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  • Neuronal specification in space and time
    Science (IF 41.058) Pub Date : 2018-10-12
    Isabel Holguera, Claude Desplan

    To understand how neurons assemble to form functional circuits, it is necessary to obtain a detailed knowledge of their diversity and to define the developmental specification programs that give rise to this diversity. Invertebrates and vertebrates appear to share common developmental principles of neuronal specification in which cascades of transcription factors temporally pattern progenitors, while spatial cues modify the outcomes of this temporal patterning. Here, we highlight these conserved mechanisms and describe how they are used in distinct neural structures. We present the questions that remain for a better understanding of neuronal specification. Single-cell RNA profiling approaches will potentially shed light on these questions, allowing not only the characterization of neuronal diversity in adult brains, but also the investigation of the developmental trajectories leading to the generation and maintenance of this diversity.

    更新日期:2018-10-12
  • Glia as architects of central nervous system formation and function
    Science (IF 41.058) Pub Date : 2018-10-12
    Nicola J. Allen, David A. Lyons

    Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function. Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function.

    更新日期:2018-10-12
  • Microglia and early brain development: An intimate journey
    Science (IF 41.058) Pub Date : 2018-10-12
    Morgane S. Thion, Florent Ginhoux, Sonia Garel

    Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex-specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole-body context.

    更新日期:2018-10-12
  • Homology, neocortex, and the evolution of developmental mechanisms
    Science (IF 41.058) Pub Date : 2018-10-12
    Steven D. Briscoe, Clifton W. Ragsdale

    The six-layered neocortex of the mammalian pallium has no clear homolog in birds or non-avian reptiles. Recent research indicates that although these extant amniotes possess a variety of divergent and nonhomologous pallial structures, they share a conserved set of neuronal cell types and circuitries. These findings suggest a principle of brain evolution: that natural selection preferentially preserves the integrity of information-processing pathways, whereas other levels of biological organization, such as the three-dimensional architectures of neuronal assemblies, are less constrained. We review the similarities of pallial neuronal cell types in amniotes, delineate candidate gene regulatory networks for their cellular identities, and propose a model of developmental evolution for the divergence of amniote pallial structures.

    更新日期:2018-10-12
  • A hot and fast ultra-stripped supernova that likely formed a compact neutron star binary
    Science (IF 41.058) Pub Date : 2018-10-12
    K. De, M. M. Kasliwal, E. O. Ofek, T. J. Moriya, J. Burke, Y. Cao, S. B. Cenko, G. B. Doran, G. E. Duggan, R. P. Fender, C. Fransson, A. Gal-Yam, A. Horesh, S. R. Kulkarni, R. R. Laher, R. Lunnan, I. Manulis, F. Masci, P. A. Mazzali, P. E. Nugent, D. A. Perley, T. Petrushevska, A. L. Piro, C. Rumsey, J. Sollerman, M. Sullivan, F. Taddia

    Compact neutron star binary systems are produced from binary massive stars through stellar evolution involving up to two supernova explosions. The final stages in the formation of these systems have not been directly observed. We report the discovery of iPTF 14gqr (SN 2014ft), a type Ic supernova with a fast-evolving light curve indicating an extremely low ejecta mass (≈0.2 solar masses) and low kinetic energy (≈2 × 1050 ergs). Early photometry and spectroscopy reveal evidence of shock cooling of an extended helium-rich envelope, likely ejected in an intense pre-explosion mass-loss episode of the progenitor. Taken together, we interpret iPTF 14gqr as evidence for ultra-stripped supernovae that form neutron stars in compact binary systems.

    更新日期:2018-10-12
  • Genome hypermobility by lateral transduction
    Science (IF 41.058) Pub Date : 2018-10-12
    John Chen, Nuria Quiles-Puchalt, Yin Ning Chiang, Rodrigo Bacigalupe, Alfred Fillol-Salom, Melissa Su Juan Chee, J. Ross Fitzgerald, José R. Penadés

    Genetic transduction is a major evolutionary force that underlies bacterial adaptation. Here we report that the temperate bacteriophages of Staphylococcus aureus engage in a distinct form of transduction we term lateral transduction. Staphylococcal prophages do not follow the previously described excision-replication-packaging pathway but instead excise late in their lytic program. Here, DNA packaging initiates in situ from integrated prophages, and large metameric spans including several hundred kilobases of the S. aureus genome are packaged in phage heads at very high frequency. In situ replication before DNA packaging creates multiple prophage genomes so that lateral-transducing particles form during normal phage maturation, transforming parts of the S. aureus chromosome into hypermobile regions of gene transfer.

    更新日期:2018-10-12
  • Entropy-driven stability of chiral single-walled carbon nanotubes
    Science (IF 41.058) Pub Date : 2018-10-12
    Yann Magnin, Hakim Amara, François Ducastelle, Annick Loiseau, Christophe Bichara

    Single-walled carbon nanotubes are hollow cylinders that can grow centimeters long via carbon incorporation at the interface with a catalyst. They display semiconducting or metallic characteristics, depending on their helicity, which is determined during their growth. To support the quest for a selective synthesis, we develop a thermodynamic model that relates the tube-catalyst interfacial energies, temperature, and the resulting tube chirality. We show that nanotubes can grow chiral because of the configurational entropy of their nanometer-sized edge, thus explaining experimentally observed temperature evolutions of chiral distributions. Taking the chemical nature of the catalyst into account through interfacial energies, we derive structural maps and phase diagrams that will guide a rational choice of a catalyst and growth parameters toward a better selectivity.

    更新日期:2018-10-12
  • Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates
    Science (IF 41.058) Pub Date : 2018-10-12
    Lucas Schreyer, Philip S. J. Kaib, Vijay N. Wakchaure, Carla Obradors, Roberta Properzi, Sunggi Lee, Benjamin List

    Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.

    更新日期:2018-10-12
  • Key-and-lock commodity self-healing copolymers
    Science (IF 41.058) Pub Date : 2018-10-12
    Marek W. Urban, Dmitriy Davydovich, Ying Yang, Tugba Demir, Yunzhi Zhang, Leah Casabianca

    Self-healing materials are notable for their ability to recover from physical or chemical damage. We report that commodity copolymers, such as poly(methyl methacrylate)/n-butyl acrylate [p(MMA/nBA)] and their derivatives, can self-heal upon mechanical damage. This behavior occurs in a narrow compositional range for copolymer topologies that are preferentially alternating with a random component (alternating/random) and is attributed to favorable interchain van der Waals forces forming key-and-lock interchain junctions. The use of van der Waals forces instead of supramolecular or covalent rebonding or encapsulated reactants eliminates chemical and physical alterations and enables multiple recovery upon mechanical damage without external intervention. Unlike other self-healing approaches, perturbation of ubiquitous van der Waals forces upon mechanical damage is energetically unfavorable for interdigitated alternating/random copolymer motifs that facilitate self-healing under ambient conditions.

    更新日期:2018-10-12
  • Ketyl radical reactivity via atom transfer catalysis
    Science (IF 41.058) Pub Date : 2018-10-12
    Lu Wang, Jeremy M. Lear, Sean M. Rafferty, Stacy C. Fosu, David A. Nagib

    Single-electron reduction of a carbonyl to a ketyl enables access to a polarity-reversed platform of reactivity for this cornerstone functional group. However, the synthetic utility of the ketyl radical is hindered by the strong reductants necessary for its generation, which also limit its reactivity to net reductive mechanisms. We report a strategy for net redox-neutral generation and reaction of ketyl radicals. The in situ conversion of aldehydes to α-acetoxy iodides lowers their reduction potential by more than 1 volt, allowing for milder access to the corresponding ketyl radicals and an oxidative termination event. Upon subjecting these iodides to a dimanganese decacarbonyl precatalyst and visible light irradiation, an atom transfer radical addition (ATRA) mechanism affords a broad scope of vinyl iodide products with high Z-selectivity.

