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时间: 2017年07月17日 | 作者: admin | 来源: 未知
1 West Antarctic Ice Sheet retreat driven by Holocene warm water incursions 【地球科学】全新世暖水入侵驱动南极西部冰盖后移 Claus-Dieter Hillenbrand, James A. Smith, David A. Hodell…Robert D. Larter Gerhard Kuhn http

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West Antarctic Ice Sheet retreat driven by Holocene warm water incursions

【地球科学】全新世暖水入侵驱动南极西部冰盖后移

Claus-Dieter Hillenbrand, James A. Smith, David A. Hodell…Robert D. Larter & Gerhard Kuhn

https://www.nature.com/nature/journal/v547/n7661/full/nature22995.html

(导读 刘威尔)环极深水(Circumpolar Deep Water, CDW)暖流入侵南极西部大陆架导致了冰架融化,影响冰架支撑的冰川并导致冰盖后移。本研究基于多重替代数据重建了全新世时期CDW流入阿蒙森海域的可变性,海洋沉积物化学成分揭示了该海域CDW上涌增强导致冰川消失。研究结果提升了当前冰盖模型预测能力的可信度。

Glaciological and oceanographic observations coupled with numerical models show that warm Circumpolar Deep Water (CDW) incursions onto the West Antarctic continental shelf cause melting of the undersides of floating ice shelves. Because these ice shelves buttress glaciers feeding into them, their ocean-induced thinning is driving Antarctic ice-sheet retreat today. Here we present a multi-proxy data based reconstruction of variability in CDW inflow to the Amundsen Sea sector, the most vulnerable part of the West Antarctic Ice Sheet, during the Holocene epoch (from 11.7 thousand years ago to the present). The chemical compositions of foraminifer shells and benthic foraminifer assemblages in marine sediments indicate that enhanced CDW upwelling, controlled by the latitudinal position of the Southern Hemisphere westerly winds, forced deglaciation of this sector from at least 10,400 years ago until 7,500 years ago—when an ice-shelf collapse may have caused rapid ice-sheet thinning further upstream—and since the 1940s. These results increase confidence in the predictive capability of current ice-sheet models.

 

2

Climate change drives expansion of Antarctic ice-free habitat

【地球科学】气候变化导致南极无冰栖息地扩大

Jasmine R. Lee, Ben Raymond, Thomas J. Bracegirdle…Justine D. Shaw & Aleks Terauds

https://www.nature.com/nature/journal/v547/n7661/full/nature22996.html

(导读 刘威尔)南极无冰区域受气候变化影响的分布和程度尚不明确。本研究利用温度指数融化模型量化两个IPCC气候胁迫情景下气候变化对无冰区域的影响,结果显示强胁迫情境下无冰区域面积在本世纪末将扩张近25%,集中在南极半岛并伴随孤立斑块融合。研究推测这一情况将导致区域尺度的生物均质化、竞争力较弱物种的灭绝及入侵种的扩散。

Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000km2 by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less-competitive species and the spread of invasive species.

 

3 Recurrent and functional regulatory mutations in breast cancer

【生物】乳腺癌中复发和功能调节相关的突变

Esther Rheinbay, Prasanna Parasuraman, Jonna GrimsbyEric S. Lander & Gad Getz

https://www.nature.com/nature/journal/v547/n7661/full/nature22992.html

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图片来源:nature.com

(导读 郭思瑶)癌症基因组分析可根据蛋白质编码区的突变鉴定出癌基因,但对于非编码区的癌症突变,我们知之甚少。科学家对360个乳腺癌样品进行深度测序并开发出鉴定重要启动子突变的计算机方法。由此鉴定出三个相关癌基因FOXA1 RMRP  NEAT1。该研究显示启动子区域存在癌症相关突变的频率与编码区相近。许多类似的区域还有待发现。

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

 

4 Cell-cycle dynamics of chromosomal organization at single-cell resolution

 

【生物】单细胞分辨率细胞周期中染色体构象的动态变化

 

Takashi Nagano, Yaniv Lubling, Csilla Várna…Peter Fraser & Amos Tanay

 

https://www.nature.com/nature/journal/v547/n7661/full/nature23001.html

 

Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.

