审校：半夏 金庄维 史静雯 访冬 赵维杰
A massive, quiescent galaxy at a redshift of 3.717
Karl Glazebrook, Corentin Schreiber, Ivo Labbé…Kim-Vy H. Tran & Tiantian Yuan
（导读 肖坤） 近红外深空巡天可以发现宇宙早期的大质量宁静星系。本研究确认了其中一个红移为3.717、质量为1.7 × 1011个太阳质量的宁静星系。分析证明其质量大部分在宇宙最初十亿年内迅速形成，暗示人们需要重新审视对早期星系会聚的认知。
Finding massive galaxies that stopped forming stars in the early Universe presents an observational challenge because their rest-frame ultraviolet emission is negligible and they can only be reliably identified by extremely deep near-infrared surveys. These surveys have revealed the presence of massive, quiescent early-type galaxies appearing as early as redshift z ≈ 2, an epoch three billion years after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy-formation models, in which they form rapidly at z ≈ 3–4, consistent with the typical masses and ages derived from their observations. Deeper surveys have reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, using coarsely sampled photometry. However, these early, massive, quiescent galaxies are not predicted by the latest generation of theoretical models. Here we report the spectroscopic confirmation of one such galaxy at redshift z = 3.717, with a stellar mass of 1.7 × 1011 solar masses. We derive its age to be nearly half the age of the Universe at this redshift and the absorption line spectrum shows no current star formation. These observations demonstrate that the galaxy must have formed the majority of its stars quickly, within the first billion years of cosmic history in a short, extreme starburst. This ancestral starburst appears similar to those being found by submillimetre-wavelength surveys. The early formation of such massive systems implies that our picture of early galaxy assembly requires substantial revision.
Background-free search for neutrinoless double-β decay of 76Ge with GERDA
M. Agostini, M. Allardt, A. M. Bakalyarov…K. Zuber & G. Zuzel for The GERDA Collaboration
（导读 腌笃鲜） 无中微子的双β衰变的存在能够证明中微子的反粒子就是自身。本研究报道了GERDA实验II期在无干扰背景条件下寻找76Ge的无中微子双β衰变。结合I期和II期的数据，实验组并未发现这种衰变的信号。
Many extensions of the Standard Model of particle physics explain the dominance of matter over antimatter in our Universe by neutrinos being their own antiparticles. This would imply the existence of neutrinoless double-β decay, which is an extremely rare lepton-number-violating radioactive decay process whose detection requires the utmost background suppression. Among the programmes that aim to detect this decay, the GERDA Collaboration is searching for neutrinoless double-β decay of 76Ge by operating bare detectors, made of germanium with an enriched 76Ge fraction, in liquid argon. After having completed Phase I of data taking, we have recently launched Phase II. Here we report that in GERDA Phase II we have achieved a background level of approximately 10−3 counts keV−1 kg−1 yr−1. This implies that the experiment is background-free, even when increasing the exposure up to design level. This is achieved by use of an active veto system, superior germanium detector energy resolution and improved background recognition of our new detectors. No signal of neutrinoless double-β decay was found when Phase I and Phase II data were combined, and we deduce a lower-limit half-life of 5.3 × 1025 years at the 90 per cent confidence level. Our half-life sensitivity of 4.0 × 1025 years is competitive with the best experiments that use a substantially larger isotope mass. The potential of an essentially background-free search for neutrinoless double-β decay will facilitate a larger germanium experiment with sensitivity levels that will bring us closer to clarifying whether neutrinos are their own antiparticles.
Continuous-wave lasing in colloidal quantum dot solids enabled by facet-selective epitaxy
Fengjia Fan, Oleksandr Voznyy, Randy P. Sabatini…Sjoerd Hoogland & Edward H. Sargent
（导读 肖坤） 胶体量子点（CQD）拥有较低的电子态简并度和较窄的发射线宽等优秀性质，然而无法用于产生稳定的激光输出。本研究开发出一种称为面选择性外延的合成策略，通过在CdSe量子点核心的（0001）面上覆盖不对称的压缩壳，从而降低光增益阈值，实现CQD固体连续激光输出。
Colloidal quantum dots (CQDs) feature a low degeneracy of electronic states at the band edges compared with the corresponding bulk material, as well as a narrow emission linewidth. Unfortunately for potential laser applications, this degeneracy is incompletely lifted in the valence band, spreading the hole population among several states at room temperature. This leads to increased optical gain thresholds, demanding high photoexcitation levels to achieve population inversion (more electrons in excited states than in ground states—the condition for optical gain). This, in turn, increases Auger recombination losses, limiting the gain lifetime to sub-nanoseconds and preventing steady laser action. State degeneracy also broadens the photoluminescence linewidth at the single-particle level. Here we demonstrate a way to decrease the band-edge degeneracy and single-dot photoluminescence linewidth in CQDs by means of uniform biaxial strain. We have developed a synthetic strategy that we term facet-selective epitaxy: we first switch off, and then switch on, shell growth on the (0001) facet of wurtzite CdSe cores, producing asymmetric compressive shells that create built-in biaxial strain, while still maintaining excellent surface passivation (preventing defect formation, which otherwise would cause non-radiative recombination losses). Our synthesis spreads the excitonic fine structure uniformly and sufficiently broadly that it prevents valence-band-edge states from being thermally depopulated. We thereby reduce the optical gain threshold and demonstrate continuous-wave lasing from CQD solids, expanding the library of solution-processed materials that may be capable of continuous-wave lasing. The individual CQDs exhibit an ultra-narrow single-dot linewidth, and we successfully propagate this into the ensemble of CQDs.
Low-temperature hydrogen production from water and methanol using Pt/α-MoC catalysts
Lili Lin, Wu Zhou（周武，中国科学院大学）, Rui Gao…Chuan Shi（石川，大连理工）, Xiao-Dong Wen（温晓东，中科院山西煤化所） & Ding Ma（马丁，北京大学）
（导读 卓思琪） 甲醇和水液相制氢反应廉价高产，能产生清洁的氢能源，但通常需在高温（200-350℃）下进行。本文报道了一种铂原子（Pt）分布在α-碳化钼（α- MoC）所组成的催化剂，它能够在较低温度（150-190℃）下催化这一反应得到游离态的氢。该方法比以往的低温催化剂所得到的游离态的氢要多。
Polymer electrolyte membrane fuel cells (PEMFCs) running on hydrogen are attractive alternative power supplies for a range of applications, with in situ release of the required hydrogen from a stable liquid offering one way of ensuring its safe storage and transportation before use. The use of methanol is particularly interesting in this regard, because it is inexpensive and can reform itself with water to release hydrogen with a high gravimetric density of 18.8 per cent by weight. But traditional reforming of methanol steam operates at relatively high temperatures (200–350 degrees Celsius), so the focus for vehicle and portable PEMFC applications has been on aqueous-phase reforming of methanol (APRM). This method requires less energy, and the simpler and more compact device design allows direct integration into PEMFC stacks. There remains, however, the need for an efficient APRM catalyst. Here we report that platinum (Pt) atomically dispersed on α-molybdenum carbide (α-MoC) enables low-temperature (150–190 degrees Celsius), base-free hydrogen production through APRM, with an average turnover frequency reaching 18,046 moles of hydrogen per mole of platinum per hour. We attribute this exceptional hydrogen production—which far exceeds that of previously reported low-temperature APRM catalysts—to the outstanding ability of α-MoC to induce water dissociation, and to the fact that platinum and α-MoC act in synergy to activate methanol and then to reform it.
