Dean P Staus, Hongli Hu, Michael J Robertson, Alissa L W Kleinhenz, Laura M Wingler, William D Capel, Naomi R Latorraca, Robert J Lefkowitz, Georgios Skiniotis
Following agonist activation, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1 . Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins2 . Here we present a cryo-electron microscopy (cryo-EM) structure of β-arrestin 1 (βarr1) in complex with muscarinic acetylcholine-2-receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 structure shows a multimodal network of flexible interactions, including binding of the βarr1 N domain to phosphorylated receptor residues and βarr1 finger loop insertion into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein structure3 ...
January 16, 2020: Nature
Weijiao Huang, Matthieu Masureel, Qu Qianhui, John Janetzko, Asuka Inoue, Hideaki E Kato, Michael J Robertson, Khanh C Nguyen, Jeffrey S Glenn, Georgios Skiniotis, Brian K Kobilka
Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization, and affecting various downstream signalling pathways1,2 . Although there is a wealth of structural information delineating the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-EM structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1ΔCT )...
January 16, 2020: Nature
S Helmrich, A Arias, G Lochead, T M Wintermantel, M Buchhold, S Diehl, S Whitlock
Self-organized criticality is an elegant explanation of how complex structures emerge and persist throughout nature1 , and why such structures often exhibit similar scale-invariant properties2-9 . Although self-organized criticality is sometimes captured by simple models that feature a critical point as an attractor for the dynamics10-15 , the connection to real-world systems is exceptionally hard to test quantitatively16-21 . Here we observe three key signatures of self-organized criticality in the dynamics of a driven-dissipative gas of ultracold potassium atoms: self-organization to a stationary state that is largely independent of the initial conditions; scale-invariance of the final density characterized by a unique scaling function; and large fluctuations of the number of excited atoms (avalanches) obeying a characteristic power-law distribution...
January 15, 2020: Nature
Florent Petitprez, Aurélien de Reyniès, Emily Z Keung, Tom Wei-Wu Chen, Cheng-Ming Sun, Julien Calderaro, Yung-Ming Jeng, Li-Ping Hsiao, Laetitia Lacroix, Antoine Bougoüin, Marco Moreira, Guillaume Lacroix, Ivo Natario, Julien Adam, Carlo Lucchesi, Yec Han Laizet, Maud Toulmonde, Melissa A Burgess, Vanessa Bolejack, Denise Reinke, Khalid M Wani, Wei-Lien Wang, Alexander J Lazar, Christina L Roland, Jennifer A Wargo, Antoine Italiano, Catherine Sautès-Fridman, Hussein A Tawbi, Wolf H Fridman
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2 . The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4 . To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups...
January 15, 2020: Nature
Will Dabney, Zeb Kurth-Nelson, Naoshige Uchida, Clara Kwon Starkweather, Demis Hassabis, Rémi Munos, Matthew Botvinick
Since its introduction, the reward prediction error theory of dopamine has explained a wealth of empirical phenomena, providing a unifying framework for understanding the representation of reward and value in the brain1-3 . According to the now canonical theory, reward predictions are represented as a single scalar quantity, which supports learning about the expectation, or mean, of stochastic outcomes. Here we propose an account of dopamine-based reinforcement learning inspired by recent artificial intelligence research on distributional reinforcement learning4-6 ...
January 15, 2020: Nature
Beth A Helmink, Sangeetha M Reddy, Jianjun Gao, Shaojun Zhang, Rafet Basar, Rohit Thakur, Keren Yizhak, Moshe Sade-Feldman, Jorge Blando, Guangchun Han, Vancheswaran Gopalakrishnan, Yuanxin Xi, Hao Zhao, Rodabe N Amaria, Hussein A Tawbi, Alex P Cogdill, Wenbin Liu, Valerie S LeBleu, Fernanda G Kugeratski, Sapna Patel, Michael A Davies, Patrick Hwu, Jeffrey E Lee, Jeffrey E Gershenwald, Anthony Lucci, Reetakshi Arora, Scott Woodman, Emily Z Keung, Pierre-Olivier Gaudreau, Alexandre Reuben, Christine N Spencer, Elizabeth M Burton, Lauren E Haydu, Alexander J Lazar, Roberta Zapassodi, Courtney W Hudgens, Deborah A Ledesma, SuFey Ong, Michael Bailey, Sarah Warren, Disha Rao, Oscar Krijgsman, Elisa A Rozeman, Daniel Peeper, Christian U Blank, Ton N Schumacher, Lisa H Butterfield, Monika A Zelazowska, Kevin M McBride, Raghu Kalluri, James Allison, Florent Petitprez, Wolf Herman Fridman, Catherine Sautès-Fridman, Nir Hacohen, Katayoun Rezvani, Padmanee Sharma, Michael T Tetzlaff, Linghua Wang, Jennifer A Wargo
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15 , although these have been less well-studied in ICB treatment16 . A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients...
