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Nature论文导读 1102

时间: 2017年11月14日 | 作者: admin | 来源: 未知
Nature20171102 1 【生物】 The dynamics of molecular evolution over 60,000 generations Benjamin H. Good, et.al 超过 6 万代的分子进化动态 https://www.nature.com/articles/nature24287 The outcomes of evolution are determined by a

Nature20171102

1【生物】The dynamics of molecular evolution over 60,000 generations

Benjamin H. Good, et.al

 

超过6万代的分子进化动态

 

https://www.nature.com/articles/nature24287

 

 

The outcomes of evolution are determined by a stochastic dynamical process that governs how mutations arise and spread through a population. However, it is difficult to observe these dynamics directly over long periods and across entire genomes. Here we analyse the dynamics of molecular evolution in twelve experimental populations of Escherichia coli, using whole-genome metagenomic sequencing at five hundred-generation intervals through sixty thousand generations. Although the rate of fitness gain declines over time, molecular evolution is characterized by signatures of rapid adaptation throughout the duration of the experiment, with multiple beneficial variants simultaneously competing for dominance in each population. Interactions between ecological and evolutionary processes play an important role, as long-term quasi-stable coexistence arises spontaneously in most populations, and evolution continues within each clade. We also present evidence that the targets of natural selection change over time, as epistasis and historical contingency alter the strength of selection on different genes. Together, these results show that long-term adaptation to a constant environment can be a more complex and dynamic process than is often assumed.

 

(导读 郭怿暄)直接观察进化过程中种群基因组在长时间的动态变化十分困难。本研究利用全基因组宏基因组测序以500代为间隔分析了超过6万代、12个实验室大肠杆菌种群的分子进化动态。发现在每个种群中同时出现多种快速适应的有益变异,在大多数种群内自发出现了长期准稳态的进化分支共存,以及自然选择的靶向基因的持续改变。这一发现揭开了一个复杂且多变的对于不变环境的长期适应过程。

 

2 【生物】Two independent modes of chromatin organization revealed by cohesin removal

Wibke Schwarzer, et.al

 

通过去除凝集素发现两种独立的染色质组织模式

 

https://www.nature.com/articles/nature24281

 

 

Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.

 

(导读 郭怿暄)细胞核中染色质组织成多层级结构,形成不同活性区域,从而影响基因组功能。本研究发现敲除小鼠肝脏中的凝集素装载因子Nipbl导致染色体折叠发生重组。亚兆碱基结构域(TAD)整体消失,但区室分隔得以保留甚至加强,更加精确地反应出表观遗传景观。这揭示了基因组的三维结构是两种独立机制共同作用的结果:不依赖凝集素、更加精细的基因组区室分离以及凝集素依赖的TAD形成。

 

3 【生物】Structure of phycobilisome from the red alga Griffithsia pacifica

Jun Zhang, , et.al

海洋红藻的光能捕捉元件——藻胆体的结构

https://www.nature.com/articles/nature24278

 

(导读 严冰)光合作用是地球生物体的能量来源,存在于蓝藻和红藻体内的藻胆体(phycobilisome, PBS)是已知最大的捕捉光能元件,由藻胆蛋白与连接蛋白组成。本文报导,利用单粒子冷冻电镜技术,解析出海洋红藻体内的大小为16.8 MDaPBS结构,包括862个蛋白质亚基和2048个发色团(chromophores)。这为进一步研究其装配和光能转化机制提供了基础。

 

Life on Earth depends on photosynthesis for its conversion of solar energy to chemical energy. Photosynthetic organisms have developed a variety of light-harvesting systems to capture sunlight. The largest light-harvesting complex is the phycobilisome (PBS), the main light-harvesting antenna in cyanobacteria and red algae. It is composed of phycobiliproteins and linker proteins but the assembly mechanisms and energy transfer pathways of the PBS are not well understood. Here we report the structure of a 16.8-megadalton PBS from a red alga at 3.5Å resolution obtained by single-particle cryo-electron microscopy. We modelled 862 protein subunits, including 4 linkers in the core, 16 rodcore linkers and 52 rod linkers, and located a total of 2,048 chromophores. This structure reveals the mechanisms underlying specific interactions between linkers and phycobiliproteins, and the formation of linker skeletons. These results provide a firm structural basis for our understanding of complex assembly and the mechanisms of energy transfer within the PBS.

