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A metabolic pathway for bile acid dehydroxylation by the gut microbiome 期刊论文
NATURE, 2020
作者:  Zhong, Miao;  Tran, Kevin;  Min, Yimeng;  Wang, Chuanhao;  Wang, Ziyun;  Dinh, Cao-Thang;  De Luna, Phil;  Yu, Zongqian;  Rasouli, Armin Sedighian;  Brodersen, Peter;  Sun, Song;  Voznyy, Oleksandr;  Tan, Chih-Shan;  Askerka, Mikhail;  Che, Fanglin;  Liu, Min;  Seifitokaldani, Ali;  Pang, Yuanjie;  Lo, Shen-Chuan;  Ip, Alexander;  Ulissi, Zachary;  Sargent, Edward H.
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/03

The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice-an important proof-of-principle for the engineering of gut microbial pathways.


The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 mu M and are known to block the growth ofClostridium difficile(1), promote hepatocellular carcinoma(2)and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref.(3)). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids(4)  the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway intoClostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool.


  
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.


  
Tertiary lymphoid structures improve immunotherapy and survival in melanoma (vol 577, pg 561, 2020) 期刊论文
NATURE, 2020
作者:  Tang, Yanhao;  Li, Lizhong;  Li, Tingxin;  Xu, Yang;  Liu, Song;  Barmak, Katayun;  Watanabe, Kenji;  Taniguchi, Takashi;  MacDonald, Allan H.;  Shan, Jie;  Mak, Kin Fai
收藏  |  浏览/下载:6/0  |  提交时间:2020/07/03

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.


  
Premature mortality related to United States cross-state air pollution 期刊论文
NATURE, 2020, 578 (7794) : 261-+
作者:  Helmink, Beth A.;  Reddy, Sangeetha M.;  Gao, Jianjun;  Zhang, Shaojun;  Basar, Rafet;  Thakur, Rohit;  Yizhak, Keren;  Sade-Feldman, Moshe;  Blando, Jorge;  Han, Guangchun;  Gopalakrishnan, Vancheswaran;  Xi, Yuanxin;  Zhao, Hao;  Amaria, Rodabe N.;  Tawbi, Hussein A.;  Cogdill, Alex P.;  Liu, Wenbin;  LeBleu, Valerie S.;  Kugeratski, Fernanda G.;  Patel, Sapna;  Davies, Michael A.;  Hwu, Patrick;  Lee, Jeffrey E.;  Gershenwald, Jeffrey E.;  Lucci, Anthony;  Arora, Reetakshi;  Woodman, Scott;  Keung, Emily Z.;  Gaudreau, Pierre-Olivier;  Reuben, Alexandre;  Spencer, Christine N.;  Burton, Elizabeth M.;  Haydu, Lauren E.;  Lazar, Alexander J.;  Zapassodi, Roberta;  Hudgens, Courtney W.;  Ledesma, Deborah A.;  Ong, SuFey;  Bailey, Michael;  Warren, Sarah;  Rao, Disha;  Krijgsman, Oscar;  Rozeman, Elisa A.;  Peeper, Daniel;  Blank, Christian U.;  Schumacher, Ton N.;  Butterfield, Lisa H.;  Zelazowska, Monika A.;  McBride, Kevin M.;  Kalluri, Raghu;  Allison, James;  Petitprez, Florent;  Fridman, Wolf Herman;  Sautes-Fridman, Catherine;  Hacohen, Nir;  Rezvani, Katayoun;  Sharma, Padmanee;  Tetzlaff, Michael T.;  Wang, Linghua;  Wargo, Jennifer A.
收藏  |  浏览/下载:37/0  |  提交时间:2020/05/13

