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The arms race between bacteria and their phage foes 期刊论文
NATURE, 2020, 577 (7790) : 327-336
作者:  Hirschey, Matthew
收藏  |  浏览/下载:20/0  |  提交时间:2020/07/03

Bacteria are under immense evolutionary pressure from their viral invaders-bacteriophages. Bacteria have evolved numerous immune mechanisms, both innate and adaptive, to cope with this pressure. The discovery and exploitation of CRISPR-Cas systems have stimulated a resurgence in the identification and characterization of anti-phage mechanisms. Bacteriophages use an extensive battery of counter-defence strategies to co-exist in the presence of these diverse phage defence mechanisms. Understanding the dynamics of the interactions between these microorganisms has implications for phage-based therapies, microbial ecology and evolution, and the development of new biotechnological tools. Here we review the spectrum of anti-phage systems and highlight their evasion by bacteriophages.


  
Mechanisms and therapeutic implications of hypermutation in gliomas 期刊论文
NATURE, 2020, 580 (7804) : 517-+
作者:  Feng, Kaibo;  Quevedo, Raundi E.;  Kohrt, Jeffrey T.;  Oderinde, Martins S.;  Reilly, Usa;  White, M. Christina
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

A high tumour mutational burden (hypermutation) is observed in some gliomas(1-5)  however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.


  
Local and global consequences of reward-evoked striatal dopamine release 期刊论文
NATURE, 2020, 580 (7802) : 239-+
作者:  Wagner, Felix R.;  Dienemann, Christian;  Wang, Haibo;  Stuetzer, Alexandra;  Tegunov, Dimitry;  Urlaub, Henning;  Cramer, Patrick
收藏  |  浏览/下载:9/0  |  提交时间:2020/07/03

The neurotransmitter dopamine is required for the reinforcement of actions by rewarding stimuli(1). Neuroscientists have tried to define the functions of dopamine in concise conceptual terms(2), but the practical implications of dopamine release depend on its diverse brain-wide consequences. Although molecular and cellular effects of dopaminergic signalling have been extensively studied(3), the effects of dopamine on larger-scale neural activity profiles are less well-understood. Here we combine dynamic dopamine-sensitive molecular imaging(4) and functional magnetic resonance imaging to determine how striatal dopamine release shapes local and global responses to rewarding stimulation in rat brains. We find that dopamine consistently alters the duration, but not the magnitude, of stimulus responses across much of the striatum, via quantifiable postsynaptic effects that vary across subregions. Striatal dopamine release also potentiates a network of distal responses, which we delineate using neurochemically dependent functional connectivity analyses. Hot spots of dopaminergic drive notably include cortical regions that are associated with both limbic and motor function. Our results reveal distinct neuromodulatory actions of striatal dopamine that extend well beyond its sites of peak release, and that result in enhanced activation of remote neural populations necessary for the performance of motivated actions. Our findings also suggest brain-wide biomarkers of dopaminergic function and could provide a basis for the improved interpretation of neuroimaging results that are relevant to learning and addiction.


Molecular and functional magnetic resonance imaging in the rat reveals distinct neuromodulatory effects of striatal dopamine that extend beyond peak release sites and activate remote neural populations necessary for performing motivated actions.


  
Coupling of Indo-Pacific climate variability over the last millennium 期刊论文
NATURE, 2020
作者:  Chow, Brian W.;  Nunez, Vicente;  Kaplan, Luke;  Granger, Adam J.;  Bistrong, Karina;  Zucker, Hannah L.;  Kumar, Payal;  Sabatini, Bernardo L.;  Gu, Chenghua
收藏  |  浏览/下载:34/0  |  提交时间:2020/05/13

Coral records indicate that the variability of the Indian Ocean Dipole over the last millennium is strongly coupled to variability in the El Nino/Southern Oscillation and that recent extremes are unusual but not unprecedented.


The Indian Ocean Dipole (IOD) affects climate and rainfall across the world, and most severely in nations surrounding the Indian Ocean(1-4). The frequency and intensity of positive IOD events increased during the twentieth century(5) and may continue to intensify in a warming world(6). However, confidence in predictions of future IOD change is limited by known biases in IOD models(7) and the lack of information on natural IOD variability before anthropogenic climate change. Here we use precisely dated and highly resolved coral records from the eastern equatorial Indian Ocean, where the signature of IOD variability is strong and unambiguous, to produce a semi-continuous reconstruction of IOD variability that covers five centuries of the last millennium. Our reconstruction demonstrates that extreme positive IOD events were rare before 1960. However, the most extreme event on record (1997) is not unprecedented, because at least one event that was approximately 27 to 42 per cent larger occurred naturally during the seventeenth century. We further show that a persistent, tight coupling existed between the variability of the IOD and the El Nino/Southern Oscillation during the last millennium. Indo-Pacific coupling was characterized by weak interannual variability before approximately 1590, which probably altered teleconnection patterns, and by anomalously strong variability during the seventeenth century, which was associated with societal upheaval in tropical Asia. A tendency towards clustering of positive IOD events is evident in our reconstruction, which-together with the identification of extreme IOD variability and persistent tropical Indo-Pacific climate coupling-may have implications for improving seasonal and decadal predictions and managing the climate risks of future IOD variability.