 

4【物理】Optical emission from a kilonova following a gravitational-wave-detected neutron-star merger

Iair Arcavi, et.al

双中子星合并后新千星的可见光辐射

https://www.nature.com/articles/nature24291

 

(导读 阿金)本研究在可见光到近红外波段,探测到与双中子星合并后产生的引力波信号、低亮度γ射线暴对应的暂现。理论预言这是千新星的辐射。观测显示,辐射迅速红移并变暗。数值模拟得出的结论是,观测数据与0.01太阳的喷射物(形成的千新星)的光变曲线大体一致。

 

The merger of two neutron stars has been predicted to produce an optical–infrared transient (lasting a few days) known as a ‘kilonova’, powered by the radioactive decay of neutron-rich species synthesized in the merger. Evidence that short γ-ray bursts also arise from neutron-star mergers has been accumulating. In models2,9 of such mergers, a small amount of mass (10−4–10−2 solar masses) with a low electron fraction is ejected at high velocities (0.1–0.3 times light speed) or carried out by winds from an accretion disk formed around the newly merged object. This mass is expected to undergo rapid neutron capture (r-process) nucleosynthesis, leading to the formation of radioactive elements that release energy as they decay, powering an electromagnetic transient. A large uncertainty in the composition of the newly synthesized material leads to various expected colours, durations and luminosities for such transients. Observational evidence for kilonovae has so far been inconclusive because it was based on cases of moderate excess emission detected in the afterglows of γ-ray bursts. Here we report optical to near-infrared observations of a transient coincident with the detection of the gravitational-wave signature of a binary neutron-star merger and with a low-luminosity short-duration γ-ray burst. Our observations, taken roughly every eight hours over a few days following the gravitational-wave trigger, reveal an initial blue excess, with fast optical fading and reddening. Using numerical models, we conclude that our data are broadly consistent with a light curve powered by a few hundredths of a solar mass of low-opacity material corresponding to lanthanide-poor (a fraction of 10−4.5 by mass) ejecta.

 

 

5 【物理】Spectroscopic identification of r-process nucleosynthesis in a double neutron-star merger

E. Pian   , et.al

双中子星合并r-过程核合成的光谱鉴

https://www.nature.com/articles/nature24298

 

(导读 阿金)本研究报道引力波事件GW170817中千新星的光谱鉴定及物理性质。千新星光谱与理论模型预言的迅速膨胀喷射物的光谱特征相似:早期以0.2倍光速快速膨胀,在1.5天内喷射半径就能达到约50个天文单位。研究人员从膨胀过程中光谱连续区上出现的宽吸收谱线,判断r过程核合成产生的原子种类。与光谱模型的比较显示,双中子星合并喷射出0.030.05太阳质量的物质,包括镧系元素。

 

The merger of two neutron stars is predicted to give rise to three major detectable phenomena: a short burst of γ-rays, a gravitational-wave signal, and a transient optical–near-infrared source powered by the synthesis of large amounts of very heavy elements via rapid neutron capture (the r-process). Such transients, named ‘macronovae’ or ‘kilonovae’, are believed to be centres of production of rare elements such as gold and platinum. The most compelling evidence so far for a kilonova was a very faint near-infrared rebrightening in the afterglow of a short γ-ray burst at redshift z = 0.356, although findings indicating bluer events have been reported. Here we report the spectral identification and describe the physical properties of a bright kilonova associated with the gravitational-wave source GW170817 and γ-ray burst GRB 170817A associated with a galaxy at a distance of 40 megaparsecs from Earth. Using a series of spectra from ground-based observatories covering the wavelength range from the ultraviolet to the near-infrared, we find that the kilonova is characterized by rapidly expanding ejecta with spectral features similar to those predicted by current models. The ejecta is optically thick early on, with a velocity of about 0.2 times light speed, and reaches a radius of about 50 astronomical units in only 1.5 days. As the ejecta expands, broad absorption-like lines appear on the spectral continuum, indicating atomic species produced by nucleosynthesis that occurs in the post-merger fast-moving dynamical ejecta and in two slower (0.05 times light speed) wind regions. Comparison with spectral models suggests that the merger ejected 0.03 to 0.05 solar masses of material, including high-opacity lanthanides.

 

 

6 【物理】The X-ray counterpart to the gravitational-wave event GW170817

E. Troja   , et.al

引力波事件GW170817X线对应体

https://www.nature.com/articles/nature24290

 

(导读 阿金)本研究报告观测到引力波事件GW170817X射线对应体。在千新星暂现位置观测到的X射线将短时伽马线暴与中子星合并引力波关联起来,并独立证实了伽马射线暴的准直特性。

 

A long-standing paradigm in astrophysics is that collisions—or mergers—of two neutron stars form highly relativistic and collimated outflows (jets) that power γ-ray bursts of short (less than two seconds) duration. The observational support for this model, however, is only indirect. A hitherto outstanding prediction is that gravitational-wave events from such mergers should be associated with γ-ray bursts, and that a majority of these bursts should be seen off-axis, that is, they should point away from Earth. Here we report the discovery observations of the X-ray counterpart associated with the gravitational-wave event GW170817. Although the electromagnetic counterpart at optical and infrared frequencies is dominated by the radioactive glow (known as a ‘kilonova’) from freshly synthesized rapid neutron capture (r-process) material in the merger ejecta, observations at X-ray and, later, radio frequencies are consistent with a short γ-ray burst viewed off-axis. Our detection of X-ray emission at a location coincident with the kilonova transient provides the missing observational link between short γ-ray bursts and gravitational waves from neutron-star mergers, and gives independent confirmation of the collimated nature of the γ-ray-burst emission.

 

 

 

7 【物理】A kilonova as the electromagnetic counterpart to a gravitational-wave source

S. J. Smartt  , et.al

千新星:引力波源的电磁对应

https://www.nature.com/articles/nature24303

 

(导读 阿金)本研究报道观测到发生在NGC4993星系中快速黯淡的电磁暂现及其物理建模。暂现的物理参数与中子星合并产生的千新星的理论预测大体相符。其电磁辐射的特征显示,千新星由  0.04 ± 0.01太阳质量的喷射物形成,不透明度小于0.5cm2/g,速度为0.2 ± 0.1倍光速。研究人员还在辐射谱中鉴别出r-过程形成的轻元素对应的谱线。暂现的黯淡的同时迅速变红,这些辐射可能来自更高不透明度、富含镧系元素的喷射物。

 

Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of −1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90–140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.

 

8 【物理】Origin of the heavy elements in binary neutron-star mergers from a gravitational-wave event

Daniel Kasen , et.al

双中子星合并中的重元素起源

https://www.nature.com/articles/nature24453

 

(导读 阿金)本研究报道了能够仔细预测千新星电磁辐射的理论模型。通过比较模型与引力波事件GW170817相关的可见光及红外辐射,研究人员认为其辐射源是千新星,并从中推断出双中子星合并的喷射物包含两种不同的组分——分别由r-过程形成的轻(原子质量数小于140)、重(原子质量数大于140)元素组成。GW170817的相关特征暗示双中子星合并产生了宇宙中大部分重元素。

 

The cosmic origin of elements heavier than iron has long been uncertain. Theoretical modelling shows that the matter that is expelled in the violent merger of two neutron stars can assemble into heavy elements such as gold and platinum in a process known as rapid neutron capture (r-process) nucleosynthesis. The radioactive decay of isotopes of the heavy elements is predicted to power a distinctive thermal glow (a ‘kilonova’). The discovery of an electromagnetic counterpart to the gravitational-wave source GW170817 represents the first opportunity to detect and scrutinize a sample of freshly synthesized r-process elements. Here we report models that predict the electromagnetic emission of kilonovae in detail and enable the mass, velocity and composition of ejecta to be derived from observations. We compare the models to the optical and infrared radiation associated with the GW170817 event to argue that the observed source is a kilonova. We infer the presence of two distinct components of ejecta, one composed primarily of light (atomic mass number less than 140) and one of heavy (atomic mass number greater than 140) r-process elements. The ejected mass and a merger rate inferred from GW170817 imply that such mergers are a dominant mode of r-process production in the Universe.

 

 

 

9 【物理】A gravitational-wave standard siren measurement of the Hubble constant

The LIGO Scientific Collaboration and The Virgo Collaboration,, et.al

利用引力波精确测量哈勃常数

https://www.nature.com/articles/nature24471

 

(导读 阿金)本研究结合引力波源的距离和对应电磁辐射中的红移信息,独立测得哈勃常数数值约为70 km/(s*Mpc),与现有测量结果一致。

 

On 17 August 2017, the Advanced LIGO and Virgo detectors observed the gravitational-wave event GW170817—a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst (GRB 170817A) was detected within a region of the sky consistent with the LIGO–Virgo-derived location of the gravitational-wave source. This sky region was subsequently observed by optical astronomy facilities, resulting in the identification of an optical transient signal within about ten arcseconds of the galaxy NGC 4993. This detection of GW170817 in both gravitational waves and electromagnetic waves represents the first ‘multi-messenger’ astronomical observation. Such observations enable GW170817 to be used as a ‘standard siren’ (meaning that the absolute distance to the source can be determined directly from the gravitational-wave measurements) to measure the Hubble constant. This quantity represents the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Here we report a measurement of the Hubble constant that combines the distance to the source inferred purely from the gravitational-wave signal with the recession velocity inferred from measurements of the redshift using the electromagnetic data. In contrast to previous measurements, ours does not require the use of a cosmic ‘distance ladder’: the gravitational-wave analysis can be used to estimate the luminosity distance out to cosmological scales directly, without the use of intermediate astronomical distance measurements. We determine the Hubble constant to be about 70 kilometres per second per megaparsec. This value is consistent with existing measurements, while being completely independent of them. Additional standard siren measurements from future gravitational-wave sources will enable the Hubble constant to be constrained to high precision.

 

 

10 【物理】Quark-level analogue of nuclear fusion with doubly heavy baryons

Marek Karliner & Jonathan L. Rosner     et.al

 

双重重子的夸克层次类核聚变反应

https://www.nature.com/articles/nature24289

 

(导读 阿金)本研究报道强结合能可导致夸克重排,发生放热反应,其中两个重子经过聚变产生双粲重子和一个中子,释放12MeV的能量。该反应在夸克层次上的类似氘氚核聚变反应。如果底夸克发生类似的反应,那么由于底夸克间结合能大得多,反应能够释放约138MeV的能量(理论计算值)。但在目前,这类反应由于夸克寿命短暂而难以投入实际应用中。

The essence of nuclear fusion is that energy can be released by the rearrangement of nucleons between the initial- and final-state nuclei. The recent discovery of the first doubly charmed baryon , which contains two charm quarks (c) and one up quark (u) and has a mass of about 3,621 megaelectronvolts (MeV) (the mass of the proton is 938 MeV) also revealed a large binding energy of about 130 MeV between the two charm quarks. Here we report that this strong binding enables a quark-rearrangement, exothermic reaction in which two heavy baryons (Λc) undergo fusion to produce the doubly charmed baryon  and a neutron n (), resulting in an energy release of 12 MeV. This reaction is a quark-level analogue of the deuterium–tritium nuclear fusion reaction (DT → 4He n). The much larger binding energy (approximately 280 MeV) between two bottom quarks (b) causes the analogous reaction with bottom quarks () to have a much larger energy release of about 138 MeV. We suggest some experimental setups in which the highly exothermic nature of the fusion of two heavy-quark baryons might manifest itself. At present, however, the very short lifetimes of the heavy bottom and charm quarks preclude any practical applications of such reactions.

 

 

11 【生物】Association analysis identifies 65 new breast cancer risk loci

Kyriaki Michailidou      et.al

基因组相关分析发现65个新的乳腺癌风险位点

 

https://www.nature.com/articles/nature24284

 

 

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10−8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

 

(导读 郭怿暄)乳腺癌的风险受到多种易感基因罕见编码变异以及非编码变异的影响。本研究通过对来自欧洲和东亚的患者和对照进行基因组相关性分析,发现65个新位点与乳腺癌风险显著相关。大量位点存在于远距离调控序列当中,可能参与调节乳腺癌相关基因。这些集中于转录因子结合位点的单核苷酸多态性可使乳腺癌遗传性增加2-5倍。这一发现有助于改善遗传风险评分在乳腺癌个体筛查及预防中的应用。