 

(导读 郭怿暄)细胞周期中染色体结构的动态变化与其功能密切相关。本研究通过单细胞高分辨率染色体构象捕获技术(single-cell Hi-C)分析数千个处于细胞周期不同阶段的小鼠胚胎干细胞,揭示了染色体区室、拓扑关联结构域(TADs)、接触绝缘区以及远距离染色体环结构随细胞周期的动态变化规律。这一发现结合基因调控信息,将有助于建立一个更加全面的动态细胞结构功能调节模型。

 

5 Single-molecule analysis of ligand efficacy in β2AR–G-protein activation

 

【生物】β2AR–G蛋白激活中配体效力的单分子水平分析

 

G. Glenn Gregorio, Matthieu Masureel, Daniel Hilger…Brian K. Kobilka & Scott C. Blanchard

 

https://www.nature.com/nature/journal/v547/n7661/full/nature22354.html

 

G-protein-coupled receptor (GPCR)-mediated signal transduction is central to human physiology and disease intervention, yet the molecular mechanisms responsible for ligand-dependent signalling responses remain poorly understood. In class A GPCRs, receptor activation and G-protein coupling entail outward movements of transmembrane helix 6 (TM6). Here, using single-molecule fluorescence resonance energy transfer imaging, we examine TM6 movements in the β2adrenergic receptor (β2AR) upon exposure to orthosteric ligands with different efficacies, in the absence and presence of the Gs heterotrimer. We show that partial and full agonists differentially affect TM6 motions to regulate the rate at which GDP-bound β2AR–Gs complexes are formed and the efficiency of nucleotide exchange leading to Gs activation. These data also reveal transient nucleotide-bound β2AR–Gs species that are distinct from known structures, and provide single-molecule perspectives on the allosteric link between ligand- and nucleotide-binding pockets that shed new light on the G-protein activation mechanism.

 

(导读 郭怿暄)G蛋白偶联受体(GPCR)介导的信号转导通路对人类生理状态和药物开发至关重要。本研究通过单分子荧光共振能量转移成像(smFRET)测定发现不同效力的配体可以通过调节跨膜螺旋6TM6)的移动控制GDP结合β2肾上腺素受体(β2AR-Gs复合体的形成速率,进而调节核酸交换和Gs的激活。

6 Three-dimensional integration of nanotechnologies for computing and data storage on a single chip

【材料】在单一芯片上实现计算和数据存储技术的三维集成

Max M. Shulaker, Gage Hills, Rebecca S. ParkH.-S. Philip Wong & Subhasish Mitra

https://www.nature.com/nature/journal/v547/n7661/full/nature22994.html

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图片来源:nature.org

(导读:阿金)为了满足日益增长的计算需求,晶体管、数据存储技术和集成电路设计需要同时得到改善。本研究提出了一种新型纳米系统原型:不同的功能层(计算、数据存储和输入输出)垂直堆叠于单一芯片上,形成三维集成电路结构,通过层间连接可实现大量数据的快速收集、存储和处理。

The computing demands of future data-intensive applications will greatly exceed the capabilities of current electronics, and are unlikely to be met by isolated improvements in transistors, data storage technologies or integrated circuit architectures alone. Instead, transformative nanosystems, which use new nanotechnologies to simultaneously realize improved devices and new integrated circuit architectures, are required. Here we present a prototype of such a transformative nanosystem. It consists of more than one million resistive random-access memory cells and more than two million carbon-nanotube field-effect transistorspromising new nanotechnologies for use in energy-efficient digital logic circuits1, 2, 3 and for dense data storage4fabricated on vertically stacked layers in a single chip. Unlike conventional integrated circuit architectures, the layered fabrication realizes a three-dimensional integrated circuit architecture with fine-grained and dense vertical connectivity between layers of computing, data storage, and input and output (in this instance, sensing). As a result, our nanosystem can capture massive amounts of data every second, store it directly on-chip, perform in situ processing of the captured data, and produce highly processedinformation. As a working prototype, our nanosystem senses and classifies ambient gases. Furthermore, because the layers are fabricated on top of silicon logic circuitry, our nanosystem is compatible with existing infrastructure for silicon-based technologies. Such complex nano-electronic systems will be essential for future high-performance and highly energy-efficient electronic systems5.

