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Nature论文导读 1109

时间: 2017年11月20日 | 作者: admin | 来源: 未知
Nature 20171109 1 【地球科学】 Abyssal ocean overturning shaped by seafloor distribution C. de Lavergne et.al 由海底 形态影响 深海翻转 环流 https://www.nature.com/articles/nature24472 (导读 阿金)了解深海翻转环

Nature 20171109

 

1 【地球科学】Abyssal ocean overturning shaped by seafloor distribution

C. de Lavergne et.al

由海底形态影响深海翻转环流

https://www.nature.com/articles/nature24472

 

(导读 阿金)了解深海翻转环流调控机制是量化百年以上时间尺度的海洋碳热储存能力的关键。本研通过分析放射性碳历史数据,发现南纬32度以北的海底深度分布迫使源自南部的高密度水在约4千米深处向北流动,至深度超2.5千米处再往南回流,说明太平洋、印度洋和大西洋盆地的地形限制了翻转环流的结构。

 

The abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows—referred to as the abyssal overturning circulation—is key to quantifying the ocean’s ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32° S, the depth distribution of the seafloor compels dense southern-origin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure.

 

2 【生态】Creation of forest edges has a global impact on forest vertebrates

M. Pfeifer et.al

 

森林边缘的形成对森林脊椎动物有整体影响

 

https://www.nature.com/articles/nature24457

 

 

Forest edges influence more than half of the world’s forests and contribute to worldwide declines in biodiversity and ecosystem functions. However, predicting these declines is challenging in heterogeneous fragmented landscapes. Here we assembled a global dataset on species responses to fragmentation and developed a statistical approach for quantifying edge impacts in heterogeneous landscapes to quantify edge-determined changes in abundance of 1,673 vertebrate species. We show that the abundances of 85% of species are affected, either positively or negatively, by forest edges. Species that live in the centre of the forest (forest core), that were more likely to be listed as threatened by the International Union for Conservation of Nature (IUCN), reached peak abundances only at sites farther than 200–400 m from sharp high-contrast forest edges. Smaller-bodied amphibians, larger reptiles and medium-sized non-volant mammals experienced a larger reduction in suitable habitat than other forest-core species. Our results highlight the pervasive ability of forest edges to restructure ecological communities on a global scale.

(导读 郭怿暄)本研究整合全球破碎化景观及其物种数据,开发全新统计方法,发现1673种脊椎动物中的85%以上丰度受到森林边缘影响,核心地带的物种在远离边缘200以上时数量才达到顶峰,小型两栖类、大型爬行类和中型非飞行哺乳类动面临更多栖息地丧失,显示森林边缘对生态系统结构具有巨大影响。

 

3 【神经】Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Jeff A. Stogsdill  et.al

神经连接蛋白控制星形胶质细胞形态发生与突触发生

https://www.nature.com/articles/nature24638

(导读 严冰)星形胶质细胞(astrocyte)可渗入神经网络,与突触相互作用。本文报导,小鼠皮层星形胶质细胞的形态发生依赖于其与神经元的相互接触,并与突触形成同时发生。星形胶质细胞表达的NL1NL2NL3神经连接蛋白(neuroligin)可通过与突触粘附分子Neurexin相互作用来控制形态发生。这一发现也说明星形胶质细胞可能与和neuroligin突变相关的神经病变有关。

 

Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.

 

4 【神经】Genetic variation in glia–neuron signalling modulates ageing rate

Jiang-An Yin  et.al

神经胶质细胞-神经元信号的遗传变异调节衰老速度

https://www.nature.com/articles/nature24463

 

(导读 阿金)每个生物个体的衰老速度差异极大,而导致差异的因素仍未被确定。本研究报道在秀丽隐杆线虫中发现源自神经胶质的rgba-1神经肽会激活多巴胺神经元和羟色胺能神经元上的NPR-28受体,从而加速行为的退化。这表明遗传变异可以调节线虫的年龄依赖性衰老,为理解健康老化的生物学基础带来了新见解。

 

The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia–neuron signalling modulates the rate of ageing in C. elegans.

