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5月14日Nature中文摘要

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 封面故事:印度科技专刊

本期Nature专刊探讨南亚超级大国印度在科研方面所具有的巨大潜力和所面临的重大挑战。一个信息图将该国的R&D情况与类似国家的R&D情况进行了比较。一篇News Feature文章分析了印度在空间、生物技术和能源方面所取得的成功以及在高等教育和研究方面所存在的官僚主义、经费不足和其他障碍。我们介绍了印度科技部生物技术司新任司长Krishnaswamy VijayRaghavan,他希望能够振兴该国的生物医学研究。印度科研领域的十个领导人就怎样提升该国的科研能力提出了建议。能源专家Arunabha Ghosh和 Karthik Ganesan强调,印度需要廉价、清洁的能源。本期封面所示为 “印度空间研究组织”的工作人员在庆祝 “火星轨道探测器”2014年9月成功进入火星轨道。封面图片:Manjunath Kiran/AFP/Getty Images; 插页: Tomatito/Shutterstock.

原文链接:A nation with ambition

原文摘要:

India is making great strides in improving its science, but it needs to look carefully at its approach and work with the rest of the world if it is to realize its full potential.

对饥渴的混合反应

动物通过设计用来重新平衡它们状态的特定行为来对生理平衡的变化做出反应。我们对为追求平衡所做出的这些调整背后的动机还不是很了解。在这篇论文中,Scott Sternson及同事对由身体自平衡神经元介导的饥渴的动机过程进行了研究。他们发现,除了促进寻找食物或水的行为外,对饥饿敏感的AGRP神经元和促进渴感的神经元还会传递被主动避开的“负价教育信号”(negative valence teaching signal)。这样所产生的净效应也许是,使动物对与食物摄取相关的提示有一个偏好,从而当动物通过食物和水的摄取达到生理平衡时抵消负价信号。

原文链接:

Neurons for hunger and thirst transmit a negative-valence teaching signal

原文摘要:

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

昆虫怎么知道它们的位置

昆虫的脑在导航过程中是怎样将视觉标志与路径整合相结合的一直不清楚。Johannes Seelig 和Vivek Jayarama对在一个虚拟现实台上行走的被绑住的果蝇的大脑进行了钙成像研究,发现“铺”在“椭球体”(ellipsoid body)上的一组带树突的神经元能够利用来自视觉标志和果蝇自身转动的信息来计算前进方向。这是关于已知对哺乳动物大脑的空间导航有贡献的“前进方向”(head direction)神经元的无脊椎动物对应物的第一个证据。

原文链接:

Neural dynamics for landmark orientation and angular path integration

原文摘要:

Many animals navigate using a combination of visual landmarks and path integration. In mammalian brains, head direction cells integrate these two streams of information by representing an animal's heading relative to landmarks, yet maintaining their directional tuning in darkness based on self-motion cues. Here we use two-photon calcium imaging in head-fixed Drosophila melanogasterwalking on a ball in a virtual reality arena to demonstrate that landmark-based orientation and angular path integration are combined in the population responses of neurons whose dendrites tile the ellipsoid body, a toroidal structure in the centre of the fly brain. The neural population encodes the fly's azimuth relative to its environment, tracking visual landmarks when available and relying on self-motion cues in darkness. When both visual and self-motion cues are absent, a representation of the animal's orientation is maintained in this network through persistent activity, a potential substrate for short-term memory. Several features of the population dynamics of these neurons and their circular anatomical arrangement are suggestive of ring attractors, network structures that have been proposed to support the function of navigational brain circuits.

