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  • Pulmonary surfactant–biomimetic nanoparticles potentiate heterosubtypic influenza immunity
    Science (IF 41.037) Pub Date : 2020-02-21
    Ji Wang, Peiyu Li, Yang Yu, Yuhong Fu, Hongye Jiang, Min Lu, Zhiping Sun, Shibo Jiang, Lu Lu, Mei X. Wu

    Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)–biomimetic liposomes encapsulating 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine–induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP–adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP–mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

    更新日期:2020-02-21
  • Vertebrate diapause preserves organisms long term through Polycomb complex members
    Science (IF 41.037) Pub Date : 2020-02-21
    Chi-Kuo Hu, Wei Wang, Julie Brind’Amour, Param Priya Singh, G. Adam Reeves, Matthew C. Lorincz, Alejandro Sánchez Alvarado, Anne Brunet

    Diapause is a state of suspended development that helps organisms survive extreme environments. How diapause protects living organisms is largely unknown. Using the African turquoise killifish (Nothobranchius furzeri), we show that diapause preserves complex organisms for extremely long periods of time without trade-offs for subsequent adult growth, fertility, and life span. Transcriptome analyses indicate that diapause is an active state, with dynamic regulation of metabolism and organ development genes. The most up-regulated genes in diapause include Polycomb complex members. The chromatin mark regulated by Polycomb, H3K27me3, is maintained at key developmental genes in diapause, and the Polycomb member CBX7 mediates repression of metabolism and muscle genes in diapause. CBX7 is functionally required for muscle preservation and diapause maintenance. Thus, vertebrate diapause is a state of suspended life that is actively maintained by specific chromatin regulators, and this has implications for long-term organism preservation.

    更新日期:2020-02-21
  • Structure of nucleosome-bound human BAF complex
    Science (IF 41.037) Pub Date : 2020-02-21
    Shuang He, Zihan Wu, Yuan Tian, Zishuo Yu, Jiali Yu, Xinxin Wang, Jie Li, Bijun Liu, Yanhui Xu

    Mammalian SWI/SNF family chromatin remodelers, BRG1/BRM-associated factor (BAF) and polybromo-associated BAF (PBAF), regulate chromatin structure and transcription, and their mutations are linked to cancers. The 3.7-angstrom-resolution cryo–electron microscopy structure of human BAF bound to the nucleosome reveals that the nucleosome is sandwiched by the base and the adenosine triphosphatase (ATPase) modules, which are bridged by the actin-related protein (ARP) module. The ATPase motor is positioned proximal to nucleosomal DNA and, upon ATP hydrolysis, engages with and pumps DNA along the nucleosome. The C-terminal α helix of SMARCB1, enriched in positively charged residues frequently mutated in cancers, mediates interactions with an acidic patch of the nucleosome. AT-rich interactive domain-containing protein 1A (ARID1A) and the SWI/SNF complex subunit SMARCC serve as a structural core and scaffold in the base module organization, respectively. Our study provides structural insights into subunit organization and nucleosome recognition of human BAF complex.

    更新日期:2020-02-21
  • Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor
    Science (IF 41.037) Pub Date : 2020-02-21
    Carl-Mikael Suomivuori, Naomi R. Latorraca, Laura M. Wingler, Stephan Eismann, Matthew C. King, Alissa L. W. Kleinhenz, Meredith A. Skiba, Dean P. Staus, Andrew C. Kruse, Robert J. Lefkowitz, Ron O. Dror

    Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

    更新日期:2020-02-21
  • Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
    Science (IF 41.037) Pub Date : 2020-02-21
    Laura M. Wingler, Meredith A. Skiba, Conor McMahon, Dean P. Staus, Alissa L. W. Kleinhenz, Carl-Mikael Suomivuori, Naomi R. Latorraca, Ron O. Dror, Robert J. Lefkowitz, Andrew C. Kruse

    Biased agonists of G protein–coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin–biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric Gq protein signaling.

    更新日期:2020-02-21
  • Cooling of a levitated nanoparticle to the motional quantum ground state
    Science (IF 41.037) Pub Date : 2020-02-21
    Uroš Delić, Manuel Reisenbauer, Kahan Dare, David Grass, Vladan Vuletić, Nikolai Kiesel, Markus Aspelmeyer

    Quantum control of complex objects in the regime of large size and mass provides opportunities for sensing applications and tests of fundamental physics. The realization of such extreme quantum states of matter remains a major challenge. We demonstrate a quantum interface that combines optical trapping of solids with cavity-mediated light-matter interaction. Precise control over the frequency and position of the trap laser with respect to the optical cavity allowed us to laser-cool an optically trapped nanoparticle into its quantum ground state of motion from room temperature. The particle comprises 108 atoms, similar to current Bose-Einstein condensates, with the density of a solid object. Our cooling technique, in combination with optical trap manipulation, may enable otherwise unachievable superposition states involving large masses.

    更新日期:2020-02-21
  • Quantum anomalous Hall effect in intrinsic magnetic topological insulator MnBi2Te4
    Science (IF 41.037) Pub Date : 2020-02-21
    Yujun Deng, Yijun Yu, Meng Zhu Shi, Zhongxun Guo, Zihan Xu, Jing Wang, Xian Hui Chen, Yuanbo Zhang

    In a magnetic topological insulator, nontrivial band topology combines with magnetic order to produce exotic states of matter, such as quantum anomalous Hall (QAH) insulators and axion insulators. In this work, we probe quantum transport in MnBi2Te4 thin flakes—a topological insulator with intrinsic magnetic order. In this layered van der Waals crystal, the ferromagnetic layers couple antiparallel to each other; atomically thin MnBi2Te4, however, becomes ferromagnetic when the sample has an odd number of septuple layers. We observe a zero-field QAH effect in a five–septuple-layer specimen at 1.4 kelvin, and an external magnetic field further raises the quantization temperature to 6.5 kelvin by aligning all layers ferromagnetically. The results establish MnBi2Te4 as an ideal arena for further exploring various topological phenomena with a spontaneously broken time-reversal symmetry.

    更新日期:2020-02-21
  • Intrinsic quantized anomalous Hall effect in a moiré heterostructure
    Science (IF 41.037) Pub Date : 2020-02-21
    M. Serlin, C. L. Tschirhart, H. Polshyn, Y. Zhang, J. Zhu, K. Watanabe, T. Taniguchi, L. Balents, A. F. Young

    The quantum anomalous Hall (QAH) effect combines topology and magnetism to produce precisely quantized Hall resistance at zero magnetic field. We report the observation of a QAH effect in twisted bilayer graphene aligned to hexagonal boron nitride. The effect is driven by intrinsic strong interactions, which polarize the electrons into a single spin- and valley-resolved moiré miniband with Chern number C = 1. In contrast to magnetically doped systems, the measured transport energy gap is larger than the Curie temperature for magnetic ordering, and quantization to within 0.1% of the von Klitzing constant persists to temperatures of several kelvin at zero magnetic field. Electrical currents as small as 1 nanoampere controllably switch the magnetic order between states of opposite polarization, forming an electrically rewritable magnetic memory.

