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时间: 2017年12月05日 | 作者: admin | 来源: 未知
Nature 20171116 1 【地球科学】 Tidal tomography constrains Earth’s deep-mantle buoyancy Harriet C. P. Lau et. al https://www.nature.com/articles/nature24452 地球固体潮断层摄影成像约束地球深层地幔的浮 力 (导读

Nature 20171116

 

1【地球科学】Tidal tomography constrains Earth’s deep-mantle buoyancy

Harriet C. P. Lau et. al

 

https://www.nature.com/articles/nature24452

 

地球固体潮断层摄影成像约束地球深层地幔的浮

 

(导读 阿金)地球固体潮对非洲和太平洋的两个大型大型低剪切速度带LLSVPs的密度非常敏感,但是对于它们的浮力仍有争议。本研究使用固体潮断层成像,测得LLSVPs的密度要比同等深度地幔的平均密度高0.5%,推测这种高密度化学物质的富集与俯冲的海洋板块或形成地球的原始物质相关。本文对地球系统的长期演化给出动力学新解释。

 

Earth’s body tide—also known as the solid Earth tide, the displacement of the solid Earth’s surface caused by gravitational forces from the Moon and the Sun—is sensitive to the density of the two Large Low Shear Velocity Provinces (LLSVPs) beneath Africa and the Pacific. These massive regions extend approximately 1,000 kilometres upward from the base of the mantle and their buoyancy remains actively debated within the geophysical community. Here we use tidal tomography to constrain Earth’s deep-mantle buoyancy derived from Global Positioning System (GPS)-based measurements of semi-diurnal body tide deformation. Using a probabilistic approach, we show that across the bottom two-thirds of the two LLSVPs the mean density is about 0.5 per cent higher than the average mantle density across this depth range (that is, its mean buoyancy is minus 0.5 per cent), although this anomaly may be concentrated towards the very base of the mantle. We conclude that the buoyancy of these structures is dominated by the enrichment of high-density chemical components, probably related to subducted oceanic plates or primordial material associated with Earth’s formation. Because the dynamics of the mantle is driven by density variations, our result has important dynamical implications for the stability of the LLSVPs and the long-term evolution of the Earth system.

 

 

2 【生物】Regeneration of the entire human epidermis using transgenic stem cells

Tobias Hirsch, et. al

 

https://www.nature.com/articles/nature24487

 

 

使用转基因干细胞再生人类整个表皮

 

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.

 

(导读 郭怿暄)表皮溶解水疱症(JEB)是由编码基底膜组成成分laminin-332基因发生突变导致的致死性遗传病,该疾病严重影响生活质量并可能发生癌变。本研究对一名7JEB患者自体转基因角化细胞进行培养再生出了全部具有完全功能的表皮。研究还发现人类表皮是由一种数量有限、长寿的干细胞维持,该干细胞在体内外中均能产生祖细胞,补充终末分化的角化细胞。

 


3 【生物】A single-cell survey of the small intestinal epithelium

Adam L. Haber, et. al

 

https://www.nature.com/articles/nature24489

 

 

小肠上皮细胞的单细胞测序

 

Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells. We also characterized the ways in which cell-intrinsic states and the proportions of different cell types respond to bacterial and helminth infections: Salmonella infection caused an increase in the abundance of Paneth cells and enterocytes, and broad activation of an antimicrobial program; Heligmosomoides polygyrus caused an increase in the abundance of goblet and tuft cells. Our survey highlights previously unidentified markers and programs, associates sensory molecules with cell types, and uncovers principles of gut homeostasis and response to pathogens.

