《自然》（20190207出版）一周論文導讀

知識 02-08

翻譯 |唐一塵

Nature, 7 February 2019, Volume 566 Issue 7742

《自然》2019年2月7日第7742期566卷

《自然》（20190207出版）一周論文導讀

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環境Environment

Global environmental consequences of twenty-first-century ice-sheet melt

21世紀冰蓋融化的全球環境影響

作者：Nicholas R. Golledge、Elizabeth D. Keller、Natalya Gomez、Kaitlin A. Naughten、Jorge Bernales、Luke D. Trusel、Tamsin L. Edwards

鏈接：

https://www.nature.com/articles/s41586-019-0889-9

摘要：

目前，各國政府承諾到2100年，將保持地球表面溫度比工業化前水平上升3至4攝氏度，而這將導致冰蓋進一步融化。耦合模型相互比較項目第5階段並沒有明確地將冰蓋排放包括在內，因此目前政府政策制定的最常用模擬方法並沒有涉及冰蓋融化對氣候的影響。

這裡，研究人員使用格陵蘭島和南極洲冰蓋衛星測量數據進行模擬，並增加了格陵蘭島融水將大幅放緩大西洋環流，以及南極洲融水將把溫水困于海平面下等相關數據。

結果顯示，未來冰蓋的融化將加劇全球溫度的變化，到2100年將導致海平面上升25厘米。然而，相關模擬存在不確定性，仍需要繼續進行觀測和多模型評估。

Abstract

Government policies currently commit us to surface warming of three to four degrees Celsius above pre-industrial levels by 2100, which will lead to enhanced ice-sheet melt. Ice-sheet discharge was not explicitly included in Coupled Model Intercomparison Project phase 5, so effects on climate from this melt are not currently captured in the simulations most commonly used to inform governmental policy. Here we show, using simulations of the Greenland and Antarctic ice sheets constrained by satellite-based measurements of recent changes in ice mass, that increasing meltwater from Greenland will lead to substantial slowing of the Atlantic overturning circulation, and that meltwater from Antarctica will trap warm water below the sea surface, creating a positive feedback that increases Antarctic ice loss. In our simulations, future ice-sheet melt enhances global temperature variability and contributes up to 25 centimetres to sea level by 2100. However, uncertainties in the way in which future changes in ice dynamics are modelled remain, underlining the need for continued observations and comprehensive multi-model assessments.

Revisiting Antarctic ice loss due to marine ice-cliff instability

重新考察海洋冰崖不穩定造成的南極冰損失

作者：Tamsin L. Edwards、Mark A. Brandon、Gael Durand、Neil R. Edwards、Nicholas R. Golledge、Philip B. Holden、Isabel J. Nias、Antony J. Payne、Catherine Ritz、Andreas Wernecke

鏈接：

https://www.nature.com/articles/s41586-019-0901-4

摘要：

由於南極洲的融化，人們對本世紀海平面上升的預測範圍從0到1米多不等。最高的預測值是由有爭議的海洋冰崖不穩定性（MICI）假說得出的，該假說認為，由於全球變暖導致的地表和次冰架融化，沿海冰崖在冰架解體後會迅速崩塌。但是人們在現代尚未觀測到MICI，而且還不清楚它是否需要重現過去地質時期的海平面變化。

在這裡，研究人員量化了原始MICI研究的冰蓋建模不確定性，並表明概率分布傾向於較低的值。然而，由於上新世中期、上一個間冰期或1992至2017年的南極冰川消融，MICI不需要重現海平面變化，並且我們發現預測結果與以前的研究一致（95%的小於43厘米）。

研究結論是，由於MICI假設未被準確利用，預測結果高估了本世紀海平面的上升，仍需要更大範圍的冰架脆弱性和冰崖崩塌的觀測模型。

Abstract

Predictions for sea-level rise this century due to melt from Antarctica range from zero to more than one metre. The highest predictions are driven by the controversial marine ice-cliff instability (MICI) hypothesis, which assumes that coastal ice cliffs can rapidly collapse after ice shelves disintegrate, as a result of surface and sub-shelf melting caused by global warming. But MICI has not been observed in the modern era and it remains unclear whether it is required to reproduce sea-level variations in the geological past. Here we quantify ice-sheet modelling uncertainties for the original MICI study and show that the probability distributions are skewed towards lower values (under very high greenhouse gas concentrations, the most likely value is 45 centimetres). However, MICI is not required to reproduce sea-level changes due to Antarctic ice loss in the mid-Pliocene epoch, the last interglacial period or 1992–2017; without it we find that the projections agree with previous studies (all 95th percentiles are less than 43 centimetres). We conclude that previous interpretations of these MICI projections over-estimate sea-level rise this century; because the MICI hypothesis is not well constrained, confidence in projections with MICI would require a greater range of observationally constrained models of ice-shelf vulnerability and ice-cliff collapse.

生物Biology

L1 drives IFN in senescent cells and promotes age-associated inflammation

L1在衰老細胞中驅動IFN並促進年齡相關性炎症

作者：Marco De Cecco、Takahiro Ito、Anna P. Petrashen、Amy E. Elias、Nicholas J. Skvir、Steven W. Criscione、John M. Sedivy，et al

鏈接：

https://www.nature.com/articles/s41586-018-0784-9

摘要：

逆轉錄轉座子在許多層面上是有害的，因此宿主監測系統對這些因子的失效可能會產生負面後果。然而，逆轉錄轉座子活性對衰老和年齡相關疾病的作用尚不清楚。

在本研究中，科學家發現在細胞衰老過程中，L1（也稱為LINE-1）逆轉錄轉座子被轉錄解除抑制，並激活I型干擾素(IFN-I)反應。IFN-I反應是一種晚期衰老的表型，有助於維持衰老相關分泌表型。IFN-I反應由細胞質L1 cDNA觸發，並被L1逆轉錄酶抑製劑拮抗。

而衰老小鼠使用了核苷逆轉錄酶抑製劑拉米夫定後IFN-I的激活和多個組織的年齡相關性炎症降低。研究人員認為，逆轉錄轉座子的激活是無菌炎症的重要組成部分，無菌炎症是衰老的標誌，L1逆轉錄酶是治療年齡相關疾病的相關靶點。

Abstract

Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline

雌性小鼠生殖系中CRISPR-Cas9調節的超孟德爾遺傳

作者：Hannah A. Grunwald、Valentino M. Gantz、Gunnar Poplawski、Xiang-Ru S. Xu、Ethan Bier、Kimberly L. Cooper

鏈接：

https://www.nature.com/articles/s41586-019-0875-2

摘要：

基因驅動能將外源基因快速引入動物群體，並由此消除相關疾病，或者對害蟲和入侵物種進行控制。近年來，高效的基因驅動系統在昆蟲中得到了發展，科學家利用CRISPR-Cas9的序列靶向DNA切割活性和內源性同源導向修復機制，將雜合子基因型轉化為純合子。然而，這種理論尚未在哺乳動物身上得到全面證實。

在這項研究中，研究人員利用CRISPR-Cas9改變雌性小鼠生殖系細胞，從而促進小鼠後代出現白色毛髮和表達一種紅色熒光蛋白。研究人員著重關注了酪氨酸酶的編碼基因（它決定著毛髮顏色）。他們將含有gRNA的基因驅動插入到酪氨酸酶基因的某個外顯子中，gRNA能夠將Cas9引導到酪氨酸酶基因和一個編碼紅色熒光蛋白的基因上。

這些結果證明了CRISPR-Cas9介導系統的可行性，該系統可以在小鼠中對所需等位基因進行編輯，並有可能改變嚙齒類動物模型在基礎和生物醫學研究中的應用。

Abstract

A gene drive biases the transmission of one of the two copies of a gene such that it is inherited more frequently than by random segregation. Highly efficient gene drive systems have recently been developed in insects, which leverage the sequence-targeted DNA cleavage activity of CRISPR–Cas9 and endogenous homology-directed repair mechanisms to convert heterozygous genotypes to homozygosity. If implemented in laboratory rodents, similar systems would enable the rapid assembly of currently impractical genotypes that involve multiple homozygous genes (for example, to model multigenic human diseases). To our knowledge, however, such a system has not yet been demonstrated in mammals. Here we use an active genetic element that encodes a guide RNA, which is embedded in the mouse tyrosinase (Tyr) gene, to evaluate whether targeted gene conversion can occur when CRISPR–Cas9 is active in the early embryo or in the developing germline. Although Cas9 efficiently induces double-stranded DNA breaks in the early embryo and male germline, these breaks are not corrected by homology-directed repair. By contrast, Cas9 expression limited to the female germline induces double-stranded breaks that are corrected by homology-directed repair, which copies the active genetic element from the donor to the receiver chromosome and increases its rate of inheritance in the next generation. These results demonstrate the feasibility of CRISPR–Cas9-mediated systems that bias inheritance of desired alleles in mice and that have the potential to transform the use of rodent models in basic and biomedical research.

Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis

組織曲度和機械張力失衡指導腫瘤形態發生

作者：Hendrik A. Messal、Silvanus Alt、Rute M. M. Ferreira、Christopher Gribben、Victoria Min-Yi Wang、Corina G. Cotoi、Guillaume Salbreux、Axel Behrens

鏈接：

https://www.nature.com/articles/s41586-019-0891-2

摘要：

管狀上皮細胞是器官的基本組成部分，也是腫瘤發生的常見部位。在腫瘤發生過程中，轉化細胞會過度增殖和上皮結構被破壞。然而，決定腫瘤組織形狀異常的生物物理參數是未知的。

本研究在小鼠胰腺中發現，上皮腫瘤的形態是由轉化細胞的細胞支架變化和現有管狀結構的相互作用決定的。為了分析腫瘤發生過程中組織結構的變化，研究人員發展了一種三維全器官成像技術，可以在單細胞解析度下進行組織活檢。研究結果表明，源上皮的直徑決定生長腫瘤的形態。而且，腫瘤生長的不同機制是由於系統的內在物理機制：張力不平衡和組織曲度是上皮性腫瘤發生的基本決定因素。

Abstract

Tubular epithelia are a basic building block of organs and a common site of cancer occurrence. During tumorigenesis, transformed cells overproliferate and epithelial architecture is disrupted. However, the biophysical parameters that underlie the adoption of abnormal tumour tissue shapes are unknown. Here we show in the pancreas of mice that the morphology of epithelial tumours is determined by the interplay of cytoskeletal changes in transformed cells and the existing tubular geometry. To analyse the morphological changes in tissue architecture during the initiation of cancer, we developed a three-dimensional whole-organ imaging technique that enables tissue analysis at single-cell resolution. Oncogenic transformation of pancreatic ducts led to two types of neoplastic growth: exophytic lesions that expanded outwards from the duct and endophytic lesions that grew inwards to the ductal lumen. Myosin activity was higher apically than basally in wild-type cells, but upon transformation this gradient was lost in both lesion types. Three-dimensional vertex model simulations and a continuum theory of epithelial mechanics, which incorporate the cytoskeletal changes observed in transformed cells, indicated that the diameter of the source epithelium instructs the morphology of growing tumours. Three-dimensional imaging revealed that—consistent with theory predictions—small pancreatic ducts produced exophytic growth, whereas large ducts deformed endophytically. Similar patterns of lesion growth were observed in tubular epithelia of the liver and lung; this finding identifies tension imbalance and tissue curvature as fundamental determinants of epithelial tumorigenesis.

天文Astronomy

Formation of massive black holes in rapidly growing pre-galactic gas clouds

在快速增長的前星系氣體雲中大質量黑洞的形成

作者：John H. Wise、John A. Regan、Brian W. O』Shea、Michael L. Norman、Turlough P. Downes、Hao Xu

鏈接：

https://www.nature.com/articles/s41586-019-0873-4

摘要：

大質量星系中心的超大質量黑洞的起源尚不清楚。直接坍縮的黑洞——質量約為太陽1萬倍的超大質量恆星的殘餘——是理想的候選者。然而，它們在早期宇宙中的存在和形成環境仍然存在爭議，而且它們被認為是稀有的，這使得對它們的形成進行建模變得困難。模型表明，無金屬暈中前星系氣體雲的快速坍縮是形成原恆星核的必要條件，而原恆星核隨後將形成一顆超大質量恆星。

在這裡，研究人員報告了早期星系形成的輻射流體動力學模擬，它產生的無金屬暈質量足夠大，並且有足夠高的質量入射率形成超大質量恆星。結果發現，前星系暈及其伴生氣體雲暴露在萊曼—沃納強度下（大約是背景輻射強度的3倍），並且在演化早期經歷至少一個質量快速增長時期，是形成超大質量恆星的理想環境。

這種快速增長導致了大量的動力加熱，放大了源自20千秒差距之外的年輕星系群的萊曼—沃納抑制。結果表明，結構形成的動力學是早期宇宙大質量黑洞形成的主要驅動力，而且大質量黑洞的種子可能比以前認為的更為常見。

Abstract

The origin of the supermassive black holes that inhabit the centres of massive galaxies remains unclear. Direct-collapse black holes—remnants of supermassive stars, with masses around 10,000 times that of the Sun—are ideal seed candidates. However, their very existence and their formation environment in the early Universe are still under debate, and their supposed rarity makes modelling their formation difficult. Models have shown that rapid collapse of pre-galactic gas (with a mass infall rate above some critical value) in metal-free haloes is a requirement for the formation of a protostellar core that will then form a supermassive star. Here we report a radiation hydrodynamics simulation of early galaxy formation that produces metal-free haloes massive enough and with sufficiently high mass infall rates to form supermassive stars. We find that pre-galactic haloes and their associated gas clouds that are exposed to a Lyman–Werner intensity roughly three times the intensity of the background radiation and that undergo at least one period of rapid mass growth early in their evolution are ideal environments for the formation of supermassive stars. The rapid growth induces substantial dynamical heating amplifying the Lyman–Werner suppression that originates from a group of young galaxies 20 kiloparsecs away. Our results strongly indicate that the dynamics of structure formation, rather than a critical Lyman–Werner flux, is the main driver of the formation of massive black holes in the early Universe. We find that the seeds of massive black holes may be much more common than previously considered in overdense regions of the early Universe, with a co-moving number density up to 10?3 per cubic megaparsec.

《自然》（20190207出版）一周論文導讀