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Nature论文导读 0810

时间: 2017年08月21日 | 作者: admin | 来源: 未知
1 【生物】 New infant cranium from the African Miocene sheds light on ape evolution 非洲中新世的幼猿头骨启示猿类演化 Isaiah Nengo et al. https://www.nature.com/nature/journal/v548/n7666/full/nature23456.html 图片来源:

1 【生物】New infant cranium from the African Miocene sheds light on ape evolution


Isaiah Nengo et al.





The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossil ape cranium yet described, recovered from the 13 million-year-old Middle Miocene site of Napudet, Kenya. The infant specimen, KNM-NP 59050, is assigned to a new species of Nyanzapithecus on the basis of its unerupted permanent teeth, visualized by synchrotron imaging. Its ear canal has a fully ossified tubular ectotympanic, a derived feature linking the species with crown catarrhines. Although it resembles some hylobatids in aspects of its morphology and dental development, it possesses no definitive hylobatid synapomorphies. The combined evidence suggests that nyanzapithecines were stem hominoids close to the origin of extant apes, and that hylobatid-like facial features evolved multiple times during catarrhine evolution.





2【生物】The complete connectome of a learning and memory centre in an insect brain


L. F. Abbott, Andreas S. Thum, Marta Zlatic, Albert Cardona et al.



Associating stimuli with positive or negative reinforcement is essential for survival, but a complete wiring diagram of a higher-order circuit supporting associative memory has not been previously available. Here we reconstruct one such circuit at synaptic resolution, the Drosophila larval mushroom body. We find that most Kenyon cells integrate random combinations of inputs but that a subset receives stereotyped inputs from single projection neurons. This organization maximizes performance of a model output neuron on a stimulus discrimination task. We also report a novel canonical circuit in each mushroom body compartment with previously unidentified connections: reciprocal Kenyon cell to modulatory neuron connections, modulatory neuron to output neuron connections, and a surprisingly high number of recurrent connections between Kenyon cells. Stereotyped connections found between output neurons could enhance the selection of learned behaviours. The complete circuit map of the mushroom body should guide future functional studies of this learning and memory centre.


(导读 郭怿暄)神经系统中涉及学习记忆的高级环路完整连接图还未得到。本研究在突触水平上,重建了果蝇幼虫蘑菇体的神经环路连接图,发现两种以不同方式整合信号的凯尼恩细胞可以帮助输出神经元对刺激做出响应,并首次发现了学习功能相关的,广泛存在于磨菇体各区域中,涉及凯尼恩细胞、调节神经元、输出神经元的新型连接模式。



3 【物理】No large population of unbound or wide-orbit Jupiter-mass planets


Przemek Mróz et al.




Planet formation theories predict that some planets may be ejected from their parent systems as result of dynamical interactions and other processes. Unbound planets can also be formed through gravitational collapse, in a way similar to that in which stars form. A handful of free-floating planetary-mass objects have been discovered by infrared surveys of young stellar clusters and star-forming regions, as well as wide-field surveys, but these studies are incomplete for objects below five Jupiter masses. Gravitational microlensing is the only method capable of exploring the entire population of free-floating planets down to Mars-mass objects, because the microlensing signal does not depend on the brightness of the lensing object. A characteristic timescale of microlensing events depends on the mass of the lens: the less massive the lens, the shorter the microlensing event. A previous analysis of 474 microlensing events found an excess of ten very short events (1–2 days)—more than known stellar populations would suggest—indicating the existence of a large population of unbound or wide-orbit Jupiter-mass planets (reported to be almost twice as common as main-sequence stars). These results, however, do not match predictions of planet-formation theories and surveys of young clusters. Here we analyse a sample of microlensing events six times larger than that of ref.  discovered during the years 2010–15. Although our survey has very high sensitivity (detection efficiency) to short-timescale (1–2 days) microlensing events, we found no excess of events with timescales in this range, with a 95 per cent upper limit on the frequency of Jupiter-mass free-floating or wide-orbit planets of 0.25 planets per main-sequence star. We detected a few possible ultrashort-timescale events (with timescales of less than half a day), which may indicate the existence of Earth-mass and super-Earth-mass free-floating planets, as predicted by planet-formation theories.