具有真核生物倾向的古生菌

真核细胞与原核生物的差别是如此之大,以至于了解真核生物起源和祖先一直是一个谜。遗传研究表明,古生菌比细菌更接近真核生物,但从生物化学上和形态上来说,古生菌与细菌的关系比与真核生物更近。但是现在,Thijs Ettema及同事从来自 “Loki’s Castle”活动热液喷发点的一个岩芯样本识别出了一些古生菌,它们符合作为一个基因组 “starter-kit”的要求,能够支持作为真核生物特征的更大的细胞和基因组复杂性。被称为Lokiarchaeota的这一新的古生菌类群在系统发生分析中是真核生物一个最相近的姐妹类群,它们所拥有的蛋白质本应是真核生物的特征。

原文链接:

Complex archaea that bridge the gap between prokaryotes and eukaryotes

原文摘要:

The origin of the eukaryotic cell remains one of the most contentious puzzles in modern biology. Recent studies have provided support for the emergence of the eukaryotic host cell from within the archaeal domain of life, but the identity and nature of the putative archaeal ancestor remain a subject of debate. Here we describe the discovery of ‘Lokiarchaeota’, a novel candidate archaeal phylum, which forms a monophyletic group with eukaryotes in phylogenomic analyses, and whose genomes encode an expanded repertoire of eukaryotic signature proteins that are suggestive of sophisticated membrane remodelling capabilities. Our results provide strong support for hypotheses in which the eukaryotic host evolved from a bona fide archaeon, and demonstrate that many components that underpin eukaryote-specific features were already present in that ancestor. This provided the host with a rich genomic ‘starter-kit’ to support the increase in the cellular and genomic complexity that is characteristic of eukaryotes.

牛皮癣的抗体治疗

Sauzanne Khalilieh 及同事报告了一项“概念证明”I-期临床试验,该试验显示:用“tildrakizumab”(与IL-23的p19亚单元相结合的一个抗体)来定向处理促炎性细胞因子“白介素-23” (IL-23),会导致患中度到重度牛皮癣的患者疾病症状有所改善。这种抗体耐受性很好,说明选择性地以IL-23为目标进行定向治疗值得进一步研究。

原文链接:

Clinical improvement in psoriasis with specific targeting of interleukin-23

原文摘要:

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being1, 2, 3. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg−1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg−1 group and 13 out of 14 subjects in the 10 mg kg−1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

HIV-1的染色体目标

“1-型人免疫缺陷病毒” (HIV-1)的感染需要将病毒基因组整合到寄主DNA中,该病毒已知会优先整合到一个子类的转录活性基因中。Mauro Giacca及同事在这篇论文中报告说,核位置影响目标基因的选择。他们发现,被该病毒优先作为目标的热点,在细胞核中最靠近核孔的外壳中比在中心位置更普遍,这说明,也许由于HIV-1整合酶的半衰期较短,该病毒会与它在进入细胞核途中所碰到的第一批开放染色质区域发生相互作用。

原文链接:

Nuclear architecture dictates HIV-1 integration site selection

原文摘要:

Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome1, 2, 3, 4. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains5 and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.

酵母 V-ATP酶的转动状态

 这项研究采用低温电镜来确定一种真核V-ATP酶的三个主要转动状态的结构,让我们首次对在旋转催化过程中发生的构形变化有所认识。V-ATP酶是旋转酶,利用ATP水解所释放的能量来将质子泵输穿过一个脂质双层,从而控制很多细胞内腔室的pH值。来自酿酒酵母的这种酶的三个结构显示了几个大的构形变化,它们可以解释这种ATP酶的可溶催化区域的转动是怎样与结合到膜上的、能够对质子进行转位的区域耦合在一起的。这些结构还显示,a-亚单元中的两个长的、高度倾斜的跨膜α-螺旋与c-环发生相互作用。

原文链接:

Electron cryomicroscopy observation of rotational states in a eukaryotic V-ATPase

原文摘要:

