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Nature-20170511 審校

時間: 2017年05月22日 | 作者: admin | 來源: 未知

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

【地球科學】亞洲冰川是抵禦乾旱的重要區域

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.

（導讀 吳媛媛）亞洲高山區冰川密度全球最高。研究發現冰川融水可滿足1.36億人基本需求，包括巴基斯坦、塔吉克、土庫曼、烏茲別克和吉爾吉斯斯坦5國市政和工業絕大部分需求，冰川損失造成的水分脅迫會加劇人口增長和耗水經濟的負面影響。

3.5

2 Whole-genome landscapes of major melanoma subtypes

【生物】主要黑色素瘤亞型的全基因組格局

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

圖片來源：nature.com

(導讀 郭思瑤) 黑色素瘤是歐洲人的常見癌症。研究人員報道了皮膚，肢端和粘膜的黑色素瘤亞型細胞全基因組測序結果。皮膚黑色素瘤中多為紫外線導致的新型標誌性突變,而肢端和粘膜的黑色素瘤主要是結構改變和未知病因的突變。該結果顯示了不同腫瘤亞型中多樣的致癌過程，有些與太陽輻射無關，且將致病的可能性擴展至非編碼基因。

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(導讀 郭思瑤) 皮膚黑色素瘤是歐洲人中的常見癌症。研究人員報道了皮膚，肢端和粘膜黑色素瘤細胞的全基因組測序結果。皮膚黑色素瘤細胞中，編碼和非編碼序列都含有大量由紫外線照射導致的突變，而肢端和粘膜黑色素瘤細胞中的主要突變為基因結構改變和未知來源的突變。該結果顯示有些黑色素瘤的發生與太陽輻射無關。

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 included BRAF,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】額葉-丘腦環路持續神經活動的維持

Zengcai V. Guo（清華大學 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.

（導讀 董堃）小鼠前外側運動皮層（ALM）神經元的持續活性與即將發生的動作有關。本研究通過使用光遺傳技術發現與ALM連接的小鼠丘腦神經元也表現出選擇性延遲的持續活性並且這種活性可以預測他們運動的方向。這表明丘腦是運動準備的環路中心並且持續的神經元活化需要多個腦區之間的相互激活。

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

【生物】 可視化並靶向Lgr5 +人結腸癌幹細胞

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

圖片來源：nature.com

(導讀 郭思瑤)癌症幹細胞（CSC）增殖的動態機理與可塑性尚不清楚。研究人員展示了人類LGR5⁺結直腸癌細胞可在癌症組織中充當CSC。選擇性除去類器官中的LGR5⁺CSC可導致腫瘤退化。該研究顯示了CSC的可塑性以及其作為結腸癌靶標的可能。

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】鈣泵晶體結構揭示蛋白質-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.

（導讀 吳媛媛）傳統的X射線結晶學方法無法可視化磷脂雙分子層，很大程度上限制了我們對磷脂和蛋白質-磷脂互作的理解。本研究利用X射線溶劑反差調變的結晶學方法，解析了鈣泵的四種狀態，首次揭示出脂質雙分子層積极參与鈣泵連續構象轉變的動力學過程。

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（導讀 吳媛媛）傳統的X射線晶體學方法無法可視化磷脂雙分子層，很大程度上限制了對磷脂和蛋白質-磷脂互作的理解。本研究利用X射線溶劑反差調變的結晶學方法，解析了鈣泵的四種狀態，首次揭示出脂質雙分子層積极參与鈣泵連續構象轉變的動力學過程。

4.5分（0.5扣標題沒改）

6 Multi-phase volcanic resurfacing at Loki Patera on Io

【天文】木衛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

（導讀 卓思琪）Loki Parera是太陽系裡最強的活火山，其內部是一片圍繞著中心島的火山噴口樣地面。本研究報道了整個地面的溫度和熔岩冷卻年代圖。結果暗示地面的表面重修是個多相過程，該過程中兩個波動圍繞著中心島傳播和匯聚，其不同的傳播速度與開始時間表明了Patera地區熔岩氣體含量、地殼體積密度的不均勻。

The Jovian moon Io hosts the most powerful persistently active volcano in the Solar System, Loki Patera^{1, 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 process^{4, 5, 6, 7, 8, 9}, which has been seen to occur typically every one to three years since the 1980s^{5, 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 patera^{5, 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】單分子離子單一量子力學狀態的製備與相干操控

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

（導讀 卓思琪）原子的激光冷卻和捕獲技術已相對成熟，但分子的激光冷卻和捕獲較為困難，這是由於分子的量子力學狀態難以控制。本文利用量子邏輯光譜學技術，實現了對帶電分子離子單一量子力學狀態的製備、檢測和控制。該技術是向精確分子光譜、量子計算等應用邁出的重要一步。

4分（金老師忙直播，我看不懂亂改的。去掉了些細節，多寫了寫解決了什麼問題）

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.

