机器人学/化学

 

Robotics/chemistry

 

 

 

Particle robotics based on statistical mechanics of loosely coupled components

 

基于松散耦合元件统计力学的机器人

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

经过设计的模块化或群机器人系统可以模拟生物学行为，如自组装、修复和搬运，但大部分系统需要集中控制或具有会限制系统能力和可扩展性的复杂设计。

 

 

 

本论文描述了一种能模拟生物细胞集体迁移的机器人。

 

 

 

这种机器人由简单的盘状“粒子”组成，相比复杂的机器人，它们的制造更简单，也易于形成规模。

 

 

 

单个机器人粒子无法移动，只能像相机光圈那样伸缩；但是松散聚集在一起后，程序能让它们对单梯度信号（如光线）作出响应，并按照偏移模式振荡，集体朝着刺激源移动。

 

 

 

研究人员用25个物理机器人粒子展示了移动、物体搬运以及向光刺激移动的行为，并用10万个粒子的模拟实验表明了该系统可扩展性。

 

 

 

此外，该系统还能搬运“失效粒子”——模拟预测，在20%粒子失效的情况下，系统仍能继续运动。

 

 

 

▲ 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

 

使用可重新编程DNA自组装的分子算法

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

分子生物学提供了一个鼓舞人心的原理证明，即化学系统可以存储和处理信息，以指导分子活动，例如从分子组分制备复杂结构。

 

 

 

为了将信息化学发展为一种编程技术，使物质以生物系统中看不到的方式发挥作用，有必要了解分子相互作用如何编码和执行算法。

 

 

 

然而，许多信息技术显示出一种复杂性阈值，超过这个阈值，可重新编程系统的功率就会定性地增加，而且目前还不清楚DNA自组装的生物物理学是否允许超过这个阈值。

 

 

 

在这里，研究人员报告设计和实验验证的DNA分子瓦集包含355个单链分子瓦，可以通过简单的选择，重新编程，以实现各种6位算法，并且结果显示错误率较低。

 

 

 

这些发现表明，在可编程化学系统中，分子自组装可能是一个可靠的算法组件。

 

 

 

▲ 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.

 

 

 

肿瘤学Oncology

 

 

 

Gboxinis an oxidative phosphorylation inhibitor that targets glioblastoma

 

Gboxin是针对胶质母细胞瘤的氧化磷酸化抑制剂

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

胶质母细胞瘤是中枢神经系统中原发性恶性肿瘤。

 

 

 

目前的治疗以放射疗法和化学疗法为主，通过伤害正常增殖细胞来靶向增殖的肿瘤细胞，并诱导非常强的毒副作用。而且，肿瘤中相对静止的癌症干细胞可能会逃避传统的治疗策略。

 

 

 

此外，尽管增殖性肿瘤细胞依赖于有氧糖酵解，但缓慢循环的肿瘤细胞可能更喜欢线粒体呼吸作为能量的主要来源。

 

 

 

本论文描述了一种特异性抑制原代小鼠和人胶质母细胞瘤细胞生长的小分子Gboxin，但该小分子并不会抑制鼠胚胎成纤维细胞或新生星形胶质细胞的生长。

 

 

 

研究人员表示，Gboxin能迅速且不可逆转地损害胶质母细胞瘤细胞中的氧消耗。它以其正电荷依赖于线粒体氧化磷酸化复合物，其依赖于线粒体内膜的质子梯度，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

 

乳腺癌复发动力学揭示晚期复发相关基因组亚群

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

乳腺癌患者的癌症复发风险因肿瘤生物学特征不同而具有显著差异。更好地了解这些风险有助于改善长期疗法，提高患者结局。

 

 

 

本论文揭示了特定乳腺癌患者群体的远期复发风险，有利于更好地鉴别高危患者，并为这些群体找到新疗法。

 

 

 

研究人员对3240名英国和加拿大乳腺癌患者的不同复发风险和死亡率进行了建模。模型考虑了不同疾病阶段（如复发肿瘤与原发瘤的距离）、术后复发时间，以及年龄和肿瘤大小等其他已知会影响死亡率的因素。

 

 

 

研究鉴定出了4种远期复发肿瘤亚型，涵盖了26%的雌激素受体阳性（ER+）和人表皮生长因子受体2阴性（HER2-）的肿瘤。但仍需开展进一步研究才能确认更精准的靶向治疗是否能改变不同乳腺癌亚型的结局。

 

 

 

▲ 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.

 

 

 

免疫学Immunology

 

 

 

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

 

STING低温电镜结构揭示了其cGAS激活机制

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

之前有研究显示，在外源DNA侵入细胞后感知DNA的环鸟苷酸-腺苷酸合成酶（cGAS），并且发现，与DNA结合的cGAS会催化生成信号分子环鸟腺苷酸（cGAMP），信号分子继而与内质网膜上的干扰素刺激蛋白STING结合。

 

 

 

被激活的STING蛋白招募并激活丝氨酸苏氨酸蛋白激酶（TBK1），激活下游的一系列转录因子，诱导与炎症相关的基因表达。

 

 

 

本研究分析了cGAS-STING通路中STING蛋白被信使分子cGAMP激活的分子机制。研究团队结合冷冻电镜技术和生化实验，首次对跨膜蛋白STING的全长结构做出解析，回答了蛋白二聚体如何活化的问题。

 

 

 

该论文得到了人类和鸡的全长STING，处于无活性的二聚体状态（大小约80kDa），以及二聚体和四聚体状态的cGAMP结合鸡源STING冷冻电子显微镜结构。这对于进一步了解STING信号转导有积极的意义。

 

 

 

▲ 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复合物结构基础及TBK1磷酸化修饰

 

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

 

▲ 链接：

 

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

 

 

 

▲ 摘要：

 

哺乳动物细胞质受到来自感染性病原体的微生物DNA或来自细胞核或线粒体的自身DNA的入侵，是一种警告宿主免疫系统的危险信号。

 

 

 

环GMP-AMP合成酶 (cGAS) 是一种细胞质DNA传感器，可激活I型干扰素通路。而STING招募并激活TBK1，最终诱导与炎症相关的基因表达。

 

 

 

本研究进一步报道了STING-TBK1复合物的低温电镜结构，揭示了STING招募并激活TBK1，进而被TBK1磷酸化修饰的结构基础和分子机制。

 

 

 

研究人员提出了一种模型，其中STINGG的cGAMP诱导的高级寡聚化提供了用于募集和激活TBK1的信号传导平台。

 

 

 

研究发现，STING的C末端特异性地插入TBK1二聚体的沟槽内，实现对TBK1的招募；而TBK1反过来又磷酸化STING。关键位点的突变分析进一步验证了STING与TBK1聚合体相互作用的这个信号传导模式。

 

 

 

▲ 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.