Outdoor air pollution adversely affects human health and is estimated to be responsible for five to ten per cent of the total annual premature mortality in the contiguous United States(1-3). Combustion emissions from a variety of sources, such as power generation or road traffic, make a large contribution to harmful air pollutants such as ozone and fine particulate matter (PM2.5)(4). Efforts to mitigate air pollution have focused mainly on the relationship between local emission sources and local air quality(2). Air quality can also be affected by distant emission sources, however, including emissions from neighbouring federal states(5,6). This cross-state exchange of pollution poses additional regulatory challenges. Here we quantify the exchange of air pollution among the contiguous United States, and assess its impact on premature mortality that is linked to increased human exposure to PM2.5 and ozone from seven emission sectors for 2005 to 2018. On average, we find that 41 to 53 per cent of air-quality-related premature mortality resulting from a state'  s emissions occurs outside that state. We also find variations in the cross-state contributions of different emission sectors and chemical species to premature mortality, and changes in these variations over time. Emissions from electric power generation have the greatest cross-state impacts as a fraction of their total impacts, whereas commercial/residential emissions have the smallest. However, reductions in emissions from electric power generation since 2005 have meant that, by 2018, cross-state premature mortality associated with the commercial/residential sector was twice that associated with power generation. In terms of the chemical species emitted, nitrogen oxides and sulfur dioxide emissions caused the most cross-state premature deaths in 2005, but by 2018 primary PM2.5 emissions led to cross-state premature deaths equal to three times those associated with sulfur dioxide emissions. These reported shifts in emission sectors and emission species that contribute to premature mortality may help to guide improvements to air quality in the contiguous United States.


  
Hydrogen peroxide sensor HPCA1 is an LRR receptor kinase in Arabidopsis 期刊论文
NATURE, 2020, 578 (7796) : 577-+
作者:  Bogomilov, M.;  Tsenov, R.;  Vankova-Kirilova, G.;  Song, Y. P.;  Tang, J. Y.;  Li, Z. H.;  Bertoni, R.;  Bonesini, M.;  Chignoli, F.;  Mazza, R.;  Palladino, V;  de Bari, A.;  Orestano, D.;  Tortora, L.;  Kuno, Y.;  Sakamoto, H.;  Sato, A.;  Ishimoto, S.;  Chung, M.;  Sung, C. K.;  Filthaut, F.;  Jokovic, D.;  Maletic, D.;  Savic, M.;  Jovancevic, N.;  Nikolov, J.;  Vretenar, M.;  Ramberger, S.;  Asfandiyarov, R.;  Blondel, A.;  Drielsma, F.;  Karadzhov, Y.;  Boyd, S.;  Greis, J. R.;  Lord, T.;  Pidcott, C.;  Taylor, I;  Charnley, G.;  Collomb, N.;  Dumbell, K.;  Gallagher, A.;  Grant, A.;  Griffiths, S.;  Hartnett, T.;  Martlew, B.;  Moss, A.;  Muir, A.;  Mullacrane, I;  Oates, A.;  Owens, P.;  Stokes, G.;  Warburton, P.;  White, C.;  Adams, D.;  Bayliss, V;  Boehm, J.;  Bradshaw, T. W.;  Brown, C.;  Courthold, M.;  Govans, J.;  Hills, M.;  Lagrange, J-B;  Macwaters, C.;  Nichols, A.;  Preece, R.;  Ricciardi, S.;  Rogers, C.;  Stanley, T.;  Tarrant, J.;  Tucker, M.;  Watson, S.;  Wilson, A.;  Bayes, R.;  Nugent, J. C.;  Soler, F. J. P.;  Chatzitheodoridis, G. T.;  Dick, A. J.;  Ronald, K.;  Whyte, C. G.;  Young, A. R.;  Gamet, R.;  Cooke, P.;  Blackmore, V. J.;  Colling, D.;  Dobbs, A.;  Dornan, P.;  Franchini, P.;  Hunt, C.;  Jurj, P. B.;  Kurup, A.;  Long, K.;  Martyniak, J.;  Middleton, S.;  Pasternak, J.;  Uchida, M. A.;  Cobb, J. H.;  Booth, C. N.;  Hodgson, P.;  Langlands, J.;  Overton, E.;  Pec, V;  Smith, P. J.;  Wilbur, S.;  Ellis, M.;  Gardener, R. B. S.;  Kyberd, P.;  Nebrensky, J. J.;  DeMello, A.;  Gourlay, S.;  Lambert, A.;  Li, D.;  Luo, T.;  Prestemon, S.;  Virostek, S.;  Palmer, M.;  Witte, H.;  Adey, D.;  Bross, A. D.;  Bowring, D.;  Liu, A.;  Neuffer, D.;  Popovic, M.;  Rubinov, P.;  Freemire, B.;  Hanlet, P.;  Kaplan, D. M.;  Mohayai, T. A.;  Rajaram, D.;  Snopok, P.;  Torun, Y.;  Cremaldi, L. M.;  Sanders, D. A.;  Summers, D. J.;  Coney, L. R.;  Hanson, G. G.;  Heidt, C.
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues(1-4). H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca(2+)increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.


