《自然》（20190418出版）一周論文導讀

翻譯 | 唐一塵

Nature, 18 April 2019, Volume 568 Issue 7752

《自然》2019年4月18日，第7752期568卷

生物學Biology

Restoration of brain circulation and cellular functions hours post-mortem

死亡數小時後腦循環和細胞功能恢復

作者：Zvonimir Vrselja、Zhao Liu、Stephen G.Waxman、Nenad Sestan，et al

鏈接：

https://www.nature.com/articles/s41586-019-1099-1

摘要：

哺乳動物大腦對供氧水平下降極其敏感；短時的血流中斷可引起氧氣和能量存儲快速消耗，據信這會引起神經元死亡和不可修復的腦損傷。

但這種損傷級聯反應在血流中斷後的短時間內是否不可避免？

本研究開發了BrainEx系統，旨在正常體溫下模擬脈動血流。

在該研究中，32個來自食品加工廠的豬腦在死亡數小時之後被接入BrainEx系統。作者觀察發現，在6個小時的灌注期內，細胞死亡有所減少，而且發現了部分細胞功能（包括突觸活性）得到恢復的證據。

但是，實驗期間沒有發現全網路活動或全腦功能的證據。

這表明，大腦擁有的細胞恢復功能強於此前預期，而血流中斷後的細胞功能退化可能是一個緩慢而非快速的過程。

Abstract

The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extra corporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vasculardilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocortic ographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an under appreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.

Nitrosative stress drives heart failure with preserved ejection fraction

亞硝化應激能導致射血分數保留的心力衰竭

作者：Gabriele G. Schiattarella、Francisco Altamirano、Thomas G.Gillette、Joseph A.Hill，etal

鏈接：

https://www.nature.com/articles/s41586-019-1100-z

摘要：

射血分數保留的心力衰竭（HfpEF）是一種常見的高發病率和高死亡率的綜合征，目前尚無循證治療。

在HFpEF中，心肌變得太僵硬而不能有效地泵血。大多數HFpEF患者肥胖，患有糖尿病，並患有代謝綜合征。

之前的HFpEF心力衰竭模型側重於提高一種稱為一氧化氮合酶的酶的水平。

研究人員在小鼠中使用高脂肪飲食和抑制組成型一氧化氮合酶的Nω-硝基-L-精氨酸甲酯，可以引起代謝和高血壓壓力，重現HFpEF在人體中的全身和心血管疾病特徵。

研究人員發現，在HFpEF中，X-盒結合蛋白1（XBP1）的剪接形式的表達減少，XBP1的減少是由誘導型一氧化氮合酶（iNOS）的活性增加和內切核酸酶肌醇需要蛋白1α的S-亞硝基化引起的，最終導致XBP1剪接缺陷。

iNOS的藥理學或遺傳抑制，或XBP1的心肌細胞限制性過表達，各自改善了HFpEF表型。

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are noevidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice—elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-argininemethyl ester (L-NAME)—recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced inthe myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, orcardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α–XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

Stem cell competition orchestrates skin homeostasis and ageing

幹細胞競爭協調皮膚的穩態和老化

作者：Nan Liu、Hiroyuki Matsumura、Tomoki Kato、Emi K.Nishimura，etal

鏈接：

https://www.nature.com/articles/s41586-019-1085-7

摘要：

皮膚老化的特徵包括皮膚變薄、脆弱、傷口癒合延遲以及皮膚細胞（如角化細胞和黑素細胞）含量減少。

本研究顯示，由膠原蛋白COL17A1驅動的幹細胞間競爭對於維持小鼠的「年輕態」皮膚至關重要，但是隨著時間的推移，這種競爭也會導致皮膚老化。

幹細胞間競爭指一些幹細胞的無性系後代生長超越另一些幹細胞的無性系後代，這一現象對於維持組織健康具有一定影響。

這裡，科學家研究了幹細胞間競爭在小鼠尾部皮膚老化中的作用，小鼠尾巴上的皮膚與人類皮膚有很多共同點，而且也以類似的方式老化。

研究表明幹細胞間競爭由膠原蛋白COL17A1驅動，而COL17A1的表達隨著年齡的增長而下降，並在不同幹細胞間存在差異，COL17A1表達水平較高的幹細胞會牢固地錨定於基底膜，且對稱分裂，會將附近COL17A1表達水平較低的細胞排擠出去。

這樣的細胞間競爭有助於維持皮膚的整體結構和完整性。但是，COL17A1的表達會隨年齡增長而下降，也會因為應激（如氧化或紫外線輻射）而下降。

最終，所有幹細胞中的COL17A1表達水平都下降，皮膚隨之老化。

研究人員還鑒定出了兩種能維持人體角化細胞內COL17A1表達的化合物——Y27632和夾竹桃麻素。這類藥物也可以促進小鼠的傷口癒合。

Abstract

Stem cells underlie tissue homeostasis, but their dynamics during ageing—and the relevance of these dynamics to organ ageing—remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermalstem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 inindividual stem cells generates a driving force for cell competition. In vivoclonal analysis in mice and in vitro 3D modelling show that clones that express high levels of COL17A1, which divide symmetrically, outcompete and eliminate adjacent stressed clones that express low levels of COL17A1, which divide asymmetrically. Stem cells with higher potential or quality are thus selected for homeostasis, but their eventual loss of COL17A1 limits their competition, thereby causing ageing. The resultant hemidesmosome fragility and stem celldelamination deplete adjacent melanocytes and fibroblasts to promote skinageing. Conversely, the forced maintenance of COL17A1 rescues skin organageing, thereby indicating potential angles for anti-ageing the rapeutic intervention.

全球變暖Global warming

Global glacier mass changes and their contributions to sea-level rise from 1961 to 2016

1961年至2016年全球冰川質量變化及其對海平面上升的影響

作者：M. Zemp、M. Huss、L. Thomson、J. G. Cogley，et al

鏈接：

https://www.nature.com/articles/s41586-019-1071-0

摘要：

剔除格陵蘭島和南極的冰蓋，全球冰川體積估計為17萬立方千米。但是，受方法上的限制，一直難以準確確定冰川體積和質量的變化對海平面上升有何影響。

本研究採用基於兩種不同方法收集到的關於1.9萬座冰川的觀測數據，確定1961年至2016年的冰川質量變化。

結果表明，冰川促使同期的全球海平面平均上升了約27毫米。之後，研究人員計算了2006年至2016年的冰川質量變化速率，發現在此10年間，冰川就使海平面每年上升了近1毫米。

這意味著當前冰川推升海平面的速率與格陵蘭島冰蓋相當，但是超過了南極冰蓋。

研究人員認為部分山脈的冰川到2100年可能會幾近消失（包括高加索、中歐、西加拿大、美國和紐西蘭的山脈）。但是，冰川數量眾多的區域將在本世紀之後繼續推動海平面上升。

Abstract

Glaciers distinct from the Greenland and Antarctic icesheets cover an area of approximately 706,000 square kilometres globally, with an estimated total volume of 170,000 cubic kilometres, or 0.4 metres ofpotential sea-level-rise equivalent. Retreating and thinning glaciers are iconsof climate change and affect regional runoff as well as global sea level. In past reports from the Intergovernmental Panel on Climate Change, estimates of changes in glacier mass were based on the multiplication of averaged or interpolated results from available observations of a few hundred glaciersby defined regional glacier areas. For data-scarce regions, these results had to be complemented with estimates based on satellite altimetry and gravimetry. These past approaches were challenged by the small number and heterogeneous spatiotemporal distribution of in situ measurement series and their often unknown ability to represent their respective mountain ranges, as well as by the spatial limitations of satellite altimetry (for which only point data are available) and gravimetry (with its coarse resolution). Here we use an extrapolation of glaciological and geodetic observations to show that glaciers contributed 27 ± 22 millimetres to global mean sea-level rise from 1961 to 2016. Regional specific-mass-change rates for 2006–2016 range from ?0.1metres to ?1.2 metres of water equivalent per year,resulting in a global sea-level contribution of 335 ± 144 gigatonnes, or 0.92 ± 0.39millimetres, per year. Although statistical uncertainty ranges overlap, our conclusions suggest that glacier mass loss may be larger than previously reported. The present glacier mass loss is equivalent to the sea-level contribution of the Greenland Ice Sheet, clearly exceeds the loss from the Antarctic Ice Sheet, and accounts for 25 to 30 per cent of the total observed sea-level rise. Present mass-loss rates indicate that glaciers could almost disappear in some mountain ranges in this century, while heavily glacierized regions will continue to contribute to sea-level rise beyond 2100.