January 15, 2020: Nature
Wenchuan Ma, James F Lutsko, Jeffrey D Rimer, Peter G Vekilov
Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments1-5 ; however, laboratory efforts have focused on the crystallization of pure solutes6,7 and the effects of single growth modifiers8,9 . Here we examine the molecular mechanisms employed by pairs of inhibitors in blocking the crystallization of haematin, which is a model organic compound with relevance to the physiology of malaria parasites10,11 . We use a combination of scanning probe microscopy and molecular modelling to demonstrate that inhibitor pairs, whose constituents adopt distinct mechanisms of haematin growth inhibition, kink blocking and step pinning12,13 , exhibit both synergistic and antagonistic cooperativity depending on the inhibitor combination and applied concentrations...
January 15, 2020: Nature
Hiroyuki Imachi, Masaru K Nobu, Nozomi Nakahara, Yuki Morono, Miyuki Ogawara, Yoshihiro Takaki, Yoshinori Takano, Katsuyuki Uematsu, Tetsuro Ikuta, Motoo Ito, Yohei Matsui, Masayuki Miyazaki, Kazuyoshi Murata, Yumi Saito, Sanae Sakai, Chihong Song, Eiji Tasumi, Yuko Yamanaka, Takashi Yamaguchi, Yoichi Kamagata, Hideyuki Tamaki, Ken Takai
The origin of eukaryotes remains unclear1-4 . Current data suggest that eukaryotes may have emerged from an archaeal lineage known as 'Asgard' archaea5,6 . Despite the eukaryote-like genomic features that are found in these archaea, the evolutionary transition from archaea to eukaryotes remains unclear, owing to the lack of cultured representatives and corresponding physiological insights. Here we report the decade-long isolation of an Asgard archaeon related to Lokiarchaeota from deep marine sediment. The archaeon-'Candidatus Prometheoarchaeum syntrophicum' strain MK-D1-is an anaerobic, extremely slow-growing, small coccus (around 550 nm in diameter) that degrades amino acids through syntrophy...
January 15, 2020: Nature
Andrew W Senior, Richard Evans, John Jumper, James Kirkpatrick, Laurent Sifre, Tim Green, Chongli Qin, Augustin Žídek, Alexander W R Nelson, Alex Bridgland, Hugo Penedones, Stig Petersen, Karen Simonyan, Steve Crossan, Pushmeet Kohli, David T Jones, David Silver, Koray Kavukcuoglu, Demis Hassabis
Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1 . This problem is of fundamental importance as the structure of a protein largely determines its function2 ; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3 ...
January 15, 2020: Nature
Rita Cabrita, Martin Lauss, Adriana Sanna, Marco Donia, Mathilde Skaarup Larsen, Shamik Mitra, Iva Johansson, Bengt Phung, Katja Harbst, Johan Vallon-Christersson, Alison van Schoiack, Kristina Lövgren, Sarah Warren, Karin Jirström, Håkan Olsson, Kristian Pietras, Christian Ingvar, Karolin Isaksson, Dirk Schadendorf, Henrik Schmidt, Lars Bastholt, Ana Carneiro, Jennifer A Wargo, Inge Marie Svane, Göran Jönsson
Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1 . Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3 . Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables...
January 15, 2020: Nature
Suijuan Zhong, Wenyu Ding, Le Sun, Yufeng Lu, Hao Dong, Xiaoying Fan, Zeyuan Liu, Ruiguo Chen, Shu Zhang, Qiang Ma, Fuchou Tang, Qian Wu, Xiaoqun Wang
The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and the consolidation of information from short-term memory to long-term memory1,2 . Here we use single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis to illustrate the cell types, cell linage, molecular features and transcriptional regulation of the developing human hippocampus. Using the transcriptomes of 30,416 cells from the human hippocampus at gestational weeks 16-27, we identify 47 cell subtypes and their developmental trajectories...
