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Nature一周论文导读(2017年3月2日)

时间: 2017年03月13日 | 作者: admin | 来源: Nature
审校:半夏 赵维杰 邓卓 本期 Nature刊登中科院植物所 沈建仁研究组工作;论文链接可点。 【天文学】 The response of relativistic outflowing gas to the inner accretion disk of a black hole 相对论气体从

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审校:半夏 赵维杰 邓卓

本期Nature刊登中科院植物所沈建仁研究组工作;论文链接可点。

 

【天文学】

The response of relativistic outflowing gas to the inner accretion disk of a black hole

相对论气体从黑洞吸积盘内流出的响应

Michael L. Parker, Ciro Pinto, Andrew C. Fabian…Daniel R. Wilkins & Abderahmen Zoghbi

http://www.nature.com/nature/journal/v543/n7643/full/nature21385.html

(导读 高胜寒)  从超大黑洞中流出的超快气体到目前为止也无法通过X射线谱对其速度和光学深度进行表征本研究观测到了活跃星系核IRAS 13224-3809流出的超快磁盘风的X射线吸收谱,证明了吸收强度与吸积盘内部释放的X射线呈强负相关,并且指出吸积过程间的联系发生在非常不同的级别上。

The brightness of an active galactic nucleus is set by the gas falling onto it from the galaxy, and the gas infall rate is regulated by the brightness of the active galactic nucleus; this feedback loop is the process by which supermassive black holes in the centres of galaxies may moderate the growth of their hosts1. Gas outflows (in the form of disk winds) release huge quantities of energy into the interstellar medium2, potentially clearing the surrounding gas. The most extreme (in terms of speed and energy) of these—the ultrafast outflows—are the subset of X-ray-detected outflows with velocities higher than 10,000 kilometres per second, believed to originate in relativistic (that is, near the speed of light) disk winds a few hundred gravitational radii from the black hole3. The absorption features produced by these outflows are variable4, but no clear link has been found between the behaviour of the X-ray continuum and the velocity or optical depth of the outflows, owing to the long timescales of quasar variability. Here we report the observation of multiple absorption lines from an extreme ultrafast gas flow in the X-ray spectrum of the active galactic nucleus IRAS 132243809, at 0.236±0.006 times the speed of light (71,000 kilometres per second), where the absorption is strongly anti-correlated with the emission of X-rays from the inner regions of the accretion disk. If the gas flow is identified as a genuine outflow then it is in the fastest five per cent of such winds, and its variability is hundreds of times faster than in other variable winds, allowing us to observe in hours what would take months in a quasar. We find X-ray spectral signatures of the wind simultaneously in both low- and high-energy detectors, suggesting a single ionized outflow, linking the low- and high-energy absorption lines. That this disk wind is responding to the emission from the inner accretion disk demonstrates a connection between accretion processes occurring on very different scales: the X-ray emission from within a few gravitational radii of the black hole ionizing the disk wind hundreds of gravitational radii further away as the X-ray flux rises.

 

【物理】

Supersolid formation in a quantum gas breaking a continuous translational symmetry

在量子气体中打破连续平移对称的超固体

Julian Léonard, Andrea Morales, Philip Zupancic, Tilman Esslinger & Tobias Donner

http://www.nature.com/nature/journal/v543/n7643/full/nature21067.html

(导读 高胜寒)  对超固体的实验验证一直以来都未能实现。本研究报导了在量子气体中沿着一个方向打破连续平移对称所形成的超固体。通过测量光场中晶格位置的波动,本研究发现在超固体中存在较高的基态简并度。 研究方法对于设计和研究可控的基态简并无序态的多相体系具有指导意义。