 

7 Selective sp3 C–H alkylation via polarity-match-based cross-coupling

【化学】通过极性匹配的交叉耦合实现sp3 C-H选择性烷基化

Chip Le, Yufan Liang, Ryan W. Evans, Ximing Li & David W. C. MacMillan

https://www.nature.com/nature/journal/v547/n7661/full/nature22813.html

 

(导读 卓思琪)本文通过光氧化、镍以及氢原子转移三者组合,催化了基于极性匹配的sp3 C-H选择性烷基化。该方法同时应用三种催化循环来实现负电 C-H 键的取代(通过极性匹配实现)、烷基卤化物氧化加成和还原消除,从而达成烷基-烷基片段的耦合。这种交叉耦合方案在从头合成和后期官能化化学中可能得到广泛应用。

The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

 

8 Episodic kinematics in continental rifts modulated by changes in mantle melt fraction

【地球科学】地幔分裂部分的变化对大陆裂谷幕式运动学的影响

Simon Lamb, James D. P. Moore, Euan Smith & Tim Stern

https://www.nature.com/nature/journal/v547/n7661/full/nature22962.html

 

(导读 卓思琪)本研究通过对新西兰北岛陶波火山带大陆裂谷系统的10年监测,发现它以每年6-15mm的速率扩张,裂谷轴向承受巨大水平收缩力且伴随快速下沉,符合弹性地壳挠褶相关的简单模型,推测挠褶是在由裂谷轴下方地幔流产生的熔岩诱发的阶段变化引起。

 

Oceanic crust is created by the extraction of molten rock from underlying mantle at the seafloor ‘spreading centres’ found between diverging tectonic plates. Modelling studies have suggested that mantle melting can occur through decompression as the mantle flows upwards beneath spreading centres1, but direct observation of this process is difficult beneath the oceans. Continental rifts, however—which are also associated with mantle melt production—are amenable to detailed measurements of their short-term kinematics using geodetic techniques. Here we show that such data can provide evidence for an upwelling mantle flow, as well as information on the dimensions and timescale of mantle melting. For North Island, New Zealand, around ten years of campaign and continuous GPS measurements in the continental rift system known as the Taupo volcanic zone reveal that it is extending at a rate of 6–15millimetres per year. However, a roughly 70-kilometre-long segment of the rift axis is associated with strong horizontal contraction and rapid subsidence, and is flanked by regions of extension and uplift. These features fit a simple model that involves flexure of an elastic upper crust, which is pulled downwards or pushed upwards along the rift axis by a driving force located at a depth greater than 15kilometres. We propose that flexure is caused by melt-induced episodic changes in the vertical flow forces that are generated by upwelling mantle beneath the rift axis, triggering a transient lower-crustal flow. A drop in the melt fraction owing to melt extraction raises the mantle flow viscosity and drives subsidence, whereas melt accumulation reduces viscosity and allows uplift—processes that are also likely to occur in oceanic spreading centres.

 

 

9 Quantifiable predictive features define epitope-specific T cell receptor repertoires

 

【生物】可量化的预测性特征决定表位特异性T细胞受体库 

 

Pradyot Dash, Andrew J. Fiore-Gartland, Tomer Hertz…Philip Bradley & Paul G. Thomas

 

https://www.nature.com/nature/journal/v547/n7661/full/nature22383.html

 

T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 1015 (ref.1) to as high as 1061 (ref. 2) possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity. Here we report the in-depth characterization of ten epitope-specific TCR repertoires of CD8+ T cells from mice and humans, representing over 4,600 in-frame single-cell-derived TCRαβ sequence pairs from 110 subjects. We developed analytical tools to characterize these epitope-specific repertoires: a distance measure on the space of TCRs that permits clustering and visualization, a robust repertoire diversity metric that accommodates the low number of paired public receptors observed when compared to single-chain analyses, and a distance-based classifier that can assign previously unobserved TCRs to characterized repertoires with robust sensitivity and specificity. Our analyses demonstrate that each epitope-specific repertoire contains a clustered group of receptors that share core sequence similarities, together with a dispersed set of diverse ‘outlier’ sequences. By identifying shared motifs in core sequences, we were able to highlight key conserved residues driving essential elements of TCR recognition. These analyses provide insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition.

