当前位置:首页 > 热点关注 > 中文摘要 > 正文

5月21日Nature中文摘要

 

 封面故事:最早已知石器记录又被打破

本期封面所示为来自肯尼亚图尔卡纳湖西岸 “Lomekwi 3”发掘点的石器。当Louis Leakey 及同事50多年前在坦桑尼亚奥杜威峡谷发现与早期人类化石相关的石器(现在被认为距今180万年前)时,人们假设工具制作是我们这个属(人属)所独有的。自那时以来,工具制作开始的年代也变得愈加久远,与人属关联的排他性也变得越来越差。有一段时间,最早已知利刃石器(距今约260万年前)曾来自埃塞俄比亚。在来自埃塞俄比亚、距今约330万年前的动物骨头上发现的切痕,过去被有争议地与非人类的人族对工具的使用关联了起来。考古记录这一更早的开始时间现在被Sonia Harmand等人所报告的、在“Lomekwi 3”发掘点取得的距今330万年前的发现证实了,它比几个星期前报告的当前最早已知(距今280万年前)的人属化石早大约50万年。这些新发现的石器与在奥杜威和其他地方发现的“奥杜威”工具不同,可能构成一个 “人属前”工具文化,作者建议将该文化称作。

原文链接:

3.3-million-year-old stone tools from Lomekwi 3, West Turkana, Kenya

原文摘要:

Human evolutionary scholars have long supposed that the earliest stone tools were made by the genus Homo and that this technological development was directly linked to climate change and the spread of savannah grasslands. New fieldwork in West Turkana, Kenya, has identified evidence of much earlier hominin technological behaviour. We report the discovery of Lomekwi 3, a 3.3-million-year-old archaeological site wher in situ stone artefacts occur in spatiotemporal association with Pliocene hominin fossils in a wooded palaeoenvironment. The Lomekwi 3 knappers, with a developing understanding of stone’s fracture properties, combined core reduction with battering activities. Given the implications of the Lomekwi 3 assemblage for models aiming to converge environmental change, hominin evolution and technological origins, we propose for it the name ‘Lomekwian’, which predates the Oldowan by 700,000 years and marks a new beginning to the known archaeological record.

另一种干细胞状态

胚胎干细胞和外胚层干细胞代表着两个被普遍接受的多能状态,它们来自小鼠胚胎发生过程的不同时间点。通过调制用于从小鼠外胚层提取多能干细胞的培养基中的信号传导成分,Izpisua Belmonte及同事识别出了具有与这两类干细胞截然不同特点的另一个干细胞状态。这些细胞能被植入小鼠外胚层的特定区域,因而被称为 “区域选择性多能干细胞”(rsPSCs)。具有相似特性的细胞也从小鼠和灵长类多能干细胞系的培养中获得了。对rsPSCs进行研究将使我们对哺乳动物发育有进一步的认识。

原文标题:An alternative pluripotent state confers interspecies chimaeric competency

原文摘要:Pluripotency, the ability to generate any cell type of the body, is an evanescent attribute of embryonic cells. Transitory pluripotent cells can be captured at different time points during embryogenesis and maintained as embryonic stem cells or epiblast stem cells in culture. Since ontogenesis is a dynamic process in both space and time, it seems counterintuitive that these two temporal states represent the full spectrum of organismal pluripotency. Here we show that by modulating culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selecive pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans. The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications. The unique ability of human rsPSCs to generate post-implantation interspecies chimaeric embryos may facilitate our understanding of early human development and evolution.

多巴胺运输蛋白的结构

多巴胺运输蛋白是一种膜蛋白,能将神经传输物质多巴胺从突触裂隙清除,将其运送到周围细胞的胞液内,从而终止神经传输物质的信号。Eric Gouaux及同事获得了与包括可卡因、右旋苯丙胺、甲基苯丙胺、多巴胺和两种抗抑郁剂在内的各种小分子结合在一起的果蝇多巴胺运输蛋白的X-射线晶体结构。除了让我们能够首次看到一种神经传输物质是怎样与一种生源胺运输蛋白相结合的、以及可卡因是怎样与一种生源胺运输蛋白相结合的外,该结构还是一种蛋白的配体结合点何以能够通过重塑自己来结合和适应具有不同形状和大小、在结构上不相关的小分子的一个很好例子。

原文标题:Neurotransmitter and psychostimulant recognition by the dopamine transporter

原文摘要:Na+/Cl–-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

过量BCR信号传导的抗癌作用

Markus Müschen 及同事分析,在某些具有组成性 “B细胞受体”(BCR)信号传导的B细胞恶性肿瘤(携带BCR-ABL转位的“急性淋巴细胞白血病”)中,也许有可能通过一个中等水平的BCR信号传导来改变有利于B细胞的正常选择过程,反而来驱动BCR信号传导水平超过一个阈限,在这个阈限之上,恶性B细胞就无法存活了。他们显示,这一点在一个小鼠模型中比如说就可以通过激酶SYK的超活化做到。在该小鼠模型中,一个SYK通道的药理活化可以抑制来自患者的肿瘤异种移植物的生长。这一概念与寻求阻断BCR信号传导的B淋巴瘤治疗方法截然不同,也许值得在临床上进行探索。