 

(导读 郭怿暄)小肠上皮细胞负责吸收营养,发挥屏障功能,并对微生物的入侵进行免疫应答。本研究通过对来自小鼠小肠和类器官的53193个上皮细胞进行单细胞测序,发现多种全新具有激素分泌功能的内分泌细胞亚型,并且明确了在细菌和寄生虫感染时细胞的内在状态及不同细胞类型的比例。这一发现将为揭开肠道稳态以及对病原的应答方式提供巨大帮助。

 

4 Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity

【生物】炎症诱导的IgA+细胞解除抗肝癌的免疫作用

 

Shabnam Shalapour, Xue-Jia Lin, Ingmar N. Bastian, John Brain, Alastair D. Burt, Alexander A. Aksenov, Alison F. Vrbanac, Weihua Li, Andres Perkins, Takaji Matsutani, Zhenyu Zhong, Debanjan Dhar, Jose A. Navas-Molina, Jun Xu, Rohit Loomba, Michael Downes, Ruth T. Yu, Ronald M. Evans, Pieter C. Dorrestein, Rob Knight, Christopher Benner, Quentin M. Anstee & Michael Karin

http://www.nature.com/articles/nature24302

 

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

(导读 齐睿娟)适应性免疫在肿瘤早期发生发展的作用是有争议的。本文发现在非酒精性脂肪肝的患者和小鼠模型中,慢性炎症和纤维化伴随肝脏内表达IgAPD-L1IL-10的细胞的积累。干预IgA+细胞生成则会减慢肝细胞癌发生并诱导由杀伤性CD8+T淋巴细胞介导的肝细胞癌的退化。这些研究结果提示由炎症介导的抑制细胞毒性CD8+T淋巴细胞活化作用是促肿瘤生长的重要机制。

 

5 【生物】Dynamics of P-type ATPase transport revealed by single-molecule FRET

Mateusz Dyla   et. al

 

https://www.nature.com/articles/nature24296

 

利用单分子FRET揭示PATP酶转运动力

 

 图片3.jpg

(导读 阿金)磷酸化型PATP蛋白酶是广泛分布的阳离子转运蛋白,其转运能量由磷酸化酶中间体的动态生成而来。本研究利用单分子FRET技术,直接观察到了单核细胞增生李斯特菌Ca2+-ATP酶(LMCA1)在转运过程中的构象变化,鉴定出了尚无晶体结构的关键中间体,并构建出了转运过程中LMCA1结构变化和钙离子、ADP释放的机制模型。

 

Phosphorylation-type (P-type) ATPases are ubiquitous primary transporters that pump cations across cell membranes through the formation and breakdown of a phosphoenzyme intermediate. Structural investigations suggest that the transport mechanism is defined by conformational changes in the cytoplasmic domains of the protein that are allosterically coupled to transmembrane helices so as to expose ion binding sites to alternate sides of the membrane. Here, we have used single-molecule fluorescence resonance energy transfer to directly observe conformational changes associated with the functional transitions in the Listeria monocytogenes Ca2+-ATPase (LMCA1), an orthologue of eukaryotic Ca2+-ATPases. We identify key intermediates with no known crystal structures and show that Ca2+ efflux by LMCA1 is rate-limited by phosphoenzyme formation. The transport process involves reversible steps and an irreversible step that follows release of ADP and extracellular release of Ca2+.

 

6 【天文】Haze heats Pluto’s atmosphere yet explains its cold temperature

Xi Zhang     et. al

雾霾导致冥王星低温

 

https://www.nature.com/articles/nature24465

 

 

(导读 雷鸣)近期观测表明,冥王大气温度远低于预测数值。本研究发现,冥王星大气中的雾霾颗粒比气体分子(特别是水蒸气)更能合理解释上述落差。雾霾颗粒的太阳能升温速率及热冷却速率都明显高于气体分子,主导从地面到海拨700千米的大气辐射平衡。据此推断,冥王星在中红外波段应该比之前设想的明亮得多。

 