    更新日期:2020-02-21
  • Disassembling 2D van der Waals crystals into macroscopic monolayers and reassembling into artificial lattices
    Science (IF 41.037) Pub Date : 2020-02-21
    Fang Liu, Wenjing Wu, Yusong Bai, Sang Hoon Chae, Qiuyang Li, Jue Wang, James Hone, X.-Y. Zhu

    Two-dimensional materials from layered van der Waals (vdW) crystals hold great promise for electronic, optoelectronic, and quantum devices, but technological implementation will be hampered by the lack of high-throughput techniques for exfoliating single-crystal monolayers with sufficient size and high quality. Here, we report a facile method to disassemble vdW single crystals layer by layer into monolayers with near-unity yield and with dimensions limited only by bulk crystal sizes. The macroscopic monolayers are comparable in quality to microscopic monolayers from conventional Scotch tape exfoliation. The monolayers can be assembled into macroscopic artificial structures, including transition metal dichalcogenide multilayers with broken inversion symmetry and substantially enhanced nonlinear optical response. This approach takes us one step closer to mass production of macroscopic monolayers and bulk-like artificial materials with controllable properties.

    更新日期:2020-02-21
  • Old carbon reservoirs were not important in the deglacial methane budget
    Science (IF 41.037) Pub Date : 2020-02-21
    M. N. Dyonisius, V. V. Petrenko, A. M. Smith, Q. Hua, B. Yang, J. Schmitt, J. Beck, B. Seth, M. Bock, B. Hmiel, I. Vimont, J. A. Menking, S. A. Shackleton, D. Baggenstos, T. K. Bauska, R. H. Rhodes, P. Sperlich, R. Beaudette, C. Harth, M. Kalk, E. J. Brook, H. Fischer, J. P. Severinghaus, R. F. Weiss

    Permafrost and methane hydrates are large, climate-sensitive old carbon reservoirs that have the potential to emit large quantities of methane, a potent greenhouse gas, as the Earth continues to warm. We present ice core isotopic measurements of methane (Δ14C, δ13C, and δD) from the last deglaciation, which is a partial analog for modern warming. Our results show that methane emissions from old carbon reservoirs in response to deglacial warming were small (<19 teragrams of methane per year, 95% confidence interval) and argue against similar methane emissions in response to future warming. Our results also indicate that methane emissions from biomass burning in the pre-Industrial Holocene were 22 to 56 teragrams of methane per year (95% confidence interval), which is comparable to today.

    更新日期:2020-02-21
  • Bumble bees display cross-modal object recognition between visual and tactile senses
    Science (IF 41.037) Pub Date : 2020-02-21
    Cwyn Solvi, Selene Gutierrez Al-Khudhairy, Lars Chittka

    Many animals can associate object shapes with incentives. However, such behavior is possible without storing images of shapes in memory that are accessible to more than one sensory modality. One way to explore whether there are modality-independent internal representations of object shapes is to investigate cross-modal recognition—experiencing an object in one sensory modality and later recognizing it in another. We show that bumble bees trained to discriminate two differently shaped objects (cubes and spheres) using only touch (in darkness) or vision (in light, but barred from touching the objects) could subsequently discriminate those same objects using only the other sensory information. Our experiments demonstrate that bumble bees possess the ability to integrate sensory information in a way that requires modality-independent internal representations.

    更新日期:2020-02-21
  • Ancient origins of allosteric activation in a Ser-Thr kinase
    Science (IF 41.037) Pub Date : 2020-02-21
    Adelajda Hadzipasic, Christopher Wilson, Vy Nguyen, Nadja Kern, Chansik Kim, Warintra Pitsawong, Janice Villali, Yuejiao Zheng, Dorothee Kern

    A myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2), to experimentally characterize the evolutionary path of allosteric activation. Autophosphorylation of the activation loop is the most ancient activation mechanism; it is fully developed in the oldest kinase ancestor and has remained stable over 1 billion years of evolution. As the microtubule-associated protein TPX2 appeared, efficient kinase binding to TPX2 evolved, likely owing to increased fitness by virtue of colocalization. Subsequently, TPX2-mediated allosteric kinase regulation gradually evolved. Surprisingly, evolution of this regulation is encoded in the kinase and did not arise by a dominating mechanism of coevolution.

    更新日期:2020-02-21
  • Biocatalytic synthesis of planar chiral macrocycles
    Science (IF 41.037) Pub Date : 2020-02-21
    Christina Gagnon, Éric Godin, Clémentine Minozzi, Johann Sosoe, Corentin Pochet, Shawn K. Collins

    Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features.

    更新日期:2020-02-21
  • How mycorrhizal associations drive plant population and community biology
    Science (IF 41.037) Pub Date : 2020-02-21
    Leho Tedersoo, Mohammad Bahram, Martin Zobel

    Mycorrhizal fungi provide plants with a range of benefits, including mineral nutrients and protection from stress and pathogens. Here we synthesize current information about how the presence and type of mycorrhizal association affect plant communities. We argue that mycorrhizal fungi regulate seedling establishment and species coexistence through stabilizing and equalizing mechanisms such as soil nutrient partitioning, feedback to soil antagonists, differential mycorrhizal benefits, and nutrient trade. Mycorrhizal fungi have strong effects on plant population and community biology, with mycorrhizal type–specific effects on seed dispersal, seedling establishment, and soil niche differentiation, as well as interspecific and intraspecific competition and hence plant diversity.

    更新日期:2020-02-21
  • A cell atlas of human thymic development defines T cell repertoire formation
    Science (IF 41.037) Pub Date : 2020-02-21
    Jong-Eun Park, Rachel A. Botting, Cecilia Domínguez Conde, Dorin-Mirel Popescu, Marieke Lavaert, Daniel J. Kunz, Issac Goh, Emily Stephenson, Roberta Ragazzini, Elizabeth Tuck, Anna Wilbrey-Clark, Kenny Roberts, Veronika R. Kedlian, John R. Ferdinand, Xiaoling He, Simone Webb, Daniel Maunder, Niels Vandamme, Krishnaa T. Mahbubani, Krzysztof Polanski, Lira Mamanova, Liam Bolt, David Crossland, Fabrizio de Rita, Andrew Fuller, Andrew Filby, Gary Reynolds, David Dixon, Kourosh Saeb-Parsy, Steven Lisgo, Deborah Henderson, Roser Vento-Tormo, Omer A. Bayraktar, Roger A. Barker, Kerstin B. Meyer, Yvan Saeys, Paola Bonfanti, Sam Behjati, Menna R. Clatworthy, Tom Taghon, Muzlifah Haniffa, Sarah A. Teichmann

    The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.

    更新日期:2020-02-21
  • Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab
    Science (IF 41.037) Pub Date : 2020-02-20
    Lionel Rougé, Nancy Chiang, Micah Steffek, Christine Kugel, Tristan I. Croll, Christine Tam, Alberto Estevez, Christopher P. Arthur, Christopher M. Koth, Claudio Ciferri, Edward Kraft, Jian Payandeh, Gerald Nakamura, James T. Koerber, Alexis Rohou

    Cluster of Differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and auto-immune disorders, but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX crosslinks CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface markers.

