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Nature论文导读 1207

时间: 2017年12月20日 | 作者: admin | 来源: 未知
Nature 20171207 1 【地球注册新宝GG】 Greater future global warming inferred from Earth’s recent energy budget 由地球近期的能源预算推断,未来全球变暖将会更加严重 Patrick T. Brown Ken Caldeira https://www.nature.com

Nature 20171207

 

1【地球注册新宝GG】Greater future global warming inferred from Earth’s recent energy budget

由地球近期的能源预算推断,未来全球变暖将会更加严重

Patrick T. Brown & Ken Caldeira  

https://www.nature.com/articles/nature24672

 

(导读 刘晓娟)气候模式是预测二十一世纪后期全球变暖的核心方法。本研究表明地球顶层大气能量预算的若干基本属性的全球空间格局和预测的全球变暖幅度之间存在强烈的跨模型关系。通过观测来约束后,我们在几种预测中获得了更大的均值和更窄的范围。实现任何全球温度稳定目标将需要减少更多的温室气体排放。

 

Climate models provide the principal means of projecting global warming over the remainder of the twenty-first century but modelled estimates of warming vary by a factor of approximately two even under the same radiative forcing scenarios. Across-model relationships between currently observable attributes of the climate system and the simulated magnitude of future warming have the potential to inform projections. Here we show that robust across-model relationships exist between the global spatial patterns of several fundamental attributes of Earth’s top-of-atmosphere energy budget and the magnitude of projected global warming. When we constrain the model projections with observations, we obtain greater means and narrows ranges of future global warming across the major radiative forcing scenarios, in general. In particular, we find that the observationally informed warming projection for the end of the twenty-first century for the steepest radiative forcing scenario is about 15 percent warmer (+0.5 degrees Celsius) with a reduction of about a third in the two-standard-deviation spread (-1.2 degrees Celsius) relative to the raw model projections reported by the Intergovernmental Panel on Climate Change. Our results suggest that achieving any global temperature stabilization target will require steeper greenhouse gas emissions reductions than previously calculated.

2 【生物】Structure of PINK1 in complex with its substrate ubiquitin

PINK1与其底物泛素复合物的结构

Alexander F. Schubert     et.al

https://www.nature.com/articles/nature24645

 

导读 柳寒石常染色体隐性青少年帕金森综合征AR-JP是由一些PARK基因的突变所引起的包括Parkin引起线粒体自噬的上游蛋白激酶PINK1。研究人员通过解析一种纳米体稳定PINK1与其底物泛素复合物的晶体结构揭示了PINK1通过其N端的特殊插入方式来与泛素结合,这也解释了部分突变通过阻断泛素结合以导致AR-JP分子基础。

 

Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin (PARK2, also known as PRKN) and its upstream protein kinase PINK1 (also known as PARK6). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to ubiquitin in the ‘C-terminally retracted’ (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding.

 

3 【生物】A transfer-RNA-derived small RNA regulates ribosome biogenesis

由转运RNA衍生的小RNA调节核糖体生物合成

Hak Kyun Kim     et.al

https://www.nature.com/articles/nature25005

 

(导读 郭怿暄)转运RNA衍生的小RNAstsRNAs)是一类非常丰富的小非编码RNA但其生物功能尚不清楚。本研究发现LeuCAG3′tsRNA至少可结合RPS28RPS15两种核糖体mRNAs从而增强其翻译。对其进行特异性抑制可使RPS28 mRNA翻译水平下降,阻断pre-18S核糖体RNA的加工,造成核糖体40S亚基的数量降低。在体外以及患者来源的原位小鼠肝癌模型中均可诱导快速分裂中的细胞发生凋亡,可作为新的癌症治疗靶点。

 

Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3′tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.

 

 

4 【物理】 Direct detection of a break in the teraelectronvolt cosmic-ray spectrum of electrons and positrons

电子和正电子TeV宇宙射线能谱拐折的直接探测

DAMPE Collaboration     et.al

https://www.nature.com/articles/nature24475

 

(导读 阿金)高能宇宙线电子和正电子(CREs能谱可帮助观暗物质粒子湮灭、衰变等现象。本研究报道中国暗物质粒子探测卫星“悟空”(DAMPE25 GeV-4.6 TeV能量范围内,以高分辨率及低背景干扰,对CREs进行了直接测量。结果显示,“悟空”号首次直接测量到电子宇宙射线能谱在0.9 TeV处的拐折。

 

High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes and may enable the observation of phenomena such as dark-matter particle annihilation or decay. The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon- or space-borne experiments , and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov γ-ray telescope arrays. Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements, although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE) with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a ‘smoothly broken power-law’ model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements, clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.

