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Effects of Vegetation and Topography on the Boundary Layer Structure above the Amazon Forest 期刊论文
Journal of the Atmospheric Sciences, 2020
作者:  Chamecki, Marcelo;  Freire, Livia S.;  Dias, Nelson L.;  Chen, Bicheng;  Dias-Junior, Cléo Quaresma;  Toledo Machado, Luiz Augusto;  Sörgel, Matthias;  Tsokankunku, Anywhere;  Araújo, Alessandro C. de
收藏  |  浏览/下载:6/0  |  提交时间:2020/08/18
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease 期刊论文
NATURE, 2020, 577 (7790) : 399-+
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:6/0  |  提交时间:2020/07/03

Alzheimer'  s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function(1). However, little is known about the contribution of the adaptive immune response in Alzheimer'  s disease(2). Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer'  s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer'  s disease that consists of increased numbers of CD8(+) T effector memory CD45RA(+) (T-EMRA) cells. In a second cohort, we found that CD8(+) T-EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8(+) T-EMRA cells in the cerebrospinal fluid of patients with Alzheimer'  s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer'  s disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer'  s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


  
Impaired cell fate through gain-of-function mutations in a chromatin reader 期刊论文
NATURE, 2020, 577 (7788) : 121-+
作者:  Wan, Liling;  Chong, Shasha;  Xuan, Fan;  Liang, Angela;  Cui, Xiaodong;  Gates, Leah;  Carroll, Thomas S.;  Li, Yuanyuan;  Feng, Lijuan;  Chen, Guochao;  Wang, Shu-Ping;  Ortiz, Michael V.;  Daley, Sara K.;  Wang, Xiaolu;  Xuan, Hongwen;  Kentsis, Alex;  Muir, Tom W.;  Roeder, Robert G.;  Li, Haitao;  Li, Wei;  Tjian, Robert;  Wen, Hong;  Allis, C. David
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by '  reader'  proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatinreader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.


  
Structure and mechanism of human diacylglycerol O-acyltransferase 1 期刊论文
NATURE, 2020, 581 (7808) : 329-+
作者:  Wu, Fan;  Zhao, Su;  Yu, Bin;  Chen, Yan-Mei;  Wang, Wen;  Song, Zhi-Gang;  Hu, Yi;  Tao, Zhao-Wu;  Tian, Jun-Hua;  Pei, Yuan-Yuan;  Yuan, Ming-Li;  Zhang, Yu-Ling;  Dai, Fa-Hui;  Liu, Yi;  Wang, Qi-Min;  Zheng, Jiao-Jiao;  Xu, Lin;  Holmes, Edward C.;  Zhang, Yong-Zhen
收藏  |  浏览/下载:24/0  |  提交时间:2020/07/03

The structure of human diacylglycerol O-acyltransferase 1, a membrane protein that synthesizes triacylglycerides, is solved with cryo-electron microscopy, providing insight into its function and mechanism of enzymatic activity.


Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans(1). DGAT1 belongs to the membrane-bound O-acyltransferase (MBOAT) superfamily, members of which are found in all kingdoms of life and are involved in the acylation of lipids and proteins(2,3). How human DGAT1 and other mammalian members of the MBOAT family recognize their substrates and catalyse their reactions is unknown. The absence of three-dimensional structures also hampers rational targeting of DGAT1 for therapeutic purposes. Here we present the cryo-electron microscopy structure of human DGAT1 in complex with an oleoyl-CoA substrate. Each DGAT1 protomer has nine transmembrane helices, eight of which form a conserved structural fold that we name the MBOAT fold. The MBOAT fold in DGAT1 forms a hollow chamber in the membrane that encloses highly conserved catalytic residues. The chamber has separate entrances for each of the two substrates, fatty acyl-CoA and diacylglycerol. DGAT1 can exist as either a homodimer or a homotetramer and the two forms have similar enzymatic activity. The N terminus of DGAT1 interacts with the neighbouring protomer and these interactions are required for enzymatic activity.