    更新日期:2020-02-21
  • Colorado River flow dwindles as warming-driven loss of reflective snow energizes evaporation
    Science (IF 41.037) Pub Date : 2020-02-20
    P. C. D. Milly, K. A. Dunne

    The sensitivity of river discharge to climate-system warming is highly uncertain and governing processes are poorly understood, impeding climate-change adaptation. A prominent exemplar is the Colorado River, where meteorological drought and warming have been shrinking a water resource that supports more than USD 1 trillion per year of economic activity. Monte-Carlo simulation with a radiation-aware hydrologic model resolves the longstanding, wide disparity in sensitivity estimates and reveals the controlling physical processes. We estimate that annual-mean discharge has been decreasing by 9.3% per °C of warming due to increased evapotranspiration, mainly driven by snow loss and consequent decrease of reflection of solar radiation. Projected precipitation increases likely will not suffice to counter fully the robust, thermodynamically induced drying. Increasing risk of severe water shortages is expected.

    更新日期:2020-02-21
  • Electrical power generation from moderate-temperature radiative thermal sources
    Science (IF 41.037) Pub Date : 2020-02-20
    Paul S. Davids, Jared Kirsch, Andrew Starbuck, Robert Jarecki, Joshua Shank, David Peters

    Moderate-temperature thermal sources (100–400°C) that radiate waste heat are often the by-product of mechanical work, chemical or nuclear reactions, or information processing. We demonstrate conversion of thermal radiation into electrical power using a bipolar grating-coupled complimentary metal-oxide-silicon (CMOS) tunnel diode. A two-step photon-assisted tunneling charge pumping mechanism results in separation of charge carriers in pn junction wells leading to a large open-circuit voltage developed across a load. Electrical power generation from a broadband blackbody thermal source has been experimentally demonstrated with converted power densities of 27–61 μW/cm2 for thermal sources between 250–400°C. Scalable, efficient conversion of radiated waste heat into electrical power can be utilized to reduce energy consumption, or to power electronics and sensors.

    更新日期:2020-02-21
  • Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
    Science (IF 41.037) Pub Date : 2020-02-19
    Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett, Jory A. Goldsmith, Ching-Lin Hsieh, Olubukola Abiona, Barney S. Graham, Jason S. McLellan

    The outbreak of a novel betacoronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure (MCM) development, we determined a 3.5 Å-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also show biophysical and structural evidence that the 2019-nCoV S binds ACE2 with higher affinity than SARS-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable rapid development and evaluation of MCMs to address the ongoing public health crisis.

    更新日期:2020-02-20
  • Transcription factor AP2 controls cnidarian germ cell induction
    Science (IF 41.037) Pub Date : 2020-02-14
    Timothy Q. DuBuc, Christine E. Schnitzler, Eleni Chrysostomou, Emma T. McMahon, Febrimarsa, James M. Gahan, Tara Buggie, Sebastian G. Gornik, Shirley Hanley, Sofia N. Barreira, Paul Gonzalez, Andreas D. Baxevanis, Uri Frank

    Clonal animals do not sequester a germ line during embryogenesis. Instead, they have adult stem cells that contribute to somatic tissues or gametes. How germ fate is induced in these animals, and whether this process is related to bilaterian embryonic germline induction, is unknown. We show that transcription factor AP2 (Tfap2), a regulator of mammalian germ lines, acts to commit adult stem cells, known as i-cells, to the germ cell fate in the clonal cnidarian Hydractinia symbiolongicarpus. Tfap2 mutants lacked germ cells and gonads. Transplanted wild-type cells rescued gonad development but not germ cell induction in Tfap2 mutants. Forced expression of Tfap2 in i-cells converted them to germ cells. Therefore, Tfap2 is a regulator of germ cell commitment across germ line–sequestering and germ line–nonsequestering animals.

    更新日期:2020-02-13
  • The pan-genome effector-triggered immunity landscape of a host-pathogen interaction
    Science (IF 41.037) Pub Date : 2020-02-14
    Bradley Laflamme, Marcus M. Dillon, Alexandre Martel, Renan N. D. Almeida, Darrell Desveaux, David S. Guttman

    Effector-triggered immunity (ETI), induced by host immune receptors in response to microbial effectors, protects plants against virulent pathogens. However, a systematic study of ETI prevalence against species-wide pathogen diversity is lacking. We constructed the Pseudomonas syringae Type III Effector Compendium (PsyTEC) to reduce the pan-genome complexity of 5127 unique effector proteins, distributed among 70 families from 494 strains, to 529 representative alleles. We screened PsyTEC on the model plant Arabidopsis thaliana and identified 59 ETI-eliciting alleles (11.2%) from 19 families (27.1%), with orthologs distributed among 96.8% of P. syringae strains. We also identified two previously undescribed host immune receptors, including CAR1, which recognizes the conserved effectors AvrE and HopAA1, and found that 94.7% of strains harbor alleles predicted to be recognized by either CAR1 or ZAR1.

    更新日期:2020-02-13
  • Pascal conductance series in ballistic one-dimensional LaAlO3/SrTiO3 channels
    Science (IF 41.037) Pub Date : 2020-02-14
    Megan Briggeman, Michelle Tomczyk, Binbin Tian, Hyungwoo Lee, Jung-Woo Lee, Yuchi He, Anthony Tylan-Tyler, Mengchen Huang, Chang-Beom Eom, David Pekker, Roger S. K. Mong, Patrick Irvin, Jeremy Levy

    One-dimensional electronic systems can support exotic collective phases because of the enhanced role of electron correlations. We describe the experimental observation of a series of quantized conductance steps within strongly interacting electron waveguides formed at the lanthanum aluminate–strontium titanate (LaAlO3/SrTiO3) interface. The waveguide conductance follows a characteristic sequence within Pascal’s triangle: (1, 3, 6, 10, 15, …) ⋅ e2/h, where e is the electron charge and h is the Planck constant. This behavior is consistent with the existence of a family of degenerate quantum liquids formed from bound states of n = 2, 3, 4, … electrons. Our experimental setup could provide a setting for solid-state analogs of a wide range of composite fermionic phases.

    更新日期:2020-02-13
  • Ionoelastomer junctions between polymer networks of fixed anions and cations
    Science (IF 41.037) Pub Date : 2020-02-14
    Hyeong Jun Kim, Baohong Chen, Zhigang Suo, Ryan C. Hayward

    Soft ionic conductors have enabled stretchable and transparent devices, but liquids in such devices tend to leak and evaporate. In this study, we demonstrate diodes and transistors using liquid-free ionoelastomers, in which either anions or cations are fixed to an elastomer network and the other ionic species are mobile. The junction of the two ionoelastomers of opposite polarity yields an ionic double layer, which is capable of rectifying and switching ionic currents without electrochemical reactions. The entropically driven depletion of mobile ions creates a junction of tough adhesion, and the stretchability of the junction enables electromechanical transduction.

    更新日期:2020-02-13
  • Dry reforming of methane by stable Ni–Mo nanocatalysts on single-crystalline MgO
    Science (IF 41.037) Pub Date : 2020-02-14
    Youngdong Song, Ercan Ozdemir, Sreerangappa Ramesh, Aldiar Adishev, Saravanan Subramanian, Aadesh Harale, Mohammed Albuali, Bandar Abdullah Fadhel, Aqil Jamal, Dohyun Moon, Sun Hee Choi, Cafer T. Yavuz

    Large-scale carbon fixation requires high-volume chemicals production from carbon dioxide. Dry reforming of methane could provide an economically feasible route if coke- and sintering-resistant catalysts were developed. Here, we report a molybdenum-doped nickel nanocatalyst that is stabilized at the edges of a single-crystalline magnesium oxide (MgO) support and show quantitative production of synthesis gas from dry reforming of methane. The catalyst runs more than 850 hours of continuous operation under 60 liters per unit mass of catalyst per hour reactive gas flow with no detectable coking. Synchrotron studies also show no sintering and reveal that during activation, 2.9 nanometers as synthesized crystallites move to combine into stable 17-nanometer grains at the edges of MgO crystals above the Tammann temperature. Our findings enable an industrially and economically viable path for carbon reclamation, and the “Nanocatalysts On Single Crystal Edges” technique could lead to stable catalyst designs for many challenging reactions.