 

5 【生物】Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns

具有任意图案的微米级DNA折纸技术阵列的分形组装

Grigory Tikhomirov     et.al

https://www.nature.com/articles/nature2465

 

(导读 阿金)DNA折纸技术制造的自组装纳米结构可实现精确的纳米级图案,但尺寸限制在0.05平方微米,且无足够稳健技术实现大结构。本研究展示一种分形组装方法,使用简单局部自装规则,拼造出尺寸为0.5平方微米,高达8704像素的DNA折纸阵列,画出任意图案。且不受表面图案变化影响。为进一步构建尺寸相近的细菌材料和备件提供新方法。

 

Self-assembled DNA nanostructures enable nanometre-precise patterning that can be used to create programmable molecular machines and arrays of functional materials. DNA origami is particularly versatile in this context because each DNA strand in the origami nanostructure occupies a unique position and can serve as a uniquely addressable pixel. However, the scale of such structures has been limited to about 0.05 square micrometres, hindering applications that demand a larger layout and integration with more conventional patterning methods. Hierarchical multistage assembly of simple sets of tiles can in principle overcome this limitation, but so far has not been sufficiently robust to enable successful implementation of larger structures using DNA origami tiles. Here we show that by using simple local assembly rules that are modified and applied recursively throughout a hierarchical, multistage assembly process, a small and constant set of unique DNA strands can be used to create DNA origami arrays of increasing size and with arbitrary patterns. We illustrate this method, which we term ‘fractal assembly’, by producing DNA origami arrays with sizes of up to 0.5 square micrometres and with up to 8,704 pixels, allowing us to render images such as the Mona Lisa and a rooster. We find that self-assembly of the tiles into arrays is unaffected by changes in surface patterns on the tiles, and that the yield of the fractal assembly process corresponds to about 0.95m1 for arrays containing m tiles. When used in conjunction with a software tool that we developed that converts an arbitrary pattern into DNA sequences and experimental protocols, our assembly method is readily accessible and will facilitate the construction of sophisticated materials and devices with sizes similar to that of a bacterium using DNA nanostructures.

 

6 生物Programmable self-assembly of three-dimensional nanostructures from 10,000 unique components

10000个单独组件块组成的可编程自组装三维纳米结构

Luvena L. Ong     et.al

https://www.nature.com/articles/nature24648

 

(导读 阿金)传统DNA折纸技术需用DNA长链支架短链互锁模块搭建纳米尺度结构,但构建更大结构仍面临挑战。本研究展示,数万个结合区长度为13个核苷酸的DNA“积木块,可自组装成0.1-1千兆道尔顿的三维结构。其结构可在分子画布上形成字母、螺旋等图形。为进一步优化结构设计、短链合成和组装大结构提供新思路。

 

Nucleic acids (DNA and RNA) are widely used to construct nanometre-scale structures with ever increasing complexity, with possible application in fields such as structural biology, biophysics, synthetic biology and photonics. The nanostructures are formed through one-pot self-assembly, with early kilodalton-scale examples containing typically tens of unique DNA strands. The introduction of DNA origami, which uses many staple strands to fold one long scaffold strand into a desired structure, has provided access to megadalton-scale nanostructures that contain hundreds of unique DNA strands. Even larger DNA origami structures are possible, but manufacturing and manipulating an increasingly long scaffold strand remains a challenge. An alternative and more readily scalable approach involves the assembly of DNA bricks, which each consist of four short binding domains arranged so that the bricks can interlock. This approach does not require a scaffold; instead, the short DNA brick strands self-assemble according to specific inter-brick interactions. First-generation bricks used to create three-dimensional structures are 32 nucleotides long, consisting of four eight-nucleotide binding domains. Protocols have been designed to direct the assembly of hundreds of distinct bricks into well formed structures, but attempts to create larger structures have encountered practical challenges and had limited success. Here we show that DNA bricks with longer, 13-nucleotide binding domains make it possible to self-assemble 0.1–1-gigadalton, three-dimensional nanostructures from tens of thousands of unique components, including a 0.5-gigadalton cuboid containing about 30,000 unique bricks and a 1-gigadalton rotationally symmetric tetramer. We also assembled a cuboid that contains around 10,000 bricks and about 20,000 uniquely addressable, 13-base-pair ‘voxels’ that serves as a molecular canvas for three-dimensional sculpting. Complex, user-prescribed, three-dimensional cavities can be produced within this molecular canvas, enabling the creation of shapes such as letters, a helicoid and a teddy bear. We anticipate that with further optimization of structure design, strand synthesis and assembly procedure even larger structures could be accessible, which could be useful for applications such as positioning functional components.