The concept of a supersolid state combines the crystallization of a many-body system with dissipationless flow of the atoms from which it is built. This quantum phase requires the breaking of two continuous symmetries: the phase invariance of a superfluid and the continuous translational invariance to form the crystal12. Despite having been proposed for helium almost 50 years ago34, experimental verification of supersolidity remains elusive56. A variant with only discrete translational symmetry breaking on a preimposed lattice structure—the ‘lattice supersolid’7—has been realized, based on self-organization of a Bose–Einstein condensate89. However, lattice supersolids do not feature the continuous ground-state degeneracy that characterizes the supersolid state as originally proposed. Here we report the realization of a supersolid with continuous translational symmetry breaking along one direction in a quantum gas. The continuous symmetry that is broken emerges from two discrete spatial symmetries by symmetrically coupling a Bose–Einstein condensate to the modes of two optical cavities. We establish the phase coherence of the supersolid and find a high ground-state degeneracy by measuring the crystal position over many realizations through the light fields that leak from the cavities. These light fields are also used to monitor the position fluctuations in real time. Our concept provides a route to creating and studying glassy many-body systems with controllably lifted ground-state degeneracies, such as supersolids in the presence of disorder.

 

A stripe phase with supersolid properties in spin–orbit-coupled Bose–Einstein condensates

自旋-轨道耦合的玻色-爱因斯坦凝聚中具有超固体特性的条纹相

Jun-Ru Li, Jeongwon Lee, Wujie Huang…Alan O. Jamison & Wolfgang Ketterle

http://www.nature.com/nature/journal/v543/n7643/full/nature21431.html

(导读 王子清)  从自旋-轨道耦合的玻色-爱因斯坦凝聚态中观察到带有超固体特征的条纹相一直未能通过实验来证实。本研究在保证动量突变分布前提下,利用布拉格反射法观测到了条纹相的密度调制,并建立了一套伴随集体激发和超流体行为的具有连续对称性破缺的系统。

 

Supersolidity combines superfluid flow with long-range spatial periodicity of solids, two properties that are often mutually exclusive. The original discussion of quantum crystals and supersolidity focused on solid 4He and triggered extensive experimental efforts that, instead of supersolidity, revealed exotic phenomena including quantum plasticity and mass supertransport. The concept of supersolidity was then generalized from quantum crystals to other superfluid systems that break continuous translational symmetry. Bose–Einstein condensates with spin–orbit coupling are predicted to possess a stripe phase with supersolid properties. Despite several recent studies of the miscibility of the spin components of such a condensate, the presence of stripes has not been detected. Here we observe the predicted density modulation of this stripe phase using Bragg reflection (which provides evidence for spontaneous long-range order in one direction) while maintaining a sharp momentum distribution (the hallmark of superfluid Bose–Einstein condensates). Our work thus establishes a system with continuous symmetry-breaking properties, associated collective excitations and superfluid behaviour.

 

【材料科学】

Abiotic tooth enamel

非生物牙釉质

Bongjun Yeom, Trisha Sain, Naida Lacevic, Daria Bukharina, Sang-Ho Cha, Anthony M. Waas, Ellen M. Arruda & Nicholas A. Kotov

http://www.nature.com/nature/journal/v543/n7643/full/nature21410.html

(导读 王腾)  牙釉质通常是由平行的微纳结构陶瓷阵列或交错柱体柔软蛋白质基体所共同构成。本研究通过生长氧化锌纳米线并其周围组装聚合物基体制备了可模拟牙釉质的纳米复合物。其机械性能可和牙釉质相媲美,且具有原本很难兼得的特性——高刚度、高阻尼重量轻。

 

Tooth enamel comprises parallel microscale and nanoscale ceramic columns or prisms interlaced with a soft protein matrix123. This structural motif is unusually consistent across all species from all geological eras456. Such invariability—especially when juxtaposed with the diversity of other tissues—suggests the existence of a functional basis. Here we performed ex vivo replication of enamel-inspired columnar nanocomposites by sequential growth of zinc oxide nanowire carpets followed by layer-by-layer deposition of a polymeric matrix around these. We show that the mechanical properties of these nanocomposites, including hardness, are comparable to those of enamel despite the nanocomposites having a smaller hard-phase content. Our abiotic enamels have viscoelastic figures of merit (VFOM) and weight-adjusted VFOM that are similar to, or higher than, those of natural tooth enamels—we achieve values that exceed the traditional materials limits of 0.6 and 0.8, respectively. VFOM values describe resistance to vibrational damage, and our columnar composites demonstrate that light-weight materials of unusually high resistance to structural damage from shocks, environmental vibrations and oscillatory stress can be made using biomimetic design. The previously inaccessible combinations of high stiffness, damping and light weight that we achieve in these layer-by-layer composites are attributed to efficient energy dissipation in the interfacial portion of the organic phase. The in vivo contribution of this interfacial portion to macroscale deformations along the tooth’s normal is maximized when the architecture is columnar, suggesting an evolutionary advantage of the columnar motif in the enamel of living species. We expect our findings to apply to all columnar composites and to lead to the development of high-performance load-bearing materials.

 

【地球科学】

Crystallization of silicon dioxide and compositional evolution of the Earths core

二氧化硅结晶与地核成分演化

Kei Hirose, Guillaume Morard, Ryosuke Sinmyo, Koichio Umemoto, John Hernlund, George Helffrich & Stéphane Labrosse

http://www.nature.com/nature/journal/v543/n7643/full/nature21367.html

(导读 许雅澜)  研究人员在地核压力下对激光加热的金刚石压砧单元中的液态Fe-Si-O合金进行了熔融实验,发现在该三相系统的富铁部分中,SiO2的液相范围意外地宽,以至于Fe-Si-O核冷却时会使SiO2结晶。若结晶在地核外部进行,释放出的浮力足够驱动液态地核的对流和地球发电机从冥古宙开始的工作。

 

The Earth's core is about ten per cent less dense than pure iron (Fe), suggesting that it contains light elements as well as iron. Modelling of core formation at high pressure (around 40–60 gigapascals) and high temperature (about 3,500 kelvin) in a deep magma ocean1, 2, 3, 4, 5 predicts that both silicon (Si) and oxygen (O) are among the impurities in the liquid outer core6, 7, 8, 9. However, only the binary systems Fe–Si and Fe–O have been studied in detail at high pressures, and little is known about the compositional evolution of the Fe–Si–O ternary alloy under core conditions. Here we performed melting experiments on liquid Fe–Si–O alloy at core pressures in a laser-heated diamond-anvil cell. Our results demonstrate that the liquidus field of silicon dioxide (SiO2) is unexpectedly wide at the iron-rich portion of the Fe–Si–O ternary, such that an initial Fe–Si–O core crystallizes SiO2 as it cools. If crystallization proceeds on top of the core, the buoyancy released should have been more than sufficient to power core convection and a dynamo, in spite of high thermal conductivity10, 11, from as early on as the Hadean eon12. SiO2 saturation also sets limits on silicon and oxygen concentrations in the present-day outer core.

 

 

【古生物学】

Evidence for early life in Earth’s oldest hydrothermal vent precipitates

地球最古老的深海热泉沉淀物给出早期生命的证据

Matthew S. Dodd, Dominic Papineau, Tor Grenne…Jonathan O’Neil & Crispin T. S. Little

http://www.nature.com/nature/journal/v543/n7643/full/nature21377.html

(导读 肖坤  37.7亿年前地球就可能存在生命。研究人员在加拿大魁北克努夫亚吉图克绿岩带(Nuvvuagittuq belt)发现距今37.7亿42.8亿年左右深海热泉沉积物,这些岩石中的状或丝状结构与其它深海热泉的微生物沉积颇为类似,岩石中包含的碳酸盐和铁矿颗粒也同样证明了这一发现

 

Although it is not known when or where life on Earth began, some of the earliest habitable environments may have been submarine-hydrothermal vents. Here we describe putative fossilized microorganisms that are at least 3,770 million and possibly 4,280 million years old in ferruginous sedimentary rocks, interpreted as seafloor-hydrothermal vent-related precipitates, from the Nuvvuagittuq belt in Quebec, Canada. These structures occur as micrometre-scale haematite tubes and filaments with morphologies and mineral assemblages similar to those of filamentous microorganisms from modern hydrothermal vent precipitates and analogous microfossils in younger rocks. The Nuvvuagittuq rocks contain isotopically light carbon in carbonate and carbonaceous material, which occurs as graphitic inclusions in diagenetic carbonate rosettes, apatite blades intergrown among carbonate rosettes and magnetite–haematite granules, and is associated with carbonate in direct contact with the putative microfossils. Collectively, these observations are consistent with an oxidized biomass and provide evidence for biological activity in submarine-hydrothermal environments more than 3,770 million years ago.

 

【分子生物学】

Intragenic DNA methylation prevents spurious transcription initiation

基因内的DNA甲基化修饰可防止转录起始于错误位点

Francesco Neri, Stefania Rapelli, Anna Krepelova…Francesca Anselmi & Salvatore Oliviero

http://www.nature.com/nature/journal/v543/n7643/full/nature21373.html

图片2.png 

表观遗传信号通路的交互作用机制。图片来源:nature

(导读 严冰)  研究发现在小鼠胚胎干细胞内,结合于RNA聚合酶II的SetD2对组蛋白H3K36位点进行三甲基化修饰,被修饰的组蛋白招募DNA甲基转移酶Dnmt3b,对基因内的DNA序列进行甲基化修饰,从而阻止RNA聚合酶II结合于基因内部并在非起始位点开始转录。本研究填补了基因内部DNA甲基化修饰功能研究的空白。

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.

 

【神经生物学】

Prefrontal cortex output circuits guide reward seeking through divergent cue encoding

前额叶皮层输出环路通过不同的线索编码指导寻求奖赏

James M. Otis, Vijay M. K. Namboodiri, Ana M. Matan…Mark A. Rossi & Garret D. Stuber

http://www.nature.com/nature/journal/v543/n7643/full/nature21376.html

(导读 董堃)  前额叶皮层奖赏激励的摄食行为相关,本文通过双光子钙成像技术监测巴浦洛夫经典条件反射下小鼠被腹侧前额叶神经元的活动,发现在学习过程中纹状体神经元加强而丘脑神经元抑制奖赏激励的摄食行为,说明前额叶神经环路通过这两个细胞群反向活动实现对奖赏激励摄食行为动态调控。

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species123. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus4. While connectivity among these structures contributes to appetitive behaviours5678910111213, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.

 

 

【生物化学】

Elucidation of the biosynthesis of the methane catalyst coenzyme F430

对甲烷催化辅酶F430生物合成的成研究

Simon J. Moore, Sven T. Sowa, Christopher Schuchardt…Gunhild Layer & Martin J. Warren

http://www.nature.com/nature/journal/v543/n7643/full/nature21427.html

图片3.png 

辅酶F430和产甲烷菌中生物合成基因簇。(Moore S J et al. 2017)

(导读 韩宇)  辅酶F430可催化甲烷的生物合成,但其合成机制尚不清楚。本研究发现了由sirohydrochlorin合成F430过程中的一系列酶:CfbA-CfbE,并描述了其活性。此研究有助于对四吡咯基色素家族合成机制的了解。

Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilization of methane through anaerobic methane oxidation. The enzyme uses an ancillary factor called coenzyme F430, a nickel-containing modified tetrapyrrole that promotes catalysis through a methyl radical/Ni(II)-thiolate intermediate. However, it is unclear how coenzyme F430 is synthesized from the common primogenitor uroporphyrinogen III, incorporating 11 steric centres into the macrocycle, although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamization and carbocyclic ring formation. Here we identify the proteins that catalyse the biosynthesis of coenzyme F430 from sirohydrochlorin, termed CfbA–CfbE, and demonstrate their activity. The research completes our understanding of how the repertoire of tetrapyrrole-based pigments are constructed, permitting the development of recombinant systems to use these metalloprosthetic groups more widely.

 

Mechanical stretch triggers rapid epithelial cell division through Piezo1

机械牵张引起上皮细胞通过Piezo1快速分裂

S. A. Gudipaty, J. Lindblom, P. D. Loftus…V. Krishnegowda & J. Rosenblatt

http://www.nature.com/nature/journal/v543/n7643/full/nature21407.html

(导读 陈月欣)  上皮细胞有着机体中最快的更新速度,但如何保持细胞的分裂-死亡平衡至今未知。本研究发现,当细胞密度低且受到牵张时,Piezo1通道被激活,使得处于G2期的上皮细胞再次开始分裂。Piezo1通过感受机械挤压和牵张调节上皮细胞的分裂平衡,其机理可能与Piezo1的激活环境及方式有关。

Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions. 

