Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016 Science (IF 41.058) Pub Date : 2018-09-21 Hawre Jalal, Jeanine M. Buchanich, Mark S. Roberts, Lauren C. Balmert, Kun Zhang, Donald S. Burke
Better understanding of the dynamics of the current U.S. overdose epidemic may aid in the development of more effective prevention and control strategies. We analyzed records of 599,255 deaths from 1979 through 2016 from the National Vital Statistics System in which accidental drug poisoning was identified as the main cause of death. By examining all available data on accidental poisoning deaths back to 1979 and showing that the overall 38-year curve is exponential, we provide evidence that the current wave of opioid overdose deaths (due to prescription opioids, heroin, and fentanyl) may just be the latest manifestation of a more fundamental longer-term process. The 38+ year smooth exponential curve of total U.S. annual accidental drug poisoning deaths is a composite of multiple distinctive subepidemics of different drugs (primarily prescription opioids, heroin, methadone, synthetic opioids, cocaine, and methamphetamine), each with its own specific demographic and geographic characteristics.
Reconfigurable system for automated optimization of diverse chemical reactions Science (IF 41.058) Pub Date : 2018-09-21 Anne-Catherine Bédard, Andrea Adamo, Kosi C. Aroh, M. Grace Russell, Aaron A. Bedermann, Jeremy Torosian, Brian Yue, Klavs F. Jensen, Timothy F. Jamison
Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (SNAr), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus.
Suppressing spatiotemporal lasing instabilities with wave-chaotic microcavities Science (IF 41.058) Pub Date : 2018-09-21 Stefan Bittner, Stefano Guazzotti, Yongquan Zeng, Xiaonan Hu, Hasan Yılmaz, Kyungduk Kim, Sang Soon Oh, Qi Jie Wang, Ortwin Hess, Hui Cao
Spatiotemporal instabilities are widespread phenomena resulting from complexity and nonlinearity. In broad-area edge-emitting semiconductor lasers, the nonlinear interactions of multiple spatial modes with the active medium can result in filamentation and spatiotemporal chaos. These instabilities degrade the laser performance and are extremely challenging to control. We demonstrate a powerful approach to suppress spatiotemporal instabilities using wave-chaotic or disordered cavities. The interference of many propagating waves with random phases in such cavities disrupts the formation of self-organized structures such as filaments, resulting in stable lasing dynamics. Our method provides a general and robust scheme to prevent the formation and growth of nonlinear instabilities for a large variety of high-power lasers.
Asteroseismic detection of latitudinal differential rotation in 13 Sun-like stars Science (IF 41.058) Pub Date : 2018-09-21 O. Benomar, M. Bazot, M. B. Nielsen, L. Gizon, T. Sekii, M. Takata, H. Hotta, S. Hanasoge, K. R. Sreenivasan, J. Christensen-Dalsgaard
The differentially rotating outer layers of stars are thought to play a role in driving their magnetic activity, but the underlying mechanisms that generate and sustain differential rotation are poorly understood. We report the measurement using asteroseismology of latitudinal differential rotation in the convection zones of 40 Sun-like stars. For the most significant detections, the stars’ equators rotate approximately twice as fast as their midlatitudes. The latitudinal shear inferred from asteroseismology is much larger than predictions from numerical simulations.
Unlocking P(V): Reagents for chiral phosphorothioate synthesis Science (IF 41.058) Pub Date : 2018-09-21 Kyle W. Knouse, Justine N. deGruyter, Michael A. Schmidt, Bin Zheng, Julien C. Vantourout, Cian Kingston, Stephen E. Mercer, Ivar M. Mcdonald, Richard E. Olson, Ye Zhu, Chao Hang, Jason Zhu, Changxia Yuan, Qinggang Wang, Peter Park, Martin D. Eastgate, Phil S. Baran
Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.
Measurement of a superconducting qubit with a microwave photon counter Science (IF 41.058) Pub Date : 2018-09-21 A. Opremcak, I. V. Pechenezhskiy, C. Howington, B. G. Christensen, M. A. Beck, E. Leonard, J. Suttle, C. Wilen, K. N. Nesterov, G. J. Ribeill, T. Thorbeck, F. Schlenker, M. G. Vavilov, B. L. T. Plourde, R. McDermott
Fast, high-fidelity measurement is a key ingredient for quantum error correction. Conventional approaches to the measurement of superconducting qubits, involving linear amplification of a microwave probe tone followed by heterodyne detection at room temperature, do not scale well to large system sizes. We introduce an approach to measurement based on a microwave photon counter demonstrating raw single-shot measurement fidelity of 92%. Moreover, the intrinsic damping of the photon counter is used to extract the energy released by the measurement process, allowing repeated high-fidelity quantum nondemolition measurements. Our scheme provides access to the classical outcome of projective quantum measurement at the millikelvin stage and could form the basis for a scalable quantum-to-classical interface.
Self-assembly of lattices with high structural complexity from a geometrically simple molecule Science (IF 41.058) Pub Date : 2018-09-21 Hiroshi Yamagishi, Hiroshi Sato, Akihiro Hori, Yohei Sato, Ryotaro Matsuda, Kenichi Kato, Takuzo Aida
Here we report an anomalous porous molecular crystal built of C–H···N-bonded double-layered roof-floor components and wall components of a segregatively interdigitated architecture. This complicated porous structure consists of only one type of fully aromatic multijoint molecule carrying three identical dipyridylphenyl wedges. Despite its high symmetry, this molecule accomplishes difficult tasks by using two of its three wedges for roof-floor formation and using its other wedge for wall formation. Although a C–H···N bond is extremely labile, the porous crystal maintains its porosity until thermal breakdown of the C–H···N bonds at 202°C occurs, affording a nonporous polymorph. Though this nonporous crystal survives even at 325°C, it can retrieve the parent porosity under acetonitrile vapor. These findings show how one can translate simplicity into ultrahigh complexity.
Ancient steroids establish the Ediacaran fossil Dickinsonia as one of the earliest animals Science (IF 41.058) Pub Date : 2018-09-21 Ilya Bobrovskiy, Janet M. Hope, Andrey Ivantsov, Benjamin J. Nettersheim, Christian Hallmann, Jochen J. Brocks
The enigmatic Ediacara biota (571 million to 541 million years ago) represents the first macroscopic complex organisms in the geological record and may hold the key to our understanding of the origin of animals. Ediacaran macrofossils are as “strange as life on another planet” and have evaded taxonomic classification, with interpretations ranging from marine animals or giant single-celled protists to terrestrial lichens. Here, we show that lipid biomarkers extracted from organically preserved Ediacaran macrofossils unambiguously clarify their phylogeny. Dickinsonia and its relatives solely produced cholesteroids, a hallmark of animals. Our results make these iconic members of the Ediacara biota the oldest confirmed macroscopic animals in the rock record, indicating that the appearance of the Ediacara biota was indeed a prelude to the Cambrian explosion of animal life.