January 15, 2020: Nature
Lin Wang, Juehui Wu, Jun Li, Hua Yang, Tianqi Tang, Haijiao Liang, Mianyong Zuo, Jie Wang, Haipeng Liu, Feng Liu, Jianxia Chen, Zhonghua Liu, Yang Wang, Cheng Peng, Xiangyang Wu, Ruijuan Zheng, Xiaochen Huang, Yajun Ran, Zihe Rao, Baoxue Ge
Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2 , but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines...
January 15, 2020: Nature
Eric Song, Tianyang Mao, Huiping Dong, Ligia Simoes Braga Boisserand, Salli Antila, Marcus Bosenberg, Kari Alitalo, Jean-Leon Thomas, Akiko Iwasaki
Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain1-3 . Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear...
January 15, 2020: Nature
Januka S Athukoralage, Stephen A McMahon, Changyi Zhang, Sabine Grüschow, Shirley Graham, Mart Krupovic, Rachel J Whitaker, Tracey M Gloster, Malcolm F White
The CRISPR system in bacteria and archaea provides adaptive immunity against mobile genetic elements. Type III CRISPR systems detect viral RNA, resulting in the activation of two regions of the Cas10 protein: an HD nuclease domain (which degrades viral DNA)1,2 and a cyclase domain (which synthesizes cyclic oligoadenylates from ATP)3-5 . Cyclic oligoadenylates in turn activate defence enzymes with a CRISPR-associated Rossmann fold domain6 , sculpting a powerful antiviral response7-10 that can drive viruses to extinction7,8 ...
January 15, 2020: Nature
Yong Wang, Hayden M Carder, Alison E Wendlandt
Glycans have diverse physiological functions, ranging from energy storage and structural integrity to cell signalling and the regulation of intracellular processes1 . Although biomass-derived carbohydrates (such as (D)-glucose, (D)-xylose and (D)-galactose) are extracted on commercial scales, and serve as renewable chemical feedstocks and building blocks2,3 , there are many hundreds of distinct monosaccharides that typically cannot be isolated from their natural sources and must instead be prepared through multistep chemical or enzymatic syntheses4,5 ...
January 15, 2020: Nature
Jizhai Cui, Tian-Yun Huang, Zhaochu Luo, Paolo Testa, Hongri Gu, Xiang-Zhong Chen, Bradley J Nelson, Laura J Heyderman
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
January 15, 2020: Nature
Jie Su, Sophie M Morgani, Charles J David, Qiong Wang, Ekrem Emrah Er, Yun-Han Huang, Harihar Basnet, Yilong Zou, Weiping Shu, Rajesh K Soni, Ronald C Hendrickson, Anna-Katerina Hadjantonakis, Joan Massagué
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
January 15, 2020: Nature
Haizhen Long, Liwei Zhang, Mengjie Lv, Zengqi Wen, Wenhao Zhang, Xiulan Chen, Peitao Zhang, Tongqing Li, Luyuan Chang, Caiwei Jin, Guozhao Wu, Xi Wang, Fuquan Yang, Jianfeng Pei, Ping Chen, Raphael Margueron, Haiteng Deng, Mingzhao Zhu, Guohong Li
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
January 14, 2020: Nature
Giuseppe Faraco, Karin Hochrainer, Steven G Segarra, Samantha Schaeffer, Monica M Santisteban, Ajay Menon, Hong Jiang, David M Holtzman, Josef Anrather, Costantino Iadecola
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
January 14, 2020: Nature
N W Hendrickx, D P Franke, A Sammak, G Scappucci, M Veldhorst
Universal quantum information processing requires the execution of single-qubit and two-qubit logic. Across all qubit realizations1 , spin qubits in quantum dots have great promise to become the central building block for quantum computation2 . Excellent quantum dot control can be achieved in gallium arsenide3-5 , and high-fidelity qubit rotations and two-qubit logic have been demonstrated in silicon6-9 , but universal quantum logic implemented with local control has yet to be demonstrated. Here we make this step by combining all of these desirable aspects using hole quantum dots in germanium...
January 13, 2020: Nature
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