HPCA1, a member of a previously uncharacterized subfamily of leucine-rich-repeat receptor-like kinases, is the hydrogen-peroxide sensor at the plasma membrane in Arabidopsis.


  
Recurrent interactions in local cortical circuits 期刊论文
NATURE, 2020, 579 (7798) : 256-+
作者:  Liu, Yang;  Nguyen, Phong T.;  Wang, Xun;  Zhao, Yuting;  Meacham, Corbin E.;  Zou, Zhongju;  Bordieanu, Bogdan;  Johanns, Manuel;  Vertommen, Didier;  Wijshake, Tobias;  May, Herman;  Xiao, Guanghua;  Shoji-Kawata, Sanae;  Rider, Mark H.
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

Most cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing pattern completion and other computations(1-4). Cortical circuits contain subnetworks that consist of neurons with similar receptive fields and increased connectivity relative to the network average(5,6). Cortical neurons that encode different types of information are spatially intermingled and distributed over large brain volumes(5-7), and this complexity has hindered attempts to probe the function of these subnetworks by perturbing them individually(8). Here we use computational modelling, optical recordings and manipulations to probe the function of recurrent coupling in layer 2/3 of the mouse vibrissal somatosensory cortex during active tactile discrimination. A neural circuit model of layer 2/3 revealed that recurrent excitation enhances sensory signals by amplification, but only for subnetworks with increased connectivity. Model networks with high amplification were sensitive to damage: loss of a few members of the subnetwork degraded stimulus encoding. We tested this prediction by mapping neuronal selectivity(7) and photoablating(9,10) neurons with specific selectivity. Ablation of a small proportion of layer 2/3 neurons (10-20, less than 5% of the total) representing touch markedly reduced responses in the spared touch representation, but not in other representations. Ablations most strongly affected neurons with stimulus responses that were similar to those of the ablated population, which is also consistent with network models. Recurrence among cortical neurons with similar selectivity therefore drives input-specific amplification during behaviour.


Computational modelling, imaging and single-cell ablation in layer 2/3 of the mouse vibrissal somatosensory cortex reveals that recurrent activity in cortical neurons can drive input-specific amplification during behaviour.


  
Mechanical regulation of glycolysis via cytoskeleton architecture 期刊论文
NATURE, 2020, 578 (7796) : 621-+
作者:  Faivre, Emily J.;  McDaniel, Keith F.;  Albert, Daniel H.;  Mantena, Srinivasa R.;  Plotnik, Joshua P.;  Wilcox, Denise;  Zhang, Lu;  Bui, Mai H.;  Sheppard, George S.;  Wang, Le;  Sehgal, Vasudha;  Lin, Xiaoyu;  Huang, Xiaoli;  Lu, Xin;  Uziel, Tamar;  Hessler, Paul;  Lam, Lloyd T.;  Bellin, Richard J.;  Mehta, Gaurav;  Fidanze, Steve;  Pratt, John K.;  Liu, Dachun;  Hasvold, Lisa A.;  Sun, Chaohong;  Panchal, Sanjay C.;  Nicolette, John J.;  Fossey, Stacey L.;  Park, Chang H.;  Longenecker, Kenton;  Bigelow, Lance;  Torrent, Maricel;  Rosenberg, Saul H.;  Kati, Warren M.;  Shen, Yu
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility(1-3). Although all of these processes consume energy(4,5), it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.


Glycolysis in normal epithelial cells responds to microenvironmental mechanics via the modulation of actin bundles that sequester the phosphofructokinase-targeting ubiquitin ligase TRIM21, a process superseded by persistent actin bundles in cancer cells.