    更新日期:2018-10-12
  • Electrical generation and detection of spin waves in a quantum Hall ferromagnet
    Science (IF 41.058) Pub Date : 2018-10-12
    Di S. Wei, Toeno van der Sar, Seung Hwan Lee, Kenji Watanabe, Takashi Taniguchi, Bertrand I. Halperin, Amir Yacoby

    Spin waves are collective excitations of magnetic systems. An attractive setting for studying long-lived spin-wave physics is the quantum Hall (QH) ferromagnet, which forms spontaneously in clean two-dimensional electron systems at low temperature and in a perpendicular magnetic field. We used out-of-equilibrium occupation of QH edge channels in graphene to excite and detect spin waves in magnetically ordered QH states. Our experiments provide direct evidence for long-distance spin-wave propagation through different ferromagnetic phases in the N = 0 Landau level, as well as across the insulating canted antiferromagnetic phase. Our results will enable experimental investigation of the fundamental magnetic properties of these exotic two-dimensional electron systems.

    更新日期:2018-10-12
  • Systemic control of legume susceptibility to rhizobial infection by a mobile microRNA
    Science (IF 41.058) Pub Date : 2018-10-12
    Daniela Tsikou, Zhe Yan, Dennis B. Holt, Nikolaj B. Abel, Dugald E. Reid, Lene H. Madsen, Hemal Bhasin, Moritz Sexauer, Jens Stougaard, Katharina Markmann

    Nitrogen-fixing root nodules on legumes result from two developmental processes, bacterial infection and nodule organogenesis. To balance symbiosis and plant growth, legume hosts restrict nodule numbers through an inducible autoregulatory process. Here, we present a mechanism where repression of a negative regulator ensures symbiotic susceptibility of uninfected roots of the host Lotus japonicus. We show that microRNA miR2111 undergoes shoot-to-root translocation to control rhizobial infection through posttranscriptional regulation of the symbiosis suppressor TOO MUCH LOVE in roots. miR2111 maintains a susceptible default status in uninfected hosts and functions as an activator of symbiosis downstream of LOTUS HISTIDINE KINASE1–mediated cytokinin perception in roots and HYPERNODULATION ABERRANT ROOT FORMATION1, a shoot factor in autoregulation. The miR2111-TML node ensures activation of feedback regulation to balance infection and nodulation events.

    更新日期:2018-10-12
  • Systematic discovery of natural CRISPR-Cas12a inhibitors
    Science (IF 41.058) Pub Date : 2018-10-12
    Kyle E. Watters, Christof Fellmann, Hua B. Bai, Shawn M. Ren, Jennifer A. Doudna

    Cas12a (Cpf1) is a CRISPR-associated nuclease with broad utility for synthetic genome engineering, agricultural genomics, and biomedical applications. Although bacteria harboring CRISPR-Cas9 or CRISPR-Cas3 adaptive immune systems sometimes acquire mobile genetic elements encoding anti-CRISPR proteins that inhibit Cas9, Cas3, or the DNA-binding Cascade complex, no such inhibitors have been found for CRISPR-Cas12a. Here we use a comprehensive bioinformatic and experimental screening approach to identify three different inhibitors that block or diminish CRISPR-Cas12a–mediated genome editing in human cells. We also find a widespread connection between CRISPR self-targeting and inhibitor prevalence in prokaryotic genomes, suggesting a straightforward path to the discovery of many more anti-CRISPRs from the microbial world.

    更新日期:2018-10-12
  • Discovery of widespread type I and type V CRISPR-Cas inhibitors
    Science (IF 41.058) Pub Date : 2018-10-12
    Nicole D. Marino, Jenny Y. Zhang, Adair L. Borges, Alexander A. Sousa, Lina M. Leon, Benjamin J. Rauch, Russell T. Walton, Joel D. Berry, J. Keith Joung, Benjamin P. Kleinstiver, Joseph Bondy-Denomy

    Bacterial CRISPR-Cas systems protect their host from bacteriophages and other mobile genetic elements. Mobile elements, in turn, encode various anti-CRISPR (Acr) proteins to inhibit the immune function of CRISPR-Cas. To date, Acr proteins have been discovered for type I (subtypes I-D, I-E, and I-F) and type II (II-A and II-C) but not other CRISPR systems. Here, we report the discovery of 12 acr genes, including inhibitors of type V-A and I-C CRISPR systems. AcrVA1 inhibits a broad spectrum of Cas12a (Cpf1) orthologs—including MbCas12a, Mb3Cas12a, AsCas12a, and LbCas12a—when assayed in human cells. The acr genes reported here provide useful biotechnological tools and mark the discovery of acr loci in many bacteria and phages.

    更新日期:2018-10-12
  • Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy
    Science (IF 41.058) Pub Date : 2018-10-12
    Razvan Cristescu, Robin Mogg, Mark Ayers, Andrew Albright, Erin Murphy, Jennifer Yearley, Xinwei Sher, Xiao Qiao Liu, Hongchao Lu, Michael Nebozhyn, Chunsheng Zhang, Jared K. Lunceford, Andrew Joe, Jonathan Cheng, Andrea L. Webber, Nageatte Ibrahim, Elizabeth R. Plimack, Patrick A. Ott, Tanguy Y. Seiwert, Antoni Ribas, Terrill K. McClanahan, Joanne E. Tomassini, Andrey Loboda, David Kaufman

    Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.

    更新日期:2018-10-12
  • Thyroid hormone signaling specifies cone subtypes in human retinal organoids
    Science (IF 41.058) Pub Date : 2018-10-12
    Kiara C. Eldred, Sarah E. Hadyniak, Katarzyna A. Hussey, Boris Brenerman, Ping-Wu Zhang, Xitiz Chamling, Valentin M. Sluch, Derek S. Welsbie, Samer Hattar, James Taylor, Karl Wahlin, Donald J. Zack, Robert J. Johnston

    The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue (S), green (M), and red (L) cones of the retina enable high-acuity daytime and color vision. To determine the mechanism that controls S versus L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone–degrading and –activating proteins within the retina ensures low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining mechanisms of human development with promising utility for therapeutics and vision repair.

    更新日期:2018-10-12
  • Structure and dynamics of the yeast SWR1-nucleosome complex
    Science (IF 41.058) Pub Date : 2018-10-12
    Oliver Willhoft, Mohamed Ghoneim, Chia-Liang Lin, Eugene Y. D. Chua, Martin Wilkinson, Yuriy Chaban, Rafael Ayala, Elizabeth A. McCormack, Lorraine Ocloo, David S. Rueda, Dale B. Wigley

    The yeast SWR1 complex exchanges histone H2A in nucleosomes with Htz1 (H2A.Z in humans). The cryo–electron microscopy structure of the SWR1 complex bound to a nucleosome at 3.6-angstrom resolution reveals details of the intricate interactions between components of the SWR1 complex and its nucleosome substrate. Interactions between the Swr1 motor domains and the DNA wrap at superhelical location 2 distort the DNA, causing a bulge with concomitant translocation of the DNA by one base pair, coupled to conformational changes of the histone core. Furthermore, partial unwrapping of the DNA from the histone core takes place upon binding of nucleosomes to SWR1 complex. The unwrapping, as monitored by single-molecule data, is stabilized and has its dynamics altered by adenosine triphosphate binding but does not require hydrolysis.