Pluto’s atmosphere is cold and hazy1,2,3. Recent observations1 have shown it to be much colder than predicted theoretically4, suggesting an unknown cooling mechanism1. Atmospheric gas molecules, particularly water vapour, have been proposed as a coolant; however, because Pluto’s thermal structure is expected to be in radiative–conductive equilibrium4,5,6,7,8,9, the required water vapour would need to be supersaturated by many orders of magnitude under thermodynamic equilibrium conditions9. Here we report that atmospheric hazes, rather than gases, can explain Pluto’s temperature profile. We find that haze particles have substantially larger solar heating and thermal cooling rates than gas molecules, dominating the atmospheric radiative balance from the ground to an altitude of 700 kilometres, above which heat conduction maintains an isothermal atmosphere. We conclude that Pluto’s atmosphere is unique among Solar System planetary atmospheres, as its radiative energy equilibrium is controlled primarily by haze particles instead of gas molecules. We predict that Pluto is therefore several orders of magnitude brighter at mid-infrared wavelengths than previously thought—a brightness that could be detected by future telescopes.

 

7 【物理】Collective emission of matter-wave jets from driven Bose–Einstein condensates

Logan W. Clark   et. al

驱动玻色 - 爱因斯坦凝聚态中物质波喷流的集体喷射

 

https://www.nature.com/articles/nature24272

 

 

(导读 阿金)超冷原子气体可用于研究大量碰撞事例由于复杂相互作用导致的集体行为。本研究发现驱动玻色-爱因斯坦凝聚态的碰撞导致烟花一般的物质波集体喷射现象。研究结果揭示了该现象发生所需的条件,以及物质波喷射的量子本质。

 

Scattering is used to probe matter and its interactions in all areas of physics. In ultracold atomic gases, control over pairwise interactions enables us to investigate scattering in quantum many-body systems. Previous experiments on colliding Bose–Einstein condensates have revealed matter–wave interference2,3, haloes of scattered atoms four-wave mixing and correlations between counter-propagating pairs. However, a regime with strong stimulation of spontaneous collisions analogous to superradiance has proved elusive. In this regime, the collisions rapidly produce highly correlated states with macroscopic population. Here we find that runaway stimulated collisions in Bose–Einstein condensates with periodically modulated interaction strength cause the collective emission of matter-wave jets that resemble fireworks. Jets appear only above a threshold modulation amplitude and their correlations are invariant even when the number of ejected atoms grows exponentially. Hence, we show that the structures and atom occupancies of the jets stem from the quantum fluctuations of the condensate. Our findings demonstrate the conditions required for runaway stimulated collisions and reveal the quantum nature of matter-wave emission.

 

 

8 【材料】Granular materials flow like complex fluids

Binquan Kou,   et. al

颗粒材料流变行为类同于复杂流体

 

https://www.nature.com/articles/nature24062

 

 

(导读 阿金)生活中常见的颗粒材料可形成稳定的三维颗粒系统结构,其动力学属性缺乏实验手段证明。本研究利用X射线断层摄影成像技术,第一次得到了长达三个时间尺度的微观动力学过程。分析发现颗粒体系都遵从一种新的普适的微观动力学,导致一般意义上认为的颗粒固体,其实是一种处在液固边界的临界相,在外部微扰下就会流化, 更类似于复杂流体。

 

Granular materials such as sand, powders and foams are ubiquitous in daily life and in industrial and geotechnical applications. These disordered systems form stable structures when unperturbed, but in the presence of external influences such as tapping or shear they ‘relax’, becoming fluid in nature. It is often assumed that the relaxation dynamics of granular systems is similar to that of thermal glass-forming systems. However, so far it has not been possible to determine experimentally the dynamic properties of three-dimensional granular systems at the particle level. This lack of experimental data, combined with the fact that the motion of granular particles involves friction (whereas the motion of particles in thermal glass-forming systems does not), means that an accurate description of the relaxation dynamics of granular materials is lacking. Here we use X-ray tomography to determine the microscale relaxation dynamics of hard granular ellipsoids subject to an oscillatory shear. We find that the distribution of the displacements of the ellipsoids is well described by a Gumbel law6 (which is similar to a Gaussian distribution for small displacements but has a heavier tail for larger displacements), with a shape parameter that is independent of the amplitude of the shear strain and of the time. Despite this universality, the mean squared displacement of an individual ellipsoid follows a power law as a function of time, with an exponent that does depend on the strain amplitude and time. We argue that these results are related to microscale relaxation mechanisms that involve friction and memory effects (whereby the motion of an ellipsoid at a given point in time depends on its previous motion). Our observations demonstrate that, at the particle level, the dynamic behaviour of granular systems is qualitatively different from that of thermal glass-forming systems, and is instead more similar to that of complex fluids. We conclude that granular materials can relax even when the driving strain is weak.

