Nature, 21 March 2019, Volume 567 Issue 7748

《自然》2019年3月21日，第7748期567卷

Particle robotics based on statistical mechanics of loosely coupled components

基于松散耦合元件統(tǒng)計(jì)力學(xué)的機(jī)器人

▲ 作者：Shuguang Li、Richa Batra、Daniela Rus、Hod Lipson，et al

▲ 鏈接：

https://www./articles/s41586-019-1022-9

▲ 摘要：

經(jīng)過(guò)設(shè)計(jì)的模塊化或群機(jī)器人系統(tǒng)可以模擬生物學(xué)行為，如自組裝、修復(fù)和搬運(yùn)，但大部分系統(tǒng)需要集中控制或具有會(huì)限制系統(tǒng)能力和可擴(kuò)展性的復(fù)雜設(shè)計(jì)。

本論文描述了一種能模擬生物細(xì)胞集體遷移的機(jī)器人。

這種機(jī)器人由簡(jiǎn)單的盤狀“粒子”組成，相比復(fù)雜的機(jī)器人，它們的制造更簡(jiǎn)單，也易于形成規(guī)模。

單個(gè)機(jī)器人粒子無(wú)法移動(dòng)，只能像相機(jī)光圈那樣伸縮；但是松散聚集在一起后，程序能讓它們對(duì)單梯度信號(hào)（如光線）作出響應(yīng)，并按照偏移模式振蕩，集體朝著刺激源移動(dòng)。

研究人員用25個(gè)物理機(jī)器人粒子展示了移動(dòng)、物體搬運(yùn)以及向光刺激移動(dòng)的行為，并用10萬(wàn)個(gè)粒子的模擬實(shí)驗(yàn)表明了該系統(tǒng)可擴(kuò)展性。

此外，該系統(tǒng)還能搬運(yùn)“失效粒子”——模擬預(yù)測(cè)，在20%粒子失效的情況下，系統(tǒng)仍能繼續(xù)運(yùn)動(dòng)。

▲ Abstract

Biological organisms achieve robust high-level behaviours by combining and coordinating stochastic low-level components. By contrast, most current robotic systems comprise either monolithic mechanisms or modular units with coordinated motions. Such robots require explicit control of individual components to perform specific functions, and the failure of one component typically renders the entire robot inoperable. Here we demonstrate a robotic system whose overal behaviour can be successfully controlled by exploiting statistical mechanics phenomena. We achieve this by incorporating many loosely coupled ‘particles’, which are incapable of independent locomotion and do not possess individual identity or addressable position. In the proposed system, each particle is permitted to perform only uniform volumetric oscillations that are phase-modulated by a global signal. Despite the stochastic motion of the robot and lack of direct control of its individual components, we demonstrate physical robots composed of up to two dozen particles and simulated robots with up to 100,000 particles capable of robust locomotion, object transport and photo taxis (movement towards a light stimulus). Locomotion is maintained even when 20 per cent of the  particles malfunction. These findings indicate that stochastic systems may offer an alternative approach to more complex and exacting robots vialarge-scale robust amorphous robotic systems that exhibit deterministic behaviour.

Diverse and robust molecular algorithms using reprogrammable DNA self-assembly

使用可重新編程DNA自組裝的分子算法

▲ 作者：Damien Woods、David Doty、CameronMyhrvold、Erik Winfree，etal

▲ 鏈接：

https://www./articles/s41586-019-1014-9

▲ 摘要：

分子生物學(xué)提供了一個(gè)鼓舞人心的原理證明，即化學(xué)系統(tǒng)可以存儲(chǔ)和處理信息，以指導(dǎo)分子活動(dòng)，例如從分子組分制備復(fù)雜結(jié)構(gòu)。

為了將信息化學(xué)發(fā)展為一種編程技術(shù)，使物質(zhì)以生物系統(tǒng)中看不到的方式發(fā)揮作用，有必要了解分子相互作用如何編碼和執(zhí)行算法。