 

(导读 郭怿暄)T细胞受体(TCR)决定了T细胞特异性识别的抗原表位, V(D)J重组使其具有极强的多样性。本研究通过分析来自小鼠和人针对十个表位特异性的4600TCRαβ序列,开发了一套TCR库分析工具,并发现针对特异表位会有一组具有相似核心序列的TCR产生,为进一步了解TCR识别奠定基础。

 

10 Identifying specificity groups in the T cell receptor repertoire

 

【生物】T细胞受体库中特异性组的鉴定 

 

Jacob Glanville, Huang Huang, Allison Nau…Olivia M. Martinez & Mark M. Davis

 

https://www.nature.com/nature/journal/v547/n7661/full/nature22976.html

 

T cell receptor (TCR) sequences are very diverse, with many more possible sequence combinations than T cells in any one individual1234. Here we define the minimal requirements for TCR antigen specificity, through an analysis of TCR sequences using a panel of peptide and major histocompatibility complex (pMHC)-tetramer-sorted cells and structural data. From this analysis we developed an algorithm that we term GLIPH (grouping of lymphocyte interactions by paratope hotspots) to cluster TCRs with a high probability of sharing specificity owing to both conserved motifs and global similarity of complementarity-determining region 3 (CDR3) sequences. We show that GLIPH can reliably group TCRs of common specificity from different donors, and that conserved CDR3 motifs help to define the TCR clusters that are often contact points with the antigenic peptides. As an independent validation, we analysed 5,711 TCRβ chain sequences from reactive CD4 T cells from 22 individuals with latent Mycobacterium tuberculosis infection. We found 141 TCR specificity groups, including 16 distinct groups containing TCRs from multiple individuals. These TCR groups typically shared HLA alleles, allowing prediction of the likely HLA restriction, and a large number of M. tuberculosis T cell epitopes enabled us to identify pMHC ligands for all five of the groups tested. Mutagenesis and de novo TCR design confirmed that the GLIPH-identified motifs were critical and sufficient for shared-antigen recognition. Thus the GLIPH algorithm can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands.

(导读 董堃) T细胞受体(TCR)序列的多样性使其可识别不同类型的抗原。本研究通过对肽段-主要组织相容性复合物(pMHC)四聚体分选的T细胞TCR序列进行分析,确定了TCR序列和抗原特异性之间的最小需求单位。并开发了生物信息学算法可以对不同特异性的TCR进行准确聚类,这将有效地加快T细胞免疫应答和特异性配体鉴定的研究。

 

11 Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

【生物】化疗药物通过Caspase-3剪切gasdermin诱导细胞焦亡

Yupeng Wang, Wenqing Gao, Xuyan Shi…Kun Wang & Feng Shao(邵峰)

https://www.nature.com/nature/journal/v547/n7661/full/nature22393.html

 

Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme/ (also known as Dfna5/) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

 

(导读 郭怿暄)细胞焦亡是一种炎症相关的细胞程序性死亡方式,对免疫至关重要。本研究首次发现在细胞接受化疗药物后caspase-3可剪切GSDME,释放GSDME-N片段造成细胞膜穿孔,诱导细胞焦亡。由于大多数正常细胞表达GSDME,这一新发现将有助于改善化疗药物对正常组织造成的损伤。

 

12 Tracing the origins of relapse in acute myeloid leukaemia to stem cells

[生物] 急性粒细胞白血病的干细胞溯源

https://www.nature.com/nature/journal/v547/n7661/full/nature22993.html

Liran I. Shlush, Amanda Mitchell, Lawrence Heisler, Sagi Abelson, Stanley W. K. Ng, Aaron Trotman-Grant, Jessie J. F. Medeiros, Abilasha Rao-Bhatia, Ivana Jaciw-Zurakowsky, Rene Marke, Jessica L. McLeod, Monica Doedens, Gary Bader, Veronique Voisin, ChangJiang Xu, John D. McPherson, Thomas J. Hudson, Jean C. Y. Wang, Mark D. Minden & John E. Dick