 

 

9 【生态】Reductions in global biodiversity loss predicted from conservation spending

Anthony Waldronet. al

https://www.nature.com/articles/nature24295

从动物保护支出预测全球生物多样性丧失趋势的定量模型

Halting global biodiversity loss is central to the Convention on Biological Diversity and United Nations Sustainable Development Goals, but success to date has been very limited. A critical determinant of success in achieving these goals is the financing that is committed to maintaining biodiversity; however, financing decisions are hindered by considerable uncertainty over the likely impact of any conservation investment. For greater effectiveness, we need an evidence-based model that shows how conservation spending quantitatively reduces the rate of biodiversity loss. Here we demonstrate such a model, and empirically quantify how conservation investment between 1996 and 2008 reduced biodiversity loss in 109 countries (signatories to the Convention on Biological Diversity and Sustainable Development Goals), by a median average of 29% per country. We also show that biodiversity changes in signatory countries can be predicted with high accuracy, using a dual model that balances the effects of conservation investment against those of economic, agricultural and population growth (human development pressures). Decision-makers can use this model to forecast the improvement that any proposed biodiversity budget would achieve under various scenarios of human development pressure, and then compare these forecasts to any chosen policy target. We find that the impact of spending decreases as human development pressures grow, which implies that funding may need to increase over time. The model offers a flexible tool for balancing the Sustainable Development Goals of human development and maintaining biodiversity, by predicting the dynamic changes in conservation finance that will be needed as human development proceeds.

(导读 刘晓娟)为寻求用于动物保护的开支和保护效果(资金投入能在多大程度上降低生物多样性减少的速率)之间的定量关系,本研究对1996-2008年间109个国家的数据进行了定量建模。模型对生物多样性公约签约国家的精确预测可以为国家政策的制定提供帮助。

 

 

10 【古生物】Parallel palaeogenomic transects reveal complex genetic history of early European farmers

平行的古生态学剖面揭示早期欧洲农民复杂遗传史

 

Mark Lipson  et. al

 

https://www.nature.com/articles/nature24476

 

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000–2900 BC, n = 100), Germany (5500–3000 BC, n = 42) and Spain (5500–2200 BC, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

 

(导读 何伟雄)新石器时代的欧洲人是亚美尼亚移民的后代,但他们与当地狩猎采集者之间基因融合的时空动态仍不清楚。本研究对180个来自新石器时代至红铜时代不同地区的古DNA样本进行了全基因组测序与分析,发现不同血统间的融合普遍存在,但在不同地区程度各异。本研究为揭示新石器时期欧洲人口的结构变迁历程提供了帮助。

 

11 【神经】Locomotor speed control circuits in the caudal brainstem

Paolo Capelli,   et. al

 

https://www.nature.com/articles/nature24064

 

下段脑干的运动速度控制回路

 

(导读 阿金)在大脑区域中找到确切的神经元亚群有助于了解执行高速运动的神经回路机制。本研究展示小鼠下段脑干区包含有功能异质的神经元亚群,其中位于外侧巨细胞旁核(LPGi)的谷氨酸能神经元,通过来自上游中脑运动区的信号输入正向调节运动速度。而甘氨酸能抑制神经元则诱导不同形式的行为停止。