  
The online competition between pro- and anti-vaccination views 期刊论文
NATURE, 2020, 582 (7811) : 230-+
作者:  Wu, Fan;  Zhao, Su;  Yu, Bin;  Chen, Yan-Mei;  Wang, Wen;  Song, Zhi-Gang;  Hu, Yi;  Tao, Zhao-Wu;  Tian, Jun-Hua;  Pei, Yuan-Yuan;  Yuan, Ming-Li;  Zhang, Yu-Ling;  Dai, Fa-Hui;  Liu, Yi;  Wang, Qi-Min;  Zheng, Jiao-Jiao;  Xu, Lin;  Holmes, Edward C.;  Zhang, Yong-Zhen
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Insights into the interactions between pro- and anti-vaccination clusters on Facebook can enable policies and approaches that attempt to interrupt the shift to anti-vaccination views and persuade undecided individuals to adopt a pro-vaccination stance.


Distrust in scientific expertise(1-14) is dangerous. Opposition to vaccination with a future vaccine against SARS-CoV-2, the causal agent of COVID-19, for example, could amplify outbreaks(2-4), as happened for measles in 2019(5,6). Homemade remedies(7,8) and falsehoods are being shared widely on the Internet, as well as dismissals of expert advice(9-11). There is a lack of understanding about how this distrust evolves at the system level(13,14). Here we provide a map of the contention surrounding vaccines that has emerged from the global pool of around three billion Facebook users. Its core reveals a multi-sided landscape of unprecedented intricacy that involves nearly 100 million individuals partitioned into highly dynamic, interconnected clusters across cities, countries, continents and languages. Although smaller in overall size, anti-vaccination clusters manage to become highly entangled with undecided clusters in the main online network, whereas pro-vaccination clusters are more peripheral. Our theoretical framework reproduces the recent explosive growth in anti-vaccination views, and predicts that these views will dominate in a decade. Insights provided by this framework can inform new policies and approaches to interrupt this shift to negative views. Our results challenge the conventional thinking about undecided individuals in issues of contention surrounding health, shed light on other issues of contention such as climate change(11), and highlight the key role of network cluster dynamics in multi-species ecologies(15).


  
A lower X-gate in TASK channels traps inhibitors within the vestibule 期刊论文
NATURE, 2020
作者:  Chen, Tao;  Nomura, Kinya;  Wang, Xiaolin;  Sohrabi, Reza;  Xu, Jin;  Yao, Lingya;  Paasch, Bradley C.;  Ma, Li;  Kremer, James;  Cheng, Yuti;  Zhang, Li;  Wang, Nian;  Wang, Ertao;  Xin, Xiu-Fang;  He, Sheng Yang
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below  however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an '  X-gate'  -created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.


The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.


  
Electrical manipulation of a topological antiferromagnetic state 期刊论文
NATURE, 2020, 580 (7805) : 608-+
作者:  Chabon, Jacob J.;  Hamilton, Emily G.;  Kurtz, David M.;  Esfahani, Mohammad S.;  Moding, Everett J.;  Stehr, Henning;  Schroers-Martin, Joseph;  Nabet, Barzin Y.;  Chen, Binbin;  Chaudhuri, Aadel A.;  Liu, Chih Long;  Hui, Angela B.;  Jin, Michael C.;  Azad, Tej D.;  Almanza, Diego;  Jeon, Young-Jun;  Nesselbush, Monica C.;  Keh, Lyron Co Ting;  Bonilla, Rene F.;  Yoo, Christopher H.;  Ko, Ryan B.;  Chen, Emily L.;  Merriott, David J.;  Massion, Pierre P.;  Mansfield, Aaron S.;  Jen, Jin;  Ren, Hong Z.;  Lin, Steven H.;  Costantino, Christina L.;  Burr, Risa;  Tibshirani, Robert;  Gambhir, Sanjiv S.;  Berry, Gerald J.;  Jensen, Kristin C.;  West, Robert B.;  Neal, Joel W.;  Wakelee, Heather A.;  Loo, Billy W., Jr.;  Kunder, Christian A.;  Leung, Ann N.;  Lui, Natalie S.;  Berry, Mark F.;  Shrager, Joseph B.;  Nair, Viswam S.;  Haber, Daniel A.;  Sequist, Lecia V.;  Alizadeh, Ash A.;  Diehn, Maximilian
收藏  |  浏览/下载:36/0  |  提交时间:2020/07/03

Room-temperature electrical switching of a topological antiferromagnetic state in polycrystalline Mn3Sn thin films is demonstrated using the same protocol as that used for conventional ferromagnetic metals.


