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Nature 论文导读-0831

时间: 2017年09月14日 | 作者: admin | 来源: 未知
N ature 20170831 1【生物】Identification of essential genes for cancer immunotherapy 癌症免疫疗法必需基因的鉴定 Shashank J. Patel,Neville E. Sanjana,Nicholas P. Restifoet al. http://www.nature.com/nature/journal/v548/n7669/

Nature 20170831

1【生物】 Identification of essential genes for cancer immunotherapy

癌症免疫疗法必需基因的鉴定

Shashank J. Patel, Neville E. Sanjana, Nicholas P. Restifo et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23477.html

 

(导读 郭思瑶)体细胞基因突变可以改变基于T细胞的免疫疗法对癌细胞的杀伤力。本研究通过包含123,000sgRNACRISPR–Cas9文库筛选癌细胞中能损伤CD8+ T细胞效应物功能的基因突变鉴定出了APLNR等多个与抗原呈递、干扰素γ信号通路等免疫过程相关的基因,为癌细胞对癌症免疫疗法的敏感性提供了基因层面的支持。

 

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

 

2【生物】  Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers

III型CRISPR-Cas系统产生环状寡腺苷酸第二信使

Martin Jinek et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23467.html

 

(导读 郭思瑶)在许多原核生物中,III型CRISPR –Cas系统中的CRISPR相关蛋白Csm6可作为RNA酶降解入侵RNA,其机制尚不可知。本研究发现,在与目标RNA结合后,III型干扰复合体的Cas10亚基会将ATP转化为环状寡腺苷酸,环状寡腺苷酸作为第二信使与Csm6的CARF结构域结合并激活Csm6的核酸酶活性。该研究揭示了CRISPR干扰系统调控的新机制。

 

In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

 

 

3 【生物】  Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

哺乳动物将内源性基因毒性甲醛转化为一碳代谢产物

Ketan J. Patel et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23481.html

 

The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.

 

(导读 赵鹏)叶酸驱动的一碳循环是细胞基础代谢的枢纽,该循环过程会产生具有基因毒性的甲醛。本研究在、小鼠、鸡淋巴细胞发现了一条一碳代谢通路:叶酸主链氧化分解而产生甲醛在分解甲醛的解毒过程中,甲醛代谢为可以促进核苷酸合成甲酸盐,甲酸盐可为不能使用丝氨酸的细胞生长提供支持。

 

4 【物理】Fast automated analysis of strong gravitational lenses with convolutional neural networks

卷积神经网络快速自动分析强引力透镜图像

Yashar D. Hezaveh, Laurence Perreault Levasseur et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23463.html

 

图片1.png

 

图片来源:nextbigfuture.com

 

(导读:阿金)引力透镜图像能够告诉我们宇宙中物质的分布,但传统的分析方法耗时、费力。本研究报道使用深度神经网络快速、自动地估计透镜模型参数,精度可与复杂模型相比拟,但处理速度快1000万倍。这为非专家人士从大量数据样本中确定透镜模型提供了新方法。

阅读更多 原理:当神经网络遇上时空扭曲

https://mp.weixin.qq.com/s/KdPRwHqiHlSv4-w75ND00w

 

Quantifying image distortions caused by strong gravitational lensing—the formation of multiple images of distant sources due to the deflection of their light by the gravity of intervening structures—and estimating the corresponding matter distribution of these structures (the ‘gravitational lens’) has primarily been performed using maximum likelihood modelling of observations. This procedure is typically time- and resource-consuming, requiring sophisticated lensing codes, several data preparation steps, and finding the maximum likelihood model parameters in a computationally expensive process with downhill optimizers. Accurate analysis of a single gravitational lens can take up to a few weeks and requires expert knowledge of the physical processes and methods involved. Tens of thousands of new lenses are expected to be discovered with the upcoming generation of ground and space surveys. Here we report the use of deep convolutional neural networks to estimate lensing parameters in an extremely fast and automated way, circumventing the difficulties that are faced by maximum likelihood methods. We also show that the removal of lens light can be made fast and automated using independent component analysis of multi-filter imaging data. Our networks can recover the parameters of the ‘singular isothermal ellipsoid’ density profile, which is commonly used to model strong lensing systems, with an accuracy comparable to the uncertainties of sophisticated models but about ten million times faster: 100 systems in approximately one second on a single graphics processing unit. These networks can provide a way for non-experts to obtain estimates of lensing parameters for large samples of data.

 

5【天文】Proper-motion age dating of the progeny of Nova Scorpii AD 1437

固有运动确定导致天蝎座1437爆发的源头

M. M. Shara et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23644.html

 

 

(导读:阿金)激变变星(白矮星及其伴星组成的双星系统)会产生两种爆发:经典新星爆发和矮新星爆发。本研究发现了导致公元1437年经典新星爆发的双星的后代——一颗矮新星,并且通过固有运动确定了它的年龄。这为了解星体演化过程提供了新的参照。

阅读更多 星空天文:六百年前失落的一颗新星真身再现

http://mp.weixin.qq.com/s/S_e134U_4nM_C5mZiDHx2g

 

‘Cataclysmic variables’ are binary star systems in which one star of the pair is a white dwarf, and which often generate bright and energetic stellar outbursts. Classical novae are one type of outburst: when the white dwarf accretes enough matter from its companion, the resulting hydrogen-rich atmospheric envelope can host a runaway thermonuclear reaction that generates a rapid brightening. Achieving peak luminosities of up to one million times that of the Sun, all classical novae are recurrent, on timescales of months to millennia. During the century before and after an eruption, the ‘novalike’ binary systems that give rise to classical novae exhibit high rates of mass transfer to their white dwarfs. Another type of outburst is the dwarf nova: these occur in binaries that have stellar masses and periods indistinguishable from those of novalikes but much lower mass-transfer rates, when accretion-disk instabilities drop matter onto the white dwarfs. The co-existence at the same orbital period of novalike binaries and dwarf novae—which are identical but for their widely varying accretion rates—has been a longstanding puzzle. Here we report the recovery of the binary star underlying the classical nova eruption of 11 March AD 1437, and independently confirm its age by proper-motion dating. We show that, almost 500 years after a classical-nova event, the system exhibited dwarf-nova eruptions. The three other oldest recovered classical novae display nova shells, but lack firm post-eruption ages, and are also dwarf novae at present. We conclude that many old novae become dwarf novae for part of the millennia between successive nova eruptions.

 

6【物理】Magnetic antiskyrmions above room temperature in tetragonal Heusler materials

 

四方Heusler材料中室温以上的磁性反斯格明子

 

Stuart S. P. Parkin et al.

 

http://www.nature.com/nature/journal/v548/n7669/full/nature23466.html

 

 

(导读:雷鸣)磁性斯格明子是一种拓扑稳定涡状纳米磁畴结构单元有望用于制备高性能的计算机存及逻辑件。本实验拥有D2d对称性的哈斯勒Heusler)合金发现磁性反斯格明子洛仑兹电镜测显示,磁性反斯格明子能在100k到温以上温度区间稳定存在。

 

Magnetic skyrmions are topologically stable, vortex-like objects surrounded by chiral boundaries that separate a region of reversed magnetization from the surrounding magnetized material1, 2, 3. They are closely related to nanoscopic chiral magnetic domain walls, which could be used as memory and logic elements for conventional and neuromorphic computing applications that go beyond Moore’s law. Of particular interest is ‘racetrack memory’, which is composed of vertical magnetic nanowires, each accommodating of the order of 100 domain walls, and that shows promise as a solid state, non-volatile memory with exceptional capacity and performance4, 5. Its performance is derived from the very high speeds (up to one kilometre per second) at which chiral domain walls can be moved with nanosecond current pulses in synthetic antiferromagnet racetracks. Because skyrmions are essentially composed of a pair of chiral domain walls closed in on themselves, but are, in principle, more stable to perturbations than the component domain walls themselves, they are attractive for use in spintronic applications, notably racetrack memory. Stabilization of skyrmions has generally been achieved in systems with broken inversion symmetry, in which the asymmetric Dzyaloshinskii–Moriya interaction modifies the uniform magnetic state to a swirling state6, 7. Depending on the crystal symmetry, two distinct types of skyrmions have been observed experimentally, namely, Bloch7, 8 and Néel skyrmions9. Here we present the experimental manifestation of another type of skyrmion—the magnetic antiskyrmion—in acentric tetragonal Heusler compounds with D2d crystal symmetry. Antiskyrmions are characterized by boundary walls that have alternating Bloch and Néel type as one traces around the boundary. A spiral magnetic ground-state, which propagates in the tetragonal basal plane, is transformed into an antiskyrmion lattice state under magnetic fields applied along the tetragonal axis over a wide range of temperatures. Direct imaging by Lorentz transmission electron microscopy shows field-stabilized antiskyrmion lattices and isolated antiskyrmions from 100 kelvin to well beyond room temperature, and zero-field metastable antiskyrmions at low temperatures. These results enlarge the family of magnetic skyrmions and pave the way to the engineering of complex bespoke designed skyrmionic structures.

