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Nature-20170511 审校

时间: 2017年05月22日 | 作者: admin | 来源: 未知

1 Asia’s glaciers are a regionally important buffer against drought

【地球科学】亚洲冰川是抵御干旱的重要区域

Hamish D. Pritchard

The high mountains of Asia—encompassing the Himalayas, the Hindu Kush, Karakoram, Pamir Alai, Kunlun Shan, and Tian Shan mountains—have the highest concentration of glaciers globally, and 800 million people depend in part on meltwater from them. Water stress makes this region vulnerable economically and socially to drought, but glaciers are a uniquely drought-resilient source of water. Here I show that these glaciers provide summer meltwater to rivers and aquifers that is sufficient for the basic needs of 136 million people, or most of the annual municipal and industrial needs of Pakistan, Tajikistan, Turkmenistan, Uzbekistan and Kyrgyzstan. During drought summers, meltwater dominates water inputs to the upper Indus and Aral river basins. Uncertainties in mountain precipitation are poorly known, but, given the magnitude of this water supply, predicted glacier loss would add considerably to drought-related water stress. Such additional water stress increases the risk of social instability, conflict and sudden, uncontrolled population migrations triggered by water scarcity, which is already associated with the large and rapidly growing populations and hydro-economies of these basins.

（导读 吴媛媛）亚洲高山区冰川密度全球最高。研究发现冰川融水可满足1.36亿人基本需求，包括巴基斯坦、塔吉克斯坦、土库曼斯坦、乌兹别克斯坦和吉尔吉斯斯坦5国市政和工业绝大部分需求，冰川损失造成的水分胁迫会加剧人口增长和耗水经济的负面影响。

3.5

2 Whole-genome landscapes of major melanoma subtypes

【生物】主要黑色素瘤亚型的全基因组格局

Nicholas K. Hayward, James S. Wilmott, Nicola Waddell…Richard A. Scolyer & Graham J. Mann

图片来源：nature.com

(导读 郭思瑶) 黑色素瘤是欧洲人的常见癌症。研究人员报道了皮肤，肢端和粘膜的黑色素瘤亚型细胞全基因组测序结果。皮肤黑色素瘤中多为紫外线导致的新型标志性突变,而肢端和粘膜的黑色素瘤主要是结构改变和未知病因的突变。该结果显示了不同肿瘤亚型中多样的致癌过程，有些与太阳辐射无关，且将致病的可能性扩展至非编码基因。

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(导读 郭思瑶) 皮肤黑色素瘤是欧洲人中的常见癌症。研究人员报道了皮肤，肢端和粘膜黑色素瘤细胞的全基因组测序结果。皮肤黑色素瘤细胞中，编码和非编码序列都含有大量由紫外线照射导致的突变，而肢端和粘膜黑色素瘤细胞中的主要突变为基因结构改变和未知来源的突变。该结果显示有些黑色素瘤的发生与太阳辐射无关。

4.5分

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes includedBRAF,CDKN2A,NRASandTP53in cutaneous melanoma,BRAF,NRASandNF1in acral melanoma andSF3B1in mucosal melanoma. Mutations affecting theTERTpromoter were the most frequent of all; however, neither they norATRXmutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

3 Maintenance of persistent activity in a frontal thalamocortical loop

【生物】额叶-丘脑环路持续神经活动的维持

Zengcai V. Guo（清华大学 郭增才）, Hidehiko K. Inagaki, Kayvon Daie, Shaul Druckmann, Charles R. Gerfen & Karel Svoboda

Persistent neural activity maintains information that connects past and future events. Models of persistent activity often invoke reverberations within local cortical circuits, but long-range circuits could also contribute. Neurons in the mouse anterior lateral motor cortex (ALM) have been shown to have selective persistent activity that instructs future actions. The ALM is connected bidirectionally with parts of the thalamus, including the ventral medial and ventral anterior–lateral nuclei. We recorded spikes from the ALM and thalamus during tactile discrimination with a delayed directional response. Here we show that, similar to ALM neurons, thalamic neurons exhibited selective persistent delay activity that predicted movement direction. Unilateral photoinhibition of delay activity in the ALM or thalamus produced contralesional neglect. Photoinhibition of the thalamus caused a short-latency and near-complete collapse of ALM activity. Similarly, photoinhibition of the ALM diminished thalamic activity. Our results show that the thalamus is a circuit hub in motor preparation and suggest that persistent activity requires reciprocal excitation across multiple brain areas.