 

【生物医学】

Whole-genome landscape of pancreatic neuroendocrine tumours

胰腺神经内分泌肿瘤的全基因组景观

Aldo Scarpa, David K. Chang, Katia Nones…Andrew V. Biankin & Sean M. Grimmond

http://www.nature.com/nature/journal/v543/n7643/full/nature21063.html

(导读 陈月欣)  随着检测方法敏感度的提高,胰腺神经内分泌肿瘤(PanNETs)的诊断率也在上升。本研究对102个原发PanNET进行了全基因组测序,并鉴别出了与其发病相关的基因组特征,包括切除修复特征、生殖系突变中的基因、与体细胞突变相关的四个分子通路和与HIF通路有关的肿瘤亚组。

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C>T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

 

 

 

Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease

补体系统驱动戈谢病中葡糖苷酯酰鞘氨醇的沉积与炎症的发生

Manoj K. Pandey, Thomas A. Burrow, Reena Rani…Jörg Köhl & Gregory A. Grabowski

http://www.nature.com/nature/journal/v543/n7643/full/nature21368.html

图片4.png 

图片来源:nature

(导读 陈月欣)  戈谢病是由GBA1基因突变引起的,GBA1突变导致了葡糖苷酯酰鞘氨醇(GC)在免疫细胞内的沉积和慢性炎症的发生。本研究证实在小鼠中,GC沉积会激活补体系统C5a及其受体C5aR1,从而进一步加重GC的沉积并引发炎症。C5aR1或可成为治疗戈谢病的新靶点。

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4–5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

 

 

Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection

CRISPR/Cas9将嵌合抗原受体(CAR)定向至TRAC位点可提高其抗击肿瘤细胞的效果

Justin Eyquem, Jorge Mansilla-Soto, Theodoros Giavridis…Mithat Gönen & Michel Sadelain

http://www.nature.com/nature/journal/v543/n7643/full/nature21405.html

图片5.png 

图片来源:nature.com

(导读 郭思瑶)  嵌合抗原受体(Chimeric antigen receptors,CARs)是合成受体,可以重定向和重编程T细胞,使之具有抗击肿瘤细胞的能力。研究人员证明将靶定CD19的CAR定向到T细胞受体α恒定位点,可以导致广泛的CAR表达并加强T细胞效力。这项研究证明了CRISPR/Cas9基因组编辑在免疫疗法上的巨大潜力。

Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19, which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.

 

 

 

Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

染色体外癌基因扩增驱动肿瘤的进化和遗传异质性

Kristen M. Turner, Viraj Deshpande, Doruk Beyter…Vineet Bafna & Paul S. Mischel

http://www.nature.com/nature/journal/v543/n7643/full/nature21356.html

(导读 韩宇)  本研究对17种人类癌症进行全基因组测序、结构建模和细胞遗传学分析,发现近一半癌症类型存在环形染色体外DNA(ecDNA),其频率因肿瘤而异,且未在正常细胞中发现。ecDNA的扩增更有效地增加了癌基因拷贝数和肿瘤内异质性,从而驱动肿瘤进化。

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

 

Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy

营养细胞中配子发生基因的不适时表达导致单亲二倍体的出现

H. Diego Folco, Venkata R. Chalamcharla, Tomoyasu Sugiyama…Takeshi Mizuguchi & Shiv I. S. Grewal

http://www.nature.com/nature/journal/v543/n7643/full/nature21372.html

图片6.png 

配子发生基因的过早表达诱发单亲二倍体。Folco H D, et al. 2017)

(导读 韩宇)  单亲二倍体(UPD)现象与先天性疾病和癌症相关,但形成因素仍然未知。本文用裂变酵母作模型研究UPD,认为RNA干扰组分或Mmi1的缺陷导致了高水平的UPD,这与配子形成基因(如与编码减数分裂黏连蛋白Rec8)的不适时表达有关。

Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers. UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation. However, the factors that drive UPD remain unknown. Here we use the fission yeast Schizosaccharomyces pombe as a model to investigate UPD, and show that defects in the RNA interference (RNAi) machinery or in the YTH domain-containing RNA elimination factor Mmi1 cause high levels of UPD in vegetative diploid cells. This phenomenon is not due to defects in heterochromatin assembly at centromeres. Notably, in cells lacking RNAi components or Mmi1, UPD is associated with the untimely expression of gametogenic genes. Deletion of the upregulated gene encoding the meiotic cohesin Rec8 or the cyclin Crs1 suppresses UPD in both RNAi and mmi1 mutants. Moreover, overexpression of Rec8 is sufficient to trigger UPD in wild-type cells. Rec8 expressed in vegetative cells localizes to chromosomal arms and to the centromere core, where it is required for localization of the cohesin subunit Psc3. The centromeric localization of Rec8 and Psc3 promotes UPD by uniquely affecting chromosome segregation, causing a reductional segregation of one homologue. Together, these findings establish the untimely vegetative expression of gametogenic genes as a causative factor of UPD, and provide a solid foundation for understanding this phenomenon, which is linked to diverse human diseases.

 

【结构生物学】

Light-induced structural changes and the site of O=O bond formation in PSII caught by XFEL

XFEL技术捕捉到光系统II在光激发下的结构变化和氧氧键的形成机制

Michihiro Suga, Fusamichi Akita, Michihiro Sugahara…So Iwata(日本冈山大学) & Jian-Ren Shen沈建仁,冈山大学&中科院植物所

http://www.nature.com/nature/journal/v543/n7643/full/nature21400.html

图片7.png 

图片来源:nature

(导读 邸正傲  光系统II(PSII)是光合作用相关的复杂膜蛋白复合物,它可以利用光能催化水分子生成氧气。本文使用X射线自由电子激光XFEL)技术捕捉到了光激发和黑暗状PSII复合物的结构,发现了QB/非血红素铁区域和Mn4CaO5光解过程中的结构变化,从而从分子水平上揭示出氧气形成的可能机理。

 

Photosystem II (PSII) is a huge membrane-protein complex consisting of 20 different subunits with a total molecular mass of 350kDa for a monomer. It catalyses light-driven water oxidation at its catalytic centre, the oxygen-evolving complex (OEC)1, 2, 3. The structure of PSII has been analysed at 1.9Å resolution by synchrotron radiation X-rays, which revealed that the OEC is a Mn4CaO5 cluster organized in an asymmetric, ‘distorted-chair’ form4. This structure was further analysed with femtosecond X-ray free electron lasers (XFEL), providing the ‘radiation damage-free’5 structure. The mechanism of O=O bond formation, however, remains obscure owing to the lack of intermediate-state structures. Here we describe the structural changes in PSII induced by two-flash illumination at room temperature at a resolution of 2.35Å using time-resolved serial femtosecond crystallography with an XFEL provided by the SPring-8 ångström compact free-electron laser. An isomorphous difference Fourier map between the two-flash and dark-adapted states revealed two areas of apparent changes: around the QB/non-haem iron and the Mn4CaO5 cluster. The changes around the QB/non-haem iron region reflected the electron and proton transfers induced by the two-flash illumination. In the region around the OEC, a water molecule located 3.5Å from the Mn4CaO5 cluster disappeared from the map upon two-flash illumination. This reduced the distance between another water molecule and the oxygen atom O4, suggesting that proton transfer also occurred. Importantly, the two-flash-minus-dark isomorphous difference Fourier map showed an apparent positive peak around O5, a unique μ4-oxo-bridge located in the quasi-centre of Mn1 and Mn4 (refs 4,5). This suggests the insertion of a new oxygen atom (O6) close to O5, providing an O=O distance of 1.5Å between these two oxygen atoms. This provides a mechanism for the O=O bond formation consistent with that proposed previously6, 7.