 

7 【生物】Gigadalton-scale shape-programmable DNA assemblies

千兆道尔顿级的形状可编程DNA组件

Klaus F. Wagenbauer     et.al

https://www.nature.com/articles/nature24651

 

(导读 阿金)蛋白设计和RNA/DNA纳米技术试图模仿天然生物分子组装能力,但类似复杂病毒等自下而上的人工结构构建仍具挑战。本研究采用DNA折纸技术结合天然组装机制生产尺寸可控的千兆道尔顿尺度结构。用DNA序列信息来编码单个DNA折纸积木块形状,利用具备互作模式的精确设计实现效率高达90%的分层装配。为探索精确尺寸复杂结构模块提供新方法。

 

Natural biomolecular assemblies such as molecular motors, enzymes, viruses and subcellular structures often form by self-limiting hierarchical oligomerization of multiple subunits. Large structures can also assemble efficiently from a few components by combining hierarchical assembly and symmetry, a strategy exemplified by viral capsids. De novo protein design and RNA and DNA nanotechnology aim to mimic these capabilities, but the bottom-up construction of artificial structures with the dimensions and complexity of viruses and other subcellular components remains challenging. Here we show that natural assembly principles can be combined with the methods of DNA origami to produce gigadalton-scale structures with controlled sizes. DNA sequence information is used to encode the shapes of individual DNA origami building blocks, and the geometry and details of the interactions between these building blocks then control their copy numbers, positions and orientations within higher-order assemblies. We illustrate this strategy by creating planar rings of up to 350 nanometres in diameter and with atomic masses of up to 330 megadaltons, micrometre-long, thick tubes commensurate in size to some bacilli, and three-dimensional polyhedral assemblies with sizes of up to 1.2 gigadaltons and 450 nanometres in diameter. We achieve efficient assembly, with yields of up to 90 per cent, by using building blocks with validated structure and sufficient rigidity, and an accurate design with interaction motifs that ensure that hierarchical assembly is self-limiting and able to proceed in equilibrium to allow for error correction. We expect that our method, which enables the self-assembly of structures with sizes approaching that of viruses and cellular organelles, can readily be used to create a range of other complex structures with well defined sizes, by exploiting the modularity and high degree of addressability of the DNA origami building blocks used.

 

8 【生物】Biotechnological mass production of DNA origami

大规模DNA折纸原料生产技术

Florian Praetorius     et.al

https://www.nature.com/articles/nature24650

 

(导读 阿金)DNA纳米折纸技术可自下而上组装微米级三维机构,但其原料,单链DNA的合成较为困难。本研究介绍了一种可量产合成任意长度、任意序列DNA折纸原料的方法:利用噬菌体生产含目标序列和间隔自切割模块cassette的长单链DNAcassette自切割后即得到目标DNA元件该方法与现有的DNA折纸设计框架兼容,并保留模块性和可编性。为扩大DNA纳米技术的应用范围开拓新途径。

 

DNA nanotechnology, in particular DNA origami, enables the bottom-up self-assembly of micrometre-scale, three-dimensional structures with nanometre-precise features. These structures are customizable in that they can be site-specifically functionalized or constructed to exhibit machine-like or logic-gating behaviour. Their use has been limited to applications that require only small amounts of material (of the order of micrograms), owing to the limitations of current production methods. But many proposed applications, for example as therapeutic agents or in complex materials, could be realized if more material could be used. In DNA origami, a nanostructure is assembled from a very long single-stranded scaffold molecule held in place by many short single-stranded staple oligonucleotides. Only the bacteriophage-derived scaffold molecules are amenable to scalable and efficient mass production; the shorter staple strands are obtained through costly solid-phase synthesis24 or enzymatic processes. Here we show that single strands of DNA of virtually arbitrary length and with virtually arbitrary sequences can be produced in a scalable and cost-efficient manner by using bacteriophages to generate single-stranded precursor DNA that contains target strand sequences interleaved with self-excising ‘cassettes’, with each cassette comprising two Zn2+-dependent DNA-cleaving DNA enzymes. We produce all of the necessary single strands of DNA for several DNA origami using shaker-flask cultures, and demonstrate end-to-end production of macroscopic amounts of a DNA origami nanorod in a litre-scale stirred-tank bioreactor. Our method is compatible with existing DNA origami design frameworks and retains the modularity and addressability of DNA origami objects that are necessary for implementing custom modifications using functional groups. With all of the production and purification steps amenable to scaling, we expect that our method will expand the scope of DNA nanotechnology in many areas of science and technology.

 

9 【天文】Primordial clays on Mars formed beneath a steam or supercritical atmosphere

火星的原始粘土矿物由蒸汽形成

Kevin M. Cannon     et.al

https://www.nature.com/articles/nature24657

 

 

(导读 雷鸣)之前的研究认为,火星上的粘土矿物形成于41亿至37亿年前的诺亚时期,是由火星玄武岩壳与液态水相互作用产生的。这是火星上存在大量液态水的证据。但本研究认为,原初的火星壳层与处于超临界状态的水和二氧化碳相互作用形成大量粘土。研究人员提供了实验证据来验证这一设想。另外,他们还认为这些粘土由于受到撞击而分裂,并被撞击溅射物和火山喷发物质掩埋,渐渐形成今天的分布状态。这也为火星地壳密度比预期稀疏做出了合理解释。

 

On Mars, clay minerals are widespread in terrains that date back to the Noachian period (4.1 billion to 3.7 billion years ago)1,2,3,4,5. It is thought that the Martian basaltic crust reacted with liquid water during this time to form hydrated clay minerals3,6. Here we propose, however, that a substantial proportion of these clays was formed when Mars’ primary crust reacted with a dense steam or supercritical atmosphere of water and carbon dioxide that was outgassed during magma ocean cooling7,8,9. We present experimental evidence that shows rapid clay formation under conditions that would have been present at the base of such an atmosphere and also deeper in the porous crust. Furthermore, we explore the fate of a primordial clay-rich layer with the help of a parameterized crustal evolution model; we find that the primordial clay is locally disrupted by impacts and buried by impact-ejected material and by erupted volcanic material, but that it survives as a mostly coherent layer at depth, with limited surface exposures. These exposures are similar to those observed in remotely sensed orbital data from Mars1,2,3,4,5. Our results can explain the present distribution of many clays on Mars, and the anomalously low density of the Martian crust in comparison with expectations.

 

10 【进化】Reconciling taxon senescence with the Red Queen’s hypothesis

解决衰退类群的红皇后假说矛盾

Indr liobait     et.al

https://www.nature.com/articles/nature24656

 

(导读 阿金)化石记录中古老类群规律性的衰退灭绝随机绝灭假说之间有明显矛盾。本研究提出生物进化驱动力与扩张高峰有关,而非生物驱动力则适用于解释类群灭绝。红皇后假说,这个强调了生物间作用的假说却被长久用于解释灭绝,因而造成了表面上看起来的矛盾。

 

 In the fossil record, taxa exhibit a regular pattern of waxing and waning of occupancy, range or diversity between their origin and extinction. This pattern appears to contradict the law of constant extinction, which states that the probability of extinction in a given taxon is independent of that taxon’s age. It is nevertheless well established for species, genera and higher taxa of terrestrial mammals, marine invertebrates, marine microorganisms, and recent Hawaiian clades of animals and plants. Here we show that the apparent contradiction between a stochastically constant extinction rate and the seemingly deterministic waxing and waning pattern of taxa disappears when we consider their peak of expansion rather than their final extinction. To a first approximation, we find that biotic drivers of evolution pertain mainly to the peak of taxon expansion, whereas abiotic drivers mainly apply to taxon extinction. The Red Queen’s hypothesis, which emphasizes biotic interactions, was originally proposed as an explanation of the law of constant extinction. Much effort has since been devoted to determining how this hypothesis, emphasizing competition for resources, relates to the effects of environmental change. One proposed resolution is that biotic and abiotic processes operate at different scales. By focusing attention on taxon expansion rather than survival, we resolve an apparent contradiction between the seemingly deterministic waxing and waning patterns over time and the randomness of extinction that the Red Queen’s hypothesis implies.