（导读 董堃）小鼠前外侧运动皮层（ALM）神经元的持续活性与即将发生的动作有关。本研究通过使用光遗传技术发现与ALM连接的小鼠丘脑神经元也表现出选择性延迟的持续活性并且这种活性可以预测他们运动的方向。这表明丘脑是运动准备的环路中心并且持续的神经元活化需要多个脑区之间的相互激活。

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4 Visualization and targeting of LGR5+ human colon cancer stem cells

【生物】 可视化并靶向Lgr5 +人结肠癌干细胞

Mariko Shimokawa, Yuki Ohta, Shingo Nishikori…Takanori Kanai & Toshiro Sato

图片来源：nature.com

(导读 郭思瑶)癌症干细胞（CSC）增殖的动态机理与可塑性尚不清楚。研究人员展示了人类LGR5+结直肠癌细胞可在癌症组织中充当CSC。选择性除去类器官中的LGR5+CSC可导致肿瘤退化。该研究显示了CSC的可塑性以及其作为结肠癌靶标的可能。

The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele ofLGR5reveal the self-renewal and differentiation capacity of LGR5+tumour cells. Selective ablation of LGR5+CSCs inLGR5-iCaspase9knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+CSCs and contributing to tumour regrowth after LGR5+CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5+CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.

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5 Protein–phospholipid interplay revealed with crystals of a calcium pump

【生物】钙泵晶体结构揭示蛋白质-磷脂相互作用

Yoshiyuki Norimatsu, Kazuya Hasegawa, Nobutaka Shimizu & Chikashi Toyoshima

The lipid bilayer has so far eluded visualization by conventional crystallographic methods, severely limiting our understanding of phospholipid– and protein–phospholipid interactions. Here we describe electron density maps for crystals of Ca2+-ATPase in four different states obtained by X-ray solvent contrast modulation. These maps resolve the entire first layer of phospholipids surrounding the transmembrane helices, although less than half of them are hydrogen-bonded to protein residues. Phospholipids follow the movements of associated residues, causing local distortions and changes in thickness of the bilayer. Unexpectedly, the entire protein tilts during the reaction cycle, governed primarily by a belt of Trp residues, to minimize energy costs accompanying the large perpendicular movements of the transmembrane helices. A class of Arg residues extend their side chains through the cytoplasm to exploit phospholipids as anchors for conformational switching. Thus, phospholipid–Arg/Lys and phospholipid–Trp interactions have distinct functional roles in the dynamics of ion pumps and, presumably, membrane proteins in general.

（导读 吴媛媛）传统的X射线结晶学方法无法可视化磷脂双分子层，很大程度上限制了我们对磷脂和蛋白质-磷脂互作的理解。本研究利用X射线溶剂反差调变的结晶学方法，解析了钙泵的四种状态，首次揭示出脂质双分子层积极参与钙泵连续构象转变的动力学过程。

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（导读 吴媛媛）传统的X射线晶体学方法无法可视化磷脂双分子层，很大程度上限制了对磷脂和蛋白质-磷脂互作的理解。本研究利用X射线溶剂反差调变的结晶学方法，解析了钙泵的四种状态，首次揭示出脂质双分子层积极参与钙泵连续构象转变的动力学过程。

4.5分（0.5扣标题没改）

6 Multi-phase volcanic resurfacing at Loki Patera on Io

【天文】木卫Io上Loki Patera 火山口的多相表面重修

K. de Kleer, M. Skrutskie, J. Leisenring…C. Veillet & C. E. Woodward

（导读 卓思琪）Loki Parera是太阳系里最强的活火山，其内部是一片围绕着中心岛的火山喷口样地面。本研究报道了整个地面的温度和熔岩冷却年代图。结果暗示地面的表面重修是个多相过程，该过程中两个波动围绕着中心岛传播和汇聚，其不同的传播速度与开始时间表明了Patera地区熔岩气体含量、地壳体积密度的不均匀。