(导读 阿金)微引力透镜技术是唯一可以用来观测宇宙中低至木星质量的流浪行星的方法。本研究分析了在2010年至2015年之间2617事件时标12天)的微引力透镜事件,发现流浪行星的数量上限是恒星数量的0.25倍,而最大可能是恒星数量的0.05


阅读更多:热点跟踪:行星流浪汉到底有多少? | 天问专栏




4 【物理】Enhanced sensitivity at higher-order exceptional points



Mercedeh Khajavikhan et al.






Non-Hermitian degeneracies, also known as exceptional points, have recently emerged as a new way to engineer the response of open physical systems, that is, those that interact with the environment. They correspond to points in parameter space at which the eigenvalues of the underlying system and the corresponding eigenvectors simultaneously coalesce. In optics, the abrupt nature of the phase transitions that are encountered around exceptional points has been shown to lead to many intriguing phenomena, such as loss-induced transparency, unidirectional invisibility, band merging, topological chirality and laser mode selectivity. Recently, it has been shown that the bifurcation properties of second-order non-Hermitian degeneracies can provide a means of enhancing the sensitivity (frequency shifts) of resonant optical structures to external perturbations. Of particular interest is the use of even higher-order exceptional points (greater than second order), which in principle could further amplify the effect of perturbations, leading to even greater sensitivity. Although a growing number of theoretical studies have been devoted to such higher-order degeneracies, their experimental demonstration in the optical domain has so far remained elusive. Here we report the observation of higher-order exceptional points in a coupled cavity arrangement—specifically, a ternary, parity–time-symmetric photonic laser molecule—with a carefully tailored gain–loss distribution. We study the system in the spectral domain and find that the frequency response associated with this system follows a cube-root dependence on induced perturbations in the refractive index. Our work paves the way for utilizing non-Hermitian degeneracies in fields including photonics, optomechanics, microwaves and atomic physics.


(导读 阿金)称为奇异点的二阶非厄米简并点最近成为了一种调节开放性物理系统信号响应的新方法。本实验报道了在耦合光学微腔中观察到高阶奇异及高灵敏度增益-损失分布。在光谱域中研究该系统时,究人员发现其频率响应与折射率中诱导扰动的立方根呈依赖关系。该实验工作为非厄米简并的应用开拓了新道路。




5【物理】Exceptional points enhance sensing in an optical microcavity



Lan Yang(杨兰,圣路易斯华盛顿大学) et al.







Sensors play an important part in many aspects of daily life such as infrared sensors in home security systems, particle sensors for environmental monitoring and motion sensors in mobile phones. High-quality optical microcavities are prime candidates for sensing applications because of their ability to enhance light–matter interactions in a very confined volume. Examples of such devices include mechanical transducers, magnetometers, single-particle absorption spectrometers, and microcavity sensors for sizing single particles and detecting nanometre-scale objects such as single nanoparticles and atomic ions. Traditionally, a very small perturbation near an optical microcavity introduces either a change in the linewidth or a frequency shift or splitting of a resonance that is proportional to the strength of the perturbation. Here we demonstrate an alternative sensing scheme, by which the sensitivity of microcavities can be enhanced when operated at non-Hermitian spectral degeneracies known as exceptional points. In our experiments, we use two nanoscale scatterers to tune a whispering-gallery-mode micro-toroid cavity, in which light propagates along a concave surface by continuous total internal reflection, in a precise and controlled manner to exceptional points. A target nanoscale object that subsequently enters the evanescent field of the cavity perturbs the system from its exceptional point, leading to frequency splitting. Owing to the complex-square-root topology near an exceptional point, this frequency splitting scales as the square root of the perturbation strength and is therefore larger (for sufficiently small perturbations) than the splitting observed in traditional non-exceptional-point sensing schemes. Our demonstration of exceptional-point-enhanced sensitivity paves the way for sensors with unprecedented sensitivity.


(导读 阿金)传感器在生活中有许多实际用途,而高质量光学微腔则是传感应用的首选。本实验利用两根纳米光纤锥将光学微腔精确调节至奇异点处,随后用第三根光纤锥作为待测物体,来研究处于奇异点的光学微腔对外界扰动的响应。测量结果显示,奇异点附近的响应信号与待测的扰动强度的平方根呈线性关系,比传统光学微腔有更高的灵敏度。


阅读更多:兰之队登《Nature》:奇妙拓扑性质, 增强光学传感灵敏度



6【化学】High-temperature crystallization of nanocrystals into three-dimensional superlattices


Matteo Cargnello, Christopher J. Tassone et al.



Crystallization of colloidal nanocrystals into superlattices represents a practical bottom-up process with which to create ordered metamaterials with emergent functionalities. With precise control over the size, shape and composition of individual nanocrystals, various single- and multi-component nanocrystal superlattices have been produced, the lattice structures and chemical compositions of which can be accurately engineered. Nanocrystal superlattices are typically prepared by carefully controlling the assembly process through solvent evaporation or destabilization or through DNA-guided crystallization. Slow solvent evaporation or cooling of nanocrystal solutions (over hours or days) is the key element for successful crystallization processes. Here we report the rapid growth (seconds) of micrometre-sized, face-centred-cubic, three-dimensional nanocrystal superlattices during colloidal synthesis at high temperatures (more than 230 degrees Celsius). Using in situ small-angle X-ray scattering, we observe continuous growth of individual nanocrystals within the lattices, which results in simultaneous lattice expansion and fine nanocrystal size control due to the superlattice templates. Thermodynamic models demonstrate that balanced attractive and repulsive interparticle interactions dictated by the ligand coverage on nanocrystal surfaces and nanocrystal core size are responsible for the crystallization process. The interparticle interactions can also be controlled to form different superlattice structures, such as hexagonal close-packed lattices. The rational assembly of various nanocrystal systems into novel materials is thus facilitated for both fundamental research and for practical applications in the fields of magnetics, electronics and catalysis.

(导读 卓思琪)胶体纳米晶体结晶形成的超晶格具有优异性质,其关键步骤:纳米晶体溶液的蒸发或冷却过程耗时较长(几小时或几天)。本文报道了一种在胶体合成过程中,高温快速(秒级)制备微米尺寸面心立方三维纳米晶体超晶格的方法,并对此制备过程进行了微观监测和热力学模型分析。该超晶格制备法将对研究带来巨大的帮助。


7【生态】Global patterns of drought recovery


Christopher R. Schwalm et al.




Drought, a recurring phenomenon with major impacts on both human and natural systems1, 2, 3, is the most widespread climatic extreme that negatively affects the land carbon sink2, 4. Although twentieth-century trends in drought regimes are ambiguous5, 6, 7, across many regions more frequent and severe droughts are expected in the twenty-first century3, 7, 8, 9. Recovery time—how long an ecosystem requires to revert to its pre-drought functional state—is a critical metric of drought impact. Yet the factors influencing drought recovery and its spatiotemporal patterns at the global scale are largely unknown. Here we analyse three independent datasets of gross primary productivity and show that, across diverse ecosystems, drought recovery times are strongly associated with climate and carbon cycle dynamics, with biodiversity and CO2 fertilization as secondary factors. Our analysis also provides two key insights into the spatiotemporal patterns of drought recovery time: first, that recovery is longest in the tropics and high northern latitudes (both vulnerable areas of Earth’s climate system10) and second, that drought impacts11 (assessed using the area of ecosystems actively recovering and time to recovery) have increased over the twentieth century. If droughts become more frequent, as expected, the time between droughts may become shorter than drought recovery time, leading to permanently damaged ecosystems and widespread degradation of the land carbon sink.


(导读 刘威尔)旱后恢复在全球范围的影响因素及时空格局尚不明确。本研究分析了三组相互独立的总初级生产力数据,发现旱后恢复时间与气候和碳循环动态密切相关,其次生物多样性和二氧化碳施肥效应;时空格局方面,旱后恢复时间在热带和北部高纬地区最长,干旱危害在20世纪以来有所加剧。若干旱间期短于恢复时间,将对生态系统和陆地碳汇造成长久损失。


8【生态】Artificial light at night as a new threat to pollination


Eva Knop et al.




Pollinators are declining worldwide1 and this has raised concerns for a parallel decline in the essential pollination service they provide to both crops and wild plants2, 3. Anthropogenic drivers linked to this decline include habitat changes, intensive agriculture, pesticides, invasive alien species, spread of pathogens and climate change1. Recently, the rapid global increase in artificial light at night4 has been proposed to be a new threat to terrestrial ecosystems; the consequences of this increase for ecosystem function are mostly unknown5, 6. Here we show that artificial light at night disrupts nocturnal pollination networks and has negative consequences for plant reproductive success. In artificially illuminated plant–pollinator communities, nocturnal visits to plants were reduced by 62% compared to dark areas. Notably, this resulted in an overall 13% reduction in fruit set of a focal plant even though the plant also received numerous visits by diurnal pollinators. Furthermore, by merging diurnal and nocturnal pollination sub-networks, we show that the structure of these combined networks tends to facilitate the spread of the negative consequences of disrupted nocturnal pollination to daytime pollinator communities. Our findings demonstrate that artificial light at night is a threat to pollination and that the negative effects of artificial light at night on nocturnal pollination are predicted to propagate to the diurnal community, thereby aggravating the decline of the diurnal community. We provide perspectives on the functioning of plant–pollinator communities, showing that nocturnal pollinators are not redundant to diurnal communities and increasing our understanding of the human-induced decline in pollinators and their ecosystem service.


(导读 刘威尔)本研究发现,人工照明下传粉者夜间访花次数比黑暗环境降低了62%,造成实验植物座果率下降13%,并且该负面干扰会通过传粉网络结构影响日间传粉者群落。研究证明了人造光源对夜间传粉网络的干扰及对植物繁殖的负面影响,并表明夜间传粉者的重要作用



9【生态】Higher-order interactions stabilize dynamics in competitive network models


Stefano Allesina et al.




Ecologists have long sought a way to explain how the remarkable biodiversity observed in nature is maintained. On the one hand, simple models of interacting competitors cannot produce the stable persistence of very large ecological communities1, 2, 3, 4, 5. On the other hand, neutral models6, 7, 8, 9, in which species do not interact and diversity is maintained by immigration and speciation, yield unrealistically small fluctuations in population abundance10, and a strong positive correlation between a species’ abundance and its age11, contrary to empirical evidence. Models allowing for the robust persistence of large communities of interacting competitors are lacking. Here we show that very diverse communities could persist thanks to the stabilizing role of higher-order interactions12, 13, in which the presence of a species influences the interaction between other species. Although higher-order interactions have been studied for decades14, 15, 16, their role in shaping ecological communities is still unclear5. The inclusion of higher-order interactions in competitive network models stabilizes dynamics, making species coexistence robust to the perturbation of both population abundance and parameter values. We show that higher-order interactions have strong effects in models of closed ecological communities, as well as of open communities in which new species are constantly introduced. In our framework, higher-order interactions are completely defined by pairwise interactions, facilitating empirical parameterization and validation of our models.


(导读 刘威尔)目前尚缺乏能够稳定维持竞争者大型群落的研究模型。本研究在竞争网络模型中引入高阶相互作用,稳定了模型动态,使物种在种群数量和参数值两种扰动下的持久共存。结果表明,高阶相互作用对封闭和开放群落模型都有较强作用。


10 【考古】Genetic origins of the Minoans and Mycenaeans


Iosif Lazaridis, David Reich, Johannes Krause, George Stamatoyannopoulos et al.