 

(导读 梁珩) 急性粒细胞白血病的复发与初始存在的具有药物抗性的癌症干细胞相关。本研究追踪了急性粒细胞白血病复发中的干细胞起源,发现了两条复发途径,分别由具有造血干/祖细胞表型的稀有白血病干细胞,和保留了转录干性的免疫相关白血病细胞亚型引发。此两条复发途径的确认及共通点的发掘,将有助于相关药物的研发。

 

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

 

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13 mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

【生物】mTORC1依赖的AMD1调节可以维持前列腺癌中的多胺代谢

Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Natalia Martín-Martín… Katya Marjon & Arkaitz Carracedo

https://www.nature.com/nature/journal/v547/n7661/full/nature22964.html

(导读 卓思琪)本文发现雷帕霉素复合物1(mTORC1)的下游靶标可调节恶性肿瘤细胞的多胺代谢,从而促进癌细胞增殖。研究在前列腺癌小鼠模型和人类样本中发现,mTORC1可上调S-腺苷甲硫氨酸脱羧酶-1(AMD1),从而提高脱羧S-腺苷甲硫氨酸(dcSAM)和多胺的合成水平,促进癌细胞生长和增殖。该发现为mTORC1整合生长代谢信号的方式提供了图景。

Activation of the PTEN–PI3K–mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation12. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

 

14 RNase III nucleases from diverse kingdoms serve as antiviral effectors

【生物】不同生物界的核糖核酸酶RNase III都能作为抗病毒效应分子

Lauren C. Aguado, Sonja Schmid, Jared MayJean-Pierre Levraud & Benjamin R. tenOever

https://www.nature.com/nature/journal/v547/n7661/full/nature22990.html

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图片来源:nature.com

(导读 郭思瑶)科研人员发现了一种新型的生物抵抗RNA病毒方式:全部三个生物域中的Drosha酶和相关核糖核酸酶RNase III都具有靶向病毒RNA的抗病毒活动。植物,节肢动物,鱼类,哺乳动物在应答病毒入侵时,RNase III在细胞质中移动,夹住病毒RNA特定结构后阻碍RNA聚合酶的功能而起到抗病毒作用。

In contrast to the DNA-based viruses in prokaryotes, the emergence of eukaryotes provided the necessary compartmentalization and membranous environment for RNA viruses to flourish, creating the need for an RNA-targeting antiviral system1, 2. Present day eukaryotes employ at least two main defence strategies that emerged as a result of this viral shift, namely antiviral RNA interference and the interferon system2. Here we demonstrate that Drosha and related RNase III ribonucleases from all three domains of life also elicit a c RNA-targeting antiviral activity. Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops. Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses. We present evidence for cytoplasmic translocation of RNase III nucleases in response to virus in diverse eukaryotes including plants, arthropods, fish, and mammals. These data implicate RNase III recognition of viral RNA as an antiviral defence that is independent of, and possibly predates, other known eukaryotic antiviral systems.

 

 

15 Electron cryo-microscopy structure of the mechanotransduction channel NOMPC

【生物】机械传导通道NOMPC的冷冻电镜结构

Peng Jin, David Bulkley, Yanmeng GuoYuh-Nung Jan & Yifan Cheng程亦凡,加利福尼亚大学

https://www.nature.com/nature/journal/v547/n7661/full/nature22981.html

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图片来源:nature.com

 

(导读:阿金)机械传导通道将机械刺激转换为细胞内电信号,是触觉、平衡感、听觉等机械感觉形成的基础。本论文作者使用单颗粒冷冻电镜技术,解析了果蝇机械传导通道NOMPC的结构,其内部的锚蛋白重复序列(ARs)呈螺旋弹簧状,以传送细胞骨架的机械运动来打开通道。

 

Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels. The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviours such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily, and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of force-induced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell.