审校：半夏 访冬 赵维杰 金庄维
Simultaneous tracking of spin angle and amplitude beyond classical limits
Giorgio Colangelo, Ferran Martin Ciurana, Lorena C. Bianchet, Robert J. Sewell & Morgan W. Mitchell
（导读 张奕林） 以往对自旋进动的测量都是间接的，并会引入误差。本文基于不确定性原理，使用高动态范围的量子非破坏性测量手段实现了对自旋振幅和自旋角度的同时、高精度测量：稳态下自旋角的测量精度比经典极限小了2.9分贝，而自旋振幅的测量精度小了7.0分贝。该方法为探测与波谱学测量精度带来了数量级的提升。
Measurement of spin precession is central to extreme sensing in physics, geophysics, chemistry, nanotechnology and neuroscience, and underlies magnetic resonance spectroscopy. Because there is no spin-angle operator, any measurement of spin precession is necessarily indirect, for example, it may be inferred from spin projectors at different times. Such projectors do not commute, and so quantum measurement back-action—the random change in a quantum state due to measurement—necessarily enters the spin measurement record, introducing errors and limiting sensitivity. Here we show that this disturbance in the spin projector can be reduced below N1/2—the classical limit for N spins—by directing the quantum measurement back-action almost entirely into an unmeasured spin component. This generates a planar squeezed state that, because spins obey non-Heisenberg uncertainty relations, enables simultaneous precise knowledge of spin angle and spin amplitude. We use high-dynamic-range optical quantum non-demolition measurements applied to a precessing magnetic spin ensemble to demonstrate spin tracking with steady-state angular sensitivity 2.9 decibels below the standard quantum limit, simultaneously with amplitude sensitivity 7.0 decibels below the Poissonian variance. The standard quantum limit and Poissonian variance indicate the best possible sensitivity with independent particles. Our method surpasses these limits in non-commuting observables, enabling orders-of-magnitude improvements in sensitivity for state-of-the-art sensing and spectroscopy.
Mapping vibrational surface and bulk modes in a single nanocube
Maureen J. Lagos, Andreas Trügler, Ulrich Hohenester & Philip E. Batson
（导读 张奕林） 测定纳米结构的振动激发模式具有重要意义，传统上这一测量是分析电子能量损失谱间接实现的。本文用原子宽度的电子束测绘了氧化镁纳米立方体的块体与表面的光学、声学振动模式，发现表面极化声子模式的能量与对称性都是局域的并且依赖于纳米立方体的尺寸，还观察到了表面声子模式存在时的块体声子散射极限。
Imaging of vibrational excitations in and near nanostructures is essential for developing low-loss infrared nanophotonics, controlling heat transport in thermal nanodevices, inventing new thermoelectric materials and understanding nanoscale energy transport. Spatially resolved electron energy loss spectroscopy has previously been used to image plasmonic behaviour in nanostructures in an electron microscope, but hitherto it has not been possible to map vibrational modes directly in a single nanostructure, limiting our understanding of phonon coupling with photons and plasmons. Here we present spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes using an atom-wide electron beam. We find that the energy and the symmetry of the surface polariton phonon modes depend on the size of the nanocubes, and that they are localized to the surfaces of the nanocube. We also observe a limiting of bulk phonon scattering in the presence of surface phonon modes. Most phonon spectroscopies are selectively sensitive to either surface or bulk excitations; therefore, by demonstrating the excitation of both bulk and surface vibrational modes using a single probe, our work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.
Mechanical metamaterials at the theoretical limit of isotropic elastic stiffness
J. B. Berger, H. N. G. Wadley & R. M. McMeeking
（导读 许雅澜） 研究人员评估了有代表性的材料几何属性在荷载下的应变能量分布方式，发现一种材料几何属性能够达到各向同性弹性刚度的Hashin–Shtrikman上限。坚硬但分布良好的平板网格有效地将荷载在相邻的单元间转移，所得的低密度力学超材料具有很多优越性能。
A wide variety of high-performance applications require materials for which shape control is maintained under substantial stress, and that have minimal density. Bio-inspired hexagonal and square honeycomb structures and lattice materials based on repeating unit cells composed of webs or trusses, when made from materials of high elastic stiffness and low density, represent some of the lightest, stiffest and strongest materials available today. Recent advances in 3D printing and automated assembly have enabled such complicated material geometries to be fabricated at low (and declining) cost. These mechanical metamaterials have properties that are a function of their mesoscale geometry as well as their constituents leading to combinations of properties that are unobtainable in solid materials; however, a material geometry that achieves the theoretical upper bounds for isotropic elasticity and strain energy storage (the Hashin–Shtrikman upper bounds) has yet to be identified. Here we evaluate the manner in which strain energy distributes under load in a representative selection of material geometries, to identify the morphological features associated with high elastic performance. Using finite-element models, supported by analytical methods, and a heuristic optimization scheme, we identify a material geometry that achieves the Hashin–Shtrikman upper bounds on isotropic elastic stiffness. Previous work has focused on truss networks and anisotropic honeycombs, neither of which can achieve this theoretical limit. We find that stiff but well distributed networks of plates are required to transfer loads efficiently between neighbouring members. The resulting low-density mechanical metamaterials have many advantageous properties: their mesoscale geometry can facilitate large crushing strains with high energy absorption optical bandgaps and mechanically tunable acoustic bandgaps, high thermal insulation, buoyancy, and fluid storage and transport. Our relatively simple design can be manufactured using origami-like sheet folding and bonding methods.
Remote site-selective C–H activation directed by a catalytic bifunctional template
Zhipeng Zhang, Keita Tanaka & Jin-Quan Yu（余金权，美国斯克利普斯研究所）
In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively. The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta-selective C–H activation by using a covalently attached, U-shaped template. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.
Evidence for a Fe3+-rich pyrolitic lower mantle from (Al,Fe)-bearing bridgmanite elasticity data
A. Kurnosov, H. Marquardt, D. J. Frost, T. Boffa Ballaran & L. Ziberna
（导读 赵维娜） 研究者可通过地震学观测和矿物物理测试推测地球下地幔化学组成，但其中重要矿物布氏岩的实验数据尚未获得。本研究通过高压布里渊光谱和X射线衍射测量了布氏岩(Al,Fe)单晶的弹性数据，并据此对下地幔矿物构成进行了建模，模型中上地幔及下地幔浅部化学物质均一、Fe3+/Fe2+比高，更深层下地幔则不符合此性质。
The chemical composition of Earth’s lower mantle can be constrained by combining seismological observations with mineral physics elasticity measurements. However, the lack of laboratory data for Earth’s most abundant mineral, (Mg,Fe,Al)(Al,Fe,Si)O3bridgmanite (also known as silicate perovskite), has hampered any conclusive result. Here we report single-crystal elasticity data on (Al,Fe)-bearing bridgmanite (Mg0.9Fe0.1Si0.9Al0.1)O3 measured using high-pressure Brillouin spectroscopy and X-ray diffraction. Our measurements show that the elastic behaviour of (Al,Fe)-bearing bridgmanite is markedly different from the behaviour of the MgSiO3 endmember. We use our data to model seismic wave velocities in the top portion of the lower mantle, assuming a pyrolitic mantle composition and accounting for depth-dependent changes in iron partitioning between bridgmanite and ferropericlase. We find excellent agreement between our mineral physics predictions and the seismic Preliminary Reference Earth Model down to at least 1,200 kilometres depth, indicating chemical homogeneity of the upper and shallow lower mantle. A high Fe3+/Fe2+ ratio of about two in shallow-lower-mantle bridgmanite is required to match seismic data, implying the presence of metallic iron in an isochemical mantle. Our calculated velocities are in increasingly poor agreement with those of the lower mantle at depths greater than 1,200 kilometres, indicating either a change in bridgmanite cation ordering or a decrease in the ferric iron content of the lower mantle.
Bumblebee family lineage survival is enhanced in high-quality landscapes
Claire Carvell, Andrew F. G. Bourke, Stephanie Dreier et al.
（导读 许雅澜） 研究人员分析了三个大黄蜂物种的野生种群家系在一年间的存活状况，结果表明，从夏季工蜂到翌年春天的蜂后阶段，存活家系随种群周边高价值觅食地比例的增加而显著增加，这说明栖息地品质对大黄蜂种群的生存和留存有影响，也支持了增加花卉资源的保护干预措施对农业景观中野生传粉昆虫具有积极影响的观点。
Insect pollinators such as bumblebees (Bombus spp.) are in global decline. A major cause of this decline is habitat loss due to agricultural intensification. A range of global and national initiatives aimed at restoring pollinator habitats and populations have been developed. However, the success of these initiatives depends critically upon understanding how landscape change affects key population-level parameters, such as survival between lifecycle stages, in target species. This knowledge is lacking for bumblebees, because of the difficulty of systematically finding and monitoring colonies in the wild. We used a combination of habitat manipulation, land-use and habitat surveys, molecular genetics and demographic and spatial modelling to analyse between-year survival of family lineages in field populations of three bumblebee species. Here we show that the survival of family lineages from the summer worker to the spring queen stage in the following year increases significantly with the proportion of high-value foraging habitat, including spring floral resources, within 250–1,000 m of the natal colony. This provides evidence for a positive impact of habitat quality on survival and persistence between successive colony cycle stages in bumblebee populations. These findings also support the idea that conservation interventions that increase floral resources at a landscape scale and throughout the season have positive effects on wild pollinators in agricultural landscapes.
Phytoplankton can actively diversify their migration strategy in response to turbulent cues
Anupam Sengupta, Francesco Carrara & Roman Stocker
（导读 许雅澜） 研究人员发现，海洋湍流反复翻转时，向上游的一群浮游植物迅速分为向上和向下游的两小群。该行为伴随着细胞前后不对称性的调节，这与翻转后细胞应激反应增强、湍流对运动型浮游植物有害的观察结果，共同指明了种群内采取多样化的迁移方向以尽可能躲避湍流的积极适应，在一定程度上暗示了进化中的“两面下注”。
Marine phytoplankton inhabit a dynamic environment where turbulence, together with nutrient and light availability, shapes species fitness, succession and selection. Many species of phytoplankton are motile and undertake diel vertical migrations to gain access to nutrient-rich deeper layers at night and well-lit surface waters during the day. Disruption of this migratory strategy by turbulence is considered to be an important cause of the succession between motile and non-motile species when conditions turn turbulent. However, this classical view neglects the possibility that motile species may actively respond to turbulent cues to avoid layers of strong turbulence. Here we report that phytoplankton, including raphidophytes and dinoflagellates, can actively diversify their migratory strategy in response to hydrodynamic cues characteristic of overturning by Kolmogorov-scale eddies. Upon experiencing repeated overturning with timescales and statistics representative of ocean turbulence, an upward-swimming population rapidly (5–60 min) splits into two subpopulations, one swimming upward and one swimming downward. Quantitative morphological analysis of the harmful-algal-bloom-forming raphidophyte Heterosigma akashiwo together with a model of cell mechanics revealed that this behaviour was accompanied by a modulation of the cells’ fore–aft asymmetry. The minute magnitude of the required modulation, sufficient to invert the preferential swimming direction of the cells, highlights the advanced level of control that phytoplankton can exert on their migratory behaviour. Together with observations of enhanced cellular stress after overturning and the typically deleterious effects of strong turbulence on motile phytoplankton, these results point to an active adaptation of H. akashiwo to increase the chance of evading turbulent layers by diversifying the direction of migration within the population, in a manner suggestive of evolutionary bet-hedging. This migratory behaviour relaxes the boundaries between the fluid dynamic niches of motile and non-motile phytoplankton, and highlights that rapid responses to hydrodynamic cues are important survival strategies for phytoplankton in the ocean.
