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1、先祖猿类的演化 Nature 548 (2017年8月10日) 中新世（2300万-530万年前）的地球至少生活着30个属40个种的猿。但是，人们鲜少发现完整的颅骨证据。只有少数种的猿，人们掌握了除面部和上颚以外的头骨证据，因此可以指示人族和现代猿类近亲头骨状态的信息较为有限。这类证据在非洲尤其匮乏，此前未有发现1400万-1000万年前的颅骨遗骸。Isaiah Nengo及同事描述了一个在肯尼亚发现的幼猿头骨。该猿拥有1300万年的历史，被划归为Nyanzapithecus属的一个新种。证据显示，虽然它与长臂猿拥有某些相似之处，但是这些相似点非常可能由趋同适应引起，而这一新种是现存猿类共同祖先的近亲。 New infant cranium from the African Miocene sheds light on ape evolution https://www./nature/journal/v548/n7666/full/nature23456.html 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.下丘脑调控衰老速度 Nature 548 (2017年8月3日) 蔡东升和同事之前已经表明下丘脑在系统性衰老中扮演重要角色。在这篇论文中，他们观察到中年小鼠的下丘脑干细胞出现大量损失。他们在多个小鼠模型中发现，这些细胞的缺失导致了类似衰老的生理变化和寿命缩短情况。反之，当向中年小鼠移植健康的下丘脑细胞时，其老化速度减慢，寿命延长。下丘脑干细胞能分泌外泌体miRNA，增加脑脊髓液中的循环miRNA。而随着年龄增长，这些外泌体miRNA的数量也逐渐减少。这些外泌体至少在一定程度上可以延缓衰老。作者总结表示，衰老的速度部分地由下丘脑干细胞及其向脑脊髓液中分泌的外泌体miRNA调控。 Hypothalamic stem cells control ageing speed partly through exosomal miRNAs https://www./nature/journal/v548/n7665/full/nature23282.html It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs. 3.精细化定位IBD位点 Nature 547 (2017年7月13日) 炎症性肠病（IBD）的全基因组关联研究（GWAS）已经发现了200多个与该疾病有关联的位点，但是只有少数这些位点的致病变异得到解析。在本文中，黄海亮及同事运用 67,852个个体中的高密度基因分型，对94个IBD易感位点进行了精细化定位。他们采用了多项新型精细化定位方法，鉴定了139个独立关联位点，其中18个精确到单个致病变异，确定性 >95%。该研究向我们展示了如何运用大样本中的高密度基因分型进行精细化定位来解析GWAS位点的致病变异，这种方法或许能用于发现其它复杂性状。若要查看精细化定位的详细结果和注释，请访问http://finemapping.。 Fine-mapping inflammatory bowel disease loci to single-variant resolution https://www./nature/journal/v547/n7662/full/nature22969.html Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. 4.非经典基因组印迹 Nature 547 (2017年7月27日) 哺乳动物受精后，父源染色质和母源染色质的表观遗传景观存在不对称性，但是在后续的发育中会变得基本相当，除印迹基因外。在本文中，张毅及同事描述了受精卵和桑椹胚中亲本等位基因特异性的全基因组染色质可接近性，并分析了DNA甲基化和组蛋白H3K27me3的模式。他们发现，H3K27me3是一种不依赖于DNA甲基化的抑制基因组印迹内母源等位基因的机制，而且可以鉴定依赖于这种非经典机制的新的印迹基因。 Maternal H3K27me3 controls DNA methylation-independent imprinting https://www./nature/journal/v547/n7664/full/nature23262.html Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashions. After fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci, including imprinting control regions. How parental chromatin becomes equalized and how imprinting control regions escape from this reprogramming is largely unknown. Here we profile parental allele-specific DNase I hypersensitive sites in mouse zygotes and morula embryos, and investigate the epigenetic mechanisms underlying these allelic sites. Integrated analyses of DNA methylome and tri-methylation at lysine 27 of histone H3 (H3K27me3) chromatin immunoprecipitation followed by sequencing identify 76 genes with paternal allele-specific DNase I hypersensitive sites that are devoid of DNA methylation but harbour maternal allele-specific H3K27me3. Interestingly, these genes are paternally expressed in preimplantation embryos, and ectopic removal of H3K27me3 induces maternal allele expression. H3K27me3-dependent imprinting is largely lost in the embryonic cell lineage, but at least five genes maintain their imprinted expression in the extra-embryonic cell lineage. The five genes include all paternally expressed autosomal imprinted genes previously demonstrated to be independent of oocyte DNA methylation. Thus, our study identifies maternal H3K27me3 as a DNA methylation-independent imprinting mechanism. 5.早期发育阶段的染色质重组 Nature 547 (2017年7月13日) 在哺乳动物中，受精后，染色质会经历剧烈的重组，但是人们对于染色质高级结构重编程的分子基础所知不多。在本文中，颉伟及同事运用低输入Hi-C方法检查了小鼠卵母细胞和着床前胚胎内的染色质组织。他们发现，受精后，染色质大幅减少了亲本基因组的高级结构。拓扑关联结构域边界和染色质隔间开始在受精卵中出现，但是后续三维染色质结构的成熟速度却出人意料地慢。 