 

11【生物】Genetic diversity of the African malaria vector Anopheles gambiae

非洲疟疾媒介冈比亚按蚊的遗传多样性

 

The Anopheles gambiae 1000 Genomes Consortium   

冈比亚按蚊1000基因组项目联

https://www.nature.com/articles/nature24995

 

 

图片1.png 

图片来源:Nature

 

(导读 郭思瑶)非洲按蚊对杀的耐受已疾的防控工作。注册新宝GG家非洲765个按蚊行基因组测序,定出超五千万个核苷酸多性。些数据示了复的种群构和基因流模式。同时检测到了抗性基因的选择信号。表明基因向的蚊虫防控工作需要考自然种群中的遗传性。

 

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease. To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations.

 

12 【生物】Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors

恶性疟原虫的免疫逃避策略:利用RIFIN蛋白结合免疫抑制性受体

Fumiji Saito,    et.al

https://www.nature.com/articles/nature24994

 

(导读 严冰)绝大部分致命的疟疾案例都是由恶性疟原虫引起,而宿主适应性免疫对疟疾十分低效。本文报导,恶性疟原虫可利用自身编码的一系列RIFIN蛋白实现免疫逃避。这种RIFIN蛋白表达在被感染的血红细胞表面,可结合白细胞免疫受体LILRB1LAIR1;当与LILRB1结合时,可抑制LILRB1所处B细胞和NK细胞的激活;相比正常血红细胞,被恶性疟原虫感染的血红细胞更有可能与LILRB1相互作用。上述结果暗示,恶性疟原虫通过多种RIFIN蛋白结合免疫抑制受体来逃避宿主免疫效应。

 

Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths each year1. Plasmodium falciparum causes most life-threatening cases of malaria. Acquired immunity to malaria is inefficient, even after repeated exposure to P. falciparum2, but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150–200 genes per parasite genome3 that are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibit activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, although an extended study with larger sample sizes is required to confirm this finding. Our results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.

 

13 【生物】Maternal age generates phenotypic variation in Caenorhabditis elegans

母亲年龄在秀丽隐杆线虫(Caenorhabditis elegans)中产生表型变异

Marcos Francisco Perez     et.al

https://www.nature.com/articles/nature25012

 

 

(导读 郭怿暄)具有相同遗传背景生活在相同环境中的个体依旧会出现大量表型变异,这一现象的机制仍不清楚。本研究发现具有相同遗传背景的线虫因其母体年龄,在孵化时的大小,发育和生长速率,饥饿耐受程度,繁殖力等多种性状上终生呈现出表型差异,年轻母亲的后代多出现缺陷,这与母体为胚胎提供的脂蛋白复合体卵黄蛋白原随年龄变化有关。

 

Genetically identical individuals that grow in the same environment often show substantial phenotypic variation within populations of organisms as diverse as bacteria, nematodes, rodents and humans. With some exceptions, the causes are poorly understood. Here we show that isogenic Caenorhabditis elegans nematodes vary in their size at hatching, speed of development, growth rate, starvation resistance, fecundity, and also in the rate of development of their germline relative to that of somatic tissues. We show that the primary cause of this variation is the age of an individual’s mother, with the progeny of young mothers exhibiting several phenotypic impairments. We identify age-dependent changes in the maternal provisioning of the lipoprotein complex vitellogenin to embryos as the molecular mechanism that underlies the variation in multiple traits throughout the life of an animal. The production of sub-optimal progeny by young mothers may reflect a trade-off between the competing fitness traits of a short generation time and the survival and fecundity of the progeny.