A new hypothesis of dinosaur relationships and early dinosaur evolution
Matthew G. Baron, David B. Norman & Paul M. Barrett（封面文章）
For 130 years, dinosaurs have been divided into two distinct clades—Ornithischia and Saurischia. Here we present a hypothesis for the phylogenetic relationships of the major dinosaurian groups that challenges the current consensus concerning early dinosaur evolution and highlights problematic aspects of current cladistic definitions. Our study has found a sister-group relationship between Ornithischia and Theropoda (united in the new clade Ornithoscelida), with Sauropodomorpha and Herrerasauridae (as the redefined Saurischia) forming its monophyletic outgroup. This new tree topology requires redefinition and rediagnosis of Dinosauria and the subsidiary dinosaurian clades. In addition, it forces re-evaluations of early dinosaur cladogenesis and character evolution, suggests that hypercarnivory was acquired independently in herrerasaurids and theropods, and offers an explanation for many of the anatomical features previously regarded as notable convergences between theropods and early ornithischians.
Root microbiota drive direct integration of phosphate stress and immunity
Gabriel Castrillo, Paulo José Pereira Lima Teixeira, Sur Herrera Paredes …Jeffery L. Dangl
（导读 郭思瑶） 微生物和植物竞争土壤中营养，但其也有利于提高植物产量。研究人员发现调控植物磷酸盐胁迫应答的遗传网络，会影响植物对微生物的识别以及微生物群落的结构，建立了将拟南芥磷酸盐胁迫应答与微生物识别相联系的分子机制 。
Plants live in biogeochemically diverse soils with diverse microbiota. Plant organs associate intimately with a subset of these microbes, and the structure of the microbial community can be altered by soil nutrient content. Plant-associated microbes can compete with the plant and with each other for nutrients, but may also carry traits that increase the productivity of the plant. It is unknown how the plant immune system coordinates microbial recognition with nutritional cues during microbiome assembly. Here we establish that a genetic network controlling the phosphate stress response influences the structure of the root microbiome community, even under non-stress phosphate conditions. We define a molecular mechanism regulating coordination between nutrition and defence in the presence of a synthetic bacterial community. We further demonstrate that the master transcriptional regulators of phosphate stress response in Arabidopsis thaliana also directly repress defence, consistent with plant prioritization of nutritional stress over defence. Our work will further efforts to define and deploy useful microbes to enhance plant performance.
Complex multi-enhancer contacts captured by genome architecture mapping
Robert A. Beagrie, Antonio Scialdone, Markus Schueler …Mario Nicodemi & Ana Pombo
（导读 卓思琪） 本文报道了对细胞核内全基因组基因间空间相互作用的测量方法：基因组结构测绘（GAM）。研究利用GAM测绘了小鼠胚胎干细胞，发现序列上距离较远的活性基因和增强子间有复杂的相互作用，其中包含众多三组基因或增强子间的相互作用。这些结果说明活跃表达的基因会参与更多的基因/增强子间相互作用。
The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.
KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks
Michaël Imbeault, Pierre-Yves Helleboid & Didier Trono
（导读 陈月欣） 人类基因组中所含的KRAB锌指蛋白（KZFP）可能参与抑制胚胎干细胞中转座子的活性。本研究结合系统发生树与基因组学发现，KZFP蛋白家族非常古老，而且KZFP的靶点不仅限于有转座活性的转座子，还可以利用失去活性的转座子调控其他转录元件的活性。这些结果说明KZFP通过转座子参与表观遗传调控。
The human genome encodes some 350 Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the products of a rapidly evolving gene family that has been traced back to early tetrapods. The function of most KZFPs is unknown, but a few have been demonstrated to repress transposable elements in embryonic stem (ES) cells by recruiting the transcriptional regulator TRIM28 and associated mediators of histone H3 Lys9 trimethylation (H3K9me3)-dependent heterochromatin formation and DNA methylation. Depletion of TRIM28 in human or mouse ES cells triggers the upregulation of a broad range of transposable elements, and recent data based on a few specific examples have pointed to an arms race between hosts and transposable elements as an important driver of KZFP gene selection. Here, to obtain a global view of this phenomenon, we combined phylogenetic and genomic studies to investigate the evolutionary emergence of KZFP genes in vertebrates and to identify their targets in the human genome. First, we unexpectedly reassigned the root of the family to a common ancestor of coelacanths and tetrapods. Second, although we confirmed that the majority of KZFPs bind transposable elements and pinpoint cases of ongoing co-evolution, we found that most of their transposable element targets have lost all transposition potential. Third, by examining the interplay between human KZFPs and other transcriptional modulators, we obtained evidence that KZFPs exploit evolutionarily conserved fragments of transposable elements as regulatory platforms long after the arms race against these genetic invaders has ended. Together, our results demonstrate that KZFPs partner with transposable elements to build a largely species-restricted layer of epigenetic regulation.
Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1
Vaishnav Krishnan, David C. Stoppel, Yi Nong …Matthew P. Anderson
（导读 卓思琪） 中脑腹侧被盖区（VTA）谷氨酸能神经元的突触组织Cbln1受损会影响社交能力。本研究利用小鼠体内遗传学手段，发现增加的UBE3A基因量下调Cbln1；癫痫发作也会产生Cbln1抑制，并伴随着UBE3A上升。该研究扩展了自闭症蛋白网络，暗示VTA谷氨酸神经元中基因与癫痫的相互作用能抑制Cbln1，从而损坏社交能力。
Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes an ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a–seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.
Early antibody therapy can induce long-lasting immunity to SHIV
Yoshiaki Nishimura, Rajeev Gautam, Tae-Wook Chun …Michel C. Nussenzweig & Malcolm A. Martin
（导读 郭思瑶） 研究人员发现在猕猴/人免疫缺陷病毒(SHIV)模型中，高效广谱抗HIV-1中和抗体(bNAbs)的早期服用与持续病毒血症的极低水平相关，由此可建立T细胞免疫并长期控制感染。结果显示急性SHIV感染的被动免疫疗法与抗逆转录病毒联合疗法不同，前者可帮助CD8+T细胞免疫的产生，从而长期抑制病毒复制。
Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074. Viraemia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.
CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses
CD32a是CD4 T 细胞携带具有复制活性HIV前病毒的标志
Benjamin Descours, Gaël Petitjean, José-Luis López-Zaragoza …Monsef Benkirane
（导读 严冰） HIV感染一些CD4 T细胞后不裂解细胞而进入潜伏期，是治疗HIV的一大难题。本研究扫描这些T细胞，发现其中跨膜蛋白CD32a表达上调最甚。接受抗反转录病毒治疗的病人体内，0.012% CD4 T细胞表达CD32a，这些细胞含有多达3倍的HIV DNA拷贝。特异性靶向并消除CD32a+的CD4 T细胞可能有助于HIV的治愈。
The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.
DND1 maintains germline stem cells via recruitment of the CCR4–NOT complex to target mRNAs
Masashi Yamaji, Miki Jishage, Cindy Meyer …Markus Hafner & Thomas Tuschl
（导读 陈月欣） RNA结合蛋白DND1有助于维持原始生殖干细胞（PGC）活性及抑制小鼠生殖细胞肿瘤形成。本研究发现，DND1可识别未转录mRNA特定区域并招募CCR4-NOT，帮助降解目标mRNA。其中涉及到的mRNA参与调控细胞凋亡、炎症及干细胞多能性等，暗示DND1可能参与细胞分化的精确调控。
The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3′ untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4–NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.
RNA m6A methylation regulates the ultraviolet-induced DNA damage response
Yang Xiang, Benoit Laurent, Chih-Hung Hsu …Yang Shi（施扬，波士顿儿童医院）
（导读 严冰） 紫外线导致的DNA损伤会迅速引起该位点的RNA发生m6A甲基化，这是DNA损伤反应中重要的一步。该甲基化修饰多发生于转录子的poly-A尾端，由转甲基酶METTL3和脱甲基酶FTO调控，可引导DNA聚合酶κ（Pol κ）迅速定位到DNA损伤位点，进行修复。
Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m6A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) and the demethylase FTO (fat mass and obesity-associated protein). In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m6A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase. DNA polymerase κ (Pol κ), which has been implicated in both nucleotide excision repair and trans-lesion synthesis, required the catalytic activity of METTL3 for immediate localization to ultraviolet-induced DNA damage sites. Importantly, Pol κ overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m6A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m6A RNA serves as a beacon for the selective, rapid recruitment of Pol κ to damage sites to facilitate repair and cell survival.
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