Electrical manipulation of phenomena generated by nontrivial band topology is essential for the development of next-generation technology using topological protection. A Weyl semimetal is a three-dimensional gapless system that hosts Weyl fermions as low-energy quasiparticles(1-4). It has various exotic properties, such as a large anomalous Hall effect (AHE) and chiral anomaly, which are robust owing to the topologically protected Weyl nodes(1-16). To manipulate such phenomena, a magnetic version of Weyl semimetals would be useful for controlling the locations of Weyl nodes in the Brillouin zone. Moreover, electrical manipulation of antiferromagnetic Weyl metals would facilitate the use of antiferromagnetic spintronics to realize high-density devices with ultrafast operation(17,18). However, electrical control of a Weyl metal has not yet been reported. Here we demonstrate the electrical switching of a topological antiferromagnetic state and its detection by the AHE at room temperature in a polycrystalline thin film(19) of the antiferromagnetic Weyl metal Mn3Sn9,10,12,20, which exhibits zero-field AHE. Using bilayer devices composed of Mn3Sn and nonmagnetic metals, we find that an electrical current density of about 10(10) to 10(11) amperes per square metre induces magnetic switching in the nonmagnetic metals, with a large change in Hall voltage. In addition, the current polarity along the bias field and the sign of the spin Hall angle of the nonmagnetic metals-positive for Pt (ref. (21)), close to 0 for Cu and negative for W (ref. (22))-determines the sign of the Hall voltage. Notably, the electrical switching in the antiferromagnet is achieved with the same protocol as that used for ferromagnetic metals(23,24). Our results may lead to further scientific and technological advances in topological magnetism and antiferromagnetic spintronics.


  
Nanoplasma-enabled picosecond switches for ultrafast electronics (vol 579, pg 534, 2020) 期刊论文
NATURE, 2020, 580 (7803) : E8-E8
作者:  Li, Jing;  Xu, Chuanliang;  Lee, Hyung Joo;  Ren, Shancheng;  Zi, Xiaoyuan;  Zhang, Zhiming;  Wang, Haifeng;  Yu, Yongwei;  Yang, Chenghua;  Gao, Xiaofeng;  Hou, Jianguo;  Wang, Linhui;  Yang, Bo;  Yang, Qing;  Ye, Huamao;  Zhou, Tie;  Lu, Xin;  Wang, Yan;  Qu, Min;  Yang, Qingsong;  Zhang, Wenhui;  Shah, Nakul M.;  Pehrsson, Erica C.;  Wang, Shuo;  Wang, Zengjun;  Jiang, Jun;  Zhu, Yan;  Chen, Rui;  Chen, Huan;  Zhu, Feng;  Lian, Bijun;  Li, Xiaoyun;  Zhang, Yun;  Wang, Chao;  Wang, Yue;  Xiao, Guangan;  Jiang, Junfeng;  Yang, Yue;  Liang, Chaozhao;  Hou, Jianquan;  Han, Conghui;  Chen, Ming;  Jiang, Ning;  Zhang, Dahong;  Wu, Song;  Yang, Jinjian;  Wang, Tao;  Chen, Yongliang;  Cai, Jiantong;  Yang, Wenzeng;  Xu, Jun;  Wang, Shaogang;  Gao, Xu;  Wang, Ting;  Sun, Yinghao
收藏  |  浏览/下载:25/0  |  提交时间:2020/07/03
Structure of SWI/SNF chromatin remodeller RSC bound to a nucleosome 期刊论文
NATURE, 2020
作者:  Coll, Anthony P.;  Chen, Michael;  Taskar, Pranali;  Rimmington, Debra;  Patel, Satish;  Tadross, John A.;  Cimino, Irene;  Yang, Ming;  Welsh, Paul;  Virtue, Samuel;  Goldspink, Deborah A.;  Miedzybrodzka, Emily L.;  Konopka, Adam R.;  Esponda, Raul Ruiz;  Huang, Jeffrey T. -J.;  Tung, Y. C. Loraine;  Rodriguez-Cuenca, Sergio
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

The cryo-electron microscopy structure of the 16-subunit yeast SWI/SNF complex RSC in complex with a nucleosome substrate provides insights into the chromatin-remodelling function of this family of protein complexes.