The Jovian moon Io hosts the most powerful persistently active volcano in the Solar System, Loki Patera1,2. The interior of this volcanic, caldera-like feature is composed of a warm, dark floor covering 21,500 square kilometres3surrounding a much cooler central ‘island’4. The temperature gradient seen across areas of the patera indicates a systematic resurfacing process4,5,6,7,8,9, which has been seen to occur typically every one to three years since the 1980s5,10. Analysis of past data has indicated that the resurfacing progressed around the patera in an anti-clockwise direction at a rate of one to two kilometres per day, and that it is caused either by episodic eruptions that emplace voluminous lava flows or by a cyclically overturning lava lake contained within the patera5,8,9,11. However, spacecraft and telescope observations have been unable to map the emission from the entire patera floor at sufficient spatial resolution to establish the physical processes at play. Here we report temperature and lava cooling age maps of the entire patera floor at a spatial sampling of about two kilometres, derived from ground-based interferometric imaging of thermal emission from Loki Patera obtained on 8 March 2015 UT as the limb of Europa occulted Io. Our results indicate that Loki Patera is resurfaced by a multi-phase process in which two waves propagate and converge around the central island. The different velocities and start times of the waves indicate a non-uniformity in the lava gas content and/or crust bulk density across the patera.

Mark: 4/5

7 Preparation and coherent manipulation of pure quantum states of a single molecular ion

【物理】单分子离子单一量子力学状态的制备与相干操控

Chin-wen Chou, Christoph Kurz, David B. Hume, Philipp N. Plessow, David R. Leibrandt & Dietrich Leibfried

（导读 卓思琪）原子的激光冷却和捕获技术已相对成熟，但分子的激光冷却和捕获较为困难，这是由于分子的量子力学状态难以控制。本文利用量子逻辑光谱学技术，实现了对带电分子离子单一量子力学状态的制备、检测和控制。该技术是向精确分子光谱、量子计算等应用迈出的重要一步。

4分（金老师忙直播，我看不懂乱改的。去掉了些细节，多写了写解决了什么问题）

Laser cooling and trapping of atoms and atomic ions has led to advances including the observation of exotic phases of matter, the development of precision sensors and state-of-the-art atomic clocks. The same level of control in molecules could also lead to important developments such as controlled chemical reactions and sensitive probes of fundamental theories, but the vibrational and rotational degrees of freedom in molecules pose a challenge for controlling their quantum mechanical states. Here we use quantum-logic spectroscopy, which maps quantum information between two ion species, to prepare and non-destructively detect quantum mechanical states in molecular ions. We develop a general technique for optical pumping and preparation of the molecule into a pure initial state. This enables us to observe high-resolution spectra in a single ion (CaH+) and coherent phenomena such as Rabi flopping and Ramsey fringes. The protocol requires a single, far-off-resonant laser that is not specific to the molecule, so many other molecular ions, including polyatomic species, could be treated using the same methods in the same apparatus by changing the molecular source. Combined with the long interrogation times afforded by ion traps, a broad range of molecular ions could be studied with unprecedented control and precision. Our technique thus represents a critical step towards applications such as precision molecular spectroscopy, stringent tests of fundamental physics, quantum computing and precision control of molecular dynamics.

洗衣机漏水的一般情况是排水系统存在严重问题，但地盘漏水可能是机器密封性能不够好，或者放水时放入过多，超出了机器的承受能力。

8 The effect of illumination on the formation of metal halide perovskite films

【材料】光照对金属卤化物钙钛矿薄膜形成的影响

Amita Ummadisingu, Ludmilla Steier, Ji-Youn Seo, Taisuke Matsui, Antonio Abate, Wolfgang Tress & Michael Grätzel

（导读 卓思琪）优化金属卤化物钙钛矿薄膜的形态对太阳电池性能的提升十分重要。本研究发现顺序沉积和反溶剂法中，光照对钙钛矿的形成以及薄膜的形态都有着重要的影响。光照条件下，顺序沉积法制备薄膜的速度更快、形态更优，使太阳能电池效率提高；相反，反溶剂法则在暗处才能制备出最好的薄膜。

4.5分

Optimizing the morphology of metal halide perovskite films is an important way to improve the performance of solar cells1when these materials are used as light harvesters2, because film homogeneity is correlated with photovoltaic performance3. Many device architectures and processing techniques have been explored with the aim of achieving high-performance devices4, including single-step deposition5, sequential deposition6,7and anti-solvent methods1,8. Earlier studies have looked at the influence of reaction conditions on film quality3, such as the concentration of the reactants9,10and the reaction temperature11. However, the precise mechanism of the reaction and the main factors that govern it are poorly understood. The consequent lack of control is the main reason for the large variability observed in perovskite morphology and the related solar-cell performance2,3. Here we show that light has a strong influence on the rate of perovskite formation and on film morphology in both of the main deposition methods currently used: sequential deposition and the anti-solvent method. We study the reaction of a metal halide (lead iodide) with an organic compound (methylammonium iodide) using confocal laser scanning fluorescence microscopy and scanning electron microscopy. The lead iodide crystallizes before the intercalation of methylammonium iodide commences, producing the methylammonium lead iodide perovskite. We find that the formation of perovskite via such a sequential deposition is much accelerated by light. The influence of light on morphology is reflected in a doubling of solar-cell efficiency. Conversely, using the anti-solvent method to form methyl ammonium lead iodide perovskite in a single step from the same starting materials, we find that the best photovoltaic performance is obtained when films are produced in the dark. The discovery of light-activated crystallization not only identifies a previously unknown source of variability in opto-electronic properties, but also opens up new ways of tuning morphology and structuring perovskites for various applications.