    更新日期:2018-10-12
  • Dimerization quality control ensures neuronal development and survival
    Science (IF 41.058) Pub Date : 2018-10-12
    Elijah L. Mena, Rachel A. S. Kjolby, Robert A. Saxton, Achim Werner, Brandon G. Lew, John M. Boyle, Richard Harland, Michael Rape

    Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

    更新日期:2018-10-12
  • Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis–driven translocation
    Science (IF 41.058) Pub Date : 2018-10-11
    Andres H. de la Peña, Ellen A. Goodall, Stephanie N. Gates, Gabriel C. Lander, A. Martin

    The 26S proteasome is the primary eukaryotic degradation machine and thus critically involved in numerous cellular processes. The hetero-hexameric ATPase motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core, while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo-EM structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination, and how ATP-binding, hydrolysis, and phosphate-release events are coordinated within the AAA+ motor to induce conformational changes and propel the substrate through the central pore.

    更新日期:2018-10-12
  • Identity inference of genomic data using long-range familial searches
    Science (IF 41.058) Pub Date : 2018-10-11
    Yaniv Erlich, Tal Shor, Itsik Pe’er, Shai Carmi

    Consumer genomics databases have reached the scale of millions of individuals. Recently, law enforcement authorities have exploited some of these databases to identify suspects via distant familial relatives. Using genomic data of 1.28 million individuals tested with consumer genomics, we investigated the power of this technique. We project that about 60% of the searches for individuals of European-descent will result in a third cousin or closer match, which can allow their identification using demographic identifiers. Moreover, the technique could implicate nearly any US-individual of European-descent in the near future. We demonstrate that the technique can also identify research participants of a public sequencing project. Based on these results, we propose a potential mitigation strategy and policy implications to human subject research.

    更新日期:2018-10-12
  • In vivo modeling of human neuron dynamics and Down syndrome
    Science (IF 41.058) Pub Date : 2018-10-11
    Raquel Real, Manuel Peter, Antonio Trabalza, Shabana Khan, Mark A. Smith, Joana Dopp, Samuel J. Barnes, Ayiba Momoh, Alessio Strano, Emanuela Volpi, Graham Knott, Frederick J. Livesey, Vincenzo De Paola

    Harnessing the potential of human stem cells for modelling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. Here, we show that human iPSC–derived cortical neurons transplanted in the adult mouse cortex consistently organized in large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Finally, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modelling of cortical development, physiology, and pathogenesis.

    更新日期:2018-10-12
  • Controlled crack propagation for atomic precision handling of wafer-scale two-dimensional materials
    Science (IF 41.058) Pub Date : 2018-10-11
    Jaewoo Shim, Sang-Hoon Bae, Wei Kong, Doyoon Lee, Kuan Qiao, Daniel Nezich, Yong Ju Park, Ruike Zhao, Suresh Sundaram, Xin Li, Hanwool Yeon, Chanyeol Choi, Hyun Kum, Ruoyu Yue, Guanyu Zhou, Yunbo Ou, Kyusang Lee, Jagadeesh Moodera, Xuanhe Zhao, Jong-Hyun Ahn, Christopher Hinkle, Abdallah Ougazzaden, Jeehwan Kim

    Although flakes of two-dimensional (2D) heterostructures at micrometer scale can be formed with adhesive-tape methods, isolation of 2D flakes into monolayers is extremely time-consuming as it is a trial-and-error process. Controlling the number of 2D layers through direct growth also presents difficulty because of the high nucleation barrier on 2D materials. We demonstrate a layer-resolved 2D material splitting technique that permits the high-throughput production of multiple monolayers of wafer-scale (5 centimeter diameter) 2D materials by splitting single stacks of thick 2D materials grown on a single wafer. Wafer-scale uniformity of h-BN, WS2, WSe2, MoS2, and MoSe2 monolayers was verified by photoluminescence (PL) response and by substantial retention of electronic conductivity. We fabricated wafer-scale van der Waals heterostructures, including field-effect transistors, with single-atom thickness resolution.

    更新日期:2018-10-12
  • Methylammonium-free, high-performance and stable perovskite solar cells on a planar architecture
    Science (IF 41.058) Pub Date : 2018-10-11
    Silver-Hamill Turren-Cruz, Anders Hagfeldt, Michael Saliba

    Currently, perovskite solar cells (PSCs) with high performances >20% contain Br, causing a suboptimal bandgap, and the thermally unstable methylammonium (MA) molecule. Avoiding Br and especially MA can, therefore, result in more optimal bandgaps and stable perovskites. We show that inorganic cation tuning, using Rb and Cs, enables highly crystalline formamidinium-based perovskites without Br or MA. On a conventional, planar device architecture, using polymeric interlayers at the electron and hole transporting interface, we demonstrate an efficiency of 20.35% (stabilized), one of the highest for MA-free perovskites, with a drastically improved stability reached without the stabilizing influence of mesoporous interlayers. The perovskite is not heated beyond 100°C. Going MA-free is a new direction for perovskites that are inherently stable and compatible with tandems or flexible substrates which are the main routes commercializing PSCs.

    更新日期:2018-10-12
  • Observation of the topological Anderson insulator in disordered atomic wires
    Science (IF 41.058) Pub Date : 2018-10-11
    Eric J. Meier, Fangzhao Alex An, Alexandre Dauphin, Maria Maffei, Pietro Massignan, Taylor L. Hughes, Bryce Gadway

    Topology and disorder have a rich combined influence on quantum transport. In order to probe their interplay, we synthesized one-dimensional chiral symmetric wires with controllable disorder via spectroscopic Hamiltonian engineering, based on the laser-driven coupling of discrete momentum states of ultracold atoms. Measuring the bulk evolution of a topological indicator following a sudden quench, we observed the topological Anderson insulator phase, in which added disorder drives the band structure of a wire from topologically trivial to non-trivial. In addition, we observed the robustness of topologically non-trivial wires to weak disorder and measured the transition to a trivial phase in the presence of strong disorder. Atomic interactions in this quantum simulation platform may enable realizations of strongly interacting topological fluids.

    更新日期:2018-10-12
  • Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration
    Science (IF 41.058) Pub Date : 2018-10-09
    Tobias Gerber, Prayag Murawala, Dunja Knapp, Wouter Masselink, Maritta Schuez, Sarah Hermann, Malgorzata Gac-Santel, Sergej Nowoshilow, Jorge Kageyama, Shahryar Khattak, Joshua D. Currie, J. Gray Camp, Elly M. Tanaka, Barbara Treutlein

    Amputation of the axolotl forelimb results in the formation of a blastema, a transient tissue where progenitor cells accumulate prior to limb regeneration. However, the molecular understanding of blastema formation had previously suffered from the inability to identify and isolate blastema precursor cells in the adult tissue. Here we use a combination of Cre-loxP reporter lineage tracking and single-cell (sc) RNA-seq to molecularly track mature connective tissue (CT) cell heterogeneity and its transition to a limb blastema state. We uncover a multi-phasic molecular program where CT cell types found in the uninjured adult limb revert to a relatively homogenous progenitor state that recapitulates an embryonic limb bud-like phenotype including multipotency within the CT lineage. Together, our data illuminates molecular and cellular reprogramming during complex organ regeneration in a vertebrate.