Fossils reveal the complex evolutionary history of the mammalian regionalized spine Science (IF 41.058) Pub Date : 2018-09-21 K. E. Jones, K. D. Angielczyk, P. D. Polly, J. J. Head, V. Fernandez, J. K. Lungmus, S. Tulga, S. E. Pierce
A unique characteristic of mammals is a vertebral column with anatomically distinct regions, but when and how this trait evolved remains unknown. We reconstructed vertebral regions and their morphological disparity in the extinct forerunners of mammals, the nonmammalian synapsids, to elucidate the evolution of mammalian axial differentiation. Mapping patterns of regionalization and disparity (heterogeneity) across amniotes reveals that both traits increased during synapsid evolution. However, the onset of regionalization predates increased heterogeneity. On the basis of inferred homology patterns, we propose a “pectoral-first” hypothesis for region acquisition, whereby evolutionary shifts in forelimb function in nonmammalian therapsids drove increasing vertebral modularity prior to differentiation of the vertebral column for specialized functions in mammals.
Programmable protein circuits in living cells Science (IF 41.058) Pub Date : 2018-09-21 Xiaojing J. Gao, Lucy S. Chong, Matthew S. Kim, Michael B. Elowitz
Synthetic protein-level circuits could enable engineering of powerful new cellular behaviors. Rational protein circuit design would be facilitated by a composable protein-protein regulation system in which individual protein components can regulate one another to create a variety of different circuit architectures. In this study, we show that engineered viral proteases can function as composable protein components, which can together implement a broad variety of circuit-level functions in mammalian cells. In this system, termed CHOMP (circuits of hacked orthogonal modular proteases), input proteases dock with and cleave target proteases to inhibit their function. These components can be connected to generate regulatory cascades, binary logic gates, and dynamic analog signal-processing functions. To demonstrate the utility of this system, we rationally designed a circuit that induces cell death in response to upstream activators of the Ras oncogene. Because CHOMP circuits can perform complex functions yet be encoded as single transcripts and delivered without genomic integration, they offer a scalable platform to facilitate protein circuit engineering for biotechnological applications.
Engineered CRISPR-Cas9 nuclease with expanded targeting space Science (IF 41.058) Pub Date : 2018-09-21 Hiroshi Nishimasu, Xi Shi, Soh Ishiguro, Linyi Gao, Seiichi Hirano, Sae Okazaki, Taichi Noda, Omar O. Abudayyeh, Jonathan S. Gootenberg, Hideto Mori, Seiya Oura, Benjamin Holmes, Mamoru Tanaka, Motoaki Seki, Hisato Hirano, Hiroyuki Aburatani, Ryuichiro Ishitani, Masahito Ikawa, Nozomu Yachie, Feng Zhang, Osamu Nureki
The RNA-guided endonuclease Cas9 cleaves its target DNA and is a powerful genome-editing tool. However, the widely used Streptococcus pyogenes Cas9 enzyme (SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting the targetable genomic loci. Here, we report a rationally engineered SpCas9 variant (SpCas9-NG) that can recognize relaxed NG PAMs. The crystal structure revealed that the loss of the base-specific interaction with the third nucleobase is compensated by newly introduced non–base-specific interactions, thereby enabling the NG PAM recognition. We showed that SpCas9-NG induces indels at endogenous target sites bearing NG PAMs in human cells. Furthermore, we found that the fusion of SpCas9-NG and the activation-induced cytidine deaminase (AID) mediates the C-to-T conversion at target sites with NG PAMs in human cells.
Bacterial antagonism in host-associated microbial communities Science (IF 41.058) Pub Date : 2018-09-21 Leonor García-Bayona, Laurie E. Comstock
Antagonistic interactions are abundant in microbial communities and contribute not only to the composition and relative proportions of their members but also to the longer-term stability of a community. This Review will largely focus on bacterial antagonism mediated by ribosomally synthesized peptides and proteins produced by members of host-associated microbial communities. We discuss recent findings on their diversity, functions, and ecological impacts. These systems play key roles in ecosystem defense, pathogen invasion, spatial segregation, and diversity but also confer indirect gains to the aggressor from products released by killed cells. Investigations into antagonistic bacterial interactions are important for our understanding of how the microbiota establish within hosts, influence health and disease, and offer insights into potential translational applications.
The periodic coloration in birds forms through a prepattern of somite origin Science (IF 41.058) Pub Date : 2018-09-21 Nicolas Haupaix, Camille Curantz, Richard Bailleul, Samantha Beck, Annie Robic, Marie Manceau
The periodic stripes and spots that often adorn animals’ coats have been largely viewed as self-organizing patterns, forming through dynamics such as Turing’s reaction-diffusion within the developing skin. Whether preexisting positional information also contributes to the periodicity and orientation of these patterns has, however, remained unclear. We used natural variation in colored stripes of juvenile galliform birds to show that stripes form in a two-step process. Autonomous signaling from the somite sets stripe position by forming a composite prepattern marked by the expression profile of agouti. Subsequently, agouti regulates stripe width through dose-dependent control of local pigment production. These results reveal that early developmental landmarks can shape periodic patterns upstream of late local dynamics, and thus constrain their evolution.
A gut-brain neural circuit for nutrient sensory transduction Science (IF 41.058) Pub Date : 2018-09-21 Melanie Maya Kaelberer, Kelly L. Buchanan, Marguerita E. Klein, Bradley B. Barth, Marcia M. Montoya, Xiling Shen, Diego V. Bohórquez
The brain is thought to sense gut stimuli only via the passive release of hormones. This is because no connection has been described between the vagus and the putative gut epithelial sensor cell—the enteroendocrine cell. However, these electrically excitable cells contain several features of epithelial transducers. Using a mouse model, we found that enteroendocrine cells synapse with vagal neurons to transduce gut luminal signals in milliseconds by using glutamate as a neurotransmitter. These synaptically connected enteroendocrine cells are referred to henceforth as neuropod cells. The neuroepithelial circuit they form connects the intestinal lumen to the brainstem in one synapse, opening a physical conduit for the brain to sense gut stimuli with the temporal precision and topographical resolution of a synapse.