原文标题:Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia

原文摘要:B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR)1 or hyperactivation above maximum (for example, self-reactive BCR)2, 3 thresholds of signalling strength causes negative selection. In ~25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling4,5. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival6. We tested the hypothesis that targeted hyperactivation—above a maximum threshold—will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR–ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a andLair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1)9, we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

iPS细胞潜力的细胞标记

以前试图分离正处在成功的“诱导多能干”(iPS)细胞重新编程途中之细胞的努力一直基于这样一个假设:细胞渐进性地失去供体细胞身份并逐渐获得iPS细胞特性。在这项研究中,Marius Wernig及同事识别出了在该过程早期出现的表面标记,它们在最初的成纤维细胞或最终产生的多能细胞中都没有表达。通过分离和分析具有这些标记的细胞(包括CD73、CD49d和CD200)的表达,作者识别出了重新编程所需的新的转录调控因子,从而获得了对这一过程机制的认识。

原文标题:Early reprogramming regulators identified by prospective isolation and mass cytometry

原文摘要:In the context of most induced pluripotent stem (iPS) cell reprogramming methods, heterogeneous populations of non-productive and staggered productive intermediates arise at different reprogramming time points1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Despite recent reports claiming substantially increased reprogramming efficiencies using genetically modified donor cells12, 13, prospectively isolating distinct reprogramming intermediates remains an important goal to decipher reprogramming mechanisms. Previous attempts to identify surface markers of intermediate cell populations were based on the assumption that, during reprogramming, cells progressively lose donor cell identity and gradually acquire iPS cell properties1, 2, 7, 8, 10. Here we report that iPS cell and epithelial markers, such as SSEA1 and EpCAM, respectively, are not predictive of reprogramming during early phases. Instead, in a systematic functional surface marker screen, we find that early reprogramming-prone cells express a unique set of surface markers, including CD73, CD49d and CD200, that are absent in both fibroblasts and iPS cells. Single-cell mass cytometry and prospective isolation show that these distinct intermediates are transient and bridge the gap between donor cell silencing and pluripotency marker acquisition during the early, presumably stochastic, reprogramming phase2. expression profiling reveals early upregulation of the transcriptional regulators Nr0b1 and Etv5 in this reprogramming state, preceding activation of key pluripotency regulators such as Rex1 (also known as Zfp42), Dppa2, Nanog and Sox2. Both factors are required for the generation of the early intermediate state and fully reprogrammed iPS cells, and thus represent some of the earliest known regulators of iPS cell induction. Our study deconvolutes the first steps in a hierarchical series of events that lead to pluripotency acquisition.

超级增强子和干细胞可塑性

 成年干细胞能够沿一个细胞系分化,并能暂时离开它们的原始小环境,同时保持其可塑性。在这项研究中,Elaine Fuchs及同事在细胞系发展过程中和在干细胞处于它们小环境之外、暴露于一个新环境时两种情况下,对小鼠毛囊干细胞中的超级增强子和染色质动态进行了活体分析。先驱因子(pioneer factor) SOX9 (直接与凝聚染色质结合的一种转录因子)被发现在促进和维持细胞命运中是毛囊干细胞的超级增强子的一个关键调控因子。

原文链接:

Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice

原文摘要:

Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility1, 2, 3, 4. Here we show that super-enhancers5 underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters (‘epicentres’) of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.

应对当前的埃博拉疫情

封装在类脂纳米颗粒中以埃博拉病毒为目标的siRNAs (TKM-Ebola) ,以前被发现对非人类灵长类动物能够提供针对致命剂量埃博拉病毒挑战的接触后保护(post-exposure protection)。该疗法从同情角度出发在当前疫情中也曾被用于若干个人类患者,尽管它对人类的疗效尚不知道。在这项研究中,Thomas Geisbert及同事迅速针对当前疫情中的病毒类型对TKM-Ebola鸡尾酒疗法进行了改造,发现在用当前疫情中的西非EBOV分离毒株进行挑战之后3天施用,它完全能够保护非人类灵长类动物。一旦有了病毒序列数据,该药物在只有8星期的时间内就可以针对新病毒被改造和生产。

原文标题:Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates

原文摘要:The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled1. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States2. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

昆虫和脊椎动物的递归性剪接

我们对真核基因组中最长基因被准确处理的机制很不了解。过去人们认为,内含子清除通常涉及单一的切除步骤。后来的研究显示,在果蝇中,一些内含子含有内部剪接点,它们会引起 “递归性剪接”,即单个内含子是在几个连续的剪接反应中一点儿一点儿被清除的。Brenton Graveley及同事发现,果蝇这一调控机制的范围要比人们所意识到的大得多。他们识别出果蝇的近200个“零核苷酸”外显子,这些外显子是“递归性剪接”的产物。Jernej Ule及同事识别出了脊椎动物的 “递归性剪接”点,尤其是在编码在神经发育中所涉及的蛋白的长基因中。对它们剪接的机制所做分析显示,这样的剪接点可以被用来指令不同的mRNA异构型。

更多信息:

Recursive splicing in long vertebrate genes

Molecular biology: Splicing does the two-step

阅读次数:  

发表评论