Global warming impairs stock–recruitment dynamics of corals

全球變暖影響珊瑚種群更新

作者：Terry P. Hughes、James T. Kerry、Andrew H. Baird、Sean R. Connolly，et al

鏈接：

https://www.nature.com/articles/s41586-019-1081-y

摘要：

大堡礁在過去20年里經歷了4次大規模的白化事件；在正常的溫室氣體排放場景下，預計從2035年起大堡礁每十年會發生兩次白化事件，從2044年起則每年都會發生。

這裡，科學家研究了2016年和2017年大規模珊瑚白化事件發生前後，成體珊瑚存量和幼體珊瑚補充量之間的關係。

他們發現成體珊瑚減損與幼體珊瑚補充量銳減相關，而且新補充的珊瑚物種組成發生了變化。孵育型珊瑚將受精後發育形成的幼蟲排出體外，這些幼蟲一般在1天內附著，而排放型珊瑚會排出精子和卵子進行外部受精，幼蟲一般在4-7天後附著。

在貧乏的補充池中，主導種群是來自本地的孵育型珊瑚，而非更加分散和多樣化的排放型珊瑚。幼體珊瑚補充的種類變化將影響恢復中的珊瑚組合的構成，也可能影響它們應對未來白化事件的能力。

Abstract

Changes in disturbance regimes due to climate change are increasingly challenging the capacity of ecosystems to absorb recurrent shocks and reassemble afterwards, escalating the risk of widespread ecological collapse of current ecosystems and the emergence of novel assemblages. In marine systems, the production of larvae and recruitment of functionally important species are fundamental processes for rebuilding depleted adult populations, maintaining resilience and avoiding regime shifts in the face ofrising environmental pressures. Here we document a regional-scale shift instock–recruitment relationships of corals along the Great Barrier Reef—the world』slargest coral reef system—following unprecedented back-to-back mass bleaching events caused by global warming. As a consequence of mass mortality of adult brood stock in 2016 and 2017 owing to heat stress, the amount of larval recruitment declined in 2018 by 89% compared to historical levels. For the first time, brooding pocilloporids replaced spawning acroporids as the dominant taxon in the depleted recruitment pool. The collapse in stock–recruitment relationships indicates that the low resistance of adult brood stocks to repeated episodes of coral bleaching is inexorably tied to animpaired capacity for recovery, which highlights the multifaceted processes that underlie the global decline of coral reefs. The extent to which the Great Barrier Reef will be able to recover from the collapse in stock–recruitment relationships remains uncertain, given the projected increased frequency of extreme climate events over the next two decades.

可持續發展

Sustainable Development

Mapping changes in housing in sub-Saharan Africa from 2000 to 2015

繪製2000年至2015年撒哈拉以南非洲地區住房的變化

作者：Lucy S. Tusting、Donal Bisanzio、Graham Alabaster、Samir Bhatt，et al

鏈接：

https://www.nature.com/articles/s41586-019-1050-5

摘要：

獲得適當住房是一項基本人權，對人類安全、營養和健康至關重要，也是聯合國可持續發展目標的核心目標。

從全球來看，住房需求在非洲最為迫切，到2050年，非洲人口將增加1倍以上。然而，關於非洲各地住房質量的現有數據主要限於城市地區。

在這裡，研究人員結合地理統計框架內的國家調查數據，量化了2000年至2015年撒哈拉以南非洲地區的住房變化。

結果顯示，2000年至2015年，撒哈拉以南非洲城市和農村的住房發生了顯著轉變，改善住房（改善水和衛生設施、充足的居住面積和耐用建築）的普及率從約11%翻了一番，達到約23%。然而，在2015年，5300萬非洲城市居民住在沒有改善的住房中。

該研究為指導實現可持續發展目標的干預提供了機制。

Abstract

Access to adequate housing is a fundamental human right, essential to human security, nutrition and health, and a core objective of the United Nations Sustainable Development Goals. Globally, the housing needis most acute in Africa, where the population will more than double by 2050. However, existing data on housing quality across Africa are limited primarily to urban areas and are mostly recorded at the national level. Here we quantify changes in housing in sub-Saharan Africa from 2000 to 2015 by combining national survey data within a geostatistical framework. We show a marked transformation of housing in urban and rural sub-Saharan Africa between 2000 and 2015, with the prevalence of improved housing (with improved water and sanitation, sufficient living area and durable construction) doubling from 11% (95% confidence interval, 10–12%) to 23% (21–25%). However, 53 (50–57) million urban Africans (47% (44–50%) of the urban population analysed) were living in unimproved housing in 2015. We provide high-resolution, standardized estimates of housing conditions across sub-Saharan Africa. Our maps provide a baseline for measuring change and a mechanism to guide interventions during the era of the Sustainable Development Goals.

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