    更新日期:2020-02-13
  • Helical quantum Hall phase in graphene on SrTiO3
    Science (IF 41.037) Pub Date : 2020-02-14
    Louis Veyrat, Corentin Déprez, Alexis Coissard, Xiaoxi Li, Frédéric Gay, Kenji Watanabe, Takashi Taniguchi, Zheng Han, Benjamin A. Piot, Hermann Sellier, Benjamin Sacépé

    The ground state of charge-neutral graphene under perpendicular magnetic field was predicted to be a quantum Hall topological insulator with a ferromagnetic order and spin-filtered, helical edge channels. In most experiments, however, an insulating state is observed that is accounted for by lattice-scale interactions that promote a broken-symmetry state with gapped bulk and edge excitations. We tuned the ground state of the graphene zeroth Landau level to the topological phase through a suitable screening of the Coulomb interaction with the high dielectric constant of a strontium titanate (SrTiO3) substrate. Robust helical edge transport emerged at magnetic fields as low as 1 tesla and withstanding temperatures up to 110 kelvin over micron-long distances. This versatile graphene platform may find applications in spintronics and topological quantum computation.

    更新日期:2020-02-13
  • Global ecosystem thresholds driven by aridity
    Science (IF 41.037) Pub Date : 2020-02-14
    Miguel Berdugo, Manuel Delgado-Baquerizo, Santiago Soliveres, Rocío Hernández-Clemente, Yanchuang Zhao, Juan J. Gaitán, Nicolas Gross, Hugo Saiz, Vincent Maire, Anika Lehman, Matthias C. Rillig, Ricard V. Solé, Fernando T. Maestre

    Aridity, which is increasing worldwide because of climate change, affects the structure and functioning of dryland ecosystems. Whether aridification leads to gradual (versus abrupt) and systemic (versus specific) ecosystem changes is largely unknown. We investigated how 20 structural and functional ecosystem attributes respond to aridity in global drylands. Aridification led to systemic and abrupt changes in multiple ecosystem attributes. These changes occurred sequentially in three phases characterized by abrupt decays in plant productivity, soil fertility, and plant cover and richness at aridity values of 0.54, 0.7, and 0.8, respectively. More than 20% of the terrestrial surface will cross one or several of these thresholds by 2100, which calls for immediate actions to minimize the negative impacts of aridification on essential ecosystem services for the more than 2 billion people living in drylands.

    更新日期:2020-02-13
  • Major role of particle fragmentation in regulating biological sequestration of CO2 by the oceans
    Science (IF 41.037) Pub Date : 2020-02-14
    Nathan Briggs, Giorgio Dall’Olmo, Hervé Claustre

    A critical driver of the ocean carbon cycle is the downward flux of sinking organic particles, which acts to lower the atmospheric carbon dioxide concentration. This downward flux is reduced by more than 70% in the mesopelagic zone (100 to 1000 meters of depth), but this loss cannot be fully accounted for by current measurements. For decades, it has been hypothesized that the missing loss could be explained by the fragmentation of large aggregates into small particles, although data to test this hypothesis have been lacking. In this work, using robotic observations, we quantified total mesopelagic fragmentation during 34 high-flux events across multiple ocean regions and found that fragmentation accounted for 49 ± 22% of the observed flux loss. Therefore, fragmentation may be the primary process controlling the sequestration of sinking organic carbon.

    更新日期:2020-02-13
  • Twisted bulk-boundary correspondence of fragile topology
    Science (IF 41.037) Pub Date : 2020-02-14
    Zhi-Da Song, Luis Elcoro, B. Andrei Bernevig

    A topological insulator reveals its nontrivial bulk through the presence of gapless edge states: This is called the bulk-boundary correspondence. However, the recent discovery of “fragile” topological states with no gapless edges casts doubt on this concept. We propose a generalization of the bulk-boundary correspondence: a transformation under which the gap between the fragile phase and other bands must close. We derive specific twisted boundary conditions (TBCs) that can detect all the two-dimensional eigenvalue fragile phases. We develop the concept of real-space invariants, local good quantum numbers in real space, which fully characterize these phases and determine the number of gap closings under the TBCs. Realizations of the TBCs in metamaterials are proposed, thereby providing a route to their experimental verification.

    更新日期:2020-02-13
  • Experimental characterization of fragile topology in an acoustic metamaterial
    Science (IF 41.037) Pub Date : 2020-02-14
    Valerio Peri, Zhi-Da Song, Marc Serra-Garcia, Pascal Engeler, Raquel Queiroz, Xueqin Huang, Weiyin Deng, Zhengyou Liu, B. Andrei Bernevig, Sebastian D. Huber

    Symmetries crucially underlie the classification of topological phases of matter. Most materials, both natural as well as architectured, possess crystalline symmetries. Recent theoretical works unveiled that these crystalline symmetries can stabilize fragile Bloch bands that challenge our very notion of topology: Although answering to the most basic definition of topology, one can trivialize these bands through the addition of trivial Bloch bands. Here, we fully characterize the symmetry properties of the response of an acoustic metamaterial to establish the fragile nature of the low-lying Bloch bands. Additionally, we present a spectral signature in the form of spectral flow under twisted boundary conditions.

    更新日期:2020-02-13
  • Circadian rhythms in the absence of the clock gene Bmal1
    Science (IF 41.037) Pub Date : 2020-02-14
    Sandipan Ray, Utham K. Valekunja, Alessandra Stangherlin, Steven A. Howell, Ambrosius P. Snijders, Gopinath Damodaran, Akhilesh B. Reddy

    Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.

    更新日期:2020-02-13
  • Structural basis of second-generation HIV integrase inhibitor action and viral resistance
    Science (IF 41.037) Pub Date : 2020-02-14
    Nicola J. Cook, Wen Li, Dénes Berta, Magd Badaoui, Allison Ballandras-Colas, Andrea Nans, Abhay Kotecha, Edina Rosta, Alan N. Engelman, Peter Cherepanov

    Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo–electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

    更新日期:2020-02-13
  • Structural basis for strand-transfer inhibitor binding to HIV intasomes
    Science (IF 41.037) Pub Date : 2020-02-14
    Dario Oliveira Passos, Min Li, Ilona K. Jóźwik, Xue Zhi Zhao, Diogo Santos-Martins, Renbin Yang, Steven J. Smith, Youngmin Jeon, Stefano Forli, Stephen H. Hughes, Terrence R. Burke, Robert Craigie, Dmitry Lyumkis

    The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo–electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.

    更新日期:2020-02-13
  • Tropical snake diversity collapses after widespread amphibian loss
    Science (IF 41.037) Pub Date : 2020-02-14
    Elise F. Zipkin, Graziella V. DiRenzo, Julie M. Ray, Sam Rossman, Karen R. Lips

    Biodiversity is declining at unprecedented rates worldwide. Yet cascading effects of biodiversity loss on other taxa are largely unknown because baseline data are often unavailable. We document the collapse of a Neotropical snake community after the invasive fungal pathogen Batrachochytrium dendrobatidis caused a chytridiomycosis epizootic leading to the catastrophic loss of amphibians, a food source for snakes. After mass mortality of amphibians, the snake community contained fewer species and was more homogeneous across the study site, with several species in poorer body condition, despite no other systematic changes in the environment. The demise of the snake community after amphibian loss demonstrates the repercussive and often unnoticed consequences of the biodiversity crisis and calls attention to the invisible declines of rare and data-deficient species.

    更新日期:2020-02-13
  • Lineage tracing on transcriptional landscapes links state to fate during differentiation
    Science (IF 41.037) Pub Date : 2020-02-14
    Caleb Weinreb, Alejo Rodriguez-Fraticelli, Fernando D. Camargo, Allon M. Klein

    A challenge in biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Here, we used expressed DNA barcodes to clonally trace transcriptomes over time and applied this to study fate determination in hematopoiesis. We identified states of primed fate potential and located them on a continuous transcriptional landscape. We identified two routes of monocyte differentiation that leave an imprint on mature cells. Analysis of sister cells also revealed cells to have intrinsic fate biases not detectable by single-cell RNA sequencing. Finally, we benchmarked computational methods of dynamic inference from single-cell snapshots, showing that fate choice occurs earlier than is detected by state-of the-art algorithms and that cells progress steadily through pseudotime with precise and consistent dynamics.

    更新日期:2020-02-13
  • Resilience after trauma: The role of memory suppression
    Science (IF 41.037) Pub Date : 2020-02-14
    Alison Mary, Jacques Dayan, Giovanni Leone, Charlotte Postel, Florence Fraisse, Carine Malle, Thomas Vallée, Carine Klein-Peschanski, Fausto Viader, Vincent de la Sayette, Denis Peschanski, Francis Eustache, Pierre Gagnepain

    In the aftermath of trauma, little is known about why the unwanted and unbidden recollection of traumatic memories persists in some individuals but not others. We implemented neutral and inoffensive intrusive memories in the laboratory in a group of 102 individuals exposed to the 2015 Paris terrorist attacks and 73 nonexposed individuals, who were not in Paris during the attacks. While reexperiencing these intrusive memories, nonexposed individuals and exposed individuals without posttraumatic stress disorder (PTSD) could adaptively suppress memory activity, but exposed individuals with PTSD could not. These findings suggest that the capacity to suppress memory is central to positive posttraumatic adaptation. A generalized disruption of the memory control system could explain the maladaptive and unsuccessful suppression attempts often seen in PTSD, and this disruption should be targeted by specific treatments.

    更新日期:2020-02-13
  • The solar nebula origin of (486958) Arrokoth, a primordial contact binary in the Kuiper Belt
    Science (IF 41.037) Pub Date : 2020-02-13
    W. B. McKinnon, D. C. Richardson, J. C. Marohnic, J. T. Keane, W. M. Grundy, D. P. Hamilton, D. Nesvorný, O. M. Umurhan, T. R. Lauer, K. N. Singer, S. A. Stern, H. A. Weaver, J. R. Spencer, M. W. Buie, J. M. Moore, J. J. Kavelaars, C. M. Lisse, X. Mao, A. H. Parker, S. B. Porter, M. R. Showalter, C. B. Olkin, D. P. Cruikshank, H. A. Elliott, G. R. Gladstone, J. Wm. Parker, A. J. Verbiscer, L. A. Young, the New Horizons Science Team†

    The New Horizons spacecraft’s encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU69) revealed a contact-binary planetesimal. We investigate how Arrokoth formed, finding it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly due to dynamical friction and collisions within the cloud or later gas drag. Arrokoth’s contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt, so informs the accretion processes that operated in the early Solar System.

    更新日期:2020-02-13
  • The geology and geophysics of Kuiper Belt object (486958) Arrokoth
    Science (IF 41.037) Pub Date : 2020-02-13
    J. R. Spencer, S. A. Stern, J. M Moore, H. A. Weaver, K. N. Singer, C. B Olkin, A. J. Verbiscer, W. B. McKinnon, J. Wm. Parker, R. A. Beyer, J. T. Keane, T. R. Lauer, S. B. Porter, O. L. White, B. J. Buratti, M. R. El-Maarry, C. M. Lisse, A. H. Parker, H. B. Throop, S. J. Robbins, O. M. Umurhan, R. P. Binzel, D. T. Britt, M. W. Buie, A. F. Cheng, D. P. Cruikshank, H. A. Elliott, G. R. Gladstone, W. M. Grundy, M. E. Hill, M. Horanyi, D. E. Jennings, J. J. Kavelaars, I. R. Linscott, D. J. McComas, R. L. McNutt, S. Protopapa, D. C. Reuter, P. M. Schenk, M. R. Showalter, L. A. Young, A. M. Zangari, A. Y. Abedin, C. B. Beddingfield, S. D. Benecchi, E. Bernardoni, C. J. Bierson, D. Borncamp, V. J. Bray, A. L. Chaikin, R. D. Dhingra, C. Fuentes, T. Fuse, P. L Gay, S. D. J. Gwyn, D. P. Hamilton, J. D. Hofgartner, M. J. Holman, A. D. Howard, C. J. A. Howett, H. Karoji, D. E. Kaufmann, M. Kinczyk, B. H. May, M. Mountain, M. Pätzold, J. M. Petit, M. R. Piquette, I. N. Reid, H. J. Reitsema, K. D. Runyon, S. S. Sheppard, J. A. Stansberry, T. Stryk, P. Tanga, D. J. Tholen, D. E. Trilling, L. H. Wasserman

    The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, are primitive objects preserving information about Solar System formation. In January 2019, the New Horizons spacecraft flew past one of these objects, the 36-km long contact binary (486958) Arrokoth (provisional designation 2014 MU69). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 m diameter) within a radius of 8000 km. Arrokoth has a lightly-cratered smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism.

    更新日期:2020-02-13
  • Color, composition, and thermal environment of Kuiper Belt object (486958) Arrokoth
    Science (IF 41.037) Pub Date : 2020-02-13
    W. M. Grundy, M. K. Bird, D. T. Britt, J. C. Cook, D. P. Cruikshank, C. J. A. Howett, S. Krijt, I. R. Linscott, C. B. Olkin, A. H. Parker, S. Protopapa, M. Ruaud, O. M. Umurhan, L. A. Young, C. M. Dalle Ore, J. J. Kavelaars, J. T. Keane, Y. J. Pendleton, S. B. Porter, F. Scipioni, J. R. Spencer, S. A. Stern, A. J. Verbiscer, H. A. Weaver, R. P. Binzel, M. W. Buie, B. J. Buratti, A. Cheng, A. M. Earle, H. A. Elliott, L. Gabasova, G. R. Gladstone, M. E. Hill, M. Horanyi, D. E. Jennings, A. W. Lunsford, D. J. McComas, W. B. McKinnon, R. L. McNutt, J. M. Moore, J. W. Parker, E. Quirico, D. C. Reuter, P. M. Schenk, B. Schmitt, M. R. Showalter, K. N. Singer, G. E. Weigle, A. M. Zangari

    The outer Solar System object (486958) Arrokoth (provisional designation 2014 MU69) has been largely undisturbed since its formation. We study its surface composition using data collected by the New Horizons spacecraft. Methanol ice is present along with organic material, which may have formed through irradiation of simple molecules. H2O ice is not detected. This composition indicates hydrogenation of CO-rich ice and/or energetic processing of CH4+H2O ices in the cold, outer edge of the early Solar System. There are only small regional variations in color and spectra across the surface, suggesting Arrokoth formed from a homogeneous or well-mixed reservoir of solids. Microwave thermal emission from the winter night side is consistent with a mean brightness temperature of 29 ± 5 K.