    更新日期:2018-10-09
  • Glacial lake outburst floods as drivers of fluvial erosion in the Himalaya
    Science (IF 41.058) Pub Date : 2018-10-05
    Kristen L. Cook, Christoff Andermann, Florent Gimbert, Basanta Raj Adhikari, Niels Hovius

    Himalayan rivers are frequently hit by catastrophic floods that are caused by the failure of glacial lake and landslide dams; however, the dynamics and long-term impacts of such floods remain poorly understood. We present a comprehensive set of observations that capture the July 2016 glacial lake outburst flood (GLOF) in the Bhotekoshi/Sunkoshi River of Nepal. Seismic records of the flood provide new insights into GLOF mechanics and their ability to mobilize large boulders that otherwise prevent channel erosion. Because of this boulder mobilization, GLOF impacts far exceed those of the annual summer monsoon, and GLOFs may dominate fluvial erosion and channel-hillslope coupling many tens of kilometers downstream of glaciated areas. Long-term valley evolution in these regions may therefore be driven by GLOF frequency and magnitude, rather than by precipitation.

    更新日期:2018-10-04
  • Slab2, a comprehensive subduction zone geometry model
    Science (IF 41.058) Pub Date : 2018-10-05
    Gavin P. Hayes, Ginevra L. Moore, Daniel E. Portner, Mike Hearne, Hanna Flamme, Maria Furtney, Gregory M. Smoczyk

    Subduction zones are home to the most seismically active faults on the planet. The shallow megathrust interfaces of subduction zones host Earth’s largest earthquakes and are likely the only faults capable of magnitude 9+ ruptures. Despite these facts, our knowledge of subduction zone geometry—which likely plays a key role in determining the spatial extent and ultimately the size of subduction zone earthquakes—is incomplete. We calculated the three-dimensional geometries of all seismically active global subduction zones. The resulting model, called Slab2, provides a uniform geometrical analysis of all currently subducting slabs.

    更新日期:2018-10-04
  • Rapid change of superconductivity and electron-phonon coupling through critical doping in Bi-2212
    Science (IF 41.058) Pub Date : 2018-10-05
    Y. He, M. Hashimoto, D. Song, S.-D. Chen, J. He, I. M. Vishik, B. Moritz, D.-H. Lee, N. Nagaosa, J. Zaanen, T. P. Devereaux, Y. Yoshida, H. Eisaki, D. H. Lu, Z.-X. Shen

    Electron-boson coupling plays a key role in superconductivity for many systems. However, in copper-based high–critical temperature (Tc) superconductors, its relation to superconductivity remains controversial despite strong spectroscopic fingerprints. In this study, we used angle-resolved photoemission spectroscopy to find a pronounced correlation between the superconducting gap and the bosonic coupling strength near the Brillouin zone boundary in Bi2Sr2CaCu2O8+δ. The bosonic coupling strength rapidly increases from the overdoped Fermi liquid regime to the optimally doped strange metal, concomitant with the quadrupled superconducting gap and the doubled gap-to-Tc ratio across the pseudogap boundary. This synchronized lattice and electronic response suggests that the effects of electronic interaction and the electron-phonon coupling (EPC) reinforce each other in a positive-feedback loop upon entering the strange-metal regime, which in turn drives a stronger superconductivity.

    更新日期:2018-10-04
  • Quantum oscillations of electrical resistivity in an insulator
    Science (IF 41.058) Pub Date : 2018-10-05
    Z. Xiang, Y. Kasahara, T. Asaba, B. Lawson, C. Tinsman, Lu Chen, K. Sugimoto, S. Kawaguchi, Y. Sato, G. Li, S. Yao, Y. L. Chen, F. Iga, John Singleton, Y. Matsuda, Lu Li

    In metals, orbital motions of conduction electrons on the Fermi surface are quantized in magnetic fields, which is manifested by quantum oscillations in electrical resistivity. This Landau quantization is generally absent in insulators. Here, we report a notable exception in an insulator—ytterbium dodecaboride (YbB12). The resistivity of YbB12, which is of a much larger magnitude than the resistivity in metals, exhibits distinct quantum oscillations. These unconventional oscillations arise from the insulating bulk, even though the temperature dependence of the oscillation amplitude follows the conventional Fermi liquid theory of metals with a large effective mass. Quantum oscillations in the magnetic torque are also observed, albeit with a lighter effective mass.

    更新日期:2018-10-04
  • Quantifying hot carrier and thermal contributions in plasmonic photocatalysis
    Science (IF 41.058) Pub Date : 2018-10-05
    Linan Zhou, Dayne F. Swearer, Chao Zhang, Hossein Robatjazi, Hangqi Zhao, Luke Henderson, Liangliang Dong, Phillip Christopher, Emily A. Carter, Peter Nordlander, Naomi J. Halas

    Photocatalysis based on optically active, “plasmonic” metal nanoparticles has emerged as a promising approach to facilitate light-driven chemical conversions under far milder conditions than thermal catalysis. However, an understanding of the relation between thermal and electronic excitations has been lacking. We report the substantial light-induced reduction of the thermal activation barrier for ammonia decomposition on a plasmonic photocatalyst. We introduce the concept of a light-dependent activation barrier to account for the effect of light illumination on electronic and thermal excitations in a single unified picture. This framework provides insight into the specific role of hot carriers in plasmon-mediated photochemistry, which is critically important for designing energy-efficient plasmonic photocatalysts.

    更新日期:2018-10-04
  • Rapid Pliocene adaptive radiation of modern kangaroos
    Science (IF 41.058) Pub Date : 2018-10-05
    Aidan M. C. Couzens, Gavin J. Prideaux

    Differentiating between ancient and younger, more rapidly evolved clades is important for determining paleoenvironmental drivers of diversification. Australia possesses many aridity-adapted lineages, the origins of which have been closely linked to late Miocene continental aridification. Using dental macrowear and molar crown height measurements, spanning the past 25 million years, we show that the most iconic Australian terrestrial mammals, “true” kangaroos (Macropodini), adaptively radiated in response to mid-Pliocene grassland expansion rather than Miocene aridity. In contrast, low-crowned, short-faced kangaroos radiated into predominantly browsing niches as the late Cenozoic became more arid, contradicting the view that this was an interval of global browser decline. Our results implicate warm-to-cool climatic oscillations as a trigger for adaptive radiation and refute arguments attributing Pleistocene megafaunal extinction to aridity-forced dietary change.

    更新日期:2018-10-04
  • Urbanization and humidity shape the intensity of influenza epidemics in U.S. cities
    Science (IF 41.058) Pub Date : 2018-10-05
    Benjamin D. Dalziel, Stephen Kissler, Julia R. Gog, Cecile Viboud, Ottar N. Bjørnstad, C. Jessica E. Metcalf, Bryan T. Grenfell

    Influenza epidemics vary in intensity from year to year, driven by climatic conditions and by viral antigenic evolution. However, important spatial variation remains unexplained. Here we show predictable differences in influenza incidence among cities, driven by population size and structure. Weekly incidence data from 603 cities in the United States reveal that epidemics in smaller cities are focused on shorter periods of the influenza season, whereas in larger cities, incidence is more diffuse. Base transmission potential estimated from city-level incidence data is positively correlated with population size and with spatiotemporal organization in population density, indicating a milder response to climate forcing in metropolises. This suggests that urban centers incubate critical chains of transmission outside of peak climatic conditions, altering the spatiotemporal geometry of herd immunity.