  
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity (vol 483, pg 603, 2012) 期刊论文
NATURE, 2019, 565 (7738) : E5-E6
作者:  Barretina, Jordi;  Caponigro, Giordano;  Stransky, Nicolas;  Venkatesan, Kavitha;  Margolin, Adam A.;  Kim, Sungjoon;  Wilson, Christopher J.;  Lehar, Joseph;  Kryukov, Gregory V.;  Sonkin, Dmitriy;  Reddy, Anupama;  Liu, Manway;  Murray, Lauren;  Berger, Michael F.;  Monahan, John E.;  Morais, Paula;  Meltzer, Jodi;  Korejwa, Adam;  Jane-Valbuena, Judit;  Mapa, Felipa A.;  Thibault, Joseph;  Bric-Furlong, Eva;  Raman, Pichai;  Shipway, Aaron;  Engels, Ingo H.;  Cheng, Jill;  Yu, Guoying K.;  Yu, Jianjun;  Aspesi, Peter, Jr.;  de Silva, Melanie;  Jagtap, Kalpana;  Jones, Michael D.;  Wang, Li;  Hatton, Charles;  Palescandolo, Emanuele;  Gupta, Supriya;  Mahan, Scott;  Sougnez, Carrie;  Onofrio, Robert C.;  Liefeld, Ted;  MacConaill, Laura;  Winckler, Wendy;  Reich, Michael;  Li, Nanxin;  Mesirov, Jill P.;  Gabriel, Stacey B.;  Getz, Gad;  Ardlie, Kristin;  Chan, Vivien;  Myer, Vic E.;  Weber, Barbara L.;  Porter, Jeff;  Warmuth, Markus;  Finan, Peter;  Harris, Jennifer L.;  Meyerson, Matthew;  Golub, Todd R.;  Morrissey, Michael P.;  Sellers, William R.;  Schlegel, Robert;  Garraway, Levi A.
收藏  |  浏览/下载:22/0  |  提交时间:2019/11/27
Challenging local realism with human choices 期刊论文
NATURE, 2018, 557 (7704) : 212-+
作者:  Abellan, C.;  Acin, A.;  Alarcon, A.;  Alibart, O.;  Andersen, C. K.;  Andreoli, F.;  Beckert, A.;  Beduini, F. A.;  Bendersky, A.;  Bentivegna, M.;  Bierhorst, P.;  Burchardt, D.;  Cabello, A.;  Carine, J.;  Carrasco, S.;  Carvacho, G.;  Cavalcanti, D.;  Chaves, R.;  Cortes-Vega, J.;  Cuevas, A.;  Delgado, A.;  de Riedmatten, H.;  Eichler, C.;  Farrera, P.;  Fuenzalida, J.;  Garcia-Matos, M.;  Garthoff, R.;  Gasparinetti, S.;  Gerrits, T.;  Jouneghani, F. Ghafari;  Glancy, S.;  Gomez, E. S.;  Gonzalez, P.;  Guan, J-Y;  Handsteiner, J.;  Heinsoo, J.;  Heinze, G.;  Hirschmann, A.;  Jimenez, O.;  Kaiser, F.;  Knill, E.;  Knoll, L. T.;  Krinner, S.;  Kurpiers, P.;  Larotonda, M. A.;  Larsson, J-A;  Lenhard, A.;  Li, H.;  Li, M-H;  Lima, G.;  Liu, B.;  Liu, Y.;  Lopez Grande, I. H.;  Lunghi, T.;  Ma, X.;  Magana-Loaiza, O. S.;  Magnard, P.;  Magnoni, A.;  Marti-Prieto, M.;  Martinez, D.;  Mataloni, P.;  Mattar, A.;  Mazzera, M.;  Mirin, R. P.;  Mitchell, M. W.;  Nam, S.;  Oppliger, M.;  Pan, J-W;  Patel, R. B.;  Pryde, G. J.;  Rauch, D.;  Redeker, K.;  Rielander, D.;  Ringbauer, M.;  Roberson, T.;  Rosenfeld, W.;  Salathe, Y.;  Santodonato, L.;  Sauder, G.;  Scheidl, T.;  Schmiegelow, C. T.;  Sciarrino, F.;  Seri, A.;  Shalm, L. K.;  Shi, S-C;  Slussarenko, S.;  Stevens, M. J.;  Tanzilli, S.;  Toledo, F.;  Tura, J.;  Ursin, R.;  Vergyris, P.;  Verma, V. B.;  Walter, T.;  Wallraff, A.;  Wang, Z.;  Weinfurter, H.;  Weston, M. M.;  White, A. G.;  Wu, C.;  Xavier, G. B.;  You, L.;  Yuan, X.;  Zeilinger, A.;  Zhang, Q.;  Zhang, W.;  Zhong, J.
收藏  |  浏览/下载:13/0  |  提交时间:2019/11/27
Global translational reprogramming is a fundamental layer of immune regulation in plants 期刊论文
NATURE, 2017, 545 (7655) : 487-+
作者:  Xu, Guoyong;  Greene, George H.;  Yoo, Heejin;  Liu, Lijing;  Marques, Jorge;  Motley, Jonathan;  Dong, Xinnian
收藏  |  浏览/下载:5/0  |  提交时间:2019/04/09