 

14 【生物】IL-11 is a crucial determinant of cardiovascular fibrosis

IL-11是心血管纤维化的决定性因素

Sebastian Schafer    et.al

https://www.nature.com/articles/nature24676

 

(导读 齐睿娟)纤维化常发生于心血管疾病。转化生长因子β1TGFβ1)是主要的促纤维化因子,但其作用的多效性使得针对其的抑制作用带来诸多副作用。本研究于原代人成纤维细胞中发现,在TGFβ1暴露条件下,白细胞介素-11IL-11)的表达上调且与促纤维作用有关。 IL-11及其受体(IL11RA)在成纤维细胞中特异性表达,其通过非经典ERK依赖性自分泌信号传导机制促进纤维化蛋白的合成。本研究证实说明抑制IL-11是治疗纤维化疾病的潜在治疗策略。

 

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

 

15 【生物】Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth

DNA修复的失活触发新抗原产生阻止肿瘤生长

Giovanni Germano   et.al

https://www.nature.com/articles/nature24673

 

(导读 严冰)DNA错配修复(MMR)缺陷的癌症在临床上大多表现为预后良好和发展迟缓。本文报导在小鼠多种癌细胞中失活MLH1基因并不影响肿瘤细胞在体外和免疫缺陷型小鼠中的生长。但在免疫功能正常的小鼠中,MLH1失活癌细胞具有更高的突变率和肿瘤新抗原,导致免疫监视水平的提高从而阻止其生长。该结果表明,DNA修复过程可能成为肿瘤治疗的新靶标。

 

Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression1. Cancers deficient in MMR frequently show favourable prognosis and indolent progression2. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited in therapeutic approaches.

 

16 【生物】PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

PD-1是一种单倍体不足的T细胞淋巴瘤发生抑制因子

Tim Wartewig,   et.al

https://www.nature.com/articles/nature24649

 

(导读 严冰)T细胞淋巴瘤常常伴有T细胞受体(TCR)信号分子的获得功能性突变。本文报导,TCR信号通路致癌基因的急剧变化可促进体内细胞剧烈扩增,然而这一反应很快就被细胞自身机制所抵消。随后通过T细胞特异性转座子突变的全基因组扫描发现编码PD-1PDCD1基因是TCR通路被抑制的原因。而在T细胞淋巴瘤中也经常可见PDCD1的单或双等位基因的缺失。分子机制的研究结果表明,PD-1是一种有效的单倍体不足的T细胞淋巴瘤抑制因子,可能成为将来的治疗靶标。

 

T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules1,2,3,4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.

 

17 【生物】Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control

启动子结合的METTL3通过m6A依赖性翻译控制维持髓系白血病

Isaia Barbieri,   et.al

https://www.nature.com/articles/nature24678

 

(导读 大头)N6-甲基腺苷(m6A)是在编码和非编码RNA中常见的修饰,由METTL3-METTL14甲基转移酶催化形成。本文发现METTL3是维持髓系白血病状态的关键基因。METTL3可以不依赖于METTL14结合在活跃表达基因的转录起始位点,诱导其转录mRNA编码区的m6A修饰从而提高翻译效率。以上结果表明,METTL3作为染色质的调节子,可以成为髓系白血病的治疗靶点。

 

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding1 and non-coding RNAs2,3 that is catalysed by the METTL3–METTL14 methyltransferase complex4. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site5, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.

 

18 【生物】Genetically programmed chiral organoborane synthesis

基因编码下的手性有机硼烷合成

S. B. Jennifer Kan,   et.al

https://www.nature.com/articles/nature24996

 

(导读 阿金)酶的工程化和设计可催化天然产物合成,但要让其催化的化学反应发生在生物体内依然有难度。本研究报道含有来源于海洋红嗜热盐菌细胞色素cRma cyt c)的大肠杆菌可以作为全细胞活体催化剂,在路易斯碱-硼烷复合物存在下形成硼碳键,从而开发出在细菌中生产手性有机硼烷的基因编码平台。Rma cyt c 进行定向突变还可以大幅度提升催化活性和手性选择性,实现生产可调节性

 

Recent advances in enzyme engineering and design have expanded nature’s catalytic repertoire to functions that are new to biology. However, only a subset of these engineered enzymes can function in living systems. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus (Rma cyt c) were found to form carbon–boron bonds in the presence of borane–Lewis base complexes, through carbene insertion into boron–hydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100h–1, a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems.