortality in old mice
    Science (IF 47.728) Pub Date : 2021-07-16
    Christina D. Camell, Matthew J. Yousefzadeh, Yi Zhu, Larissa G. P. Langhi Prata, Matthew A. Huggins, Mark Pierson, Lei Zhang, Ryan D. O’Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J. Atkinson, Christina L. Inman, Kurt O. Johnson, Stephanie H. Cholensky, Timothy W. Carlson, Nathan K. LeBrasseur, Sundeep

    The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs)

  • Design and applications of surfaces that control the accretion of matter
    Science (IF 47.728) Pub Date : 2021-07-16
    Abhishek Dhyani, Jing Wang, Alex Kate Halvey, Brian Macdonald, Geeta Mehta, Anish Tuteja

    Surfaces that provide control over liquid, solid, or vapor accretion provide an evolutionary advantage to numerous plants, insects, and animals. Synthetic surfaces inspired by these natural surfaces can have a substantial impact on diverse commercial applications. Engineered liquid and solid repellent surfaces are often designed to impart control over a single state of matter, phase, or fouling length

  • Expression of Foxp3 by T follicular helper cells in end-stage germinal centers
    Science (IF 47.728) Pub Date : 2021-07-16
    Johanne T. Jacobsen, Wei Hu, Tiago B. R. Castro, Sigrid Solem, Alice Galante, Zeran Lin, Samuel J. Allon, Luka Mesin, Angelina M. Bilate, Ariën Schiepers, Alex K. Shalek, Alexander Y. Rudensky, Gabriel D. Victora

    Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction

  • A human apolipoprotein L with detergent-like activity kills intracellular pathogens
    Science (IF 47.728) Pub Date : 2021-07-16
    Ryan G. Gaudet, Shiwei Zhu, Anushka Halder, Bae-Hoon Kim, Clinton J. Bradfield, Shuai Huang, Dijin Xu, Agnieszka Mamiñska, Thanh Ngoc Nguyen, Michael Lazarou, Erdem Karatekin, Kallol Gupta, John D. MacMicking

    Activation of cell-autonomous defense by the immune cytokine interferon-γ (IFN-γ) is critical to the control of life-threatening infections in humans. IFN-γ induces the expression of hundreds of host proteins in all nucleated cells and tissues, yet many of these proteins remain uncharacterized. We screened 19,050 human genes by CRISPR-Cas9 mutagenesis and identified IFN-γ–induced apolipoprotein L3

  • Structural basis for target-site selection in RNA-guided DNA transposition systems
    Science (IF 47.728) Pub Date : 2021-07-15
    Jung-Un Park, Amy Tsai, Eshan Mehrotra, Michael T. Petassi, Shan-Chi Hsieh, Ailong Ke, Joseph E. Peters, Elizabeth H. Kellogg

    CRISPR-associated transposition systems allow guide RNA-directed integration of a single DNA cargo in one orientation at a fixed distance from a programmable target sequence. We define the mechanism explaining this process by characterizing the transposition regulator, TnsC, from a type V-K CRISPR-transposase system using cryo-electron microscopy (cryo-EM). Polymerization of ATP-bound TnsC helical

  • Low thermal conductivity in a modular inorganic material with bonding anisotropy and mismatch
    Science (IF 47.728) Pub Date : 2021-07-15
    Quinn D. Gibson, Tianqi Zhao, Luke M. Daniels, Helen C. Walker, Ramzy Daou, Sylvie Hébert, Marco Zanella, Matthew S. Dyer, John B. Claridge, Ben Slater, Michael W. Gaultois, Furio Corà, Jonathan Alaria, Matthew J. Rosseinsky

    The thermal conductivity of crystalline materials cannot be arbitrarily low as the intrinsic limit depends on the phonon dispersion. We used complementary strategies to suppress the contribution of the longitudinal and transverse phonons to heat transport in layered materials containing different types of intrinsic chemical interface. BiOCl and Bi2O2Se encapsulate these design principles for longitudinal

  • Multicomponent superconducting order parameter in UTe2
    Science (IF 47.728) Pub Date : 2021-07-15
    I. M. Hayes, D. S. Wei, T. Metz, J. Zhang, Y. S. Eo, S. Ran, S. R. Saha, J. Collini, N. P. Butch, D. F. Agterberg, A. Kapitulnik, J. Paglione

    An unconventional superconducting state was recently discovered in UTe2, where spin-triplet superconductivity emerges from the paramagnetic normal state of a heavy fermion material. The coexistence of magnetic fluctuations and superconductivity, together with the crystal structure of this material, suggest that a unique set of symmetries, magnetic properties, and topology underlie the superconducting

  • Gut microbiome heritability is nearly universal but environmentally contingent
    Science (IF 47.728) Pub Date : 2021-07-09
    Laura Grieneisen, Mauna Dasari, Trevor J. Gould, Johannes R. Björk, Jean-Christophe Grenier, Vania Yotova, David Jansen, Neil Gottel, Jacob B. Gordon, Niki H. Learn, Laurence R. Gesquiere, Tim L. Wango, Raphael S. Mututua, J. Kinyua Warutere, Long’ida Siodi, Jack A. Gilbert, Luis B. Barreiro, Susan C. Alberts, Jenny Tung, Elizabeth A. Archie, Ran Blekhman

    Relatives have more similar gut microbiomes than nonrelatives, but the degree to which this similarity results from shared genotypes versus shared environments has been controversial. Here, we leveraged 16,234 gut microbiome profiles, collected over 14 years from 585 wild baboons, to reveal that host genetic effects on the gut microbiome are nearly universal. Controlling for diet, age, and socioecological

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