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Nature 论文导读0525

时间: 2017年06月05日 | 作者: admin | 来源: 未知
1 Therapeutic T cell engineering 【肿瘤免疫学】 设计改造 治疗性 T细胞 Michel Sadelain et al. http://www.nature.com/nature/journal/v545/n7655/full/nature22395.html (导读 柳寒石)基因工程改造的 T细胞为癌症病

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1 Therapeutic T cell engineering

【肿瘤免疫学】设计改造治疗性T细胞

Michel Sadelain et al.

http://www.nature.com/nature/journal/v545/n7655/full/nature22395.html

(导读 柳寒石)基因工程改造的T细胞为癌症病人提供了治愈的希望。改造后的T细胞与嵌合型抗原受体(CARs)结合理论上可用于治疗多种肿瘤,而未来的研究将致力于鉴定合适的靶抗原、克服免疫抑制的肿瘤微环境、降低毒性,并防止抗原逃逸。最优T细胞的选择、基因工程以及细胞制备技术的发展,将拓宽这一新疗法并且推进其在感染性疾病和自体免疫方面的应用。

 

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.

 

2 Haematopoietic stem and progenitor cells from human pluripotent stem cells

 

【造血干细胞】源自人类多能干细胞的祖细胞和造血干细胞

 

George Q. Daley et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22370.html

(导读 卓思琪)为了产生功能性人类造血干细胞,研究者使多功能干细胞由形态发生素引导分化为造血内皮细胞,然后筛选出26个造血干细胞特定转录因子来促进小鼠造血移植。研究者们结合形态发生素导向分化和转录因子调节细胞命运的方式最终从多功能干细胞获得了造血干细胞和祖细胞,为造血系统疾病的研究治疗带来了前景。

 

A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

 

3 Conversion of adult endothelium to immunocompetent haematopoietic stem cells

成年内皮细胞向免疫活性造血干细胞的转化

【细胞生物学】

 

Shahin Rafii et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22326.html

 

图片1.png 

图片来源:www.nature.com

 

(导读 郭思瑶)调控内皮细胞向造血干细胞转化的发育通路尚不清楚。研究人员通过瞬时表达转录因子编码基因Fosb, Gfi1, Runx1 Spi1和血管分泌因子将成年小鼠内皮细胞完全重编程为造血干细胞(rEC-HSC)rEC-HSC拥有一套转录组和长时程自我更新,可用于克隆移植和包括获得性免疫应答在内的多个谱系的重建。该研究将有助于造血机能紊乱的治疗。

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0–8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8–20), RUNX1+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20–28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.

 

4 Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

 

【肿瘤异质性】ctDNA的系统进化分析描述了早期肺癌进化

 

Charles Swanton et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22364.html

 

(导读 卓思琪)研究者利用肿瘤特异性的系统进化途径分析了TRACERx(在治疗中跟踪非小细胞肺癌进化)病人的ctDNA(血液循环中的肿瘤DNA)。研究确立ctDNA释放的独立预测因子,并分析肿瘤体积的检测限制。通过对术后血浆的盲分析,观察到了辅助化疗的耐受性,并能确定出肺癌可能复发的病人。该项研究表明对ctDNA的系统进化分析跟踪了肺癌转移和复发的亚克隆性质,为ctDNA相关的治疗研究提供了新方法。

 

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

 

 

5 Chromatin states define tumour-specific T cell dysfunction and reprogramming

 

肿瘤特异性T细胞的功能失常与重编程能力与其染色质状态有关

 

Andrea Schietinger et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22367.html

 

(导读 严冰)CD8+ T细胞的功能失常可导致实体瘤的发展,但其过程中的表观遗传调控与治疗性重编程(如免疫检查点抑制疗法)背后的机制至今尚不清楚。本研究表明,在小鼠肿瘤内,功能失常的T细胞可根据染色质状态分为两种——一种处于能够恢复正常功能的可塑状态,另一种则处于难以通过重编程恢复功能的固定失常状态——并在这两种状态的T细胞表面分别发现不同的表型相关标记。这对进一步理解T细胞功能失常和治疗性重编程的发展有很大帮助。

 

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.