    更新日期:2020-02-13
  • ZGLP1 is a determinant for the oogenic fate in mice
    Science (IF 41.037) Pub Date : 2020-02-13
    So I. Nagaoka, Fumio Nakaki, Hidetaka Miyauchi, Yoshiaki Nosaka, Hiroshi Ohta, Yukihiro Yabuta, Kazuki Kurimoto, Katsuhiko Hayashi, Tomonori Nakamura, Takuya Yamamoto, Mitinori Saitou

    Mammalian sexual reproduction relies on the dichotomy of male and female germ cell development. However, the underlying mechanisms remain unclear. Here, we show that ZGLP1, a conserved transcriptional regulator with GATA-like zinc fingers, determines the oogenic fate in mice. ZGLP1 acts downstream of bone morphogenetic protein (BMP), but not retinoic acid (RA), and is essential for the oogenic program and meiotic entry. ZGLP1 overexpression induces differentiation of in vitro primordial germ cell-like cells (PGCLCs) into fetal oocytes by activating the oogenic programs repressed by Polycomb activities, whereas RA signaling contributes to the oogenic program maturation and PGC program repression. Our findings elucidate the mechanism for mammalian oogenic fate determination, providing a foundation for promoting in vitro gametogenesis and reproductive medicine.

    更新日期:2020-02-13
  • A sustainable wood biorefinery for low–carbon footprint chemicals production
    Science (IF 41.037) Pub Date : 2020-02-13
    Yuhe Liao, Steven-Friso Koelewijn, Gil Van den Bossche, Joost Van Aelst, Sander Van den Bosch, Tom Renders, Kranti Navare, Thomas Nicolaï, Korneel Van Aelst, Maarten Maesen, Hironori Matsushima, Johan Thevelein, Karel Van Acker, Bert Lagrain, Danny Verboekend, Bert F. Sels

    Profitability and sustainability of future biorefineries are dependent on efficient feedstock utilization. It is essential to valorize lignin when using wood. We have developed an integrated biorefinery that converts 78 wt.% of birch into xylochemicals. Reductive catalytic fractionation of wood gives a carbohydrate pulp amenable to bioethanol production and a lignin oil. After extraction of lignin oil, the crude, unseparated mixture of phenolic monomers is catalytically funneled into 20 wt.% of phenol and 9 wt.% of propylene (on lignin basis) by gas-phase hydroprocessing/dealkylation, whereas the residual phenolic oligomers (30 wt.%) are used in printing ink as replacements for controversial para-nonylphenol. Techno-economic analysis predicts an economically competitive production, and life-cycle assessment estimates a lower CO2 footprint relative to fossil-based production.

    更新日期:2020-02-13
  • Structure of the secretory immunoglobulin A core
    Science (IF 41.037) Pub Date : 2020-02-06
    Nikit Kumar, Christopher P. Arthur, Claudio Ciferri, Marissa L. Matsumoto

    Secretory immunoglobulin A (sIgA) represents the immune system’s first-line of defense against mucosal pathogens. IgAs are transported across the epithelium, as dimers and higher-order polymers, by the polymeric immunoglobulin receptor (pIgR). Upon reaching the luminal side, sIgAs mediate host protection and pathogen neutralization. In recent years, an increasing amount of attention has been given to IgA as a novel therapeutic antibody. Despite extensive studies sIgA structures have remained elusive. Here, we determine the atomic-resolution structures of dimeric, tetrameric, and pentameric IgA-Fc linked by the joining chain (JC) and in complex with the secretory component of the pIgR. We suggest a mechanism where the JC templates IgA oligomerization and imparts asymmetry for pIgR binding and transcytosis. This framework will inform the design of future IgA-based therapeutics.

    更新日期:2020-02-07
  • Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
    Science (IF 41.037) Pub Date : 2020-02-07
    Stephan Wilmes, Maximillian Hafer, Joni Vuorio, Julie A. Tucker, Hauke Winkelmann, Sara Löchte, Tess A. Stanly, Katiuska D. Pulgar Prieto, Chetan Poojari, Vivek Sharma, Christian P. Richter, Rainer Kurre, Stevan R. Hubbard, K. Christopher Garcia, Ignacio Moraga, Ilpo Vattulainen, Ian S. Hitchcock, Jacob Piehler

    Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.

    更新日期:2020-02-07
  • An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis
    Science (IF 41.037) Pub Date : 2020-02-07
    Peng Zhao, Xiaoli Sun, Cynthia Chaggan, Zhongji Liao, Kai in Wong, Feng He, Seema Singh, Rohit Loomba, Michael Karin, Joseph L. Witztum, Alan R. Saltiel

    Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)–activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK–caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.

    更新日期:2020-02-07
  • CO2 electrolysis to multicarbon products at activities greater than 1 A cm−2
    Science (IF 41.037) Pub Date : 2020-02-07
    F. Pelayo García de Arquer, Cao-Thang Dinh, Adnan Ozden, Joshua Wicks, Christopher McCallum, Ahmad R. Kirmani, Dae-Hyun Nam, Christine Gabardo, Ali Seifitokaldani, Xue Wang, Yuguang C. Li, Fengwang Li, Jonathan Edwards, Lee J. Richter, Steven J. Thorpe, David Sinton, Edward H. Sargent

    Electrolysis offers an attractive route to upgrade greenhouse gases such as carbon dioxide (CO2) to valuable fuels and feedstocks; however, productivity is often limited by gas diffusion through a liquid electrolyte to the surface of the catalyst. Here, we present a catalyst:ionomer bulk heterojunction (CIBH) architecture that decouples gas, ion, and electron transport. The CIBH comprises a metal and a superfine ionomer layer with hydrophobic and hydrophilic functionalities that extend gas and ion transport from tens of nanometers to the micrometer scale. By applying this design strategy, we achieved CO2 electroreduction on copper in 7 M potassium hydroxide electrolyte (pH ≈ 15) with an ethylene partial current density of 1.3 amperes per square centimeter at 45% cathodic energy efficiency.