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

【材料】光照對金屬鹵化物鈣鈦礦薄膜形成的影響

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

（導讀 卓思琪）優化金屬鹵化物鈣鈦礦薄膜的形態對太陽電池性能的提升十分重要。本研究發現順序沉積和反溶劑法中，光照對鈣鈦礦的形成以及薄膜的形態都有著重要的影響。光照條件下，順序沉積法製備薄膜的速度更快、形態更優，使太陽能電池效率提高；相反，反溶劑法則在暗處才能製備出最好的薄膜。

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 deposition^{6, 7}and anti-solvent methods^{1, 8}. Earlier studies have looked at the influence of reaction conditions on film quality³, such as the concentration of the reactants^{9, 10}and 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 performance^{2, 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

【化學】脫羧烯基化反應

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

（導讀 卓思琪）本文描述了一種利用烷基羧酸這一常見模塊進行烯烴合成的方法。該反應可由醯胺鍵合成的原理來解釋，在鎳或鐵的催化下，烷基羧酸脫掉羧基，並與有機鋅衍生烯烴的烯基相連接。研究者利用一系列烷基羧酸底物製備了60多種烯烴，並通過10個家族16鐘不同天然產物的製備說明，該反應可以對逆合成分析法進行簡化。

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依賴的血管發育的代謝調控

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

（導讀 卓思琪）纖維細胞生長因子（FGFs）與血管發育的關係少有人知。本研究發現FGF受體（FGFR）信號通過糖酵解己糖激酶（HK2）調控內皮細胞的增殖和遷移。而HK2過表達能部分挽救抑制FGF信號帶來的損害。因此，FGF依賴的內皮細胞糖酵解調節是血管發育的關鍵過程。

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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 metabolism^{2, 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】人類多能幹細胞反覆地獲得和擴大P53顯性負性突變

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 culture^{1, 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.

（導讀 吳媛媛）人類多能幹細胞的不斷自我更新特性有利於臨床再生性治療，而這與產生具有生長優勢的突變相關。本研究通過對140種不同的人類胚胎幹細胞進行測序和分析已發表的測序數據，發現有多個幹細胞帶有P53基因的顯性負性突變，且在正常培養條件下具有生長優勢。研究人員建議在將幹細胞投入基礎研究或臨床應用之前必須進行基因檢測的篩查。

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

【生物】Wnt激動劑替代品模擬經典Wnt和β-連環蛋白信號

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

（導讀 卓思琪）Wnt蛋白通過Wnt受體Frizzled（FZD）以及共受體LRP5和LRP6誘導β-連環蛋白信號來調節細胞增殖分化。本研究開發了Wnt激動劑替代品：水溶性FZD–LRP5/LRP6異二聚體形成促進劑。這些替代品具有FZD選擇性，並能在小鼠肝臟中系統表達並表現出Wnt活性。該研究表明經典的Wnt信號能由誘導受體二聚化的雙特異性配體所激活。此外，還推進了Wnt信號的研究以及Wnt激動劑在再生醫學上的應用。

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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 +小腸幹細胞自我更新中Wnt和R-螺旋體配體的非等價性

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

（導讀 卓思琪）本文揭示了Wnt和RSP0配體在腸隱窩幹細胞（ISCs）環境中存在不同性質的功能。Wnt蛋白不能誘導Lgr5+ ISCs自我更新，但卻能讓RSP0受體表達，從而使RSP0配體驅動並指定幹細胞的擴增程度。這兩種配體間功能上非等效，但卻相互合作，是哺乳動物幹細胞調節的先驅，對組織再生的精確控制具有廣泛的影響。

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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 transactivation^{1, 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 ligands^{2, 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 classes^{10, 11, 12, 13}, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growthin vitroand Lgr5⁺ISCsin vivo^{8, 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】抗原特異性調節性T細胞在HLA連鎖自身免疫疾病中的保護作用

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

（導讀 嚴冰）自身免疫疾病的易感性與HLA等位基因有關。在CD4+ T細胞主導的肺出血-腎炎綜合征(Goodpasture綜合征)中，HLA等位基因DR15與DR1分別為該疾病的易感基因與保護基因，表現出不同的多肽特性與結合偏好，將疾病涉及的主要自身表位α3_135–145呈現在不同的結合區域，以誘導不同亞型的T細胞。其中DR1誘導形成的調節性T細胞是是否形成自身免疫疾病的決定性因素。

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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 ? extends model of transcription initiation complex

【生物】3.4?的核心中介體結構擴展了轉錄起始複合體的模型

Kayo Nozawa, Thomas R. Schneider & Patrick Cramer

（導讀 卓思琪）中介體是一種連接著轉錄起始前複合物（PIC）的多蛋白共激活因子，其頭部和中間的模塊組成重要核心中介體（cMed）。本文報道了解析度3.4?下粟酒裂殖酵母（Schizosaccharomyces pombe）的15亞基cMed的晶體結構。結合核心PIC（cPIC）的3.6?低溫電子顯微鏡結構，可推斷模塊間的相互作用，為理解中介體提供了框架。

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Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II^{1, 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 Mediator^{5, 8, 9, 10}and its position on the PIC⁵are known, but atomic details are limited to Mediator subcomplexes^{11, 12}. Here we report the crystal structure of the 15-subunit cMed fromSchizosaccharomyces pombeat 3.4 ? resolution. The structure shows an unaltered head module^{13, 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 ? 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.

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