Allelic reprogramming of 3D chromatin architecture during early mammalian development https://www./nature/journal/v547/n7662/full/nature23263.html In mammals, chromatin organization undergoes drastic reprogramming after fertilization. However, the three-dimensional structure of chromatin and its reprogramming in preimplantation development remain poorly understood. Here, by developing a low-input Hi-C (genome-wide chromosome conformation capture) approach, we examined the reprogramming of chromatin organization during early development in mice. We found that oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, we show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, our data suggest that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development. 6.关于AMPK活化的新认识 Nature 548 (2017年8月3日) AMPK是代谢平衡的主要调控因子，如果它功能失常，就可能导致糖尿病、肥胖和癌症等疾病。已知AMPK会在压力条件下被激活，比如葡萄糖饥饿。科学家一直假设在缺糖损伤的条件下，AMPK激活以经典的AMP/ADP依赖性方式发生，即葡萄糖代谢减弱导致ATP减少，AMP和ADP增加。在这篇论文中，林圣彩和同事证明事实并非如此，葡萄糖饥饿通过另一种途径激活AMPK，而该过程并不依赖AMP/ADP。在糖酵解过程中，葡萄糖被转化为果糖-1,6-二磷酸酶（FBP），之后则会被FBP醛缩酶处理。作者表明，葡萄糖的缺乏导致FBP醛缩酶减少，从而触发LKB1磷酸化和AMPK的活化。这项研究表明FBP是一种指示葡萄糖可用程度的关键代谢物，而FBP醛缩酶是将该信息传递给AMPK的传感器。 Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK https://www./nature/journal/v548/n7665/full/nature23275.html The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK. 7.单细胞生物学 Nature 547 (2017年7月6日) 在本周的特刊中，《自然》将目光瞄准了生命最基本的组成部分：细胞。技术进步为此前无法在单细胞层面完成的研究分析提供了可能。因此，研究人员终于开始统计在复杂有机体中存在多少种不同类型的细胞，它们的作用是什么，以及它们如何发育变化。一篇新闻特写（p.20）仔细分析了追踪细胞谱系的过程，并且刊登了Aviv Regev的人物简介（p.24）——她带领编录了所有人体细胞种类。在另一篇文章中，研究人员探索了在细胞分裂周期内，小鼠细胞基因组是如何包装的（p.61），以及这对于探索三维基因组交互可能存在的意义（p.34）。Amir Giladi和Ido Amit讨论了对免疫细胞的集中研究可以如何帮助我们对抗癌症等疾病（p.27）。一篇职业采访讲述了进入单细胞研究领域的原因（p.129），工具箱文章则重点讨论了如何以最佳方式探查随着领域的扩展而不断产生的数据（p.125）。 Cell-cycle dynamics of chromosomal organization at single-cell resolution http://www./nature/journal/v547/n7661/full/nature23001.html Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle. 8.利用纳米技术实现数据存储的逻辑步骤 Nature 547 (2017年7月6日) 在过去的几十年里，虽然计算机的功能越来越强大，但是要进一步实现重大性能突破却遇到了不少瓶颈，原因在于新开发的应用程序对计算机处理大量数据的速度要求越来越高。其中一个主要难题是如何在片外储存器和片上逻辑电路之间传输数据。Max Shulaker等人为专门处理特定数据密集型应用程序的计算机，提出了一种全新设计方案——将计算和存储以更高效的方式集成起来。他们所创造的三维单片纳米集成系统融合了多种新兴技术，它能通过低功率的纳米传感器感知环境中的气体，将数据储存在超过一百万个非易失存储器中，并且利用碳纳米管逻辑操作对其进行分类。最重要的是，所有这些层都被组装在同一个芯片上，而且和硅基技术兼容。他们的方案指引了计算机发展新方向，也就是将逻辑计算与数据存储集成起来 Three-dimensional integration of nanotechnologies for computing and data storage on a single chiphttps://www./nature/journal/v547/n7661/full/nature22994.htmlThe computing demands of future data-intensive applications will greatly exceed the capabilities of current electronics, and are unlikely to be met by isolated improvements in transistors, data storage technologies or integrated circuit architectures alone. Instead, transformative nanosystems, which use new nanotechnologies to simultaneously realize improved devices and new integrated circuit architectures, are required. Here we present a prototype of such a transformative nanosystem. It consists of more than one million resistive random-access memory cells and more than two million carbon-nanotube field-effect transistors—promising new nanotechnologies for use in energy-efficient digital logic circuits1, 2, 3 and for dense data storage4—fabricated on vertically stacked layers in a single chip. Unlike conventional integrated circuit architectures, the layered fabrication realizes a three-dimensional integrated circuit architecture with fine-grained and dense vertical connectivity between layers of computing, data storage, and input and output (in this instance, sensing). As a result, our nanosystem can capture massive amounts of data every second, store it directly on-chip, perform in situ processing of the captured data, and produce ‘highly processed’ information. As a working prototype, our nanosystem senses and classifies ambient gases. Furthermore, because the layers are fabricated on top of silicon logic circuitry, our nanosystem is compatible with existing infrastructure for silicon-based technologies. Such complex nano-electronic systems will be essential for future high-performance and highly energy-efficient electronic systems. 来源：Nature |
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