Chromatin-remodelling complexes of the SWI/SNF family function in the formation of nucleosome-depleted, transcriptionally active promoter regions (NDRs)(1,2). In the yeast Saccharomyces cerevisiae, the essential SWI/SNF complex RSC3 contains 16 subunits, including the ATP-dependent DNA translocase Sth1(4,5). RSC removes nucleosomes from promoter regions(6,7) and positions the specialized +1 and -1 nucleosomes that flank NDRs(8,9). Here we present the cryo-electron microscopy structure of RSC in complex with a nucleosome substrate. The structure reveals that RSC forms five protein modules and suggests key features of the remodelling mechanism. The body module serves as a scaffold for the four flexible modules that we call DNA-interacting, ATPase, arm and actin-related protein (ARP) modules. The DNA-interacting module binds extra-nucleosomal DNA and is involved in the recognition of promoter DNA elements(8,10,11) that influence RSC functionality(12). The ATPase and arm modules sandwich the nucleosome disc with the Snf2 ATP-coupling (SnAC) domain and the finger helix, respectively. The translocase motor of the ATPase module engages with the edge of the nucleosome at superhelical location +2. The mobile ARP module may modulate translocase-nucleosome interactions to regulate RSC activity(5). The RSC-nucleosome structure provides a basis for understanding NDR formation and the structure and function of human SWI/SNF complexes that are frequently mutated in cancer(13).


  
Neuronal programming by microbiota regulates intestinal physiology 期刊论文
NATURE, 2020, 578 (7794) : 284-+
作者:  Li, Yilong;  Roberts, Nicola D.;  Wala, Jeremiah A.;  Shapira, Ofer;  Schumacher, Steven E.;  Kumar, Kiran;  Khurana, Ekta;  Waszak, Sebastian;  Korbel, Jan O.;  Haber, James E.;  Imielinski, Marcin;  Weischenfeldt, Joachim;  Beroukhim, Rameen;  Campbell, Peter J.;  Akdemir, Kadir C.;  Alvarez, Eva G.;  Baez-Ortega, Adrian;  Boutros, Paul C.;  Bowtell, David D. L.;  Brors, Benedikt;  Burns, Kathleen H.;  Chan, Kin;  Chen, Ken;  Cortes-Ciriano, Isidro;  Dueso-Barroso, Ana;  Dunford, Andrew J.;  Edwards, Paul A.;  Estivill, Xavier;  Etemadmoghadam, Dariush;  Feuerbach, Lars;  Fink, J. Lynn;  Frenkel-Morgenstern, Milana;  Garsed, Dale W.;  Gerstein, Mark;  Gordenin, Dmitry A.;  Haan, David;  Hess, Julian M.;  Hutter, Barbara;  Jones, David T. W.;  Ju, Young Seok;  Kazanov, Marat D.;  Klimczak, Leszek J.;  Koh, Youngil;  Lee, Eunjung Alice;  Lee, Jake June-Koo;  Lynch, Andy G.;  Macintyre, Geoff;  Markowetz, Florian;  Martincorena, Inigo;  Martinez-Fundichely, Alexander;  Meyerson, Matthew;  Miyano, Satoru;  Nakagawa, Hidewaki;  Navarro, Fabio C. P.;  Ossowski, Stephan;  Park, Peter J.;  Pearson, John, V;  Puiggros, Montserrat;  Rippe, Karsten;  Roberts, Steven A.;  Rodriguez-Martin, Bernardo;  Scully, Ralph;  Shackleton, Mark;  Sidiropoulos, Nikos;  Sieverling, Lina;  Stewart, Chip;  Torrents, David;  Tubio, Jose M. C.;  Villasante, Izar;  Waddell, Nicola;  Yang, Lixing;  Yao, Xiaotong;  Yoon, Sung-Soo;  Zamora, Jorge;  Zhang, Cheng-Zhong
收藏  |  浏览/下载:39/0  |  提交时间:2020/07/03

Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders(1). Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility(2-5), but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.


In a mouse model, aryl hydrocarbon receptor signalling in enteric neurons is revealed as a mechanism that helps to maintain gut homeostasis by integrating the luminal environment with the physiology of intestinal neural circuits.