    更新日期:2018-10-04
  • Impacts of species richness on productivity in a large-scale subtropical forest experiment
    Science (IF 41.058) Pub Date : 2018-10-05
    Yuanyuan Huang, Yuxin Chen, Nadia Castro-Izaguirre, Martin Baruffol, Matteo Brezzi, Anne Lang, Ying Li, Werner Härdtle, Goddert von Oheimb, Xuefei Yang, Xiaojuan Liu, Kequan Pei, Sabine Both, Bo Yang, David Eichenberg, Thorsten Assmann, Jürgen Bauhus, Thorsten Behrens, François Buscot, Xiao-Yong Chen, Douglas Chesters, Bing-Yang Ding, Walter Durka, Alexandra Erfmeier, Jingyun Fang, Markus Fischer, Liang-Dong Guo, Dali Guo, Jessica L. M. Gutknecht, Jin-Sheng He, Chun-Ling He, Andy Hector, Lydia Hönig, Ren-Yong Hu, Alexandra-Maria Klein, Peter Kühn, Yu Liang, Shan Li, Stefan Michalski, Michael Scherer-Lorenzen, Karsten Schmidt, Thomas Scholten, Andreas Schuldt, Xuezheng Shi, Man-Zhi Tan, Zhiyao Tang, Stefan Trogisch, Zhengwen Wang, Erik Welk, Christian Wirth, Tesfaye Wubet, Wenhua Xiang, Mingjian Yu, Xiao-Dong Yu, Jiayong Zhang, Shouren Zhang, Naili Zhang, Hong-Zhang Zhou, Chao-Dong Zhu, Li Zhu, Helge Bruelheide, Keping Ma, Pascal A. Niklaus, Bernhard Schmid

    Biodiversity experiments have shown that species loss reduces ecosystem functioning in grassland. To test whether this result can be extrapolated to forests, the main contributors to terrestrial primary productivity, requires large-scale experiments. We manipulated tree species richness by planting more than 150,000 trees in plots with 1 to 16 species. Simulating multiple extinction scenarios, we found that richness strongly increased stand-level productivity. After 8 years, 16-species mixtures had accumulated over twice the amount of carbon found in average monocultures and similar amounts as those of two commercial monocultures. Species richness effects were strongly associated with functional and phylogenetic diversity. A shrub addition treatment reduced tree productivity, but this reduction was smaller at high shrub species richness. Our results encourage multispecies afforestation strategies to restore biodiversity and mitigate climate change.

    更新日期:2018-10-04
  • The role of education interventions in improving economic rationality
    Science (IF 41.058) Pub Date : 2018-10-05
    Hyuncheol Bryant Kim, Syngjoo Choi, Booyuel Kim, Cristian Pop-Eleches

    Schooling rewards people with labor market returns and nonpecuniary benefits in other realms of life. However, there is no experimental evidence showing that education interventions improve individual economic rationality. We examine this hypothesis by studying a randomized 1-year financial support program for education in Malawi that reduced absence and dropout rates and increased scores on a qualification exam of female secondary school students. We measure economic rationality 4 years after the intervention by using lab-in-the-field experiments to create scores of consistency with utility maximization that are derived from revealed preference theory. We find that students assigned to the intervention had higher scores of rationality. The results remain robust after controlling for changes in cognitive and noncognitive skills. Our results suggest that education enhances the quality of economic decision-making.

    更新日期:2018-10-04
  • Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy
    Science (IF 41.058) Pub Date : 2018-10-05
    Leonela Amoasii, John C. W. Hildyard, Hui Li, Efrain Sanchez-Ortiz, Alex Mireault, Daniel Caballero, Rachel Harron, Thaleia-Rengina Stathopoulou, Claire Massey, John M. Shelton, Rhonda Bassel-Duby, Richard J. Piercy, Eric N. Olson

    Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

    更新日期:2018-10-04
  • Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage
    Science (IF 41.058) Pub Date : 2018-10-05
    Jung Wook Park, John K. Lee, Katherine M. Sheu, Liang Wang, Nikolas G. Balanis, Kim Nguyen, Bryan A. Smith, Chen Cheng, Brandon L. Tsai, Donghui Cheng, Jiaoti Huang, Siavash K. Kurdistani, Thomas G. Graeber, Owen N. Witte

    The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.

    更新日期:2018-10-04
  • A radiation belt of energetic protons located between Saturn and its rings
    Science (IF 41.058) Pub Date : 2018-10-05
    E. Roussos, P. Kollmann, N. Krupp, A. Kotova, L. Regoli, C. Paranicas, D. G. Mitchell, S. M. Krimigis, D. Hamilton, P. Brandt, J. Carbary, S. Christon, K. Dialynas, I. Dandouras, M. E. Hill, W. H. Ip, G. H. Jones, S. Livi, B. H. Mauk, B. Palmaerts, E. C. Roelof, A. Rymer, N. Sergis, H. T. Smith

    Saturn has a sufficiently strong dipole magnetic field to trap high-energy charged particles and form radiation belts, which have been observed outside its rings. Whether stable radiation belts exist near the planet and inward of the rings was previously unknown. The Cassini spacecraft’s Magnetosphere Imaging Instrument obtained measurements of a radiation belt that lies just above Saturn’s dense atmosphere and is decoupled from the rest of the magnetosphere by the planet’s A- to C-rings. The belt extends across the D-ring and comprises protons produced through cosmic ray albedo neutron decay and multiple charge-exchange reactions. These protons are lost to atmospheric neutrals and D-ring dust. Strong proton depletions that map onto features on the D-ring indicate a highly structured and diverse dust environment near Saturn.

    更新日期:2018-10-04
  • The low-frequency source of Saturn’s kilometric radiation
    Science (IF 41.058) Pub Date : 2018-10-05
    L. Lamy, P. Zarka, B. Cecconi, R. Prangé, W. S. Kurth, G. Hospodarsky, A. Persoon, M. Morooka, J.-E. Wahlund, G. J. Hunt

    Understanding how auroral radio emissions are produced by magnetized bodies requires in situ measurements within their source region. Saturn’s kilometric radiation (SKR) has been widely used as a remote proxy of Saturn’s magnetosphere. We present wave and plasma measurements from the Cassini spacecraft during its ring-grazing high-inclination orbits, which passed three times through the high-altitude SKR emission region. Northern dawn-side, narrow-banded radio sources were encountered at frequencies of 10 to 20 kilohertz, within regions of upward currents mapping to the ultraviolet auroral oval. The kilometric waves were produced on the extraordinary mode by the cyclotron maser instability from 6– to 12–kilo–electron volt electron beams and radiated quasi-perpendicularly to the auroral magnetic field lines. The SKR low-frequency sources appear to be strongly controlled by time-variable magnetospheric electron densities.

