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Synthesis and properties of free-standing monolayer amorphous carbon 期刊论文
NATURE, 2020, 577 (7789) : 199-+
作者:  Toh, Chee-Tat;  Zhang, Hongji;  Lin, Junhao;  Mayorov, Alexander S.;  Wang, Yun-Peng;  Orofeo, Carlo M.;  Ferry, Darim Badur;  Andersen, Henrik;  Kakenov, Nurbek;  Guo, Zenglong;  Abidi, Irfan Haider;  Sims, Hunter;  Suenaga, Kazu;  Pantelides, Sokrates T.;  Ozyilmaz, Barbaros
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Bulk amorphous materials have been studied extensively and are widely used, yet their atomic arrangement remains an open issue. Although they are generally believed to be Zachariasen continuous random networks(1), recent experimental evidence favours the competing crystallite model in the case of amorphous silicon(2-4). In two-dimensional materials, however, the corresponding questions remain unanswered. Here we report the synthesis, by laser-assisted chemical vapour deposition(5), of centimetre-scale, free-standing, continuous and stable monolayer amorphous carbon, topologically distinct from disordered graphene. Unlike in bulk materials, the structure of monolayer amorphous carbon can be determined by atomic-resolution imaging. Extensive characterization by Raman and X-ray spectroscopy and transmission electron microscopy reveals the complete absence of long-range periodicity and a threefold-coordinated structure with a wide distribution of bond lengths, bond angles, and five-, six-, seven- and eight-member rings. The ring distribution is not a Zachariasen continuous random network, but resembles the competing (nano)crystallite model(6). We construct a corresponding model that enables density-functional-theory calculations of the properties of monolayer amorphous carbon, in accordance with observations. Direct measurements confirm that it is insulating, with resistivity values similar to those of boron nitride grown by chemical vapour deposition. Free-standing monolayer amorphous carbon is surprisingly stable and deforms to a high breaking strength, without crack propagation from the point of fracture. The excellent physical properties of this stable, free-standing monolayer amorphous carbon could prove useful for permeation and diffusion barriers in applications such as magnetic recording devices and flexible electronics.


  
Internal state dynamics shape brainwide activity and foraging behaviour 期刊论文
NATURE, 2020, 577 (7789) : 239-+
作者:  Marques, Joao C.;  Li, Meng;  Schaak, Diane;  Robson, Drew N.;  Li, Jennifer M.
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

The brain has persistent internal states that can modulate every aspect of an animal'  s mental experience(1-4). In complex tasks such as foraging, the internal state is dynamic(5-8). Caenorhabditis elegans alternate between local search and global dispersal(5). Rodents and primates exhibit trade-offs between exploitation and exploration(6,7). However, fundamental questions remain about how persistent states are maintained in the brain, which upstream networks drive state transitions and how state-encoding neurons exert neuromodulatory effects on sensory perception and decision-making to govern appropriate behaviour. Here, using tracking microscopy to monitor whole-brain neuronal activity at cellular resolution in freely moving zebrafish larvae(9), we show that zebrafish spontaneously alternate between two persistent internal states during foraging for live prey (Paramecia). In the exploitation state, the animal inhibits locomotion and promotes hunting, generating small, localized trajectories. In the exploration state, the animal promotes locomotion and suppresses hunting, generating long-ranging trajectories that enhance spatial dispersion. We uncover a dorsal raphe subpopulation with persistent activity that robustly encodes the exploitation state. The exploitation-state-encoding neurons, together with a multimodal trigger network that is associated with state transitions, form a stochastically activated nonlinear dynamical system. The activity of this oscillatory network correlates with a global retuning of sensorimotor transformations during foraging that leads to marked changes in both the motivation to hunt for prey and the accuracy of motor sequences during hunting. This work reveals an important hidden variable that shapes the temporal structure of motivation and decision-making.


  
Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc 期刊论文
NATURE, 2020, 579 (7798) : 297-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:40/0  |  提交时间:2020/07/03

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit beta-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis(1). Additionally, beta-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins(2). In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of beta-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of beta-arrestin 1 (beta arr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-beta arr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of beta arr1 to phosphorylated receptor residues and insertion of the finger loop of beta arr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G(o) protein complex(3). Moreover, the cryo-electron microscopy map reveals that the C-edge of beta arr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, beta arr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.