 

Locomotion is a universal behaviour that provides animals with the ability to move between places. Classical experiments have used electrical microstimulation to identify brain regions that promote locomotion, but the identity of neurons that act as key intermediaries between higher motor planning centres and executive circuits in the spinal cord has remained controversial. Here we show that the mouse caudal brainstem encompasses functionally heterogeneous neuronal subpopulations that have differential effects on locomotion. These subpopulations are distinguishable by location, neurotransmitter identity and connectivity. Notably, glutamatergic neurons within the lateral paragigantocellular nucleus (LPGi), a small subregion in the caudal brainstem, are essential to support high-speed locomotion, and can positively tune locomotor speed through inputs from glutamatergic neurons of the upstream midbrain locomotor region. By contrast, glycinergic inhibitory neurons can induce different forms of behavioural arrest mapping onto distinct caudal brainstem regions. Anatomically, descending pathways of glutamatergic and glycinergic LPGi subpopulations communicate with distinct effector circuits in the spinal cord. Our results reveal that behaviourally opposing locomotor functions in the caudal brainstem were historically masked by the unexposed diversity of intermingled neuronal subpopulations. We demonstrate how specific brainstem neuron populations represent essential substrates to implement key parameters in the execution of motor programs.

 

 

12 【生物】Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence

Peng Li,  et. al

 

https://www.nature.com/articles/nature24467

 

志贺氏杆菌效应器对GBPs的泛素化降解抑制宿主防御

 

(导读 卓思琪)干扰素诱导的鸟苷酸连接蛋白(GBPs)调节细胞自主抗菌。本研究发现志贺氏杆菌感染后诱导的人类GBP1的快速蛋白酶体降解。研究通过转座子筛选发现志贺氏杆菌基因ipaH9.8通过泛素化靶向结合GBP促进其降解,从而促进细菌复制导致小鼠死亡。该功能模型强调了GBPs在抗菌方面的重要性,而IpaH9.8和志贺氏杆菌为解析GBP调节的免疫的机制提供了独一无二的系统。

 

 

Interferon-inducible guanylate-binding proteins (GBPs) mediate cell-autonomous antimicrobial defences1,2. Shigella flexneri, a Gram-negative cytoplasmic free-living bacterium that causes bacillary dysentery3, encodes a repertoire of highly similar type III secretion system effectors called invasion plasmid antigen Hs (IpaHs)4. IpaHs represent a large family of bacterial ubiquitin-ligases5,6,7,8, but their function is poorly understood. Here we show that S. flexneri infection induces rapid proteasomal degradation of human guanylate binding protein-1 (hGBP1). We performed a transposon screen to identify a mutation in the S. flexneri gene ipaH9.8 that prevented hGBP1 degradation. IpaH9.8 targets hGBP1 for degradation via Lys48-linked ubiquitination. IpaH9.8 targets multiple GBPs in the cytoplasm independently of their nucleotide-bound states and their differential function in antibacterial defence, promoting S. flexneri replication and resulting in the death of infected mice. In the absence of IpaH9.8, or when binding of GBPs to IpaH9.8 was disrupted, GBPs such as hGBP1 and mouse GBP2 (mGBP2) translocated to intracellular S. flexneri and inhibited bacterial replication. Like wild-type mice, mutant mice deficient in GBP13, 5 and 7 succumbed to S. flexneri infection, but unlike wild-type mice, mice deficient in these GBPs were also susceptible to S. flexneri lacking ipaH9.8. The mode of IpaH9.8 action highlights the functional importance of GBPs in antibacterial defences. IpaH9.8 and S. flexneri provide a unique system for dissecting GBP-mediated immunity.