    更新日期:2018-10-04
  • Dust grains fall from Saturn’s D-ring into its equatorial upper atmosphere
    Science (IF 41.058) Pub Date : 2018-10-05
    D. G. Mitchell, M. E. Perry, D. C. Hamilton, J. H. Westlake, P. Kollmann, H. T. Smith, J. F. Carbary, J. H. Waite, R. Perryman, H.-W. Hsu, J.-E. Wahlund, M. W. Morooka, L. Z. Hadid, A. M. Persoon, W. S. Kurth

    The sizes of Saturn’s ring particles range from meters (boulders) to nanometers (dust). Determination of the rings’ ages depends on loss processes, including the transport of dust into Saturn’s atmosphere. During the Grand Finale orbits of the Cassini spacecraft, its instruments measured tiny dust grains that compose the innermost D-ring of Saturn. The nanometer-sized dust experiences collisions with exospheric (upper atmosphere) hydrogen and molecular hydrogen, which forces it to fall from the ring into the ionosphere and lower atmosphere. We used the Magnetospheric Imaging Instrument to detect and characterize this dust transport and also found that diffusion dominates above and near the altitude of peak ionospheric density. This mechanism results in a mass deposition into the equatorial atmosphere of ~5 kilograms per second, constraining the age of the D-ring.

    更新日期:2018-10-04
  • Chemical interactions between Saturn’s atmosphere and its rings
    Science (IF 41.058) Pub Date : 2018-10-05
    J. H. Waite, R. S. Perryman, M. E. Perry, K. E. Miller, J. Bell, T. E. Cravens, C. R. Glein, J. Grimes, M. Hedman, J. Cuzzi, T. Brockwell, B. Teolis, L. Moore, D. G. Mitchell, A. Persoon, W. S. Kurth, J.-E. Wahlund, M. Morooka, L. Z. Hadid, S. Chocron, J. Walker, A. Nagy, R. Yelle, S. Ledvina, R. Johnson, W. Tseng, O. J. Tucker, W.-H. Ip

    The Pioneer and Voyager spacecraft made close-up measurements of Saturn’s ionosphere and upper atmosphere in the 1970s and 1980s that suggested a chemical interaction between the rings and atmosphere. Exploring this interaction provides information on ring composition and the influence on Saturn’s atmosphere from infalling material. The Cassini Ion Neutral Mass Spectrometer sampled in situ the region between the D ring and Saturn during the spacecraft’s Grand Finale phase. We used these measurements to characterize the atmospheric structure and material influx from the rings. The atmospheric He/H2 ratio is 10 to 16%. Volatile compounds from the rings (methane; carbon monoxide and/or molecular nitrogen), as well as larger organic-bearing grains, are flowing inward at a rate of 4800 to 45,000 kilograms per second.

    更新日期:2018-10-04
  • In situ collection of dust grains falling from Saturn’s rings into its atmosphere
    Science (IF 41.058) Pub Date : 2018-10-05
    Hsiang-Wen Hsu, Jürgen Schmidt, Sascha Kempf, Frank Postberg, Georg Moragas-Klostermeyer, Martin Seiß, Holger Hoffmann, Marcia Burton, ShengYi Ye, William S. Kurth, Mihály Horányi, Nozair Khawaja, Frank Spahn, Daniel Schirdewahn, James O’Donoghue, Luke Moore, Jeff Cuzzi, Geraint H. Jones, Ralf Srama

    Saturn’s main rings are composed of >95% water ice, and the nature of the remaining few percent has remained unclear. The Cassini spacecraft’s traversals between Saturn and its innermost D ring allowed its cosmic dust analyzer (CDA) to collect material released from the main rings and to characterize the ring material infall into Saturn. We report the direct in situ detection of material from Saturn’s dense rings by the CDA impact mass spectrometer. Most detected grains are a few tens of nanometers in size and dynamically associated with the previously inferred “ring rain.” Silicate and water-ice grains were identified, in proportions that vary with latitude. Silicate grains constitute up to 30% of infalling grains, a higher percentage than the bulk silicate content of the rings.

    更新日期:2018-10-04
  • Saturn’s magnetic field revealed by the Cassini Grand Finale
    Science (IF 41.058) Pub Date : 2018-10-05
    Michele K. Dougherty, Hao Cao, Krishan K. Khurana, Gregory J. Hunt, Gabrielle Provan, Stephen Kellock, Marcia E. Burton, Thomas A. Burk, Emma J. Bunce, Stanley W. H. Cowley, Margaret G. Kivelson, Christopher T. Russell, David J. Southwood

    During 2017, the Cassini fluxgate magnetometer made in situ measurements of Saturn’s magnetic field at distances ~2550 ± 1290 kilometers above the 1-bar surface during 22 highly inclined Grand Finale orbits. These observations refine the extreme axisymmetry of Saturn’s internal magnetic field and show displacement of the magnetic equator northward from the planet’s physical equator. Persistent small-scale magnetic structures, corresponding to high-degree (>3) axisymmetric magnetic moments, were observed. This suggests secondary shallow dynamo action in the semiconducting region of Saturn’s interior. Some high-degree magnetic moments could arise from strong high-latitude concentrations of magnetic flux within the planet’s deep dynamo. A strong field-aligned current (FAC) system is located between Saturn and the inner edge of its D-ring, with strength comparable to the high-latitude auroral FACs.

    更新日期:2018-10-04
  • Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex
    Science (IF 41.058) Pub Date : 2018-10-05
    Xiaofeng Qi, Philip Schmiege, Elias Coutavas, Xiaochun Li

    Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo–electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.

    更新日期:2018-10-04
  • Structural basis of the nucleosome transition during RNA polymerase II passage
    Science (IF 41.058) Pub Date : 2018-10-04
    Tomoya Kujirai, Haruhiko Ehara, Yuka Fujino, Mikako Shirouzu, Shun-ichi Sekine, Hitoshi Kurumizaka

    Genomic DNA forms chromatin, in which the nucleosome is the repeating unit. The mechanism by which RNA polymerase II (RNAPII) transcribes the nucleosomal DNA remains unclear. Here we report the cryo–electron microscopy structures of RNAPII-nucleosome complexes, in which RNAPII pauses at the superhelical locations, SHL(-6), SHL(-5), SHL(-2), and SHL(-1), of the nucleosome. RNAPII pauses at the major histone-DNA contact sites, and the nucleosome interactions with the RNAPII subunits stabilize the pause. These structures reveal snapshots of nucleosomal transcription, where RNAPII gradually tears DNA from the histone surface, while preserving the histone octamer. Interestingly, the nucleosomes in the SHL(-1) complexes are bound to a “foreign” DNA segment, which might explain the histone transfer mechanism. These results provide the foundations for understanding chromatin transcription and epigenetic regulation.

    更新日期:2018-10-04
  • Reversible self-assembly of superstructured networks
    Science (IF 41.058) Pub Date : 2018-10-04
    Ronit Freeman, Ming Han, Zaida Álvarez, Jacob A. Lewis, James R. Wester, Nicholas Stephanopoulos, Mark T. McClendon, Cheyenne Lynsky, Jacqueline M. Godbe, Hussain Sangji, Erik Luijten, Samuel I. Stupp

    Soft structures in nature such as protein assemblies can organize reversibly into functional and often hierarchical architectures through noncovalent interactions. Molecularly encoding this dynamic capability in synthetic materials has remained an elusive goal. We report on hydrogels of peptide-DNA conjugates and peptides that organize into superstructures of intertwined filaments that disassemble upon the addition of molecules or changes in charge density. Experiments and simulations demonstrate that this response requires large scale spatial redistribution of molecules directed by strong noncovalent interactions among them. Simulations also suggest that the chemically reversible structures can only occur within a limited range of supramolecular cohesive energies. Storage moduli of the hydrogels change reversibly as superstructures form and disappear, as does the phenotype of neural cells in contact with these materials.