 

 

7【生物】Molecular machines open cell membranes

分子机器穿透细胞膜

· Jacob T. Robinson, Gufeng Wang, Robert Pal, James M. Tour et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23657.html

 

Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes1. These include using electric2 and magnetic3 fields, temperature4, ultrasound5 or light6 to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis). More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications789. Here we show that molecular machines can drill through cellular bilayers using their molecular-scale actuation, specifically nanomechanical action. Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells. We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitro applications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation10.

图片2.png

 

(导读 吴媛媛)细胞膜的脂质双分子层可借由物理方法打开,以释放分子物质或诱导细胞凋亡和坏死。本研究设计了在紫外光激发下,可产生精确纳米机械作用并导致细胞膜穿孔的分子机器。在该分子机器上附加短肽,可使其选择性地作用于细胞表面特异识别位点。研究人员希望体外实验结果可被应用于体内并设计出可被其他方式激活的穿膜分子机器。

 

 

8 【地质or地球科学Very large release of mostly volcanic carbon during the Palaeocene–Eocene Thermal Maximum

源自火山的大量碳释放引发古新世-始新世极热事件

Marcus Gutjahr et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23646.html

 

图片来源:nature.com

 

(导读:阿金)引发古新世-始新世极热事件(PETM)全球变暖的原因尚有争议。本研究将代表海水PH值的硼同位素数据与地球系统魔性中的成对碳同位素记录相结合,发现北大西洋火成岩的火山二氧化碳大量释放是引发PETM主因的有力证据而有机物埋葬的增加可能对隔绝释放的碳及加速地球系统恢复很重要。

 

The Palaeocene–Eocene Thermal Maximum1, 2 (PETM) was a global warming event that occurred about 56 million years ago, and is commonly thought to have been driven primarily by the destabilization of carbon from surface sedimentary reservoirs such as methane hydrates3. However, it remains controversial whether such reservoirs were indeed the source of the carbon that drove the warming1, 3, 4, 5. Resolving this issue is key to understanding the proximal cause of the warming, and to quantifying the roles of triggers versus feedbacks. Here we present boron isotope data—a proxy for seawater pH—that show that the ocean surface pH was persistently low during the PETM. We combine our pH data with a paired carbon isotope record in an Earth system model in order to reconstruct the unfolding carbon-cycle dynamics during the event6, 7. We find strong evidence for a much larger (more than 10,000 petagrams)—and, on average, isotopically heavier—carbon source than considered previously8, 9. This leads us to identify volcanism associated with the North Atlantic Igneous Province10, 11, rather than carbon from a surface reservoir, as the main driver of the PETM. This finding implies that climate-driven amplification of organic carbon feedbacks probably played only a minor part in driving the event. However, we find that enhanced burial of organic matter seems to have been important in eventually sequestering the released carbon and accelerating the recovery of the Earth system12

 

 

 

 

9【进化The rise of algae in Cryogenian oceans and the emergence of animals

成冰纪海洋藻类的繁荣促使动物的出现

Jochen J. Brocks et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23457.html

 

图片3.png

 

图片来源:rebrn.com

 

(导读:阿金)海洋初级真核生物繁荣的时间、原因与动物进化的关系依然不清。本研究分析了一真核生物类固醇分子化石,发现成冰纪与南沱冰期之间(距今6.596.45亿年)的短时间内海洋浮游藻类数量猛增,产生了更多的营养物质和能量传输途径,促进生态系统进化出更复杂的生物,为动物的诞生创造了条件。

 

The transition from dominant bacterial to eukaryotic marine primary productivity was one of the most profound ecological revolutions in the Earth’s history, reorganizing the distribution of carbon and nutrients in the water column and increasing energy flow to higher trophic levels. But the causes and geological timing of this transition, as well as possible links with rising atmospheric oxygen levels and the evolution of animals, remain obscure. Here we present a molecular fossil record of eukaryotic steroids demonstrating that bacteria were the only notable primary producers in the oceans before the Cryogenian period (720–635million years ago). Increasing steroid diversity and abundance marks the rapid rise of marine planktonic algae (Archaeplastida) in the narrow time interval between the Sturtian and Marinoan ‘snowball Earth’ glaciations, 659–645million years ago. We propose that the incumbency of cyanobacteria was broken by a surge of nutrients supplied by the Sturtian deglaciation. The ‘Rise of Algae’ created food webs with more efficient nutrient and energy transfers, driving ecosystems towards larger and increasingly complex organisms. This effect is recorded by the concomitant appearance of biomarkers for sponges and predatory rhizarians, and the subsequent radiation of eumetazoans in the Ediacaran period.

 

 

10【生物】Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep

大脑未定带的LHX6阳性伽马氨基丁酸神经元促进睡眠

Seth Blackshaw et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23663.html

 

 

(导读:阿金)我们已经找到哺乳动物大脑中大部分促清醒的神经元,但是对促睡眠的神经元还缺乏认识。本研究在小鼠腹侧未定带发现一种表达LHX6γ-氨基丁酸神经元(GABA)神经元可在睡眠压力下被激活,并直接抑制清醒相关的神经元。该发现为进一步开发治疗睡眠紊乱药物提供了新思路。

 

Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified. Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid γ-氨基丁酸)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep–wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep.

 

 

11【生物】Feedback regulation of steady-state epithelial turnover and organ size

【封面】调节上皮细胞更新和器官大小的反馈机制

Lucy Erin O’Brien et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23678.html

 

(导读:阿金)上皮组织中细胞的产生和消亡受到严格控制,但科学家仍不清楚其平衡机制。本研究通过研究果蝇肠道揭示了一种反馈机制:健康肠上皮细胞中的钙粘蛋白通过抑制表皮生长因子(EGF)分泌阻止干细胞分裂,而衰老的上皮细胞则通过下调钙粘蛋白诱导蛋白酶,激活EGF受体进行细胞分裂。以此来保证器官的稳定大小。

 

 

Epithelial organs undergo steady-state turnover throughout adult life, with old cells being continually replaced by the progeny of stem cell divisions. To avoid hyperplasia or atrophy, organ turnover demands strict equilibration of cell production and loss. However, the mechanistic basis of this equilibrium is unknown. Here we show that robustly precise turnover of the adult Drosophila intestine arises through a coupling mechanism in which enterocyte apoptosis breaks feedback inhibition of stem cell division. Healthy enterocytes inhibit stem cell division through E-cadherin, which prevents secretion of mitogenic epidermal growth factors (EGFs) by repressing transcription of the EGF maturation factor rhomboid. Individual apoptotic enterocytes promote divisions by loss of E-cadherin, which releases cadherin-associated β-catenin (Armadillo in Drosophila) and p120-catenin to induce rhomboid. Induction of rhomboid in the dying enterocyte triggers activation of the EGF receptor (Egfr) in stem cells within a discrete radius. When we blocked apoptosis, E-cadherin-controlled feedback suppressed divisions, and the organ retained the same number of cells. When we disrupted feedback, apoptosis and divisions were uncoupled, and the organ developed either hyperplasia or atrophy. Together, our results show that robust cellular balance hinges on the obligate coupling of divisions to apoptosis, which limits the proliferative potential of a stem cell to the precise time and place at which a replacement cell is needed. In this way, localized cell–cell communication gives rise to tissue-level homeostatic equilibrium and constant organ size.