 

12 【生物】Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites

Asaf Poran    et.al

单细胞RNA测序揭示恶性疟原虫中性裂殖子-雌雄配子体分化的表观遗传调控元件

https://www.nature.com/articles/nature24280

 

(导读 严冰)恶性疟原虫的裂殖子在人体红细胞内通过无性生殖形成中性裂殖子,在约1-30%裂殖子内,ap2-g基因被激活,促使裂殖子分化为雌雄配子体,可在蚊子体内进行有性繁殖。本文报导,通过分别对AP2-G 敲除系与NF54野生型疟原虫进行单细胞RNA测序,发现AP2-G+成熟裂殖体内某些调控元件表达特异性上调,包括其他AP2转录元件、组蛋白修饰酶和核小体定位调控元件。表观遗传调控元件的表达可能在配子体发育中是必须的。

 

Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes1配子体. Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite裂殖子 and ends, 48hours later, with a schizont裂殖体 releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes2,3. Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600)4,5, the master regulator of sexual development, from an epigenetically silenced state during asexual replication6,7. AP2-G expression during this ‘commitment cycle’ prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism2,4. To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1–30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling8. Here we use highly parallel, single-cell RNA sequencing9 of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G+ mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histone-modifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.

 

 

13 【生物】Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte

Ziqing Liu    et.al

单细胞转录组学揭示从成纤维细胞到心肌细胞重编程背后细胞命运的转变过程

https://www.nature.com/articles/nature24454

(导读 严冰)直接的细胞谱系转换技术(Direct lineage conversion)为组织再生和疾病模型建立提供了新策略。本文报导,利用单细胞RNA测序技术分析成纤维细胞-心肌细胞重编程过程中的全基因表达变化,发现mRNA处理和剪接相关元件的表达下调,其中剪接元件Ptbp1是成纤维细胞获得心肌细胞特异性剪接模式的一大障碍。同时,通过定量分析也发现了一系列心肌细胞富集的表面标记。

 

Direct lineage conversion offers a new strategy for tissue regeneration and disease modelling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs)1,2,3,4. Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction.

 

14 【生物】Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation

Song Zhang    et.al

解除SKI–SMAD4介导的抑制作用是TH17细胞分化必需的

https://www.nature.com/articles/nature24283

 

(导读:阿金)转化生长因子βTGFβ)调节TH17细胞分化的机制目前尚未清楚。本研究通过蛋白质组分析,揭示由TGFβ信号可以降解SKI,解除SKI-SMAD4相互作用介导的RORγt表达抑制,从而促进TH17细胞分化。了解此关键机制为治疗与TH17相关疾病提供新的靶向。

 

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables TH17 cell differentiation remains elusive. Here we reveal that TGFβ enables TH17 cell differentiation by reversing SKI–SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI–SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls TH17 cell differentiation and uncovers the SKI–SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.

 

15 【生物】IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Martina Molgora     et.al

IL-1R8NK细胞中调节抗肿瘤和抗病毒活性的检查

https://www.nature.com/articles/nature24293

 

(导读 陈月欣) 白介素1受体8IL-1R8)对ILRTLR通路及炎症反应起到反向调节的作用。NK细胞可以对抗病原体入侵并抑制造血系统的癌变,但通常认为在抗实体瘤中的作用微小。本研究发现,IL-1R8NK细胞成熟及行使功能的检查点。IL-1R8表达下调使NK细胞表现出对于肝癌、血源性肝、肺癌转移和人类巨细胞病毒的抗性。

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection.

 

 

16  【生物】Glucose feeds the TCA cycle via circulating lactate

Sheng Hui,    et.al

葡萄糖以循环的乳酸形式间接进入TCA循环

https://www.nature.com/articles/nature24057

(导读 严冰)此前认为在哺乳动物中葡萄糖在有氧条件下主要直接进入TCA循环生成CO2,也可通过糖酵解代谢为乳酸来供给组织营养。本文报导,乳酸可作为TCA循环的主要碳来源与能量来源。通过给小鼠注射13C标记的营养物,发现乳酸的循环量是各种代谢物中最高的,在喂食和禁食小鼠体内,分别是葡萄糖的1.1倍和2.5倍;在禁食阶段,除了大脑外所有组织中葡萄糖都主要通过乳酸进入TCA循环;在经基因改造的肺与胰腺癌肿瘤内,TCA循环也更多利用乳酸而非葡萄糖。

 

Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues1 and tumours2,3,4,5. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.