  
VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours 期刊论文
NATURE, 2020, 577 (7792) : 689-+
作者:  Toll, Velle;  Christensen, Matthew;  Quaas, Johannes;  Bellouin, Nicolas
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.


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 brain(1-3). 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. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.


  
Structure of SAGA and mechanism of TBP deposition on gene promoters 期刊论文
NATURE, 2020, 577 (7792) : 711-+
作者:  Xue, Jenny Y.;  Zhao, Yulei;  Aronowitz, Jordan;  Mai, Trang T.;  Vides, Alberto;  Qeriqi, Besnik;  Kim, Dongsung;  Li, Chuanchuan;  de Stanchina, Elisa;  Mazutis, Linas;  Risso, Davide;  Lito, Piro
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

SAGA (Spt-Ada-Gcn5-acetyltransferase) is a 19-subunit complex that stimulates transcription via two chromatin-modifying enzymatic modules and by delivering the TATA box binding protein (TBP) to nucleate the pre-initiation complex on DNA, a pivotal event in the expression of protein-encoding genes(1). Here we present the structure of yeast SAGA with bound TBP. The core of the complex is resolved at 3.5 angstrom resolution (0.143 Fourier shell correlation). The structure reveals the intricate network of interactions that coordinate the different functional domains of SAGA and resolves an octamer of histone-fold domains at the core of SAGA. This deformed octamer deviates considerably from the symmetrical analogue in the nucleosome and is precisely tuned to establish a peripheral site for TBP, where steric hindrance represses binding of spurious DNA. Complementary biochemical analysis points to a mechanism for TBP delivery and release from SAGA that requires transcription factor IIA and whose efficiency correlates with the affinity of DNA to TBP. We provide the foundations for understanding the specific delivery of TBP to gene promoters and the multiple roles of SAGA in regulating gene expression.


Structural studies on the yeast transcription coactivator complex SAGA (Spt-Ada-Gcn5-acetyltransferase) provide insights into the mechanism of initiation of regulated transcription by this multiprotein complex, which is conserved among eukaryotes.


  
Improved protein structure prediction using potentials from deep learning 期刊论文
NATURE, 2020, 577 (7792) : 706-+
作者:  Ma, Runze;  Cao, Duanyun;  Zhu, Chongqin;  Tian, Ye;  Peng, Jinbo;  Guo, Jing;  Chen, Ji;  Li, Xin-Zheng;  Francisco, Joseph S.;  Zeng, Xiao Cheng;  Xu, Li-Mei;  Wang, En-Ge;  Jiang, Ying
收藏  |  浏览/下载:156/0  |  提交时间:2020/07/03

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence(1). This problem is of fundamental importance as the structure of a protein largely determines its function(2)  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 structures(3). Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force(4) that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction(5) (CASP13)-a blind assessment of the state of the field-AlphaFold created high-accuracy structures (with template modelling (TM) scores(6) of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined(7).


  
Network spandrels reflect ecological assembly 期刊论文
ECOLOGY LETTERS, 2018, 21 (3) : 324-334
作者:  Maynard, Daniel S.;  Servan, Carlos A.;  Allesina, Stefano
收藏  |  浏览/下载:11/0  |  提交时间:2019/04/09
Coexistence  community assembly  interspecific competition  network structure  stability  
Contact networks structured by sex underpin sex-specific epidemiology of infection 期刊论文
ECOLOGY LETTERS, 2018, 21 (2) : 309-318
作者:  Silk, Matthew J.;  Weber, Nicola L.;  Steward, Lucy C.;  Hodgson, David J.;  Boots, Mike;  Croft, Darren P.;  Delahay, Richard J.;  McDonald, Robbie A.
收藏  |  浏览/下载:15/0  |  提交时间:2019/04/09
Badger  bovine tuberculosis  epidemiology  exponential random graph model  multilayer network  reproductive behaviour  Social structure  zoonotic disease  
Spatial structure, inequality and trading community of renewable energy networks: A comparative study of solar and hydro energy product trades 期刊论文
ENERGY POLICY, 2017, 106
作者:  Fu, Xin;  Yang, Yu;  Dong, Wen;  Wang, Changjian;  Liu, Yi
收藏  |  浏览/下载:18/0  |  提交时间:2019/04/09
Renewable energy  Complex network analysis  Inequality  Community structure