 

 

 

 

12【生物】Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model

人类iPS细胞诱导分化的多巴胺能神经元在灵长类帕金森病模型中发挥功能

Jun Takahashi et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23664.html

 

 

Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson’s disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

 

(导读 郭怿暄)iPS细胞的诱导分化可以为帕金森病的细胞治疗提供来源,然而至今尚无应用。这一研究首次将人类iPS细胞产生的多巴胺能神经元移植到食蟹猴的帕金森病模型中,发现细胞可以存活且发挥功能,移植后猴子自发活动增多,成熟的多巴胺能神经元的轴突向宿主纹状体中延伸,并且安全性可靠。这表明iPS细胞在帕金森病的临床治疗中拥有巨大潜能。

 

 

13【生物】Public antibodies to malaria antigens generated by two LAIR1 insertion modalities

由两种LAIR1插入模式产生的疟疾抗原的公共抗体

· Antonio Lanzavecchia et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23670.html

(导读 寒雨)在先前两例供体中已经发现LAIR1(胶原蛋白结合抑制受体)插入抗体的VDJ片段之间产生针对RIFINs的广泛反应性抗体,为探究响应疟疾感染时这种抗体的产生频率,本研究筛选了疟疾流行区两个群体的血浆,发现5-10%的个体中含LAIR1抗体的水平较高,并发现了第二种插入模式,揭示了不同LAIR1插入模式的结构和新的抗体多样性产生机制,为B细胞工程改造提供思路。

In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes2. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5–10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.

14【生物】Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

肝激酶LKB1信号通路调控调节性T细胞(Treg)的代谢和功能稳态

· Hongbo Chi et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23665.html

(导读 寒雨)调节性T细胞(Treg细胞)在调节免疫自我耐受性和内稳态方面有重要作用。本研究发现Treg特异性的肝激酶LKB1缺失不仅扰乱了Treg的存活和代谢,同时诱导了免疫调控分子PD-1等的异常表达,从而使小鼠发生致命性炎症。而阻断PD-1活性能够恢复LKB1功能缺陷Treg细胞的抑制能力。

Regulatory T cells (Treg cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis12. Transcriptional programming of regulatory mechanisms facilitates the functional activation of Treg cells in the prevention of diverse types of inflammatory responses34. It remains unclear how Treg cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with a Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-type-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signalling or the mTORC1–HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient Treg cells to suppress TH2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, Treg cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.

 

15【生物】ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference

ISWI染色质重塑因子通过感知核小体的修饰来决定底物的偏好

Tom W. Muir et al.

http://www.nature.com/nature/journal/v548/n7669/full/nature23671.html

 

 

ATP-dependent chromatin remodellers regulate access to genetic information by controlling nucleosome positions in vivo. However, the mechanism by which remodellers discriminate between different nucleosome substrates is poorly understood. Many chromatin remodelling proteins possess conserved protein domains that interact with nucleosomal features. Here we used a quantitative high-throughput approach, based on the use of a DNA-barcoded mononucleosome library, to profile the biochemical activity of human ISWI family remodellers in response to a diverse set of nucleosome modifications. We show that accessory (non-ATPase) subunits of ISWI remodellers can distinguish between differentially modified nucleosomes, directing remodelling activity towards specific nucleosome substrates according to their modification state. Unexpectedly, we show that the nucleosome acidic patch is necessary for maximum activity of all ISWI remodellers evaluated. This dependence also extends to CHD and SWI/SNF family remodellers, suggesting that the acidic patch may be generally required for chromatin remodelling. Critically, remodelling activity can be regulated by modifications neighbouring the acidic patch, signifying that it may act as a tunable interaction hotspot for ATP-dependent chromatin remodellers and, by extension, many other chromatin effectors that engage this region of the nucleosome surface.

 

(导读 郭怿暄)ATP依赖的染色质重塑因子可以通过控制核小体的位置来调节染色质的结构,但其分辨不同核小体的机制尚不清楚。这一研究发现人类ISWI家族重塑因子中,非ATPase亚基可以区分核小体的修饰,针对不同的修饰状态,对特定的核小体进行重塑。并且核小体的酸性区域作为一个可调节的相互作用热点,对染色质重塑活性至关重要。