 

5 【生物】Structures of transcription pre-initiation complex with TFIIH and Mediator

S. Schilbach  et.al

 

包含TFIIHMediator的转录启始前复合物结构

 

https://www.nature.com/articles/nature24282

 

图片1.png 

For the initiation of transcription, RNA polymerase II (Pol II) assembles with general transcription factors on promoter DNA to form the pre-initiation complex (PIC). Here we report cryo-electron microscopy structures of the Saccharomyces cerevisiae PIC and PIC–core Mediator complex at nominal resolutions of 4.7 Å and 5.8 Å, respectively. The structures reveal transcription factor IIH (TFIIH), and suggest how the core and kinase TFIIH modules function in the opening of promoter DNA and the phosphorylation of Pol II, respectively. The TFIIH core subunit Ssl2 (a homologue of human XPB) is positioned on downstream DNA by the ‘E-bridge’ helix in TFIIE, consistent with TFIIE-stimulated DNA opening. The TFIIH kinase module subunit Tfb3 (MAT1 in human) anchors the kinase Kin28 (CDK7), which is mobile in the PIC but preferentially located between the Mediator hook and shoulder in the PIC–core Mediator complex. Open spaces between the Mediator head and middle modules may allow access of the kinase to its substrate, the C-terminal domain of Pol II.

 

 

(导读 郭怿暄)在基因转录启始过程中,RNA 聚合酶II(RNA Pol II)首先与多种转录因子结合于启动子DNA上形成转录启始前复合物(PIC)。本研究利用冷冻电镜,解析了酵母PIC,以及PIC-核心中介体(Mediator)复合物的结构,进一步揭示了TFIIH核心和蛋白激酶亚基打开启动子DNA和磷酸化Pol II的分子机制。

 

6 【天文】Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star

Iair Arcavi  et.al

持续的能量爆发引发大质量恒星形成独特的富氢爆炸

 

https://www.nature.com/articles/nature24030

 

(导读 阿金)一般认为,超新星是恒星演化的最后阶段,爆炸产生的光亮会持续100天,随后变得黯淡。本研究观测到超新星iPTF14hls的特殊爆发事件,光谱显示这是颗富氢的核坍缩超新星。但不同寻常的是,它的持续发光时间超过600天,光变曲线至少有五个峰;吸收谱线显示喷射物并无降速迹象;总爆发能量是普通超新星的百倍。该发现对研究超新星的形成和爆发机制提出新的挑战。

 

Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining1. Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability2,3,4,5. That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required.

 

7 【物理】History-independent cyclic response of nanotwinned metals

Qingsong Pan  et.al

纳米孪晶铜的抗疲劳循环响应

https://www.nature.com/articles/nature24266

 

(导读 阿金)在循环应力下的材料疲劳,常被认为是由不稳定的损伤累计形成的历史依赖过程。本研究通过在低于金属拉伸强度的应力幅值下的原子模拟和拉-压变幅应变控制实验,发现含有高度取向的纳米孪晶铜与疲劳历史无关的稳定循环响应,其内部的位错结构有助于保持双边界的稳定性和可逆损伤。

 

 

Nearly 90 per cent of service failures of metallic components and structures are caused by fatigue at cyclic stress amplitudes much lower than the tensile strength of the materials involved1. Metals typically suffer from large amounts of cumulative, irreversible damage to microstructure during cyclic deformation, leading to cyclic responses that are unstable (hardening or softening)2,3,4 and history-dependent5,6,7,8. Existing rules for fatigue life prediction, such as the linear cumulative damage rule1,9, cannot account for the effect of loading history, and engineering components are often loaded by complex cyclic stresses with variable amplitudes, mean values and frequencies10,11, such as aircraft wings in turbulent air. It is therefore usually extremely challenging to predict cyclic behaviour and fatigue life under a realistic load spectrum1,11. Here, through both atomistic simulations and variable-strain-amplitude cyclic loading experiments at stress amplitudes lower than the tensile strength of the metal, we report a history-independent and stable cyclic response in bulk copper samples that contain highly oriented nanoscale twins. We demonstrate that this unusual cyclic behaviour is governed by a type of correlated ‘necklace’ dislocation consisting of multiple short component dislocations in adjacent twins, connected like the links of a necklace. Such dislocations are formed in the highly oriented nanotwinned structure under cyclic loading and help to maintain the stability of twin boundaries and the reversible damage, provided that the nanotwins are tilted within about 15 degrees of the loading axis. This cyclic deformation mechanism is distinct from the conventional strain localizing mechanisms associated with irreversible microstructural damage in single-crystal12,13, coarse-grained1,14, ultrafine-grained and nanograined metals4,15,16.