 

13 【生物】BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation

Simon Raffel  et. al

 

https://www.nature.com/articles/nature24294

 

AML干细胞中BCAT1限制αKG水平导致了IDHmutDNA超甲基化

 

(导读 卓思琪)支链氨基酸转氨酶1(BCAT1)和实体癌的侵袭有关,但相关机制仍不清楚。本研究发现BCAT1蛋白在急性髓性白血病(AML)干细胞中过表达,BCAT1可将α-酮戊二酸(αKG)氨基化,αKG水平降低提高HIF1α蛋白稳定性并导致DNA超甲基化,综合效果与异柠檬酸脱氢酶突变(IDHmut)的细胞类似。该结果表明BCAA-BCAT1-αKG途径可以作为IDHWTTET2WTAML患者的治疗靶标。

 

The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML13 were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAABCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.

 

14 【生物】A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair

Joshua R. Brickner et. al

 

https://www.nature.com/articles/nature24484

 

ALKBH介导DNA脱烷基化修复过程中特有的泛素依赖性信号

 

(导读 阿金)人类细胞能够自发修复烷基化DNA损伤,但其上游的损伤识别和修复启动机制仍不清楚。本研究发现,烷基化修复复合物ASCC可识别K63多聚泛素化位点,从而正确定位于烷基化损伤位点并确认RNF113AK63泛素化所需的E3连接酶。鉴于烷基化化疗药物在癌症治疗中的广泛应用,该研究可为研发靶向抗癌药物提供新思路。

 

DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation. Here we demonstrate that human cells have a previously unrecognized signalling mechanism for sensing damage induced by alkylation. We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents. These foci associate with alkylated nucleotides, and coincide spatially with elongating RNA polymerase II and splicing components. Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE (coupling of ubiquitin conjugation to ER degradation) domain of the subunit ASCC2. Loss of this subunit impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents, but not other forms of DNA damage. We identify RING finger protein 113A (RNF113A) as the E3 ligase responsible for upstream ubiquitin signalling in the ASCC pathway. Cells from patients with X-linked trichothiodystrophy, which harbour a mutation in RNF113A, are defective in ASCC foci formation and are hypersensitive to alkylating agents. Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage, shedding light on the molecular mechanism of X-linked trichothiodystrophy.

 

15 【生物】Structure and assembly of the Ebola virus nucleocapsid

埃博拉病毒核衣壳的结构和组装

William Wan et. al

https://www.nature.com/articles/nature24490

(导读 严冰)埃博拉病毒基因组是不分段的单股负链RNA,其核衣壳对病毒组装、基因组转录和复制有重要意义。本文应用冷冻电子断层成像(Cryo-ET)和断层叠加技术,解析出埃博拉病毒核衣壳分别在(i)完整病毒颗粒中和(ii)重组的类核衣壳装配中的结构揭示了核衣壳的各个成分和它们的组装方式。

 

Ebola and Marburg viruses are filoviruses: filamentous, enveloped viruses that cause haemorrhagic fever. Filoviruses are within the order Mononegavirales, which also includes rabies virus, measles virus, and respiratory syncytial virus. Mononegaviruses have non-segmented, single-stranded negative-sense RNA genomes that are encapsidated by nucleoprotein and other viral proteins to form a helical nucleocapsid. The nucleocapsid acts as a scaffold for virus assembly and as a template for genome transcription and replication. Insights into nucleoprotein–nucleoprotein interactions have been derived from structural studies of oligomerized, RNA-encapsidating nucleoprotein, and cryo-electron microscopy of nucleocapsid or nucleocapsid-like structures. There have been no high-resolution reconstructions of complete mononegavirus nucleocapsids. Here we apply cryo-electron tomography and subtomogram averaging to determine the structure of Ebola virus nucleocapsid within intact viruses and recombinant nucleocapsid-like assemblies. These structures reveal the identity and arrangement of the nucleocapsid components, and suggest that the formation of an extended α-helix from the disordered carboxy-terminal region of nucleoprotein-core links nucleoprotein oligomerization, nucleocapsid condensation, RNA encapsidation, and accessory protein recruitment.