Eukaryotic vacuolar H+-ATPases (V-ATPases) are rotary enzymes that use energy from hydrolysis of ATP to ADP to pump protons across membranes and control the pH of many intracellular compartments. ATP hydrolysis in the soluble catalytic region of the enzyme is coupled to proton translocation through the membrane-bound region by rotation of a central rotor subcomplex, with peripheral stalks preventing the entire membrane-bound region from turning with the rotor. The eukaryotic V-ATPase is the most complex rotary ATPase: it has three peripheral stalks, a hetero-oligomeric proton-conducting proteolipid ring, several subunits not found in other rotary ATPases, and is regulated by reversible dissociation of its catalytic and proton-conducting regions1, 2. Studies of ATP synthases, V-ATPases, and bacterial/archaeal V/A-ATPases have suggested that flexibility is necessary for the catalytic mechanism of rotary ATPases3, 4, 5, but the structures of different rotational states have never been observed experimentally. Here we use electron cryomicroscopy to obtain structures for three rotational states of the V-ATPase from the yeast Saccharomyces cerevisiae. The resulting series of structures shows ten proteolipid subunits in the c-ring, setting the ATP:H+ ratio for proton pumping by the V-ATPase at 3:10, and reveals long and highly tilted transmembrane α-helices in the a-subunit that interact with the c-ring. The three different maps reveal the conformational changes that occur to couple rotation in the symmetry-mismatched soluble catalytic region to the membrane-bound proton-translocating region. Almost all of the subunits of the enzyme undergo conformational changes during the transitions between these three rotational states. The structures of these states provide direct evidence that deformation during rotation enables the smooth transmission of power through rotary ATPases.

一个谜一样的电子对

钛酸锶是一种异乎寻常的半导体,在其中电子被认为不仅在超导状态下成对,而且在没有超导性的更高温度下也成对。现在,Guanglei Cheng及同事发表了这一系统中在远高于超导转变温度的温度下电子成对的直接证据。作者认为,这些是人们长期寻找的预先形成的电子对,它们在较低温度下凝聚,以在这一系统中产生非传统的超导状态。

原文链接:

Electron pairing without superconductivity

原文摘要:

Strontium titanate (SrTiO3) is the first and best known superconducting semiconductor1. It exhibits an extremely low carrier density threshold for superconductivity2, and possesses a phase diagram similar to that of high-temperature superconductors3, 4—two factors that suggest an unconventional pairing mechanism. Despite sustained interest for 50 years, direct experimental insight into the nature of electron pairing in SrTiO3 has remained elusive. Here we perform transport experiments with nanowire-based single-electron transistors at the interface between SrTiO3 and a thin layer of lanthanum aluminate, LaAlO3. Electrostatic gating reveals a series of two-electron conductance resonances—paired electron states—that bifurcate above a critical pairing field Bp of about 1–4 tesla, an order of magnitude larger than the superconducting critical magnetic field. For magnetic fields below Bp, these resonances are insensitive to the applied magnetic field; for fields in excess of Bp, the resonances exhibit a linear Zeeman-like energy splitting. Electron pairing is stable at temperatures as high as 900 millikelvin, well above the superconducting transition temperature (about 300 millikelvin). These experiments demonstrate the existence of a robust electronic phase in which electrons pair without forming a superconducting state. Key experimental signatures are captured by a model involving an attractive Hubbard interaction that describes real-space electron pairing as a precursor to superconductivity.

Xist的基因沉默机制

Xist是雌性哺乳动物一个X染色体的转录沉默所需的一个长非编码RNA。Mitchell Guttman及同事采用基于质谱的方法识别出与Xist直接发生相互作用的几种蛋白,其中包括转录抑制因子SHARP。SHARP和另一个抑制因子HDAC3是胚胎干细胞中整个X染色体上“多梳”(polycomb)的转录沉默和由Xist介导的招募所必需的。

原文链接:

The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3

原文摘要:

 

Many long non-coding RNAs (lncRNAs) affect gene expression1, but the mechanisms by which they act are still largely unknown2. One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals3, 4. Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role3. The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell5. Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins—SHARP, SAF-A and LBR—are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor6 that activates HDAC37, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome.

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