 

8 【物理】Role of stacking disorder in ice nucleation

Laura Lupi,  et.al

无序堆积在冰核形成中的作用

https://www.nature.com/articles/nature24279

 

(导读 阿金) 准确的天气和气候预报依赖于对冰成核速率的稳定预测。各种模型的模拟表明,在大气温度下,冰核的形成和生长都是无序堆积的:由立方和六方冰层随机堆叠而成。本研究报告一个简单的水模型的模拟和能量计算,表明无序堆积的冰晶比六角冰晶更稳定,且成核率比经典理论的预言高出3个数量级。该结果表明经典成核理论亟待修正。

 

The freezing of water affects the processes that determine Earth’s climate. Therefore, accurate weather and climate forecasts hinge on good predictions of ice nucleation rates1. Such rate predictions are based on extrapolations using classical nucleation theory1,2, which assumes that the structure of nanometre-sized ice crystallites corresponds to that of hexagonal ice, the thermodynamically stable form of bulk ice. However, simulations with various water models find that ice nucleated and grown under atmospheric temperatures is at all sizes stacking-disordered, consisting of random sequences of cubic and hexagonal ice layers3,4,5,6,7,8. This implies that stacking-disordered ice crystallites either are more stable than hexagonal ice crystallites or form because of non-equilibrium dynamical effects. Both scenarios challenge central tenets of classical nucleation theory. Here we use rare-event sampling9,10,11 and free energy calculations12 with the mW water model13 to show that the entropy of mixing cubic and hexagonal layers makes stacking-disordered ice the stable phase for crystallites up to a size of at least 100,000 molecules. We find that stacking-disordered critical crystallites at 230 kelvin are about 14 kilojoules per mole of crystallite more stable than hexagonal crystallites, making their ice nucleation rates more than three orders of magnitude higher than predicted by classical nucleation theory. This effect on nucleation rates is temperature dependent, being the most pronounced at the warmest conditions, and should affect the modelling of cloud formation and ice particle numbers, which are very sensitive to the temperature dependence of ice nucleation rates1. We conclude that classical nucleation theory needs to be corrected to include the dependence of the crystallization driving force on the size of the ice crystallite when interpreting and extrapolating ice nucleation rates from experimental laboratory conditions to the temperatures that occur in clouds.

 

9 【社会科学】Detecting evolutionary forces in language change

Mitchell G,  et.al

 

发现语言变化中的进化力量

 

https://www.nature.com/articles/nature24455

 

 

Both language and genes evolve by transmission over generations with opportunity for differential replication of forms. The understanding that gene frequencies change at random by genetic drift, even in the absence of natural selection, was a seminal advance in evolutionary biology. Stochastic drift must also occur in language as a result of randomness in how linguistic forms are copied between speakers. Here we quantify the strength of selection relative to stochastic drift in language evolution. We use time series derived from large corpora of annotated texts dating from the 12th to 21st centuries to analyse three well-known grammatical changes in English: the regularization of past-tense verbs, the introduction of the periphrastic ‘do’, and variation in verbal negation. We reject stochastic drift in favour of selection in some cases but not in others. In particular, we infer selection towards the irregular forms of some past-tense verbs, which is likely driven by changing frequencies of rhyming patterns over time. We show that stochastic drift is stronger for rare words, which may explain why rare forms are more prone to replacement than common ones. This work provides a method for testing selective theories of language change against a null model and reveals an underappreciated role for stochasticity in language evolution.