Challenges for commercializing perovskite solar cells Science (IF 41.058) Pub Date : 2018-09-21 Yaoguang Rong, Yue Hu, Anyi Mei, Hairen Tan, Makhsud I. Saidaminov, Sang Il Seok, Michael D. McGehee, Edward H. Sargent, Hongwei Han
Perovskite solar cells (PSCs) have witnessed rapidly rising power conversion efficiencies, together with advances in stability and upscaling. Despite these advances, their limited stability and need to prove upscaling remain crucial hurdles on the path to commercialization. We summarize recent advances toward commercially viable PSCs and discuss challenges that remain. We expound the development of standardized protocols to distinguish intrinsic and extrinsic degradation factors in perovskites. We review accelerated aging tests in both cells and modules and discuss the prediction of lifetimes on the basis of degradation kinetics. Mature photovoltaic solutions, which have demonstrated excellent long-term stability in field applications, offer the perovskite community valuable insights into clearing the hurdles to commercialization.
Cellular checkpoint control using programmable sequential logic Science (IF 41.058) Pub Date : 2018-09-21 Lauren B. Andrews, Alec A. K. Nielsen, Christopher A. Voigt
Biological processes that require orderly progression, such as growth and differentiation, proceed via regulatory checkpoints where the cell waits for signals before continuing to the next state. Implementing such control would allow genetic engineers to divide complex tasks into stages. We present genetic circuits that encode sequential logic to instruct Escherichia coli to proceed through a linear or cyclical sequence of states. These are built with 11 set-reset latches, designed with repressor-based NOR gates, which can connect to each other and sensors. The performance of circuits with up to three latches and four sensors, including a gated D latch, closely match predictions made by using nonlinear dynamics. Checkpoint control is demonstrated by switching cells between multiple circuit states in response to external signals over days.
Photon-mediated interactions between quantum emitters in a diamond nanocavity Science (IF 41.058) Pub Date : 2018-09-20 R. E. Evans, M. K. Bhaskar, D. D. Sukachev, C. T. Nguyen, A. Sipahigil, M. J. Burek, B. Machielse, G. H. Zhang, A. S. Zibrov, E. Bielejec, H. Park, M. Lončar, M. D. Lukin
Photon-mediated interactions between quantum systems are essential for realizing quantum networks and scalable quantum information processing. We demonstrate such interactions between pairs of silicon-vacancy (SiV) color centers coupled to a diamond nanophotonic cavity. When the optical transitions of the two color centers are tuned into resonance, the coupling to the common cavity mode results in a coherent interaction between them, leading to spectrally-resolved superradiant and subradiant states. We use the electronic spin degrees of freedom of the SiV centers to control these optically-mediated interactions. Such controlled interactions will be crucial in developing cavity-mediated quantum gates between spin qubits and for realizing scalable quantum network nodes.
Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization Science (IF 41.058) Pub Date : 2018-09-20 Shibin Zhao, Tobias Gensch, Benjamin Murray, Zachary L. Niemeyer, Matthew S. Sigman, Mark R. Biscoe
Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Herein we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.
Generation of human oogonia from induced pluripotent stem cells in vitro Science (IF 41.058) Pub Date : 2018-09-20 Chika Yamashiro, Kotaro Sasaki, Yukihiro Yabuta, Yoji Kojima, Tomonori Nakamura, Ikuhiro Okamoto, Shihori Yokobayashi, Yusuke Murase, Yukiko Ishikura, Kenjiro Shirane, Hiroyuki Sasaki, Takuya Yamamoto, Mitinori Saitou
Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell-like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (~four months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming, i.e., genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs, and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.
A tailless aerial robotic flapper reveals that flies use torque coupling in rapid banked turns Science (IF 41.058) Pub Date : 2018-09-14 Matěj Karásek, Florian T. Muijres, Christophe De Wagter, Bart D. W. Remes, Guido C. H. E. de Croon
Insects are among the most agile natural flyers. Hypotheses on their flight control cannot always be validated by experiments with animals or tethered robots. To this end, we developed a programmable and agile autonomous free-flying robot controlled through bio-inspired motion changes of its flapping wings. Despite being 55 times the size of a fruit fly, the robot can accurately mimic the rapid escape maneuvers of flies, including a correcting yaw rotation toward the escape heading. Because the robot’s yaw control was turned off, we showed that these yaw rotations result from passive, translation-induced aerodynamic coupling between the yaw torque and the roll and pitch torques produced throughout the maneuver. The robot enables new methods for studying animal flight, and its flight characteristics allow for real-world flight missions.
Organic and solution-processed tandem solar cells with 17.3% efficiency Science (IF 41.058) Pub Date : 2018-09-14 Lingxian Meng, Yamin Zhang, Xiangjian Wan, Chenxi Li, Xin Zhang, Yanbo Wang, Xin Ke, Zuo Xiao, Liming Ding, Ruoxi Xia, Hin-Lap Yip, Yong Cao, Yongsheng Chen
Although organic photovoltaic (OPV) cells have many advantages, their performance still lags far behind that of other photovoltaic platforms. A fundamental reason for their low performance is the low charge mobility of organic materials, leading to a limit on the active-layer thickness and efficient light absorption. In this work, guided by a semi-empirical model analysis and using the tandem cell strategy to overcome such issues, and taking advantage of the high diversity and easily tunable band structure of organic materials, a record and certified 17.29% power conversion efficiency for a two-terminal monolithic solution-processed tandem OPV is achieved.
A designed heme-[4Fe-4S] metalloenzyme catalyzes sulfite reduction like the native enzyme Science (IF 41.058) Pub Date : 2018-09-14 Evan N. Mirts, Igor D. Petrik, Parisa Hosseinzadeh, Mark J. Nilges, Yi Lu
Multielectron redox reactions often require multicofactor metalloenzymes to facilitate coupled electron and proton movement, but it is challenging to design artificial enzymes to catalyze these important reactions, owing to their structural and functional complexity. We report a designed heteronuclear heme-[4Fe-4S] cofactor in cytochrome c peroxidase as a structural and functional model of the enzyme sulfite reductase. The initial model exhibits spectroscopic and ligand-binding properties of the native enzyme, and sulfite reduction activity was improved—through rational tuning of the secondary sphere interactions around the [4Fe-4S] and the substrate-binding sites—to be close to that of the native enzyme. By offering insight into the requirements for a demanding six-electron, seven-proton reaction that has so far eluded synthetic catalysts, this study provides strategies for designing highly functional multicofactor artificial enzymes.
Quantum entanglement of the spin and orbital angular momentum of photons using metamaterials Science (IF 41.058) Pub Date : 2018-09-14 Tomer Stav, Arkady Faerman, Elhanan Maguid, Dikla Oren, Vladimir Kleiner, Erez Hasman, Mordechai Segev
Metamaterials constructed from deep subwavelength building blocks have been used to demonstrate phenomena ranging from negative refractive index and ε-near-zero to cloaking, emulations of general relativity, and superresolution imaging. More recently, metamaterials have been suggested as a new platform for quantum optics. We present the use of a dielectric metasurface to generate entanglement between the spin and orbital angular momentum of photons. We demonstrate the generation of the four Bell states on a single photon by using the geometric phase that arises from the photonic spin-orbit interaction and subsequently show nonlocal correlations between two photons that interacted with the metasurface. Our results show that metamaterials are suitable for the generation and manipulation of entangled photon states, introducing the area of quantum optics metamaterials.