    更新日期:2020-02-07
  • Na+-gated water-conducting nanochannels for boosting CO2 conversion to liquid fuels
    Science (IF 41.037) Pub Date : 2020-02-07
    Huazheng Li, Chenglong Qiu, Shoujie Ren, Qiaobei Dong, Shenxiang Zhang, Fanglei Zhou, Xinhua Liang, Jianguo Wang, Shiguang Li, Miao Yu

    Robust, gas-impeding water-conduction nanochannels that can sieve water from small gas molecules such as hydrogen (H2), particularly at high temperature and pressure, are desirable for boosting many important reactions severely restricted by water (the major by-product) both thermodynamically and kinetically. Identifying and constructing such nanochannels into large-area separation membranes without introducing extra defects is challenging. We found that sodium ion (Na+)–gated water-conduction nanochannels could be created by assembling NaA zeolite crystals into a continuous, defect-free separation membrane through a rationally designed method. Highly efficient in situ water removal through water-conduction nanochannels led to a substantial increase in carbon dioxide (CO2) conversion and methanol yield in CO2 hydrogenation for methanol production.

    更新日期:2020-02-07
  • Room temperature magnetoelectric coupling in a molecular ferroelectric ytterbium(III) complex
    Science (IF 41.037) Pub Date : 2020-02-07
    Jérôme Long, Maxim S. Ivanov, Vladimir A. Khomchenko, Ekaterina Mamontova, Jean-Marc Thibaud, Jérôme Rouquette, Mickaël Beaudhuin, Dominique Granier, Rute A. S. Ferreira, Luis D. Carlos, Bruno Donnadieu, Marta S. C. Henriques, José António Paixão, Yannick Guari, Joulia Larionova

    Magnetoelectric (ME) materials combine magnetic and electric polarizabilities in the same phase, offering a basis for developing high-density data storage and spintronic or low-consumption devices owing to the possibility of triggering one property with the other. Such applications require strong interaction between the constitutive properties, a criterion that is rarely met in classical inorganic ME materials at room temperature. We provide evidence of a strong ME coupling in a paramagnetic ferroelectric lanthanide coordination complex with magnetostrictive phenomenon. The properties of this molecular material suggest that it may be competitive with inorganic magnetoelectrics.

    更新日期:2020-02-07
  • Total synthesis of the complex taxane diterpene canataxpropellane
    Science (IF 41.037) Pub Date : 2020-02-07
    Fabian Schneider, Konstantin Samarin, Simone Zanella, Tanja Gaich

    Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C–C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (–)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (–)-canataxpropellane (2) was assembled in two steps using a Diels–Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels–Alder reaction.

    更新日期:2020-02-07
  • Mosquito heat seeking is driven by an ancestral cooling receptor
    Science (IF 41.037) Pub Date : 2020-02-07
    Chloe Greppi, Willem J. Laursen, Gonzalo Budelli, Elaine C. Chang, Abigail M. Daniels, Lena van Giesen, Andrea L. Smidler, Flaminia Catteruccia, Paul A. Garrity

    Mosquitoes transmit pathogens that kill >700,000 people annually. These insects use body heat to locate and feed on warm-blooded hosts, but the molecular basis of such behavior is unknown. Here, we identify ionotropic receptor IR21a, a receptor conserved throughout insects, as a key mediator of heat seeking in the malaria vector Anopheles gambiae. Although Ir21a mediates heat avoidance in Drosophila, we find it drives heat seeking and heat-stimulated blood feeding in Anopheles. At a cellular level, Ir21a is essential for the detection of cooling, suggesting that during evolution mosquito heat seeking relied on cooling-mediated repulsion. Our data indicate that the evolution of blood feeding in Anopheles involves repurposing an ancestral thermoreceptor from non–blood-feeding Diptera.

    更新日期:2020-02-07
  • Climate change contributes to widespread declines among bumble bees across continents
    Science (IF 41.037) Pub Date : 2020-02-07
    Peter Soroye, Tim Newbold, Jeremy Kerr

    Climate change could increase species’ extinction risk as temperatures and precipitation begin to exceed species’ historically observed tolerances. Using long-term data for 66 bumble bee species across North America and Europe, we tested whether this mechanism altered likelihoods of bumble bee species’ extinction or colonization. Increasing frequency of hotter temperatures predicts species’ local extinction risk, chances of colonizing a new area, and changing species richness. Effects are independent of changing land uses. The method developed in this study permits spatially explicit predictions of climate change–related population extinction-colonization dynamics within species that explains observed patterns of geographical range loss and expansion across continents. Increasing frequencies of temperatures that exceed historically observed tolerances help explain widespread bumble bee species decline. This mechanism may also contribute to biodiversity loss more generally.

    更新日期:2020-02-07
  • Microglia mediate forgetting via complement-dependent synaptic elimination
    Science (IF 41.037) Pub Date : 2020-02-07
    Chao Wang, Huimin Yue, Zhechun Hu, Yuwen Shen, Jiao Ma, Jie Li, Xiao-Dong Wang, Liang Wang, Binggui Sun, Peng Shi, Lang Wang, Yan Gu

    Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.

    更新日期:2020-02-07
  • Valence and patterning of aromatic residues determine the phase behavior of prion-like domains
    Science (IF 41.037) Pub Date : 2020-02-07
    Erik W. Martin, Alex S. Holehouse, Ivan Peran, Mina Farag, J. Jeremias Incicco, Anne Bremer, Christy R. Grace, Andrea Soranno, Rohit V. Pappu, Tanja Mittag

    Prion-like domains (PLDs) can drive liquid-liquid phase separation (LLPS) in cells. Using an integrative biophysical approach that includes nuclear magnetic resonance spectroscopy, small-angle x-ray scattering, and multiscale simulations, we have uncovered sequence features that determine the overall phase behavior of PLDs. We show that the numbers (valence) of aromatic residues in PLDs determine the extent of temperature-dependent compaction of individual molecules in dilute solutions. The valence of aromatic residues also determines full binodals that quantify concentrations of PLDs within coexisting dilute and dense phases as a function of temperature. We also show that uniform patterning of aromatic residues is a sequence feature that promotes LLPS while inhibiting aggregation. Our findings lead to the development of a numerical stickers-and-spacers model that enables predictions of full binodals of PLDs from their sequences.

    更新日期:2020-02-07
  • Structure of an active human histone pre-mRNA 3′-end processing machinery
    Science (IF 41.037) Pub Date : 2020-02-07
    Yadong Sun, Yixiao Zhang, Wei Shen Aik, Xiao-Cui Yang, William F. Marzluff, Thomas Walz, Zbigniew Dominski, Liang Tong

    The 3′-end processing machinery for metazoan replication-dependent histone precursor messenger RNAs (pre-mRNAs) contains the U7 small nuclear ribonucleoprotein and shares the key cleavage module with the canonical cleavage and polyadenylation machinery. We reconstituted an active human histone pre-mRNA processing machinery using 13 recombinant proteins and two RNAs and determined its structure by cryo–electron microscopy. The overall structure is highly asymmetrical and resembles an amphora with one long handle. We captured the pre-mRNA in the active site of the endonuclease, the 73-kilodalton subunit of the cleavage and polyadenylation specificity factor, poised for cleavage. The endonuclease and the entire cleavage module undergo extensive rearrangements for activation, triggered through the recognition of the duplex between the authentic pre-mRNA and U7 small nuclear RNA (snRNA). Our study also has notable implications for understanding canonical and snRNA 3′-end processing.