9 Decarboxylative alkenylation

【化学】脱羧烯基化反应

Jacob T. Edwards, Rohan R. Merchant, Kyle S. McClymont…Martin D. Eastgate & Phil S. Baran

（导读 卓思琪）本文描述了一种利用烷基羧酸这一常见模块进行烯烃合成的方法。该反应可由酰胺键合成的原理来解释，在镍或铁的催化下，烷基羧酸脱掉羧基，并与有机锌衍生烯烃的烯基相连接。研究者利用一系列烷基羧酸底物制备了60多种烯烃，并通过10个家族16钟不同天然产物的制备说明，该反应可以对逆合成分析法进行简化。

4分

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter1. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis2being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

11 FGF-dependent metabolic control of vascular development

【生物】FGF依赖的血管发育的代谢调控

Pengchun Yu, Kerstin Wilhelm, Alexandre Dubrac…Michael Potente & Michael Simons

（导读 卓思琪）纤维细胞生长因子（FGFs）与血管发育的关系少有人知。本研究发现FGF受体（FGFR）信号通过糖酵解己糖激酶（HK2）调控内皮细胞的增殖和迁移。而HK2过表达能部分挽救抑制FGF信号带来的损害。因此，FGF依赖的内皮细胞糖酵解调节是血管发育的关键过程。

4.5/5

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes1. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism2,3, little is understood about the role of fibroblast growth factors (FGFs) in this context4. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specificHk2knockouts phenocopy blood and/or lymphatic vascular defects seen inFgfr1/Fgfr3double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.

12 Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations

【生物】人类多能干细胞反复地获得和扩大P53显性负性突变

Florian T. Merkle, Sulagna Ghosh, Nolan Kamitaki…Steven A. McCarroll & Kevin Eggan

Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture1,2,3. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use4. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line5. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in theTP53gene that encodes the tumour suppressor P53. TheTP53mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that theTP53mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nineTP53mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at theTP53locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.

（导读 吴媛媛）人类多能干细胞的不断自我更新特性有利于临床再生性治疗，而这与产生具有生长优势的突变相关。本研究通过对140种不同的人类胚胎干细胞进行测序和分析已发表的测序数据，发现有多个干细胞带有P53基因的显性负性突变，且在正常培养条件下具有生长优势。研究人员建议在将干细胞投入基础研究或临床应用之前必须进行基因检测的筛查。

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13 Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling

【生物】Wnt激动剂替代品模拟经典Wnt和β-连环蛋白信号

Claudia Y. Janda, Luke T. Dang, Changjiang You…Calvin J. Kuo & K. Christopher Garcia

（导读 卓思琪）Wnt蛋白通过Wnt受体Frizzled（FZD）以及共受体LRP5和LRP6诱导β-连环蛋白信号来调节细胞增殖分化。本研究开发了Wnt激动剂替代品：水溶性FZD–LRP5/LRP6异二聚体形成促进剂。这些替代品具有FZD选择性，并能在小鼠肝脏中系统表达并表现出Wnt活性。该研究表明经典的Wnt信号能由诱导受体二聚化的双特异性配体所激活。此外，还推进了Wnt信号的研究以及Wnt激动剂在再生医学上的应用。

目前市场当中出现了很多家庭影院相关的产品，各大品牌和商家打造家庭影院的名头，混淆了普通投影仪和激光投影仪之间。

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Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues1. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors2, 3, 4. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD–LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

14 Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

【生物】Lgr5 +小肠干细胞自我更新中Wnt和R-螺旋体配体的非等价性

Kelley S. Yan, Claudia Y. Janda, Junlei Chang…K. Christopher Garcia & Calvin J. Kuo