Quantum metasurface for multiphoton interference and state reconstruction Science (IF 41.058) Pub Date : 2018-09-14 Kai Wang, James G. Titchener, Sergey S. Kruk, Lei Xu, Hung-Pin Chung, Matthew Parry, Ivan I. Kravchenko, Yen-Hung Chen, Alexander S. Solntsev, Yuri S. Kivshar, Dragomir N. Neshev, Andrey A. Sukhorukov
Metasurfaces based on resonant nanophotonic structures have enabled innovative types of flat-optics devices that often outperform the capabilities of bulk components, yet these advances remain largely unexplored for quantum applications. We show that nonclassical multiphoton interferences can be achieved at the subwavelength scale in all-dielectric metasurfaces. We simultaneously image multiple projections of quantum states with a single metasurface, enabling a robust reconstruction of amplitude, phase, coherence, and entanglement of multiphoton polarization-encoded states. One- and two-photon states are reconstructed through nonlocal photon correlation measurements with polarization-insensitive click detectors positioned after the metasurface, and the scalability to higher photon numbers is established theoretically. Our work illustrates the feasibility of ultrathin quantum metadevices for the manipulation and measurement of multiphoton quantum states, with applications in free-space quantum imaging and communications.
Classifying drivers of global forest loss Science (IF 41.058) Pub Date : 2018-09-14 Philip G. Curtis, Christy M. Slay, Nancy L. Harris, Alexandra Tyukavina, Matthew C. Hansen
Global maps of forest loss depict the scale and magnitude of forest disturbance, yet companies, governments, and nongovernmental organizations need to distinguish permanent conversion (i.e., deforestation) from temporary loss from forestry or wildfire. Using satellite imagery, we developed a forest loss classification model to determine a spatial attribution of forest disturbance to the dominant drivers of land cover and land use change over the period 2001 to 2015. Our results indicate that 27% of global forest loss can be attributed to deforestation through permanent land use change for commodity production. The remaining areas maintained the same land use over 15 years; in those areas, loss was attributed to forestry (26%), shifting agriculture (24%), and wildfire (23%). Despite corporate commitments, the rate of commodity-driven deforestation has not declined. To end deforestation, companies must eliminate 5 million hectares of conversion from supply chains each year.
Glutamate triggers long-distance, calcium-based plant defense signaling Science (IF 41.058) Pub Date : 2018-09-14 Masatsugu Toyota, Dirk Spencer, Satoe Sawai-Toyota, Wang Jiaqi, Tong Zhang, Abraham J. Koo, Gregg A. Howe, Simon Gilroy
Animals require rapid, long-range molecular signaling networks to integrate sensing and response throughout their bodies. The amino acid glutamate acts as an excitatory neurotransmitter in the vertebrate central nervous system, facilitating long-range information exchange via activation of glutamate receptor channels. Similarly, plants sense local signals, such as herbivore attack, and transmit this information throughout the plant body to rapidly activate defense responses in undamaged parts. Here we show that glutamate is a wound signal in plants. Ion channels of the GLUTAMATE RECEPTOR–LIKE family act as sensors that convert this signal into an increase in intracellular calcium ion concentration that propagates to distant organs, where defense responses are then induced.
A continental system for forecasting bird migration Science (IF 41.058) Pub Date : 2018-09-14 Benjamin M. Van Doren, Kyle G. Horton
Billions of animals cross the globe each year during seasonal migrations, but efforts to monitor them are hampered by the unpredictability of their movements. We developed a bird migration forecast system at a continental scale by leveraging 23 years of spring observations to identify associations between atmospheric conditions and bird migration intensity. Our models explained up to 81% of variation in migration intensity across the United States at altitudes of 0 to 3000 meters, and performance remained high in forecasting events 1 to 7 days in advance (62 to 76% of variation was explained). Avian migratory movements across the United States likely exceed 500 million individuals per night during peak passage. Bird migration forecasts will reduce collisions with buildings, airplanes, and wind turbines; inform a variety of monitoring efforts; and engage the public.
An ER surface retrieval pathway safeguards the import of mitochondrial membrane proteins in yeast Science (IF 41.058) Pub Date : 2018-09-14 Katja G. Hansen, Naama Aviram, Janina Laborenz, Chen Bibi, Maren Meyer, Anne Spang, Maya Schuldiner, Johannes M. Herrmann
The majority of organellar proteins are translated on cytosolic ribosomes and must be sorted correctly to function. Targeting routes have been identified for organelles such as peroxisomes and the endoplasmic reticulum (ER). However, little is known about the initial steps of targeting of mitochondrial proteins. In this study, we used a genome-wide screen in yeast and identified factors critical for the intracellular sorting of the mitochondrial inner membrane protein Oxa1. The screen uncovered an unexpected path, termed ER-SURF, for targeting of mitochondrial membrane proteins. This pathway retrieves mitochondrial proteins from the ER surface and reroutes them to mitochondria with the aid of the ER-localized chaperone Djp1. Hence, cells use the expanse of the ER surfaces as a fail-safe to maximize productive mitochondrial protein targeting.
Semisynthetic sensor proteins enable metabolic assays at the point of care Science (IF 41.058) Pub Date : 2018-09-14 Qiuliyang Yu, Lin Xue, Julien Hiblot, Rudolf Griss, Sebastian Fabritz, Clothilde Roux, Pierre-Alain Binz, Dorothea Haas, Jürgen G. Okun, Kai Johnsson
Monitoring metabolites at the point of care could improve the diagnosis and management of numerous diseases. Yet for most metabolites, such assays are not available. We introduce semisynthetic, light-emitting sensor proteins for use in paper-based metabolic assays. The metabolite is oxidized by nicotinamide adenine dinucleotide phosphate, and the sensor changes color in the presence of the reduced cofactor, enabling metabolite quantification with the use of a digital camera. The approach makes any metabolite that can be oxidized by the cofactor a candidate for quantitative point-of-care assays, as shown for phenylalanine, glucose, and glutamate. Phenylalanine blood levels of phenylketonuria patients were analyzed at the point of care within minutes with only 0.5 microliters of blood. Results were within 15% of those obtained with standard testing methods.
Ribonucleotide incorporation enables repair of chromosome breaks by nonhomologous end joining Science (IF 41.058) Pub Date : 2018-09-14 John M. Pryor, Michael P. Conlin, Juan Carvajal-Garcia, Megan E. Luedeman, Adam J. Luthman, George W. Small, Dale A. Ramsden
The nonhomologous end–joining (NHEJ) pathway preserves genome stability by ligating the ends of broken chromosomes together. It employs end-processing enzymes, including polymerases, to prepare ends for ligation. We show that two such polymerases incorporate primarily ribonucleotides during NHEJ—an exception to the central dogma of molecular biology—both during repair of chromosome breaks made by Cas9 and during V(D)J recombination. Moreover, additions of ribonucleotides but not deoxynucleotides effectively promote ligation. Repair kinetics suggest that ribonucleotide-dependent first-strand ligation is followed by complementary strand repair with deoxynucleotides, then by replacement of ribonucleotides embedded in the first strand with deoxynucleotides. Our results indicate that as much as 65% of cellular NHEJ products have transiently embedded ribonucleotides, which promote flexibility in repair at the cost of more fragile intermediates.
Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells Science (IF 41.058) Pub Date : 2018-09-14 Daniel DiToro, Colleen J. Winstead, Duy Pham, Steven Witte, Rakieb Andargachew, Jeffrey R. Singer, C. Garrett Wilson, Carlene L. Zindl, Rita J. Luther, Daniel J. Silberger, Benjamin T. Weaver, E. Motunrayo Kolawole, Ryan J. Martinez, Henrietta Turner, Robin D. Hatton, James J. Moon, Sing Sing Way, Brian D. Evavold, Casey T. Weaver
In response to infection, naïve CD4+ T cells differentiate into two subpopulations: T follicular helper (TFH) cells, which support B cell antibody production, and non-TFH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4+ T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become TFH cells, delivered IL-2 to nonproducers destined to become non-TFH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.
Recurrent cortical circuits implement concentration-invariant odor coding Science (IF 41.058) Pub Date : 2018-09-14 Kevin A. Bolding, Kevin M. Franks
Animals rely on olfaction to find food, attract mates, and avoid predators. To support these behaviors, they must be able to identify odors across different odorant concentrations. The neural circuit operations that implement this concentration invariance remain unclear. We found that despite concentration-dependence in the olfactory bulb (OB), representations of odor identity were preserved downstream, in the piriform cortex (PCx). The OB cells responding earliest after inhalation drove robust responses in sparse subsets of PCx neurons. Recurrent collateral connections broadcast their activation across the PCx, recruiting global feedback inhibition that rapidly truncated and suppressed cortical activity for the remainder of the sniff, discounting the impact of slower, concentration-dependent OB inputs. Eliminating recurrent collateral output amplified PCx odor responses rendered the cortex steeply concentration-dependent and abolished concentration-invariant identity decoding.
Asymmetric phosphoric acid–catalyzed four-component Ugi reaction Science (IF 41.058) Pub Date : 2018-09-14 Jian Zhang, Peiyuan Yu, Shao-Yu Li, He Sun, Shao-Hua Xiang, Jun (Joelle) Wang, Kendall N. Houk, Bin Tan
The Ugi reaction constructs α-acylaminoamide compounds by combining an aldehyde or ketone, an amine, a carboxylic acid, and an isocyanide in a single flask. Its appealing features include inherent atom and step economy together with the potential to generate products of broad structural diversity. However, control of the stereochemistry in this reaction has proven to be a formidable challenge. We describe an efficient enantioselective four-component Ugi reaction catalyzed by a chiral phosphoric acid derivative that delivers more than 80 α-acylaminoamides in good to excellent enantiomeric excess. Experimental and computational studies establish the reaction mechanism and origins of stereoselectivity.
Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes Science (IF 41.058) Pub Date : 2018-09-13 David J. F. Ramrath, Moritz Niemann, Marc Leibundgut, Philipp Bieri, Céline Prange, Elke K. Horn, Alexander Leitner, Daniel Boehringer, André Schneider, Nenad Ban
Ribosomal RNA (rRNA) plays key functional and architectural roles in ribosomes. Using electron microscopy, we determined the atomic structure of a highly divergent ribosome found in mitochondria of Trypanosoma brucei, a unicellular parasite that causes sleeping sickness in humans. The trypanosomal mitoribosome features the smallest rRNAs and contains more proteins than all known ribosomes. The structure shows how the proteins have taken over the role of architectural scaffold from the rRNA: they form an autonomous outer shell that surrounds the entire particle and stabilizes and positions the functionally important regions of the rRNA. Our results also reveal the “minimal” set of conserved rRNA and protein components shared by all ribosomes that help us define the most essential functional elements.
Optical skyrmion lattice in evanescent electromagnetic fields Science (IF 41.058) Pub Date : 2018-09-07 S. Tsesses, E. Ostrovsky, K. Cohen, B. Gjonaj, N. H. Lindner, G. Bartal
Topological defects play a key role in a variety of physical systems, ranging from high-energy to solid-state physics. A skyrmion is a type of topological defect that has shown promise for applications in the fields of magnetic storage and spintronics. We show that optical skyrmion lattices can be generated using evanescent electromagnetic fields and demonstrate this using surface plasmon polaritons, imaged by phase-resolved near-field optical microscopy. We show how the optical skyrmion lattice exhibits robustness to imperfections while the topological domain walls in the lattice can be continuously tuned, changing the spatial structure of the skyrmions from bubble type to Néel type. Extending the generation of skyrmions to photonic systems provides various possibilities for applications in optical information processing, transfer, and storage.
Resonance-stabilized hydrocarbon-radical chain reactions may explain soot inception and growth Science (IF 41.058) Pub Date : 2018-09-07 K. O. Johansson, M. P. Head-Gordon, P. E. Schrader, K. R. Wilson, H. A. Michelsen
Mystery surrounds the transition from gas-phase hydrocarbon precursors to terrestrial soot and interstellar dust, which are carbonaceous particles formed under similar conditions. Although polycyclic aromatic hydrocarbons (PAHs) are known precursors to high-temperature carbonaceous-particle formation, the molecular pathways that initiate particle formation are unknown. We present experimental and theoretical evidence for rapid molecular clustering–reaction pathways involving radicals with extended conjugation. These radicals react with other hydrocarbon species to form covalently bound complexes that promote further growth and clustering by regenerating resonance-stabilized radicals through low-barrier hydrogen-abstraction and hydrogen-ejection reactions. Such radical–chain reaction pathways may lead to covalently bound clusters of PAHs and other hydrocarbons that would otherwise be too small to condense at high temperatures, thus providing the key mechanistic steps for rapid particle formation and surface growth by hydrocarbon chemisorption.
Direct measurements of two-way wave-particle energy transfer in a collisionless space plasma Science (IF 41.058) Pub Date : 2018-09-07 N. Kitamura, M. Kitahara, M. Shoji, Y. Miyoshi, H. Hasegawa, S. Nakamura, Y. Katoh, Y. Saito, S. Yokota, D. J. Gershman, A. F. Vinas, B. L. Giles, T. E. Moore, W. R. Paterson, C. J. Pollock, C. T. Russell, R. J. Strangeway, S. A. Fuselier, J. L. Burch
Particle acceleration by plasma waves and spontaneous wave generation are fundamental energy and momentum exchange processes in collisionless plasmas. Such wave-particle interactions occur ubiquitously in space. We present ultrafast measurements in Earth’s magnetosphere by the Magnetospheric Multiscale spacecraft that enabled quantitative evaluation of energy transfer in interactions associated with electromagnetic ion cyclotron waves. The observed ion distributions are not symmetric around the magnetic field direction but are in phase with the plasma wave fields. The wave-ion phase relations demonstrate that a cyclotron resonance transferred energy from hot protons to waves, which in turn nonresonantly accelerated cold He+ to energies up to ~2 kilo–electron volts. These observations provide direct quantitative evidence for collisionless energy transfer in plasmas between distinct particle populations via wave-particle interactions.
All-optical machine learning using diffractive deep neural networks Science (IF 41.058) Pub Date : 2018-09-07 Xing Lin, Yair Rivenson, Nezih T. Yardimci, Muhammed Veli, Yi Luo, Mona Jarrahi, Aydogan Ozcan
Deep learning has been transforming our ability to execute advanced inference tasks using computers. Here we introduce a physical mechanism to perform machine learning by demonstrating an all-optical diffractive deep neural network (D2NN) architecture that can implement various functions following the deep learning–based design of passive diffractive layers that work collectively. We created 3D-printed D2NNs that implement classification of images of handwritten digits and fashion products, as well as the function of an imaging lens at a terahertz spectrum. Our all-optical deep learning framework can perform, at the speed of light, various complex functions that computer-based neural networks can execute; will find applications in all-optical image analysis, feature detection, and object classification; and will also enable new camera designs and optical components that perform distinctive tasks using D2NNs.
Zeolitic imidazolate framework membranes made by ligand-induced permselectivation Science (IF 41.058) Pub Date : 2018-09-07 Xiaoli Ma, Prashant Kumar, Nitish Mittal, Alexandra Khlyustova, Prodromos Daoutidis, K. Andre Mkhoyan, Michael Tsapatsis
Zeolitic imidazolate framework (ZIF) membranes are emerging as a promising energy-efficient separation technology. However, their reliable and scalable manufacturing remains a challenge. We demonstrate the fabrication of ZIF nanocomposite membranes by means of an all-vapor-phase processing method based on atomic layer deposition (ALD) of ZnO in a porous support followed by ligand-vapor treatment. After ALD, the obtained nanocomposite exhibits low flux and is not selective, whereas after ligand-vapor (2-methylimidazole) treatment, it is partially transformed to ZIF and shows stable performance with high mixture separation factor for propylene over propane (an energy-intensive high-volume separation) and high propylene flux. Membrane synthesis through ligand-induced permselectivation of a nonselective and impermeable deposit is shown to be simple and highly reproducible and holds promise for scalability.
Regulating the femtosecond excited-state lifetime of a single molecule Science (IF 41.058) Pub Date : 2018-09-07 K. R. Rusimova, R. M. Purkiss, R. Howes, F. Lee, S. Crampin, P. A. Sloan
The key to controlling reactions of molecules induced with the current of a scanning tunneling microscope (STM) tip is the ultrashort intermediate excited ionic state. The initial condition of the excited state is set by the energy and position of the injected current; thereafter, its dynamics determines the reaction outcome. We show that a STM can directly and controllably influence the excited-state dynamics. For the STM-induced desorption of toluene molecules from the Si(111)-7x7 surface, as the tip approaches the molecule, the probability of manipulation drops by two orders of magnitude. A two-channel quenching of the excited state is proposed, consisting of an invariant surface channel and a tip height–dependent channel. We conclude that picometer tip proximity regulates the lifetime of the excited state from 10 femtoseconds to less than 0.1 femtoseconds.
Fast molecular outflow from a dusty star-forming galaxy in the early Universe Science (IF 41.058) Pub Date : 2018-09-07 J. S. Spilker, M. Aravena, M. Béthermin, S. C. Chapman, C.-C. Chen, D. J. M. Cunningham, C. De Breuck, C. Dong, A. H. Gonzalez, C. C. Hayward, Y. D. Hezaveh, K. C. Litke, J. Ma, M. Malkan, D. P. Marrone, T. B. Miller, W. R. Morningstar, D. Narayanan, K. A. Phadke, J. Sreevani, A. A. Stark, J. D. Vieira, A. Weiß
Galaxies grow inefficiently, with only a small percentage of the available gas converted into stars each free-fall time. Feedback processes, such as outflowing winds driven by radiation pressure, supernovae, or supermassive black hole accretion, can act to halt star formation if they heat or expel the gas supply. We report a molecular outflow launched from a dust-rich star-forming galaxy at redshift 5.3, 1 billion years after the Big Bang. The outflow reaches velocities up to 800 kilometers per second relative to the galaxy, is resolved into multiple clumps, and carries mass at a rate within a factor of 2 of the star formation rate. Our results show that molecular outflows can remove a large fraction of the gas available for star formation from galaxies at high redshift.
Climate model shows large-scale wind and solar farms in the Sahara increase rain and vegetation Science (IF 41.058) Pub Date : 2018-09-07 Yan Li, Eugenia Kalnay, Safa Motesharrei, Jorge Rivas, Fred Kucharski, Daniel Kirk-Davidoff, Eviatar Bach, Ning Zeng
Wind and solar farms offer a major pathway to clean, renewable energies. However, these farms would significantly change land surface properties, and, if sufficiently large, the farms may lead to unintended climate consequences. In this study, we used a climate model with dynamic vegetation to show that large-scale installations of wind and solar farms covering the Sahara lead to a local temperature increase and more than a twofold precipitation increase, especially in the Sahel, through increased surface friction and reduced albedo. The resulting increase in vegetation further enhances precipitation, creating a positive albedo–precipitation–vegetation feedback that contributes ~80% of the precipitation increase for wind farms. This local enhancement is scale dependent and is particular to the Sahara, with small impacts in other deserts.
Is ungulate migration culturally transmitted? Evidence of social learning from translocated animals Science (IF 41.058) Pub Date : 2018-09-07 Brett R. Jesmer, Jerod A. Merkle, Jacob R. Goheen, Ellen O. Aikens, Jeffrey L. Beck, Alyson B. Courtemanch, Mark A. Hurley, Douglas E. McWhirter, Hollie M. Miyasaki, Kevin L. Monteith, Matthew. J. Kauffman
Ungulate migrations are assumed to stem from learning and cultural transmission of information regarding seasonal distribution of forage, but this hypothesis has not been tested empirically. We compared the migratory propensities of bighorn sheep and moose translocated into novel habitats with those of historical populations that had persisted for hundreds of years. Whereas individuals from historical populations were largely migratory, translocated individuals initially were not. After multiple decades, however, translocated populations gained knowledge about surfing green waves of forage (tracking plant phenology) and increased their propensity to migrate. Our findings indicate that learning and cultural transmission are the primary mechanisms by which ungulate migrations evolve. Loss of migration will therefore expunge generations of knowledge about the locations of high-quality forage and likely suppress population abundance.
A single transcription factor promotes both yield and immunity in rice Science (IF 41.058) Pub Date : 2018-09-07 Jing Wang, Lian Zhou, Hui Shi, Mawsheng Chern, Hong Yu, Hong Yi, Min He, Junjie Yin, Xiaobo Zhu, Yan Li, Weitao Li, Jiali Liu, Jichun Wang, Xiaoqiong Chen, Hai Qing, Yuping Wang, Guifu Liu, Wenming Wang, Ping Li, Xianjun Wu, Lihuang Zhu, Jian-Min Zhou, Pamela C. Ronald, Shigui Li, Jiayang Li, Xuewei Chen
Plant immunity often penalizes growth and yield. The transcription factor Ideal Plant Architecture 1 (IPA1) reduces unproductive tillers and increases grains per panicle, which results in improved rice yield. Here we report that higher IPA1 levels enhance immunity. Mechanistically, phosphorylation of IPA1 at amino acid Ser163 within its DNA binding domain occurs in response to infection by the fungus Magnaporthe oryzae and alters the DNA binding specificity of IPA1. Phosphorylated IPA1 binds to the promoter of the pathogen defense gene WRKY45 and activates its expression, leading to enhanced disease resistance. IPA1 returns to a nonphosphorylated state within 48 hours after infection, resuming support of the growth needed for high yield. Thus, IPA1 promotes both yield and disease resistance by sustaining a balance between growth and immunity.
The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization Science (IF 41.058) Pub Date : 2018-09-07 Sarah Herberg, Krista R. Gert, Alexander Schleiffer, Andrea Pauli
Fertilization is fundamental for sexual reproduction, yet its molecular mechanisms are poorly understood. We found that an oocyte-expressed Ly6/uPAR protein, which we call Bouncer, is a crucial fertilization factor in zebrafish. Membrane-bound Bouncer mediates sperm-egg binding and is thus essential for sperm entry into the egg. Remarkably, Bouncer not only is required for sperm-egg interaction but is also sufficient to allow cross-species fertilization between zebrafish and medaka, two fish species that diverged more than 200 million years ago. Our study thus identifies Bouncer as a key determinant of species-specific fertilization in fish. Bouncer’s closest homolog in tetrapods, SPACA4, is restricted to the male germline in internally fertilizing vertebrates, which suggests that our findings in fish have relevance to human biology.
Minimal functional driver gene heterogeneity among untreated metastases Science (IF 41.058) Pub Date : 2018-09-07 Johannes G. Reiter, Alvin P. Makohon-Moore, Jeffrey M. Gerold, Alexander Heyde, Marc A. Attiyeh, Zachary A. Kohutek, Collin J. Tokheim, Alexia Brown, Rayne M. DeBlasio, Juliana Niyazov, Amanda Zucker, Rachel Karchin, Kenneth W. Kinzler, Christine A. Iacobuzio-Donahue, Bert Vogelstein, Martin A. Nowak
Metastases are responsible for the majority of cancer-related deaths. Although genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatment-naïve metastases has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients, a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Thus, single biopsies capture most of the functionally important mutations in metastases and therefore provide essential information for therapeutic decision-making.
Transient phenomena in ecology Science (IF 41.058) Pub Date : 2018-09-07 Alan Hastings, Karen C. Abbott, Kim Cuddington, Tessa Francis, Gabriel Gellner, Ying-Cheng Lai, Andrew Morozov, Sergei Petrovskii, Katherine Scranton, Mary Lou Zeeman
The importance of transient dynamics in ecological systems and in the models that describe them has become increasingly recognized. However, previous work has typically treated each instance of these dynamics separately. We review both empirical examples and model systems, and outline a classification of transient dynamics based on ideas and concepts from dynamical systems theory. This classification provides ways to understand the likelihood of transients for particular systems, and to guide investigations to determine the timing of sudden switches in dynamics and other characteristics of transients. Implications for both management and underlying ecological theories emerge.
Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model Science (IF 41.058) Pub Date : 2018-09-07 Se Hoon Choi, Enjana Bylykbashi, Zena K. Chatila, Star W. Lee, Benjamin Pulli, Gregory D. Clemenson, Eunhee Kim, Alexander Rompala, Mary K. Oram, Caroline Asselin, Jenna Aronson, Can Zhang, Sean J. Miller, Andrea Lesinski, John W. Chen, Doo Yeon Kim, Henriette van Praag, Bruce M. Spiegelman, Fred H. Gage, Rudolph E. Tanzi
Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.
Structure of the human PKD1-PKD2 complex Science (IF 41.058) Pub Date : 2018-09-07 Qiang Su, Feizhuo Hu, Xiaofei Ge, Jianlin Lei, Shengqiang Yu, Tingliang Wang, Qiang Zhou, Changlin Mei, Yigong Shi
Mutations in two genes, PKD1 and PKD2, account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo–electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five–transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.
Discovery of widespread Type I and Type V CRISPR-Cas inhibitors Science (IF 41.058) Pub Date : 2018-09-06 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. Notably, 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.
Systematic discovery of natural CRISPR-Cas12a inhibitors Science (IF 41.058) Pub Date : 2018-09-06 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. While 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 employ 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.
Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1 Science (IF 41.058) Pub Date : 2018-09-06 Xiaojing Pan, Zhangqiang Li, Qiang Zhou, Huaizong Shen, Kun Wu, Xiaoshuang Huang, Jiaofeng Chen, Juanrong Zhang, Xuechen Zhu, Jianlin Lei, Wei Xiong, Haipeng Gong, Bailong Xiao, Nieng Yan
Voltage-gated sodium channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here we report the cryo-EM structure of human Nav1.4-β1 complex at 3.2 Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, giving insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.
Dimerization quality control ensures neuronal development and survival Science (IF 41.058) Pub Date : 2018-09-06 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.
Aptamer–field-effect transistors overcome Debye length limitations for small-molecule sensing Science (IF 41.058) Pub Date : 2018-09-06 Nako Nakatsuka, Kyung-Ae Yang, John M. Abendroth, Kevin Cheung, Xiaobin Xu, Hongyan Yang, Chuanzhen Zhao, Bowen Zhu, You Seung Rim, Yang Yang, Paul S. Weiss, Milan N. Stojanović, Anne M. Andrews
Detection of analytes with field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the electrical double layer (the “Debye length” limitation). We detected small molecules under physiological high ionic-strength conditions by modifying printed ultrathin metal-oxide field-effect transistor arrays with deoxyribonucleotide aptamers selected to bind their targets adaptively. Target-induced conformational changes of negatively charged aptamer phosphodiester backbones in close proximity to semiconductor channels gated conductance in physiological buffers, resulting in highly sensitive detection. Sensing of charged and electroneutral targets (serotonin, dopamine, glucose, and sphinghosine-1-phosphate) was enabled by specifically isolated aptameric stem-loop receptors.
CRISPR-Cas guides the future of genetic engineering Science (IF 41.058) Pub Date : 2018-08-31 Gavin J. Knott, Jennifer A. Doudna
The diversity, modularity, and efficacy of CRISPR-Cas systems are driving a biotechnological revolution. RNA-guided Cas enzymes have been adopted as tools to manipulate the genomes of cultured cells, animals, and plants, accelerating the pace of fundamental research and enabling clinical and agricultural breakthroughs. We describe the basic mechanisms that set the CRISPR-Cas toolkit apart from other programmable gene-editing technologies, highlighting the diverse and naturally evolved systems now functionalized as biotechnologies. We discuss the rapidly evolving landscape of CRISPR-Cas applications, from gene editing to transcriptional regulation, imaging, and diagnostics. Continuing functional dissection and an expanding landscape of applications position CRISPR-Cas tools at the cutting edge of nucleic acid manipulation that is rewriting biology.
Emerging applications for DNA writers and molecular recorders Science (IF 41.058) Pub Date : 2018-08-31 Fahim Farzadfard, Timothy K. Lu
Natural life is encoded by evolvable, DNA-based memory. Recent advances in dynamic genome-engineering technologies, which we collectively refer to as in vivo DNA writing, have opened new avenues for investigating and engineering biology. This Review surveys these technological advances, outlines their prospects and emerging applications, and discusses the features and current limitations of these technologies for building various genetic circuits for processing and recording information in living cells.
Single-particle cryo-EM—How did it get here and where will it go Science (IF 41.058) Pub Date : 2018-08-31 Yifan Cheng
Cryo–electron microscopy, or simply cryo-EM, refers mainly to three very different yet closely related techniques: electron crystallography, single-particle cryo-EM, and electron cryotomography. In the past few years, single-particle cryo-EM in particular has triggered a revolution in structural biology and has become a newly dominant discipline. This Review examines the fascinating story of its start and evolution over the past 40-plus years, delves into how and why the recent technological advances have been so groundbreaking, and briefly considers where the technique may be headed in the future.
Visualizing and discovering cellular structures with super-resolution microscopy Science (IF 41.058) Pub Date : 2018-08-31 Yaron M. Sigal, Ruobo Zhou, Xiaowei Zhuang
Super-resolution microscopy has overcome a long-held resolution barrier—the diffraction limit—in light microscopy and enabled visualization of previously invisible molecular details in biological systems. Since their conception, super-resolution imaging methods have continually evolved and can now be used to image cellular structures in three dimensions, multiple colors, and living systems with nanometer-scale resolution. These methods have been applied to answer questions involving the organization, interaction, stoichiometry, and dynamics of individual molecular building blocks and their integration into functional machineries in cells and tissues. In this Review, we provide an overview of super-resolution methods, their state-of-the-art capabilities, and their constantly expanding applications to biology, with a focus on the latter. We will also describe the current technical challenges and future advances anticipated in super-resolution imaging.
Genomic and epidemiological monitoring of yellow fever virus transmission potential Science (IF 41.058) Pub Date : 2018-08-31 N. R. Faria, M. U. G. Kraemer, S. C. Hill, J. Goes de Jesus, R. S. Aguiar, F. C. M. Iani, J. Xavier, J. Quick, L. du Plessis, S. Dellicour, J. Thézé, R. D. O. Carvalho, G. Baele, C.-H. Wu, P. P. Silveira, M. B. Arruda, M. A. Pereira, G. C. Pereira, J. Lourenço, U. Obolski, L. Abade, T. I. Vasylyeva, M. Giovanetti, D. Yi, D. J. Weiss, G. R. W. Wint, F. M. Shearer, S. Funk, B. Nikolay, V. Fonseca, T. E. R. Adelino, M. A. A. Oliveira, M. V. F. Silva, L. Sacchetto, P. O. Figueiredo, I. M. Rezende, E. M. Mello, R. F. C. Said, D. A. Santos, M. L. Ferraz, M. G. Brito, L. F. Santana, M. T. Menezes, R. M. Brindeiro, A. Tanuri, F. C. P. dos Santos, M. S. Cunha, J. S. Nogueira, I. M. Rocco, A. C. da Costa, S. C. V. Komninakis, V. Azevedo, A. O. Chieppe, E. S. M. Araujo, M. C. L. Mendonça, C. C. dos Santos, C. D. dos Santos, A. M. Mares-Guia, R. M. R. Nogueira, P. C. Sequeira, R. G. Abreu, M. H. O. Garcia, A. L. Abreu, O. Okumoto, E. G. Kroon, C. F. C. de Albuquerque, K. Lewandowski, S. T. Pullan, M. Carroll, T. de Oliveira, E. C. Sabino, R. P. Souza, M. A. Suchard, P. Lemey, G. S. Trindade, B. P. Drumond, A. M. B. Filippis, N. J. Loman, S. Cauchemez, L. C. J. Alcantara, O. G. Pybus
The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.
The spatial footprint of injection wells in a global compilation of induced earthquake sequences Science (IF 41.058) Pub Date : 2018-08-31 Thomas H. W. Goebel, Emily E. Brodsky
Fluid injection can cause extensive earthquake activity, sometimes at unexpectedly large distances. Appropriately mitigating associated seismic hazards requires a better understanding of the zone of influence of injection. We analyze spatial seismicity decay in a global dataset of 18 induced cases with clear association between isolated wells and earthquakes. We distinguish two populations. The first is characterized by near-well seismicity density plateaus and abrupt decay, dominated by square-root space-time migration and pressure diffusion. Injection at these sites occurs within the crystalline basement. The second population exhibits larger spatial footprints and magnitudes, as well as a power law–like, steady spatial decay over more than 10 kilometers, potentially caused by poroelastic effects. Far-reaching spatial effects during injection may increase event magnitudes and seismic hazard beyond expectations based on purely pressure-driven seismicity.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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