Large historical growth in global terrestrial gross primary production
J. E. Campbell, J. A. Berry, U. Seibt…L. Bopp & M. Laine
（导读 郭思瑶） 陆地初级生产总值(GPP)的增长或许为气候变化提供负反馈。 研究人员利用长期大气硫化碳记录估计二十世纪全球性 GPP增长，结果发现该记录与假设二十世纪存在大量GPP增长的模型最相符，为全球性历史碳循环模拟提供了基准。
Growth in terrestrial gross primary production (GPP)—the amount of carbon dioxide that is ‘fixed’ into organic material through the photosynthesis of land plants—may provide a negative feedback for climate change. It remains uncertain, however, to what extent biogeochemical processes can suppress global GPP growth. As a consequence, modelling estimates of terrestrial carbon storage, and of feedbacks between the carbon cycle and climate, remain poorly constrained. Here we present a global, measurement-based estimate of GPP growth during the twentieth century that is based on long-term atmospheric carbonyl sulfide (COS) records, derived from ice-core, firn and ambient air samples. We interpret these records using a model that simulates changes in COS concentration according to changes in its sources and sinks—including a large sink that is related to GPP. We find that the observation-based COS record is most consistent with simulations of climate and the carbon cycle that assume large GPP growth during the twentieth century (31% ± 5% growth; mean ± 95% confidence interval). Although this COS analysis does not directly constrain models of future GPP growth, it does provide a global-scale benchmark for historical carbon-cycle simulations.
Smart wing rotation and trailing-edge vortices enable high frequency mosquito flight
Richard J. Bomphrey, Toshiyuki Nakata, Nathan Phillips & Simon M. Walker（封面文章）
（导读 王腾） 蚊类的扇翅运动学与其他昆虫不同，翅膀长细、振速较快（＞800Hz）而振幅较小。分析表明，除了前缘涡产生升力之外，蚊子还采用后缘涡及翅膀转动等另外两种新型动力机制。这些机制特别适用于高长宽比的蚊翼。
Mosquitoes exhibit unusual wing kinematics; their long, slender wings flap at remarkably high frequencies for their size (>800 Hz) and with lower stroke amplitudes than any other insect group. This shifts weight support away from the translation-dominated, aerodynamic mechanisms used by most insects, as well as by helicopters and aeroplanes, towards poorly understood rotational mechanisms that occur when pitching at the end of each half-stroke. Here we report free-flight mosquito wing kinematics, solve the full Navier–Stokes equations using computational fluid dynamics with overset grids, and validate our results with in vivo flow measurements. We show that, although mosquitoes use familiar separated flow patterns, much of the aerodynamic force that supports their weight is generated in a manner unlike any previously described for a flying animal. There are three key features: leading-edge vortices (a well-known mechanism that appears to be almost ubiquitous in insect flight), trailing-edge vortices caused by a form of wake capture at stroke reversal, and rotational drag. The two new elements are largely independent of the wing velocity, instead relying on rapid changes in the pitch angle (wing rotation) at the end of each half-stroke, and they are therefore relatively immune to the shallow flapping amplitude. Moreover, these mechanisms are particularly well suited to high aspect ratio mosquito wings.
Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest
Stephen A. Green, Benjamin R. Uy & Marianne E. Bronner
（导读 赵维杰） 胚胎发育过程中，有颌脊椎动物的肠道神经元由迷走神经嵴细胞迁移并分化而来。本研究发现在更原始的无颌脊椎动物海七鳃鳗中并非如此，肠道神经元是由躯干神经管中的细胞迁移并分化而成的，这部分细胞可能与施万细胞前体细胞同源。
The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey (Petromyzon marinus) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey. Rather, labelling with the lipophilic dye DiI shows that late-migrating cells, originating from the trunk neural tube and associated with nerve fibres, differentiate into neurons within the gut wall and typhlosole. We propose that these trunk-derived neural crest cells may be homologous to Schwann cell precursors, recently shown in mammalian embryos to populate post-embryonic parasympathetic ganglia, including enteric ganglia. Our results suggest that neural-crest-derived Schwann cell precursors made an important contribution to the ancient enteric nervous system of early jawless vertebrates, a role that was largely subsumed by vagal neural crest cells in early gnathostomes.