 

17【生物】A global resource allocation strategy governs growth transition kinetics of Escherichia coli

David W. Erickson,     et.al

资源分配策略控制大肠杆菌的增长转变动力学

https://www.nature.com/articles/nature24299

 

图片1.png 

图片来源:Nature

 

(导读 郭思瑶) 为了更有效地定量预测分子干预对生物代谢过程的影响,科学家研发了一个从上至下的定量模型方法,只利用到了调节过程和通量平衡的定量知识,可模拟细菌生长转变而不依赖于不可获知的动力学参数。这为描述更加广泛的动力学过程提供了有效的途径。

 

A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms and they remain a topic of active investigation. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations, they are insufficiently quantified for predictive bottom-up modelling. Here we develop a top-down approach, expanding the recently established coarse-grained proteome allocation models from steady-state growth into the kinetic regime. Using only qualitative knowledge of the underlying regulatory processes and imposing the condition of flux balance, we derive a quantitative model of bacterial growth transitions that is independent of inaccessible kinetic parameters. The resulting flux-controlled regulation model accurately predicts the time course of gene expression and biomass accumulation in response to carbon upshifts and downshifts (for example, diauxic shifts) without adjustable parameters. As predicted by the model and validated by quantitative proteomics, cells exhibit suboptimal recovery kinetics in response to nutrient shifts owing to a rigid strategy of protein synthesis allocation, which is not directed towards alleviating specific metabolic bottlenecks. Our approach does not rely on kinetic parameters, and therefore points to a theoretical framework for describing a broad range of such kinetic processes without detailed knowledge of the underlying biochemical reactions.

 

 

18 【生物】Embryonic epigenetic reprogramming by a pioneer transcription factor in plants

Zeng Tao     et.al

植物中先驱转录因子引起胚胎表观遗传的重激活

https://www.nature.com/articles/nature24300

 

 

Epigenetic modifications, including chromatin modifications and DNA methylation, have a central role in the regulation of gene expression in plants and animals. The transmission of epigenetic marks is crucial for certain genes to retain cell lineage-specific expression patterns and maintain cell fate. However, the marks that have accumulated at regulatory loci during growth and development or in response to environmental stimuli need to be deleted in gametes or embryos, particularly in organisms such as plants that do not set aside a germ line, to ensure the proper development of offspring. In Arabidopsis thaliana, prolonged exposure to cold temperatures (winter cold), in a process known as vernalization, triggers the mitotically stable epigenetic silencing of the potent floral repressor FLOWERING LOCUS C (FLC), and renders plants competent to flower in the spring; however, this silencing is reset during each generation. Here we show that the seed-specific transcription factor LEAFY COTYLEDON1 (LEC1) promotes the initial establishment of an active chromatin state at FLC and activates its expression de novo in the pro-embryo, thus reversing the silenced state inherited from gametes. This active chromatin state is passed on from the pro-embryo to post-embryonic life, and leads to transmission of the embryonic memory of FLC activation to post-embryonic stages. Our findings reveal a mechanism for the reprogramming of embryonic chromatin states in plants, and provide insights into the epigenetic memory of embryonic active gene expression in post-embryonic phases, through which an embryonic factor acts to ‘control’ post-embryonic development processes that are distinct from embryogenesis in plants.

 

(导读 郭怿暄)在动植物中,表观遗传修饰的建立和传递对基因的特异表达以及维持细胞命运非常重要。拟南芥暴露在寒冷中可诱发FLC基因出现有丝分裂稳定的表观遗传沉默,这一春化作用使植物在春季才能开花,但这一沉默每代需要重新设定。本研究发现种子特异的转录因子LEC1可以逆转配子中的沉默状态,促进FLC所处染色质进入激活状态,并在原胚中出现该基因的表达 。继而从原胚传递到后胚胎时期,使其保留FLC的激活记忆。