然而，許多信息技術(shù)顯示出一種復(fù)雜性閾值，超過(guò)這個(gè)閾值，可重新編程系統(tǒng)的功率就會(huì)定性地增加，而且目前還不清楚DNA自組裝的生物物理學(xué)是否允許超過(guò)這個(gè)閾值。

在這里，研究人員報(bào)告設(shè)計(jì)和實(shí)驗(yàn)驗(yàn)證的DNA分子瓦集包含355個(gè)單鏈分子瓦，可以通過(guò)簡(jiǎn)單的選擇，重新編程，以實(shí)現(xiàn)各種6位算法，并且結(jié)果顯示錯(cuò)誤率較低。

這些發(fā)現(xiàn)表明，在可編程化學(xué)系統(tǒng)中，分子自組裝可能是一個(gè)可靠的算法組件。

▲ Abstract

Molecular biology provides an inspiring proof-of-principle that chemical systems can store and process information to direct molecular activities such as the fabrication of complex structures from molecular components. To develop information-based chemistry as a technology for programming matter to functionin ways not seen in biological systems, it is necessary to understand how molecular interactions can encode and execute algorithms. The self-assembly of relatively simple units into complex products is particularly well suited for such investigations. Theory that combines mathematical tiling and statistical–mechanical models of molecular crystallization has shown that algorithmic behaviour can be embedded within molecular self-assembly processes,and this has been experimentally demonstrated using DNA nanotechnology with upto 22 tile types. However, many information technologies exhibit a complexity threshold—such as the minimum transistor count needed for a general-purpose computer—beyond which the power of a reprogrammable system increases qualitatively, and it has been unclear whether the biophysics of DNA self-assembly allows that threshold to be exceeded. Here we report the designand experimental validation of a DNA tile set that contains 355 single-strandedtiles and can, through simple tile selection, be reprogrammed to implement awide variety of 6-bit algorithms. We use this set to construct 21 circuits that execute algorithms including copying, sorting, recognizing palindromes and multiples of 3, random walking, obtaining an unbiased choice from a biased random source, electing a leader, simulating cellular automata, generating deterministic and randomized patterns, and counting to 63, with an overallper-tile error rate of less than 1 in 3,000. These findings suggest that molecular self-assembly could be a reliable algorithmic component within programmable chemical systems. The development of molecular machines that are reprogrammable—at a high level of abstraction and thus without requiring knowledge of the underlying physics—will establish a creative space in which molecular programmers can flourish.

Gboxinis an oxidative phosphorylation inhibitor that targets glioblastoma

Gboxin是針對(duì)膠質(zhì)母細(xì)胞瘤的氧化磷酸化抑制劑

▲ 作者：Yufeng Shi、S. Kyun Lim、Qiren Liang、Jef K. DeBrabander、Luis F.Parada，et al 

▲ 鏈接：

https://www./articles/s41586-019-0993-x

▲ 摘要：

膠質(zhì)母細(xì)胞瘤是中樞神經(jīng)系統(tǒng)中原發(fā)性惡性腫瘤。

目前的治療以放射療法和化學(xué)療法為主，通過(guò)傷害正常增殖細(xì)胞來(lái)靶向增殖的腫瘤細(xì)胞，并誘導(dǎo)非常強(qiáng)的毒副作用。而且，腫瘤中相對(duì)靜止的癌癥干細(xì)胞可能會(huì)逃避傳統(tǒng)的治療策略。

此外，盡管增殖性腫瘤細(xì)胞依賴于有氧糖酵解，但緩慢循環(huán)的腫瘤細(xì)胞可能更喜歡線粒體呼吸作為能量的主要來(lái)源。

本論文描述了一種特異性抑制原代小鼠和人膠質(zhì)母細(xì)胞瘤細(xì)胞生長(zhǎng)的小分子Gboxin，但該小分子并不會(huì)抑制鼠胚胎成纖維細(xì)胞或新生星形膠質(zhì)細(xì)胞的生長(zhǎng)。

研究人員表示，Gboxin能迅速且不可逆轉(zhuǎn)地?fù)p害膠質(zhì)母細(xì)胞瘤細(xì)胞中的氧消耗。它以其正電荷依賴于線粒體氧化磷酸化復(fù)合物，其依賴于線粒體內(nèi)膜的質(zhì)子梯度，并抑制F0F1 ATP合成酶的活性。

▲ Abstract

Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F0F1ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxinin the mitochondrial matrix. Administration of a metabolically stable Gboxinanalogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents.

Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups

乳腺癌復(fù)發(fā)動(dòng)力學(xué)揭示晚期復(fù)發(fā)相關(guān)基因組亞群

▲ 作者：Oscar M.Rueda、Stephen-JohnSammut、Jose A.Seoane、Carlos Caldas、ChristinaCurtis，et al 

▲ 鏈接：

https://www./articles/s41586-019-1007-8

▲ 摘要：

乳腺癌患者的癌癥復(fù)發(fā)風(fēng)險(xiǎn)因腫瘤生物學(xué)特征不同而具有顯著差異。更好地了解這些風(fēng)險(xiǎn)有助于改善長(zhǎng)期療法，提高患者結(jié)局。

本論文揭示了特定乳腺癌患者群體的遠(yuǎn)期復(fù)發(fā)風(fēng)險(xiǎn)，有利于更好地鑒別高?；颊?，并為這些群體找到新療法。

研究人員對(duì)3240名英國(guó)和加拿大乳腺癌患者的不同復(fù)發(fā)風(fēng)險(xiǎn)和死亡率進(jìn)行了建模。模型考慮了不同疾病階段（如復(fù)發(fā)腫瘤與原發(fā)瘤的距離）、術(shù)后復(fù)發(fā)時(shí)間，以及年齡和腫瘤大小等其他已知會(huì)影響死亡率的因素。

研究鑒定出了4種遠(yuǎn)期復(fù)發(fā)腫瘤亞型，涵蓋了26%的雌激素受體陽(yáng)性（ER ）和人表皮生長(zhǎng)因子受體2陰性（HER2-）的腫瘤。但仍需開(kāi)展進(jìn)一步研究才能確認(rèn)更精準(zhǔn)的靶向治療是否能改變不同乳腺癌亞型的結(jié)局。

▲ Abstract

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recurup to two decades after initial diagnosis. It is therefore essential to identify patients who have a high risk of late relapse. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3240 patients with breast cancer, including 1980 for whom molecular data are available, and delineate spatio temporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and ahigh risk of recurrence (mean 47–62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain atrisk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumoursize, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinicaltrials.

Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP

STING低溫電鏡結(jié)構(gòu)揭示了其cGAS激活機(jī)制

▲ 作者：Guijun Shang、ConggangZhang、Zhijian J.Chen、Xiao-chen Bai、Xuewu Zhang

▲ 鏈接：

https://www./articles/s41586-019-0998-5

▲ 摘要：

之前有研究顯示，在外源DNA侵入細(xì)胞后感知DNA的環(huán)鳥(niǎo)苷酸-腺苷酸合成酶（cGAS），并且發(fā)現(xiàn)，與DNA結(jié)合的cGAS會(huì)催化生成信號(hào)分子環(huán)鳥(niǎo)腺苷酸（cGAMP），信號(hào)分子繼而與內(nèi)質(zhì)網(wǎng)膜上的干擾素刺激蛋白STING結(jié)合。

被激活的STING蛋白招募并激活絲氨酸蘇氨酸蛋白激酶（TBK1），激活下游的一系列轉(zhuǎn)錄因子，誘導(dǎo)與炎癥相關(guān)的基因表達(dá)。

本研究分析了cGAS-STING通路中STING蛋白被信使分子cGAMP激活的分子機(jī)制。研究團(tuán)隊(duì)結(jié)合冷凍電鏡技術(shù)和生化實(shí)驗(yàn)，首次對(duì)跨膜蛋白STING的全長(zhǎng)結(jié)構(gòu)做出解析，回答了蛋白二聚體如何活化的問(wèn)題。

該論文得到了人類和雞的全長(zhǎng)STING，處于無(wú)活性的二聚體狀態(tài)（大小約80kDa），以及二聚體和四聚體狀態(tài)的cGAMP結(jié)合雞源STING冷凍電子顯微鏡結(jié)構(gòu)。這對(duì)于進(jìn)一步了解STING信號(hào)轉(zhuǎn)導(dǎo)有積極的意義。

▲ Abstract

Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS). STING isan endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in theinactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, inducedby cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.

Structuralbasis of STING binding with and phosphorylation by TBK1

STING-TBK1復(fù)合物結(jié)構(gòu)基礎(chǔ)及TBK1磷酸化修飾

▲ 作者：ConggangZhang、Guijun Shang、Xiang Gui、Xuewu Zhang、Xiao-chen Bai、Zhijian J.Chen

▲ 鏈接：

https://www./articles/s41586-019-1000-2

▲ 摘要：

哺乳動(dòng)物細(xì)胞質(zhì)受到來(lái)自感染性病原體的微生物DNA或來(lái)自細(xì)胞核或線粒體的自身DNA的入侵，是一種警告宿主免疫系統(tǒng)的危險(xiǎn)信號(hào)。

環(huán)GMP-AMP合成酶 (cGAS) 是一種細(xì)胞質(zhì)DNA傳感器，可激活I(lǐng)型干擾素通路。而STING招募并激活TBK1，最終誘導(dǎo)與炎癥相關(guān)的基因表達(dá)。

本研究進(jìn)一步報(bào)道了STING-TBK1復(fù)合物的低溫電鏡結(jié)構(gòu)，揭示了STING招募并激活TBK1，進(jìn)而被TBK1磷酸化修飾的結(jié)構(gòu)基礎(chǔ)和分子機(jī)制。

研究人員提出了一種模型，其中STINGG的cGAMP誘導(dǎo)的高級(jí)寡聚化提供了用于募集和激活TBK1的信號(hào)傳導(dǎo)平臺(tái)。

研究發(fā)現(xiàn)，STING的C末端特異性地插入TBK1二聚體的溝槽內(nèi)，實(shí)現(xiàn)對(duì)TBK1的招募；而TBK1反過(guò)來(lái)又磷酸化STING。關(guān)鍵位點(diǎn)的突變分析進(jìn)一步驗(yàn)證了STING與TBK1聚合體相互作用的這個(gè)信號(hào)傳導(dǎo)模式。

▲ Abstract

The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens orby self DNA from the nucleus or mitochondria represents a danger signal thatalerts the host immune system. Cyclic GMP–AMP synthase (cGAS) is a sensor of cytoplasmic DNA that activates the type-I interferon pathway. On binding toDNA, cGAS is activated to catalyse the synthesis of cyclic GMP–AMP (cGAMP) from GTP and ATP. cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING). STING then recruits and activates tank-binding kinase 1 (TBK1), which phosphorylates STING and the transcription factor IRF3 to induce type-I interferons and other cytokines. However, how cGAMP-bound STING activates TBK1 and IRF3 is not understood. Here we present the cryo-electron microscopy structure of human TBK1 in complex with cGAMP-bound, full-length chicken STING. The structure reveals that theC-terminal tail of STING adopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold and dimerization domain of the second subunit in the TBK1 dimer. In this bindingmode, the phosphorylation site Ser366 in the STING tail cannot reach the kinase-domain active site of bound TBK1, which suggests that STING phosphorylation by TBK1 requires the oligomerization of both proteins. Mutational analyses validate the interaction mode between TBK1 and STING and support a model in which high-order oligomerization of STING and TBK1, induced by cGAMP, leads to STING phosphorylation by TBK1.