    更新日期:2020-02-07
  • Enhanced sustainable green revolution yield via nitrogen-responsive chromatin modulation in rice
    Science (IF 41.037) Pub Date : 2020-02-07
    Kun Wu, Shuansuo Wang, Wenzhen Song, Jianqing Zhang, Yun Wang, Qian Liu, Jianping Yu, Yafeng Ye, Shan Li, Jianfeng Chen, Ying Zhao, Jing Wang, Xiaokang Wu, Meiyue Wang, Yijing Zhang, Binmei Liu, Yuejin Wu, Nicholas P. Harberd, Xiangdong Fu

    Because environmentally degrading inorganic fertilizer use underlies current worldwide cereal yields, future agricultural sustainability demands enhanced nitrogen use efficiency. We found that genome-wide promotion of histone H3 lysine 27 trimethylation (H3K27me3) enables nitrogen-induced stimulation of rice tillering: APETALA2-domain transcription factor NGR5 (NITROGEN-MEDIATED TILLER GROWTH RESPONSE 5) facilitates nitrogen-dependent recruitment of polycomb repressive complex 2 to repress branching-inhibitory genes via H3K27me3 modification. NGR5 is a target of gibberellin receptor GIBBERELLIN INSENSITIVE DWARF1 (GID1)–promoted proteasomal destruction. DELLA proteins (characterized by the presence of a conserved aspartate-glutamate-leucine-leucine-alanine motif) competitively inhibit the GID1-NGR5 interaction and explain increased tillering of green revolution varieties. Increased NGR5 activity consequently uncouples tillering from nitrogen regulation, boosting rice yield at low nitrogen fertilization levels. NGR5 thus enables enhanced nitrogen use efficiency for improved future agricultural sustainability and food security.

    更新日期:2020-02-07
  • Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells
    Science (IF 41.037) Pub Date : 2020-02-07
    Marc Rigau, Simone Ostrouska, Thomas S. Fulford, Darryl N. Johnson, Katherine Woods, Zheng Ruan, Hamish E.G. McWilliam, Christopher Hudson, Candani Tutuka, Adam K. Wheatley, Stephen J. Kent, Jose A. Villadangos, Bhupinder Pal, Christian Kurts, Jason Simmonds, Matthias Pelzing, Andrew D. Nash, Andrew Hammet, Anne M. Verhagen, Gino Vairo, Eugene Maraskovsky, Con Panousis, Nicholas A. Gherardin, Jonathan Cebon, Dale I. Godfrey, Andreas Behren, Adam P. Uldrich

    Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.

    更新日期:2020-02-07
  • The biology, function, and biomedical applications of exosomes
    Science (IF 41.037) Pub Date : 2020-02-07
    Raghu Kalluri, Valerie S. LeBleu

    The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

    更新日期:2020-02-07
  • Structural insights into immunoglobulin M
    Science (IF 41.037) Pub Date : 2020-02-06
    Yaxin Li, Guopeng Wang, Ningning Li, Yuxin Wang, Qinyu Zhu, Huarui Chu, Wenjun Wu, Ying Tan, Feng Yu, Xiao-Dong Su, Ning Gao, Junyu Xiao

    Immunoglobulin M (IgM) plays a pivotal role in both humoral and mucosal immunity. Its assembly and transport depend on the joining chain (J-chain) and the polymeric immunoglobulin receptor (pIgR), but the underlying molecular mechanisms of these processes are unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgM in complex with the J-chain and pIgR ectodomain. The IgM-Fc pentamer is formed asymmetrically, resembling a hexagon with a missing triangle. The tailpieces of IgM-Fc pack into an amyloid-like structure to stabilize the pentamer. The J-chain caps the tailpiece assembly and bridges the interaction between IgM-Fc and pIgR, which undergoes a large conformational change to engage the IgM–J complex. These results provide a structural basis for the function of IgM.

    更新日期:2020-02-07
  • Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
    Science (IF 41.037) Pub Date : 2020-02-06
    Richard Y. Ebright, Sooncheol Lee, Ben S. Wittner, Kira L. Niederhoffer, Benjamin T. Nicholson, Aditya Bardia, Samuel Truesdell, Devon F. Wiley, Benjamin Wesley, Selena Li, Andy Mai, Nicola Aceto, Nicole Vincent-Jordan, Annamaria Szabolcs, Brian Chirn, Johannes Kreuzer, Valentine Comaills, Mark Kalinich, Wilhelm Haas, David T. Ting, Mehmet Toner, Shobha Vasudevan, Daniel A. Haber, Shyamala Maheswaran, Douglas S. Micalizzi

    Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in breast cancer patient-derived CTCs to identify genes that promote their distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA-sequencing of freshly-isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.

    更新日期:2020-02-07
  • CRISPR-engineered T cells in patients with refractory cancer
    Science (IF 41.037) Pub Date : 2020-02-06
    Edward A. Stadtmauer, Joseph A. Fraietta, Megan M. Davis, Adam D. Cohen, Kristy L. Weber, Eric Lancaster, Patricia A. Mangan, Irina Kulikovskaya, Minnal Gupta, Fang Chen, Lifeng Tian, Vanessa E. Gonzalez, Jun Xu, In-young Jung, J. Joseph Melenhorst, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Anne Lamontagne, January Salas-Mckee, Andrew Fesnak, Donald L. Siegel, Bruce L. Levine, Julie K. Jadlowsky, Regina M. Young, Anne Chew, Wei-Ting Hwang, Elizabeth O. Hexner, Beatriz M. Carreno, Christopher L. Nobles, Frederic D. Bushman, Kevin R. Parker, Yanyan Qi, Ansuman T. Satpathy, Howard Y. Chang, Yangbing Zhao, Simon F. Lacey, Carl H. June

    CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase I clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene-editing for cancer immunotherapy.

    更新日期:2020-02-07
  • Neoadjuvant checkpoint blockade for cancer immunotherapy
    Science (IF 41.037) Pub Date : 2020-01-31
    Suzanne L. Topalian, Janis M. Taube, Drew M. Pardoll

    Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti–PD-1 or anti–PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti–PD-1 and anti–PD-L1 efficacy.

    更新日期:2020-01-31
  • Microglia monitor and protect neuronal function through specialized somatic purinergic junctions
    Science (IF 41.037) Pub Date : 2020-01-31
    Csaba Cserép, Balázs Pósfai, Nikolett Lénárt, Rebeka Fekete, Zsófia I. László, Zsolt Lele, Barbara Orsolits, Gábor Molnár, Steffanie Heindl, Anett D. Schwarcz, Katinka Ujvári, Zsuzsanna Környei, Krisztina Tóth, Eszter Szabadits, Beáta Sperlágh, Mária Baranyi, László Csiba, Tibor Hortobágyi, Zsófia Maglóczky, Bernadett Martinecz, Gábor Szabó, Ferenc Erdélyi, Róbert Szipőcs, Michael M. Tamkun, Benno Gesierich, Marco Duering, István Katona, Arthur Liesz, Gábor Tamás, Ádám Dénes

    Microglia are the main immune cells in the brain and have roles in brain homeostasis and neurological diseases. Mechanisms underlying microglia–neuron communication remain elusive. Here, we identified an interaction site between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia–neuron junctions have a specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria was linked with microglial junction formation, which was induced rapidly in response to neuronal activation and blocked by inhibition of P2Y12 receptors. Brain injury–induced changes at somatic junctions triggered P2Y12 receptor–dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Thus, microglial processes at these junctions could potentially monitor and protect neuronal functions.

    更新日期:2020-01-31
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