 

 

 

 

6 Rapidly star-forming galaxies adjacent to quasars at redshifts exceeding 6

【宇宙学】

R. Decarli et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22358.html

 

(导读 邓卓) 类星体的寄主星系是已知的红移量z>6 且具有超高恒星形成速率的星系,但由于其内部具有超大黑洞使得星系性质尚不明确。本研究通过单电离碳的发射谱线发现了四个z>6的类星体伴星系。基于谱线的性质研究人员猜测这四个星系内部恒星形成速率大于100太阳质量/年,且内部并不存在超大质量黑洞。

 

The existence of massive (1011 solar masses) elliptical galaxies by redshift z4 (refs 1, 2, 3; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z>6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower4. The only known galaxies with very high star-formation rates at z>6 are, with one exception5, the host galaxies of quasars6, 7, 8, 9, but these galaxies also host accreting supermassive (more than 109 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C II] at a wavelength of 158 micrometres) in four galaxies at z>6 that are companions of quasars, with velocity offsets of less than 600kilometres per second and linear offsets of less than 100kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C II] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C II] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift10, 11, 12. We find such close companions in four out of the twenty-five z>6 quasars surveyed, a fraction that needs to be accounted for in simulations13, 14. If they are representative of the bright end of the [C II] luminosity function, then they can account for the population of massive elliptical galaxies at z4 in terms of the density of cosmic space.

 

7 A cold-atom Fermi–Hubbard antiferromagnet

【量子物理】

Markus Greiner et al.

http://www.nature.com/nature/journal/v545/n7655/full/nature22362.html

 

(导读 邓卓) 对超冷费米子和量子气进行量子模拟和显微观测可以帮助了解与掺杂的哈伯德哈密顿量相关的问题。本研究在二维方形晶格的费米气中实现了反铁磁性物质。研究人员对体系进行空穴掺杂,发现反铁磁性有序矢量中保持着很强磁相关性,并展示了冷原子显微观测有助于了解低温费米-哈伯德模型。

 

Exotic phenomena in systems with strongly correlated electrons emerge from the interplay between spin and motional degrees of freedom. For example, doping an antiferromagnet is expected to give rise to pseudogap states and high-temperature superconductors1. Quantum simulation2, 3, 4, 5, 6, 7, 8 using ultracold fermions in optical lattices could help to answer open questions about the doped Hubbard Hamiltonian9, 10, 11, 12, 13, 14, and has recently been advanced by quantum gas microscopy15, 16, 17, 18, 19, 20. Here we report the realization of an antiferromagnet in a repulsively interacting Fermi gas on a two-dimensional square lattice of about 80 sites at a temperature of 0.25 times the tunnelling energy. The antiferromagnetic long-range order manifests through the divergence of the correlation length, which reaches the size of the system, the development of a peak in the spin structure factor and a staggered magnetization that is close to the ground-state value. We hole-dope the system away from half-filling, towards a regime in which complex many-body states are expected, and find that strong magnetic correlations persist at the antiferromagnetic ordering vector up to dopings of about 15 per cent. In this regime, numerical simulations are challenging21 and so experiments provide a valuable benchmark. Our results demonstrate that microscopy of cold atoms in optical lattices can help us to understand the low-temperature Fermi–Hubbard model.

 

8 Impacts and mitigation of excess diesel-related NOx emissions in 11 major vehicle markets

 

【环境】11个主要市场柴油超标氮氧化物排放的影响

 

Susan C. Anenberg, Joshua Miller et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22086.html

 

图片2.png 

图片来源:www.nature.com

 

(导读 郭思瑶)柴油氮氧化物排放占全球20%,是关键细颗粒物(PM2.5)和对流层臭氧污染源。本文显示11家主要市场占全球80%柴油车销售量,约1/3重型柴油车和过半轻型柴油车的氮氧化物(NOx)排放超过认证限量,超标排放与38000例PM2.5和臭氧相关的过早死亡有关。促进新排放标准出台可以减少此类NOx排放。

 

Vehicle emissions contribute to fine particulate matter (PM2.5) and tropospheric ozone air pollution, affecting human health, crop yields and climate worldwide. On-road diesel vehicles produce approximately 20 per cent of global anthropogenic emissions of nitrogen oxides (NOx), which are key PM2.5 and ozone precursors. Regulated NOx emission limits in leading markets have been progressively tightened, but current diesel vehicles emit far more NOx under real-world operating conditions than during laboratory certification testing. Here we show that across 11 markets, representing approximately 80 per cent of global diesel vehicle sales, nearly one-third of on-road heavy-duty diesel vehicle emissions and over half of on-road light-duty diesel vehicle emissions are in excess of certification limits. These excess emissions (totalling 4.6 million tons) are associated with about 38,000 PM2.5- and ozone-related premature deaths globally in 2015, including about 10 per cent of all ozone-related premature deaths in the 28 European Union member states. Heavy-duty vehicles are the dominant contributor to excess diesel NOx emissions and associated health impacts in almost all regions. Adopting and enforcing next-generation standards (more stringent than Euro 6/VI) could nearly eliminate real-world diesel-related NOx emissions in these markets, avoiding approximately 174,000 global PM2.5- and ozone-related premature deaths in 2040. Most of these benefits can be achieved by implementing Euro VI standards where they have not yet been adopted for heavy-duty vehicles.

 

9 The concurrent emergence and causes of double volcanic hotspot tracks on the Pacific plate

 

【地球科学】太平洋板块上双火山热点轨迹的并发现象及成因

 

T. D. Jones, D. R. Davies, I. H. Campbell, G. Iaffaldano, G. Yaxley, S. C. Kramer & C. R. Wilson

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22054.html

 

(导读 刘威尔)本研究模型显示夏威夷-天皇海山链中两条近似平行的火山轨迹(LoaKea)成因是地幔流动引发的地幔柱倾斜和太平洋板块运动的方位变化,并解释二者地球化学差异的成因。结果表明,双火山活动轨迹的形成是暂时的,并可用于识别和定位板块运动变化的时间范围。

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Mantle plumes are buoyant upwellings of hot rock that transport heat from Earth’s core to its surface, generating anomalous regions of volcanism that are not directly associated with plate tectonic processes. The best-studied example is the Hawaiian–Emperor chain, but the emergence of two sub-parallel volcanic tracks along this chain1, Loa and Kea, and the systematic geochemical differences between them2, 3 have remained unexplained.

Here we argue that the emergence of these tracks coincides with the appearance of other double volcanic tracks on the Pacific plate and a recent azimuthal change in the motion of the plate.

We propose a three-part model that explains the evolution of Hawaiian double-track volcanism: first, mantle flow beneath the rapidly moving Pacific plate strongly tilts the Hawaiian plume and leads to lateral separation between high- and low-pressure melt source regions; second, the recent azimuthal change in Pacific plate motion exposes high- and low-pressure melt products as geographically distinct volcanoes, explaining the simultaneous emergence of double-track volcanism across the Pacific; and finally, secondary pyroxenite, which is formed as eclogite melt reacts with peridotite4, dominates the low-pressure melt region beneath Loa-track volcanism, yielding the systematic geochemical differences observed between Loa- and Kea-type lavas3, 5, 6, 7, 8, 9. Our results imply that the formation of double-track volcanism is transitory and can be used to identify and place temporal bounds on plate-motion changes.

 

 

10 Identification of preoptic sleep neurons using retrograde labelling and gene profiling【生物】 

通过逆标和基因分析鉴定视叶前区睡眠神经元 

 

Yang Dan(丹扬,UC Berkeley et al.

http://www.nature.com/nature/journal/v545/n7655/full/nature22350.html

 

(导读 董堃)下丘脑视叶前区是基础睡眠调控的重要脑区,其中具体的神经环路尚未明确。本研究通过使用神经投射逆标工具、双向光遗传学操控和光极记录等方法,在视叶前区标记出了睡眠活性且可诱导睡眠的神经元。这些神经元主要是gama-氨基丁酸能的且投射到结节乳头核团。同时,翻译中核糖体亲和纯化和单细胞RNA测序鉴定了其分子标志物,这为揭示睡眠环路带来了新的希望。

 

(导读 董堃)下丘脑视前区是基础睡眠调控的重要脑区,其中具体的神经环路尚未明确。本研究通过使用示踪病毒、双向光遗传学操控和光电极记录等方法,鉴别出视叶前区投射到结节乳头核的GABA能神经元具有睡眠激活及诱导睡眠功能。随后使用翻译核糖体亲和纯化和单细胞 RNA 测序鉴定了其分子标志物。此研究为揭示睡眠环路带来了新的希望。

In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment1, 2, 3, 4, 5, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus6, 7, 8, 9. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep10. However, the sleep-active neurons are spatially intermingled with wake-active neurons6, 7, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.