 

(导读 郭怿暄)与基因类似语言在世代相传中可能产生不同复制,随机漂变对语言进化的影响尚不清楚。本研究量化分析了语言进化中随机漂变相关选择力度,针对大量12-21世纪语言资料中三种重要的语法变化展开研究,发现漂变对罕见词汇具有更大影响,使其更容易被取代。这不但提供了语言变化的理论验证方法,还解释了随机在语言进化中的作用。

 

10 【生物】 Kctd13 deletion reduces synaptic transmission via increased RhoA

Christine Ochoa Escamilla ,  et.al

Kctd13基因删除通过增加RhoA减少突触传递

https://www.nature.com/articles/nature24470

(导读 严冰)16号染色体16p11.2区域的拷贝数变异常常与神经精神性病变相关,在自闭症中最为常见,其中Kctd13被认为是该区域驱动病变的主要基因。本文报导,在小鼠中删除Kctd13基因可减少突触传递,该过程与KCTD13/CUL3泛素连接酶底物、Ras 同源基因家族成员RhoA增加相关。这说明Kctd13很可能通过调控神经元功能诱发神经精神性病变,而RhoA可能是潜在治疗靶点。

 

Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders1,2,3,4,5,6 and are among the most prevalent in autism spectrum disorders1,2,7. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes8,9. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study8, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.

 

11 【神经】Fully integrated silicon probes for high-density recording of neural activity

James J. Jun  ,  et.al

 

用于神经活动高密度记录的全集成硅基探针

 

https://www.nature.com/articles/nature24636

图片2.png 

导读 唐诗语)在自由活动的动物身上进行大面积、高时空精度的脑神经活动探测在此前尚未实现。本研究设计制造了集成于单一6 × 9 mm芯片基板的硅探针Neuropixels,它能够同时准确探测和处理几百个神经元的信号使用两支探针,研究者对一只清醒小鼠5个不同脑区中超过700个独立神经元的活动进行了记录。

 

【摘要】

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging3 offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal–oxide–semiconductor (CMOS) processing-compatible low-impedance TiN6 sites that tile a single 10-mm long, 70 × 20-μm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

 

12 【神经】Ultra-selective looming detection from radial motion opponency

Nathan C. Klapoetke  ,  et.al

 

通过相反的径向运动建立超特异性的危险探测

 

https://www.nature.com/articles/nature24626

 

(导读 卓思琪)感受危险逼近的危险探测神经元常需要处理体内混乱的信息传递。本文报道了果蝇的一种危险探测神经元LPLC2,发现单个LPLC2神经元对向外运动产生强烈响应,而每个树突臂可以接受来自相反运动方向输入的抑制信号。相反的径向运动产生的兴奋和抑制平衡使LPLC2对其他杂乱运动模式无响应,从而为果蝇对危险的识别逃脱的特异性探测提供了一个机理性的描述。

 

 

Nervous systems combine lower-level sensory signals to detect higher-order stimulus features critical to survival, such as the visual looming motion created by an imminent collision or approaching predator4. Looming-sensitive neurons have been identified in diverse animal species. Different large-scale visual features such as looming often share local cues, which means loom-detecting neurons face the challenge of rejecting confounding stimuli. Here we report the discovery of an ultra-selective looming detecting neuron, lobula plate/lobula columnar, type II (LPLC2)10 in Drosophila, and show how its selectivity is established by radial motion opponency. In the fly visual system, directionally selective small-field neurons called T4 and T5 form a spatial map in the lobula plate, where they each terminate in one of four retinotopic layers, such that each layer responds to motion in a different cardinal direction. Single-cell anatomical analysis reveals that each arm of the LPLC2 cross-shaped primary dendrites ramifies in one of these layers and extends along that layers preferred motion direction. In vivo calcium imaging demonstrates that, as their shape predicts, individual LPLC2 neurons respond strongly to outward motion emanating from the centre of the neurons receptive field. Each dendritic arm also receives local inhibitory inputs directionally selective for inward motion opposing the excitation. This radial motion opponency generates a balance of excitation and inhibition that makes LPLC2 non-responsive to related patterns of motion such as contraction, wide-field rotation or luminance change. As a population, LPLC2 neurons densely cover visual space and terminate onto the giant fibre descending neurons, which drive the jump muscle motor neuron to trigger an escape take off. Our findings provide a mechanistic description of the selective feature detection that flies use to discern and escape looming threats.