（导读 卓思琪）本文揭示了Wnt和RSP0配体在肠隐窝干细胞（ISCs）环境中存在不同性质的功能。Wnt蛋白不能诱导Lgr5+ ISCs自我更新，但却能让RSP0受体表达，从而使RSP0配体驱动并指定干细胞的扩增程度。这两种配体间功能上非等效，但却相互合作，是哺乳动物干细胞调节的先驱，对组织再生的精确控制具有广泛的影响。

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The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation1,2,3. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors1and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands2,3. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium4—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+intestinal stem cells (ISCs)5,6,7,8,9. R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes10,11,12,13, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growthin vitroand Lgr5+ISCsin vivo8,14,15,16,17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands toin vivocanonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

15 Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

【生物】抗原特异性调节性T细胞在HLA连锁自身免疫疾病中的保护作用

Joshua D. Ooi, Jan Petersen, Yu H. Tan…Jamie Rossjohn & A. Richard Kitching

（导读 严冰）自身免疫疾病的易感性与HLA等位基因有关。在CD4+ T细胞主导的肺出血-肾炎综合征(Goodpasture综合征)中，HLA等位基因DR15与DR1分别为该疾病的易感基因与保护基因，表现出不同的多肽特性与结合偏好，将疾病涉及的主要自身表位α3135–145呈现在不同的结合区域，以诱导不同亚型的T细胞。其中DR1诱导形成的调节性T细胞是是否形成自身免疫疾病的决定性因素。

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Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+T-cell self-epitope derived from the α3 chain of type IV collagen (α3135–145)1, 2, 3, 4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in transwith HLA-DR15 (ref. 2). We show that autoreactive α3135–145-specific T cells expand in patients with Goodpasture disease and, in α3135–145-immunized HLA-DR15 transgenic mice, α3135–145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135–145epitope in different binding registers. HLA-DR15-α3135–145tetramer+T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135–145tetramer+T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+regulatory T cells (Tregcells) expressing tolerogenic cytokines. HLA-DR1-induced Tregcells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+and HLA-DR1+healthy human donors display altered α3135–145-specific T-cell antigen receptor usage, HLA-DR15-α3135–145tetramer+Foxp3−Tconvand HLA-DR1-α3135–145tetramer+Foxp3+CD25hiCD127loTregdominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135–145-specific CD4+T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Tregcells that leads to protection or causation of autoimmunity.

16 Core Mediator structure at 3.4 Å extends model of transcription initiation complex

【生物】3.4Å的核心中介体结构扩展了转录起始复合体的模型

Kayo Nozawa, Thomas R. Schneider & Patrick Cramer

（导读 卓思琪）中介体是一种连接着转录起始前复合物（PIC）的多蛋白共激活因子，其头部和中间的模块组成重要核心中介体（cMed）。本文报道了分辨率3.4Å下粟酒裂殖酵母（Schizosaccharomyces pombe）的15亚基cMed的晶体结构。结合核心PIC（cPIC）的3.6Å低温电子显微镜结构，可推断模块间的相互作用，为理解中介体提供了框架。

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Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II1,2,3. The Mediator head and middle modules form the essential core Mediator (cMed)4,5,6, whereas the tail and kinase modules play regulatory roles7. The architecture of Mediator5,8,9,10and its position on the PIC5are known, but atomic details are limited to Mediator subcomplexes11,12. Here we report the crystal structure of the 15-subunit cMed fromSchizosaccharomyces pombeat 3.4 Å resolution. The structure shows an unaltered head module13,14,15, and reveals the intricate middle module, which we show is globally required for transcription. Sites of known Mediator mutations cluster at the interface between the head and middle modules, and in terminal regions of the head subunits Med6 (ref.16) and Med17 (ref.17) that tether the middle module. The structure led to a model forSaccharomyces cerevisiaecMed that could be combined5with the 3.6 Å cryo-electron microscopy structure of the core PIC (cPIC)18. The resulting atomic model of the cPIC–cMed complex informs on interactions of the submodules forming the middle module, called beam, knob, plank, connector, and hook. The hook is flexibly linked to Mediator by a conserved hinge19and contacts the transcription initiation factor IIH (TFIIH) kinase that phosphorylates the carboxy (C)-terminal domain (CTD) of Pol II and was recently positioned on the PIC20. The hook also contains residues that crosslink to the CTD and reside in a previously described cradle5. These results provide a framework for understanding Mediator function, including its role in stimulating CTD phosphorylation by TFIIH.

电子衣柜会很耗电吗？比想像中省电，因为这些产品都知道变频的压缩机，节电效果还不错。当使用最耗电的消菌功能时，每次大概用0.7度电，约0.5元左右。