 

 

11 Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes

进化导致寨卡病毒在埃及伊蚊上感染力增强

【生物】

 

Pei-Yong Shi(史佩勇,美国德克萨斯大学医学部), Gong Cheng(程功,清华) et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22365.html

 

图片3.png 

图片来源:www.nature.com

 

(导读 郭思瑶) 寨卡病毒具有非洲、亚洲两大世系,而最近美洲寨卡病毒的爆发与后者有关。。研究人员在近期美洲分离的病毒株中发现由于非结构蛋白NS1上第188位丙氨酸突变为缬氨酸,其分泌更高含量的NS1,而更高程度的NS1抗原血症可促进蚊子叮咬患者后的带毒率,从而推进了疾病的传播。该研究为近年来寨卡病毒的爆发提供了依据。

 

 Zika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013–2014) and South America (2015–2016). Phylogenetic studies have shown that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV was responsible for the recent epidemics in the Americas. However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are unclear. Non-structural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes. Here we show that NS1 antigenaemia determines ZIKV infectivity in its mosquito vector Aedes aegypti, which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have higher NS1 antigenaemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at residue 188 in NS1. ZIKV infectivity was enhanced by this amino acid substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viraemic C57BL/6 mouse deficient in type I and II interferon (IFN) receptors (AG6 mouse). Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased NS1 antigenaemia. Enhancement of NS1 antigenaemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which could have facilitated transmission during recent ZIKV epidemics.

 

 

【植物免疫】12 Global translational reprogramming is a fundamental layer of immune regulation in plants

全局翻译重编程是植物免疫调节的基本层面

Xinnian Dong (董欣年,杜克) et al.

http://www.nature.com/nature/journal/v545/n7655/full/nature22371.html

(导读 韩宇)植物细胞在免疫诱导期间的翻译转变尚不清楚。本研究使用核糖体足迹法对暴露于elf18的拟南芥进行全局翻译组分析,发现这种模式触发的免疫中,翻译受到R-motifpoly(A)结合蛋白相互作用的严格调控且与转录关系不大。

 

In the absence of specialized immune cells, the need for plants to reprogram transcription to transition from growth-related activities to defence is well understood1, 2. However, little is known about translational changes that occur during immune induction. Using ribosome footprinting, here we perform global translatome profiling on Arabidopsis exposed to the microbe-associated molecular pattern elf18. We find that during this pattern-triggered immunity, translation is tightly regulated and poorly correlated with transcription. Identification of genes with altered translational efficiency leads to the discovery of novel regulators of this immune response. Further investigation of these genes shows that messenger RNA sequence features are major determinants of the observed translational efficiency changes. In the 5′ leader sequences of transcripts with increased translational efficiency, we find a highly enriched messenger RNA consensus sequence, R-motif, consisting of mostly purines. We show that R-motif regulates translation in response to pattern-triggered immunity induction through interaction with poly(A)-binding proteins. Therefore, this study provides not only strong evidence, but also a molecular mechanism, for global translational reprogramming during pattern-triggered immunity in plants.

 


【植物免疫】13 uORF-mediated translation allows engineered plant disease resistance without fitness costs

uORF调节的翻译允许植物获得工程疾病抗性而不失适应性

Xinnian Dong (董欣年,杜克) et al.

http://www.nature.com/nature/journal/v545/n7655/full/nature22372.html

(导读 韩宇)针对植物由防御基因异位转录获得抗性而适应性降低的问题,本研究基于关键免疫调节子开发了“TBF1盒”,包含免疫诱导启动子和TBF1基因中两个响应病原体的上游开放阅读框,后者介导的翻译控制可使拟南芥和水稻在不损失适应性的前提下获得广谱抗性。

 

Controlling plant disease has been a struggle for humankind since the advent of agriculture. Studies of plant immune mechanisms have led to strategies of engineering resistant crops through ectopic transcription of plants’ own defence genes, such as the master immune regulatory gene NPR1 (ref. 1). However, enhanced resistance obtained through such strategies is often associated with substantial penalties to fitness2, making the resulting products undesirable for agricultural applications. To remedy this problem, we sought more stringent mechanisms of expressing defence proteins. On the basis of our latest finding that translation of key immune regulators, such as TBF1 (ref. 3), is rapidly and transiently induced upon pathogen challenge (see accompanying paper4), we developed a ‘TBF1-cassette’ consisting of not only the immune-inducible promoter but also two pathogen-responsive upstream open reading frames (uORFsTBF1) of the TBF1 gene. Here we demonstrate that inclusion of uORFsTBF1-mediated translational control over the production of snc1-1 (an autoactivated immune receptor) in Arabidopsis thaliana and AtNPR1 in rice enables us to engineer broad-spectrum disease resistance without compromising plant fitness in the laboratory or in the field. This broadly applicable strategy may lead to decreased pesticide use and reduce the selective pressure for resistant pathogens.

 

14 PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity

 

肿瘤相关巨噬细胞的PD-1表达抑制其吞噬作用与抗肿瘤的免疫能力

 

Irving L. Weissman et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22396.html

 

(导读 严冰)PD-1T细胞表面的一个免疫检查点受体,已知肿瘤细胞通过过表达PD-L1来逃避T细胞的免疫监视。本研究将关注点转向巨噬细胞,发现小鼠与人类的肿瘤相关巨噬细胞表面都有PD-1表达,并且其表达水平与巨噬细胞的抗肿瘤吞噬作用强度呈反比。因此,PD-1/PD-L1阻断疗法很可能在影响T细胞行为的同时也通过影响巨噬细胞行为达到抗击肿瘤细胞的目的。

 

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance1, 2. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system3, 4. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma5, 6, 7, 8, 9. Although it is well established that PD-1–PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.

 

 

15 Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia

 

【癌症代谢】髓性白血病中BCAA代谢重编程促使癌症进展

 

Takahiro Ito et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22314.html

(导读 卓思琪)支链氨基酸(BCAAs)的胞质转氨酶BCAT1在人类和小鼠慢性粒细胞白血病(CML)模型异常活跃,且为CML所必需。阻断BCAT1诱导细胞分化,并削弱CML的急性发作,而直接增加BCAA可恢复BCAT1下调带来的缺陷。同时鉴定了BCAT1的上游调节器Musashi2 (MSI2)是CML急性发作所必需的。该研究表明通过MSI2–BCAT1轴激活的BCAA代谢改变可驱动髓性白血病的进展。

 

Reprogrammed cellular metabolism is a common characteristic observed in various cancers1, 2. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2–BCAT1 axis drives cancer progression in myeloid leukaemia.

 

 

16 Architecture of the human interactome defines protein communities and disease networks

 

【生物】人类相互作用组的架构定义了蛋白质群体和疾病网络

 

Edward L. Huttlin, Steven P. Gygi, J. Wade Harper et al.

 

http://www.nature.com/nature/journal/v545/n7655/full/nature22366.html

 

(导读 卓思琪)理解人类蛋白组结构对基因组变异导致疾病的影响十分重要。本文介绍了BioPlex 2.0 (ORFeome衍生复合物的生物物理学相互作用),通过亲和纯化-质谱的方法阐明了蛋白质相互作用网和超过由25%人类编码蛋白基因成核的共配合物。BioPlex2.0超越了先前实验衍生的相互作用网,是研究未完全表征蛋白的珍贵资源,还能用于描述更大规模的蛋白质组织模式。

 

The physiology of a cell can be viewed as the product of thousands of proteins acting in concert to shape the cellular response. Coordination is achieved in part through networks of protein–protein interactions that assemble functionally related proteins into complexes, organelles, and signal transduction pathways. Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms and is critical to elucidating how genome variation contributes to disease1, 2, 3. Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification–mass spectrometry methodology4 to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far. With more than 56,000 candidate interactions, BioPlex 2.0 contains more than 29,000 previously unknown co-associations and provides functional insights into hundreds of poorly characterized proteins while enhancing network-based analyses of domain associations, subcellular localization, and co-complex formation. Unsupervised Markov clustering5 of interacting proteins identified more than 1,300 protein communities representing diverse cellular activities. Genes essential for cell fitness6, 7 are enriched within 53 communities representing central cellular functions. Moreover, we identified 442 communities associated with more than 2,000 disease annotations, placing numerous candidate disease genes into a cellular framework. BioPlex 2.0 exceeds previous experimentally derived interaction networks in depth and breadth, and will be a valuable resource for exploring the biology of incompletely characterized proteins and for elucidating larger-scale patterns of proteome organization.