The origins of the Bronze Age Minoan and Mycenaean cultures have puzzled archaeologists for more than a century. We have assembled genome-wide data from 19 ancient individuals, including Minoans from Crete, Mycenaeans from mainland Greece, and their eastern neighbours from southwestern Anatolia. Here we show that Minoans and Mycenaeans were genetically similar, having at least three-quarters of their ancestry from the first Neolithic farmers of western Anatolia and the Aegean, and most of the remainder from ancient populations related to those of the Caucasus and Iran. However, the Mycenaeans differed from Minoans in deriving additional ancestry from an ultimate source related to the hunter–gatherers of eastern Europe and Siberia, introduced via a proximal source related to the inhabitants of either the Eurasian steppe or Armenia. Modern Greeks resemble the Mycenaeans, but with some additional dilution of the Early Neolithic ancestry. Our results support the idea of continuity but not isolation in the history of populations of the Aegean, before and after the time of its earliest civilizations.



11 【生物】Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells


Konrad Hochedlinger et al.


Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore, we find that female ES cells cultured in conventional serum plus LIF medium phenocopy male ES cells cultured in 2i/L. Mechanistically, we demonstrate that the inhibition of Mek1/2 is predominantly responsible for these effects, in part through the downregulation of DNA methyltransferases and their cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as the developmental potential of ES cells. Taken together, our data suggest that, although short-term suppression of Mek1/2 in ES cells helps to maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.


(导读 韩宇)2i/L短期处理可以将小鼠胚胎干细胞(ES)诱导为与着床前胚胎内细胞团(ICM)相似的状态。本研究发现,延长2i/L处理时间,可导致小鼠ES细胞中一系列不可逆的表观遗传和基因组变化,并损害其发育潜力,而这一影响是由长时间抑制Mek1/2引发的。


12【生物】Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation


Takuya Yamamoto, Yasuhiro Yamada et al.



Inhibitors of Mek1/2 and Gsk3β, known as 2i, enhance the derivation of embryonic stem (ES) cells and promote ground-state pluripotency in rodents. Here we show that the derivation of female mouse ES cells in the presence of 2i and leukaemia inhibitory factor (2i/L ES cells) results in a widespread loss of DNA methylation, including a massive erasure of genomic imprints. Despite this global loss of DNA methylation, early-passage 2i/L ES cells efficiently differentiate into somatic cells, and this process requires genome-wide de novo DNA methylation. However, the majority of imprinting control regions (ICRs) remain unmethylated in 2i/L-ES-cell-derived differentiated cells. Consistently, 2i/L ES cells exhibit impaired autonomous embryonic and placental development by tetraploid embryo complementation or nuclear transplantation. We identified the derivation conditions of female ES cells that display 2i/L-ES-cell-like transcriptional signatures while preserving gamete-derived DNA methylation and autonomous developmental potential. Upon prolonged culture, however, female ES cells exhibited ICR demethylation regardless of culture conditions. Our results provide insights into the derivation of female ES cells reminiscent of the inner cell mass of preimplantation embryos.


(导读 郭怿暄)本研究发现使用Mek1/2Gsk3 β抑制剂(2i)和白血病抑制因子(L)处理的2i/L 胚胎干细胞(ES细胞)中会出现广泛的DNA甲基化丢失并无法完成胚胎和胎盘发育,但雌性来源的早期2i/L ES细胞可以回复配子中的DNA甲基化状态并具有分化发育潜能。雌性来源早期2i/L ES细胞可能成为研究胚胎早期发育的新平台。


13【生物】Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism

由表观调控实现的TH17细胞代谢调控Treg 细胞平衡性提升

Chen Dong, Edward M. Driggers, Sheng Ding(丁胜,清华大学) et al.


Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy)acetic acid, that reprograms the differentiation of T helper 17 (TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 cells. The accumulation of 2-hydroxyglutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards TH17 cells. Inhibition of the conversion of glutamate to α-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reduced methylation of the Foxp3 gene locus, and increased Foxp3 expression. This consequently blocked the differentiation of TH17 cells by antagonizing the function of transcription factor RORγt and promoted polarization into iTreg cells. Selective inhibition of GOT1 with (aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between TH17 and iTreg cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against TH17-mediated autoimmune diseases.


(导读 Nature自然科研)本研究发现转氨酶GOT1的小分子抑制剂氨氧基乙酸可提升小鼠免疫力,从而揭示了如下代谢变化借由表观遗传调控关键基因转录,从而影响T细胞命运决定的途径:TH17细胞中,GOT1催化合成2-羟基戊二酸二乙酯,后者可导致Foxp3基因位点超甲基化而被转录抑制,进而妨碍TH17细胞向iTreg细胞的分化。该发现可能为治疗TH17介导的自免疫疾病提供帮助。



14【生物】Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS


Neal Rosen, et al.


Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2)1. Here we characterize a third class of BRAF mutants—those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS–GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

(导读 韩宇)超过200BRAF突变与肿瘤发生相关,已知的两类BRAF激活突变体引起反馈抑制的方式是RAS非依赖性的,本文描述了RAS依赖性的第三类BRAF突变体,此类突变体的激酶活性缺失,与RAS-GTP结合能力提高并增强ERK信号。不同种癌细胞中BRAFRASERK信号通路的交互作用方式不同,对相关抑制剂药物的敏感性也不同。


15【生物】A Braf kinase-inactive mutant induces lung adenocarcinoma

Braf 激酶失活突变诱导肺腺癌发生

Mariano Barbacid, David Santamaría et al.


The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types1. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity23, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.


(导读 韩宇)近一半人肺腺癌的起始致癌事件未知。本研究发现小鼠内源性Braf激酶失活突变体D631A(对应人BRAF-D594A)可以在体内诱发肺腺癌,表明BRAF激酶失活突变是肺腺癌发生的起始事件,且MAPK通路的信号强度在肿瘤发育、起始细胞性质和肿瘤最终表型的决定中起重要作用。


16【生物】Proteins evolve on the edge of supramolecular self-assembly


Emmanuel D. Levy et al.



The self-association of proteins into symmetric complexes is ubiquitous in all kingdoms of life. Symmetric complexes possess unique geometric and functional properties, but their internal symmetry can pose a risk. In sickle-cell disease, the symmetry of haemoglobin exacerbates the effect of a mutation, triggering assembly into harmful fibrils. Here we examine the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations solely designed to increase surface hydrophobicity among 12 distinct symmetric complexes from Escherichia coli. Notably, all responded by forming supramolecular assemblies in vitro, as well as in vivo upon heterologous expression in Saccharomyces cerevisiae. Remarkably, in four cases, micrometre-long fibrils formed in vivo in response to a single point mutation. Biophysical measurements and electron microscopy revealed that mutants self-assembled in their folded states and so were not amyloid-like. Structural examination of 73 mutants identified supramolecular assembly hot spots predictable by geometry. A subsequent structural analysis of 7,471 symmetric complexes showed that geometric hot spots were buffered chemically by hydrophilic residues, suggesting a mechanism preventing mis-assembly of these regions. Thus, point mutations can frequently trigger folded proteins to self-assemble into higher-order structures. This potential is counterbalanced by negative selection and can be exploited to design nanomaterials in living cells.


(导读 郭怿暄)蛋白质自组装而成的对称性复合物可能加剧有害蛋白质纤维的形成。本研究向12种大肠杆菌对称性复合物中引入多种表面疏水点突变,这些突变体在体内和体外都可自组装成超分子结构。这些超分子纤维中的蛋白质处于折叠态,因而并非淀粉样纤维;促成自组装的热点位置被周围亲水基团化学保护,以保证组装正确进行。此工作为蛋白质结构研究及活细胞内纳米材料设计提供基础。