Cerebellar granule cells encode the expectation of reward
Mark J. Wagner, Tony Hyun Kim, Joan Savall, Mark J. Schnitzer & Liqun Luo（斯坦福大学 骆立群）
（导读 董堃） 经典理论表明小脑颗粒细胞传导感觉和运动信号使得下游浦肯野细胞能够感受精细的环境变化。本研究通过在小鼠模型中使用双光子钙成像技术，发现有相当规模的颗粒细胞能够传递奖赏期望信息。这项发现对小脑认知处理的研究可能具有重要意义。
The human brain contains approximately 60 billion cerebellar granule cells, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes. Although evidence suggests a role for the cerebellum in cognition, granule cells are known to encode only sensory and motor context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.
Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis
Aurélie Hérault, Mikhail Binnewies, Stephanie Leong…Berthold Göttgens & Emmanuelle Passegué
（导读 赵维杰） 本研究利用成像技术研究了小鼠在应急反应造血过程中，粒细胞/巨噬细胞祖细胞（GMP）会增殖聚集成细胞簇后进行分化，而在白血病性造血过程中也持续产生GMP细胞簇且缺少正常的停止机制，揭示了造血过程中细胞在骨髓中的空间组织形式。
Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1β, G-CSF, TGFβ and CXCL4) and activation of an inducible Irf8 and β-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.
Complex pectin metabolism by gut bacteria reveals novel catalytic functions
Didier Ndeh, Artur Rogowski, Alan Cartmell…Bernard Henrissat & Harry J. Gilbert
（导读 郭思瑶） 碳水化合物聚合物的代谢驱动人类肠道菌群的多样性。 研究人员发现肠道细菌中的多形拟杆菌可以利用已知结构最复杂的植物果胶型多糖，通过多个未被发现的酶家族和催化活性对鼠李糖半乳糖醛酸聚糖-II进行降解，修正了该多糖的结构模型，同时显示了个体肠道细菌是如何利用多种酶来代谢最复杂的多聚糖的。
The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiota. It is unclear, however, whether bacterial consortia or single organisms are required to depolymerize highly complex glycans. Here we show that the gut bacterium Bacteroides thetaiotaomicron uses the most structurally complex glycan known: the plant pectic polysaccharide rhamnogalacturonan-II, cleaving all but 1 of its 21 distinct glycosidic linkages. The deconstruction of rhamnogalacturonan-II side chains and backbone are coordinated to overcome steric constraints, and the degradation involves previously undiscovered enzyme families and catalytic activities. The degradation system informs revision of the current structural model of rhamnogalacturonan-II and highlights how individual gut bacteria orchestrate manifold enzymes to metabolize the most challenging glycan in the human diet.
The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors
Emma Lefrançais, Guadalupe Ortiz-Muñoz, Axelle Caudrillier…Emmanuelle Passegué & Mark R. Looney
（导读 马欢） 一直以来，骨髓常常被认为是血小板产生的主要部位。本研究通过小鼠肺部微循环直接成像发现，来自肺外（如骨髓）的巨核细胞到达肺部释放血小板，释放量占小鼠血液循环中血小板总量的50%；同时在肺部鉴定出一种造血祖细胞，该祖细胞在血小板减少或骨髓干细胞缺乏时能迁移至骨髓，恢复造血功能。
Platelets are critical for haemostasis, thrombosis, and inflammatory responses, but the events that lead to mature platelet production remain incompletely understood. The bone marrow has been proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis. Here, by directly imaging the lung microcirculation in mice, we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow, these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.
3D structures of individual mammalian genomes studied by single-cell Hi-C
Tim J. Stevens, David Lando, Srinjan Basu…Dave Klenerman & Ernest D. Laue
（导读 赵维杰） 本研究利用一种分辨率达100 kb的细胞成像和操作技术，对哺乳动物单细胞染色体组的三维结构进行了测定。结果发现细胞间的染色体三维结构各不相同，但部分主要结构元件的分布具有共性，这些元件可能在染色体折叠过程中扮演重要角色。
The folding of genomic DNA from the beads-on-a-string-like structure of nucleosomes into higher-order assemblies is crucially linked to nuclear processes. Here we calculate 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. The technique enables genome folding to be examined at a scale of less than 100 kb, and chromosome structures to be validated. The structures of individual topological-associated domains and loops vary substantially from cell to cell. By contrast, A and B compartments, lamina-associated domains and active enhancers and promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. By studying genes regulated by pluripotency factor and nucleosome remodelling deacetylase (NuRD), we illustrate how the determination of single-cell genome structure provides a new approach for investigating biological processes.
Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition
Ilya M. Flyamer, Johanna Gassler, Maxim Imakaev…Leonid A. Mirny & Kikuë Tachibana-Konwalski
（导读 赵维杰） 受精完成后，父源和母源染色质需要在受精卵中进行空间排布重组。本研究使用单细胞核Hi-C技术，实现了对小鼠卵子-合子转变过程中染色质空间重组过程的观测，发现这一重组过程十分独特，并且此过程中父源和母源染色质的重组方式不同。
Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method2. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin ‘ground state’ could potentially provide insights into reprogramming cells to a state of totipotency.
CRISPR–Cas systems exploit viral DNA injection to establish and maintain adaptive immunity
Joshua W. Modell, Wenyan Jiang & Luciano A. Marraffini
（导读 郭思瑶） CRISPR–Cas系统通过捕捉入侵病毒或质粒的DNA短序列对抗再次感染。研究发现金黄色葡萄球菌倾向获得首先注入细胞中的病毒游离DNA（cos位点），且这一过程倾向于发生在DNA注射阶段，该研究显示CRISPR–Cas系统可以利用噬菌体生命周期，形成特定间隔区序列获得模式以确保CRISPR免疫反应。
Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas systems provide protection against viral and plasmid infection by capturing short DNA sequences from these invaders and integrating them into the CRISPR locus of the prokaryotic host. These sequences, known as spacers, are transcribed into short CRISPR RNA guides that specify the cleavage site of Cas nucleases in the genome of the invader. It is not known when spacer sequences are acquired during viral infection. Here, to investigate this, we tracked spacer acquisition in Staphylococcus aureus cells harbouring a type II CRISPR–Cas9 system after infection with the staphylococcal bacteriophage ϕ12. We found that new spacers were acquired immediately after infection preferentially from the cos site, the viral free DNA end that is first injected into the cell. Analysis of spacer acquisition after infection with mutant phages demonstrated that most spacers are acquired during DNA injection, but not during other stages of the viral cycle that produce free DNA ends, such as DNA replication or packaging. Finally, we showed that spacers acquired from early-injected genomic regions, which direct Cas9 cleavage of the viral DNA immediately after infection, provide better immunity than spacers acquired from late-injected regions. Our results reveal that CRISPR–Cas systems exploit the phage life cycle to generate a pattern of spacer acquisition that ensures a successful CRISPR immune response.
DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome
Tuğçe Aktaş, İbrahim Avşar Ilık, Daniel Maticzka…Rolf Backofen & Asifa Akhtar
（导读 赵维杰） ALU元件是人类基因组中常见的转座元件，它被转录进入mRNA时可能导致RNA的环化和不稳定。本研究发现RNA解旋酶DHX9可以特异性结合于RNA上的反向重复Alu位点并抑制环状RNA的产生，解除ALU的即时负面作用，从而使ALU可以稳定存在于基因组中并发挥其在进化过程中的正面作用。
Transposable elements are viewed as ‘selfish genetic elements’, yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome. Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability. Alu elements are the main targets of the RNA-editing enzyme ADAR and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant nuclear RNA helicase, binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression.
Structural insights into adiponectin receptors suggest ceramidase activity
Ieva Vasiliauskaité-Brooks, Remy Sounier, Pascal Rochaix…Cédric Leyrat & Sébastien Granier
（导读 赵维杰） 脂联素受体（ADIPOR）是可以催化神经酰胺水解为鞘氨醇和游离脂肪酸（FFA）的膜蛋白。本研究解析了结合了FFA底物的ADIPOR2结构和修正的未结合底物的ADIPOR1结构，并结合分子动力学模拟，为这一催化过程提供了可能的部分分子机制。
Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembrane-domain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.
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