    更新日期:2018-10-04
  • An autoimmune disease variant of IgG1 modulates B cell activation and differentiation
    Science (IF 41.058) Pub Date : 2018-10-04
    Xiangjun Chen, Sun Xiao-Lin, Wei Yang, Bing Yang, Xiaozhen Zhao, Shuting Chen, Lili He, Hui Chen, Changmei Yang, Le Xiao, Zai Chang, Jianping Guo, Jing He, Fuping Zhang, Fang Zheng, Zhibin Hu, Zhiyong Yang, Jizhong Lou, Wenjie Zheng, Hai Qi, Chenqi Xu, Hong Zhang, Hongying Shan, Xujie Zhou, Qingwen Wang, Yi Shi, Luhua Lai, Zhanguo Li, Wanli Liu

    The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here, we identify a variant of human IgG1 (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog G390R knock-in mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer Grb2 dwell times in immunological synapses, leading to hyper-Grb2-Btk signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.

    更新日期:2018-10-04
  • Ancient lowland Maya complexity as revealed by airborne laser scanning of northern Guatemala
    Science (IF 41.058) Pub Date : 2018-09-28
    Marcello A. Canuto, Francisco Estrada-Belli, Thomas G. Garrison, Stephen D. Houston, Mary Jane Acuña, Milan Kováč, Damien Marken, Philippe Nondédéo, Luke Auld-Thomas, Cyril Castanet, David Chatelain, Carlos R. Chiriboga, Tomáš Drápela, Tibor Lieskovský, Alexandre Tokovinine, Antolín Velasquez, Juan C. Fernández-Díaz, Ramesh Shrestha

    Lowland Maya civilization flourished in the tropical region of the Yucatan peninsula and environs for more than 2500 years (~1000 BCE to 1500 CE). Known for its sophistication in writing, art, architecture, astronomy, and mathematics, Maya civilization still poses questions about the nature of its cities and surrounding populations because of its location in an inaccessible forest. In 2016, an aerial lidar survey across 2144 square kilometers of northern Guatemala mapped natural terrain and archaeological features over several distinct areas. We present results from these data, revealing interconnected urban settlement and landscapes with extensive infrastructural development. Studied through a joint international effort of interdisciplinary teams sharing protocols, this lidar survey compels a reevaluation of Maya demography, agriculture, and political economy and suggests future avenues of field research.

    更新日期:2018-09-28
  • Chromatin plasticity: A versatile landscape that underlies cell fate and identity
    Science (IF 41.058) Pub Date : 2018-09-28
    Tejas Yadav, Jean-Pierre Quivy, Geneviève Almouzni

    During development and throughout life, a variety of specialized cells must be generated to ensure the proper function of each tissue and organ. Chromatin plays a key role in determining cellular state, whether totipotent, pluripotent, multipotent, or differentiated. We highlight chromatin dynamics involved in the generation of pluripotent stem cells as well as their influence on cell fate decision and reprogramming. We focus on the capacity of histone variants, chaperones, modifications, and heterochromatin factors to influence cell identity and its plasticity. Recent technological advances have provided tools to elucidate the underlying chromatin dynamics for a better understanding of normal development and pathological conditions, with avenues for potential therapeutic application.

    更新日期:2018-09-28
  • Dynamic DNA methylation: In the right place at the right time
    Science (IF 41.058) Pub Date : 2018-09-28
    Chongyuan Luo, Petra Hajkova, Joseph R. Ecker

    The classical model of cytosine DNA methylation (the presence of 5-methylcytosine, 5mC) regulation depicts this covalent modification as a stable repressive regulator of promoter activity. However, whole-genome analysis of 5mC reveals widespread tissue- and cell type–specific patterns and pervasive dynamics during mammalian development. Here we review recent findings that delineate 5mC functions in developmental stages and diverse genomic compartments as well as discuss the molecular mechanisms that connect transcriptional regulation and 5mC. Beyond the newly appreciated dynamics, regulatory roles for 5mC have been suggested in new biological contexts, such as learning and memory or aging. The use of new single-cell measurement techniques and precise editing tools will enable functional analyses of 5mC in gene expression, clarifying its role in various biological processes.

    更新日期:2018-09-28
  • Developmental enhancers and chromosome topology
    Science (IF 41.058) Pub Date : 2018-09-28
    Eileen E. M. Furlong, Michael Levine

    Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal expression. Such enhancers can map quite far—one megabase or more—from the genes they regulate. How remote enhancers relay regulatory information to their target promoters is one of the central mysteries of genome organization and function. A variety of contrasting mechanisms have been proposed over the years, including enhancer tracking, linking, looping, and mobilization to transcription factories. We argue that extreme versions of these mechanisms cannot account for the transcriptional dynamics and precision seen in living cells, tissues, and embryos. We describe emerging evidence for dynamic three-dimensional hubs that combine different elements of the classical models.

    更新日期:2018-09-28
  • RNA modifications modulate gene expression during development
    Science (IF 41.058) Pub Date : 2018-09-28
    Michaela Frye, Bryan T. Harada, Mikaela Behm, Chuan He

    RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programs. They affect diverse eukaryotic biological processes, and the correct deposition of many of these modifications is required for normal development. Messenger RNA (mRNA) modifications regulate various aspects of mRNA metabolism. For example, N6-methyladenosine (m6A) affects the translation and stability of the modified transcripts, thus providing a mechanism to coordinate the regulation of groups of transcripts during cell state maintenance and transition. Similarly, some modifications in transfer RNAs are essential for RNA structure and function. Others are deposited in response to external cues and adapt global protein synthesis and gene-specific translational accordingly and thereby facilitate proper development.

    更新日期:2018-09-28
  • Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom
    Science (IF 41.058) Pub Date : 2018-09-28
    John K. Brunson, Shaun M. K. McKinnie, Jonathan R. Chekan, John P. McCrow, Zachary D. Miles, Erin M. Bertrand, Vincent A. Bielinski, Hanna Luhavaya, Miroslav Oborník, G. Jason Smith, David A. Hutchins, Andrew E. Allen, Bradley S. Moore

    Oceanic harmful algal blooms of Pseudo-nitzschia diatoms produce the potent mammalian neurotoxin domoic acid (DA). Despite decades of research, the molecular basis for its biosynthesis is not known. By using growth conditions known to induce DA production in Pseudo-nitzschia multiseries, we implemented transcriptome sequencing in order to identify DA biosynthesis genes that colocalize in a genomic four-gene cluster. We biochemically investigated the recombinant DA biosynthetic enzymes and linked their mechanisms to the construction of DA’s diagnostic pyrrolidine skeleton, establishing a model for DA biosynthesis. Knowledge of the genetic basis for toxin production provides an orthogonal approach to bloom monitoring and enables study of environmental factors that drive oceanic DA production.

    更新日期:2018-09-28
  • Ultrafast electro-optic light with subcycle control
    Science (IF 41.058) Pub Date : 2018-09-28
    David R. Carlson, Daniel D. Hickstein, Wei Zhang, Andrew J. Metcalf, Franklyn Quinlan, Scott A. Diddams, Scott B. Papp

    Light sources that are ultrafast and ultrastable enable applications like timing with subfemtosecond precision and control of quantum and classical systems. Mode-locked lasers have often given access to this regime, by using their high pulse energies. We demonstrate an adaptable method for ultrastable control of low-energy femtosecond pulses based on common electro-optic modulation of a continuous-wave laser light source. We show that we can obtain 100-picojoule pulse trains at rates up to 30 gigahertz and demonstrate sub–optical cycle timing precision and useful output spectra spanning the near infrared. Our source enters the few-cycle ultrafast regime without mode locking, and its high speed provides access to nonlinear measurements and rapid transients.