 

13 【生态】Nutrient co-limitation at the boundary of an oceanic gyre

Thomas J. Browning ,  et.al

海洋环流边界的营养共同限制

https://www.nature.com/articles/nature24063

 

(导读 阿金)亚热带寡营养环流的边界确定海洋生产力的极端转变,而营养限制机制未知。本研究在南大西洋环礁东部边界进行了全因子修正实验,发现氮和铁共同影响海洋中叶绿素a浓度,钴或维生素B12可进一步提高其产量,从而调控浮游植物生长并促进多样性。

 

Nutrient limitation of oceanic primary production exerts a fundamental control on marine food webs and the flux of carbon into the deep ocean1. The extensive boundaries of the oligotrophic sub-tropical gyres collectively define the most extreme transition in ocean productivity, but little is known about nutrient limitation in these zones1,2,3,4. Here we present the results of full-factorial nutrient amendment experiments conducted at the eastern boundary of the South Atlantic gyre. We find extensive regions in which the addition of nitrogen or iron individually resulted in no significant phytoplankton growth over 48 hours. However, the addition of both nitrogen and iron increased concentrations of chlorophyll a by up to approximately 40-fold, led to diatom proliferation, and reduced community diversity. Once nitrogen–iron co-limitation had been alleviated, the addition of cobalt or cobalt-containing vitamin B12 could further enhance chlorophyll a yields by up to threefold. Our results suggest that nitrogen–iron co-limitation is pervasive in the ocean, with other micronutrients also approaching co-deficiency. Such multi-nutrient limitations potentially increase phytoplankton community diversity.

 

14 【生物】Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Matthew J. Hangauer ,  et.al

耐药性遗留癌细胞对GPX4抑制敏感

https://www.nature.com/articles/nature24297

 

导读 阿金治疗后幸存的遗留癌细胞”(persister cell可以成为耐药性癌细胞产生以及癌症复发的基础。本研究发现,阻断小鼠遗留癌细胞中的谷胱甘肽过氧化物酶4(GPX4)可触发细胞氧化死亡,并防止肿瘤复发。因此,Gpx4抑制疗法可成为预防癌症复发的一效方法。

 

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer ‘persister’ cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.

 

15 【生物】The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution

Modi Safra ,  et.al

 

细胞质和线粒体mRNAm1A修饰的单核苷分辨率分布图景

 

https://www.nature.com/articles/nature24456

(导读 卓思琪)最近的研究表明,N1-甲基腺苷 (m1A)修饰是一种广泛存在于mRNA内部的mRNA修饰。本研究揭示了转录组水平上,单核苷酸分辨率的m1A修饰分布情况。分析表明m1A修饰可抑制mRNA翻译,为避免此种抑制,胞浆mRNA中该修饰仅在特定位点少量存在。但研究也鉴定出了线粒体中具有组织特异性,可能具有转录后调节功能的特定m1A位点。

 

Modifications on mRNA offer the potential of regulating mRNA fate post-transcriptionally. Recent studies suggested the widespread presence of N1-methyladenosine (m1A), which disrupts WatsonCrick base pairing, at internal sites of mRNAs. These studies lacked the resolution of identifying individual modified bases, and did not identify specific sequence motifs undergoing the modification or an enzymatic machinery catalysing them, rendering it challenging to validate and functionally characterize putative sites. Here we develop an approach that allows the transcriptome-wide mapping of m1A at single-nucleotide resolution. Within the cytosol, m1A is present in a low number of mRNAs, typically at low stoichiometries, and almost invariably in tRNA T-loop-like structures, where it is introduced by the TRMT6/TRMT61A complex. We identify a single m1A site in the mitochondrial ND5 mRNA, catalysed by TRMT10C, with methylation levels that are highly tissue specific and tightly developmentally controlled. m1A leads to translational repression, probably through a mechanism involving ribosomal scanning or translation. Our findings suggest that m1A on mRNA, probably because of its disruptive impact on base pairing, leads to translational repression, and is generally avoided by cells, while revealing one case in mitochondria where tight spatiotemporal control over m1A levels was adopted as a potential means of post-transcriptional regulation.