    更新日期:2018-09-28
  • Interrupted carbonyl-olefin metathesis via oxygen atom transfer
    Science (IF 41.058) Pub Date : 2018-09-28
    Jacob R. Ludwig, Rebecca B. Watson, Daniel J. Nasrallah, Joseph B. Gianino, Paul M. Zimmerman, Ren A. Wiscons, Corinna S. Schindler

    Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid–catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

    更新日期:2018-09-28
  • Arylsulfonylacetamides as bifunctional reagents for alkene aminoarylation
    Science (IF 41.058) Pub Date : 2018-09-28
    Timothy M. Monos, Rory C. McAtee, Corey R. J. Stephenson

    Alkene aminoarylation with a single, bifunctional reagent is a concise synthetic strategy. We report a catalytic protocol for the addition of arylsulfonylacetamides across electron-rich alkenes with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity to provide 2,2-diarylethylamines. In this process, single-electron alkene oxidation enables carbon-nitrogen bond formation to provide a key benzylic radical poised for a Smiles-Truce 1,5-aryl shift. This reaction is redox-neutral, exhibits broad functional group compatibility, and occurs at room temperature with loss of sulfur dioxide. As this process is driven by visible light, uses readily available starting materials, and demonstrates convergent synthesis, it is well suited for use in a variety of synthetic endeavors.

    更新日期:2018-09-28
  • Predicting global killer whale population collapse from PCB pollution
    Science (IF 41.058) Pub Date : 2018-09-28
    Jean-Pierre Desforges, Ailsa Hall, Bernie McConnell, Aqqalu Rosing-Asvid, Jonathan L. Barber, Andrew Brownlow, Sylvain De Guise, Igor Eulaers, Paul D. Jepson, Robert J. Letcher, Milton Levin, Peter S. Ross, Filipa Samarra, Gísli Víkingson, Christian Sonne, Rune Dietz

    Killer whales (Orcinus orca) are among the most highly polychlorinated biphenyl (PCB)–contaminated mammals in the world, raising concern about the health consequences of current PCB exposures. Using an individual-based model framework and globally available data on PCB concentrations in killer whale tissues, we show that PCB-mediated effects on reproduction and immune function threaten the long-term viability of >50% of the world’s killer whale populations. PCB-mediated effects over the coming 100 years predicted that killer whale populations near industrialized regions, and those feeding at high trophic levels regardless of location, are at high risk of population collapse. Despite a near-global ban of PCBs more than 30 years ago, the world’s killer whales illustrate the troubling persistence of this chemical class.

    更新日期:2018-09-28
  • An axial Hox code controls tissue segmentation and body patterning in Nematostella vectensis
    Science (IF 41.058) Pub Date : 2018-09-28
    Shuonan He, Florencia del Viso, Cheng-Yi Chen, Aissam Ikmi, Amanda E. Kroesen, Matthew C. Gibson

    Hox genes encode conserved developmental transcription factors that govern anterior-posterior (A-P) pattering in diverse bilaterian animals, which display bilateral symmetry. Although Hox genes are also present within Cnidaria, these simple animals lack a definitive A-P axis, leaving it unclear how and when a functionally integrated Hox code arose during evolution. We used short hairpin RNA (shRNA)–mediated knockdown and CRISPR-Cas9 mutagenesis to demonstrate that a Hox-Gbx network controls radial segmentation of the larval endoderm during development of the sea anemone Nematostella vectensis. Loss of Hox-Gbx activity also elicits marked defects in tentacle patterning along the directive (orthogonal) axis of primary polyps. On the basis of our results, we propose that an axial Hox code may have controlled body patterning and tissue segmentation before the evolution of the bilaterian A-P axis.

    更新日期:2018-09-28
  • Joint profiling of chromatin accessibility and gene expression in thousands of single cells
    Science (IF 41.058) Pub Date : 2018-09-28
    Junyue Cao, Darren A. Cusanovich, Vijay Ramani, Delasa Aghamirzaie, Hannah A. Pliner, Andrew J. Hill, Riza M. Daza, Jose L. McFaline-Figueroa, Jonathan S. Packer, Lena Christiansen, Frank J. Steemers, Andrew C. Adey, Cole Trapnell, Jay Shendure

    Although we can increasingly measure transcription, chromatin, methylation, and other aspects of molecular biology at single-cell resolution, most assays survey only one aspect of cellular biology. Here we describe sci-CAR, a combinatorial indexing–based coassay that jointly profiles chromatin accessibility and mRNA (CAR) in each of thousands of single cells. As a proof of concept, we apply sci-CAR to 4825 cells, including a time series of dexamethasone treatment, as well as to 11,296 cells from the adult mouse kidney. With the resulting data, we compare the pseudotemporal dynamics of chromatin accessibility and gene expression, reconstruct the chromatin accessibility profiles of cell types defined by RNA profiles, and link cis-regulatory sites to their target genes on the basis of the covariance of chromatin accessibility and transcription across large numbers of single cells.

    更新日期:2018-09-28
  • A mechanism for preventing asymmetric histone segregation onto replicating DNA strands
    Science (IF 41.058) Pub Date : 2018-09-28
    Chuanhe Yu, Haiyun Gan, Albert Serra-Cardona, Lin Zhang, Songlin Gan, Sushma Sharma, Erik Johansson, Andrei Chabes, Rui-Ming Xu, Zhiguo Zhang

    How parental histone (H3-H4)2 tetramers, the primary carriers of epigenetic modifications, are transferred onto leading and lagging strands of DNA replication forks for epigenetic inheritance remains elusive. Here we show that parental (H3-H4)2 tetramers are assembled into nucleosomes onto both leading and lagging strands, with a slight preference for lagging strands. The lagging-strand preference increases markedly in budding yeast cells lacking Dpb3 and Dpb4, two subunits of the leading strand DNA polymerase, Pol ε, owing to the impairment of parental (H3-H4)2 transfer to leading strands. Dpb3-Dpb4 binds H3-H4 in vitro and participates in the inheritance of heterochromatin. These results indicate that different proteins facilitate the transfer of parental (H3-H4)2 onto leading versus lagging strands and that Dbp3-Dpb4 plays an important role in this poorly understood process.

    更新日期:2018-09-28
  • MCM2 promotes symmetric inheritance of modified histones during DNA replication
    Science (IF 41.058) Pub Date : 2018-09-28
    Nataliya Petryk, Maria Dalby, Alice Wenger, Caroline B. Stromme, Anne Strandsby, Robin Andersson, Anja Groth

    During genome replication, parental histones are recycled to newly replicated DNA with their posttranslational modifications (PTMs). Whether sister chromatids inherit modified histones evenly remains unknown. We measured histone PTM partition to sister chromatids in embryonic stem cells. We found that parental histones H3-H4 segregate to both daughter DNA strands with a weak leading-strand bias, skewing partition at topologically associating domain (TAD) borders and enhancers proximal to replication initiation zones. Segregation of parental histones to the leading strand increased markedly in cells with histone-binding mutations in MCM2, part of the replicative helicase, exacerbating histone PTM sister chromatid asymmetry. This work reveals how histones are inherited to sister chromatids and identifies a mechanism by which the replication machinery ensures symmetric cell division.

    更新日期:2018-09-28
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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