  
Statin drugs might boost healthy gut microbes 期刊论文
NATURE, 2020, 581 (7808) : 263-264
作者:  Maxmen, Amy
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

Bacterial changes found in people taking cholesterol-lowering medication.


An analysis of faecal samples reveals that obese people who take cholesterol-lowering statin drugs have a '  healthier'  community of gut microorganisms than would be expected. What are the implications of this surprising finding?


  
Virological assessment of hospitalized patients with COVID-2019 期刊论文
NATURE, 2020
作者:  Kanarek, Naama;  Petrova, Boryana;  Sabatini, David M.
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

Detailed virological analysis of nine cases of coronavirus disease 2019 (COVID-19) provides proof of active replication of the SARS-CoV-2 virus in tissues of the upper respiratory tract.


Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 2019(1,2). Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses(3). This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung(2,4)  the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 2003(5). However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission(6-8). There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 x 10(8) RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.


  
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:36/0  |  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.


  
Processive extrusion of polypeptide loops by a Hsp100 disaggregase 期刊论文
NATURE, 2020, 578 (7794) : 317-+
作者:  Zhao, Peishen;  Liang, Yi-Lynn;  Belousoff, Matthew J.;  Deganutti, Giuseppe;  Fletcher, Madeleine M.;  Willard, Francis S.;  Bell, Michael G.;  Christe, Michael E.;  Sloop, Kyle W.;  Inoue, Asuka;  Truong, Tin T.;  Clydesdale, Lachlan;  Furness, Sebastian G. B.;  Christopoulos, Arthur;  Wang, Ming-Wei;  Miller, Laurence J.;  Reynolds, Christopher A.;  Danev, Radostin;  Sexton, Patrick M.;  Wootten, Denise
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

The ability to reverse protein aggregation is vital to cells(1,2). Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their central pore(3,4). This model of disaggregation is appealing, as it could explain how polypeptides entangled within aggregates can be extracted and subsequently refolded with the assistance of Hsp70(4,5). However, the model is also controversial, as the necessary motor activity has not been identified(6-8) and recent findings indicate non-processive mechanisms such as entropic pulling or Brownian ratcheting(9,10). How loop formation would be accomplished is also obscure. Indeed, cryo-electron microscopy studies consistently show single polypeptide strands in the Hsp100 pore(11,12). Here, by following individual ClpB-substrate complexes in real time, we unambiguously demonstrate processive translocation of looped polypeptides. We integrate optical tweezers with fluorescent-particle tracking to show that ClpB translocates both arms of the loop simultaneously and switches to single-arm translocation when encountering obstacles. ClpB is notably powerful and rapid  it exerts forces of more than 50 pN at speeds of more than 500 residues per second in bursts of up to 28 residues. Remarkably, substrates refold while exiting the pore, analogous to co-translational folding. Our findings have implications for protein-processing phenomena including ubiquitin-mediated remodelling by Cdc48 (or its mammalian orthologue p97)(13) and degradation by the 26S proteasome(14).


A combination of optical tweezers and fluorescent-particle tracking is used to dissect the dynamics of the Hsp100 disaggregase ClpB, and show that the processive extrusion of polypeptide loops is the mechanistic basis of its activity.


  
B cells and tertiary lymphoid structures promote immunotherapy response 期刊论文
NATURE, 2020, 577 (7791) : 549-+
作者:  Zhang, Liangsheng;  Chen, Fei;  Zhang, Xingtan;  Li, Zhen;  Zhao, Yiyong;  Lohaus, Rolf;  Chang, Xiaojun;  Dong, Wei;  Ho, Simon Y. W.;  Liu, Xing;  Song, Aixia;  Chen, Junhao;  Guo, Wenlei;  Wang, Zhengjia;  Zhuang, Yingyu;  Wang, Haifeng;  Chen, Xuequn;  Hu, Juan;  Liu, Yanhui;  Qin, Yuan;  Wang, Kai;  Dong, Shanshan;  Liu, Yang;  Zhang, Shouzhou;  Yu, Xianxian;  Wu, Qian;  Wang, Liangsheng;  Yan, Xueqing;  Jiao, Yuannian;  Kong, Hongzhi;  Zhou, Xiaofan;  Yu, Cuiwei;  Chen, Yuchu;  Li, Fan;  Wang, Jihua;  Chen, Wei;  Chen, Xinlu;  Jia, Qidong;  Zhang, Chi;  Jiang, Yifan;  Zhang, Wanbo;  Liu, Guanhua;  Fu, Jianyu;  Chen, Feng;  Ma, Hong;  Van de Peer, Yves;  Tang, Haibao
收藏  |  浏览/下载:43/0  |  提交时间:2020/07/03

Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.


Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers(1-10) and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity(11-15), although these have been less well-studied in ICB treatment(16). A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling(17) that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter(18)) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.


  
Locally renewing resident synovial macrophages provide a protective barrier for the joint 期刊论文
NATURE, 2019, 572 (7771) : 670-+
作者:  Culemann, Stephan;  Grueneboom, Anika;  Angel Nicolas-Avila, Jose;  Weidner, Daniela;  Laemmle, Katrin Franziska;  Rothe, Tobias;  Quintana, Juan A.;  Kirchner, Philipp;  Krljanac, Branislav;  Eberhardt, Martin;  Ferrazzi, Fulvia;  Kretzschmar, Elke;  Schicht, Martin;  Fischer, Kim;  Gelse, Kolja;  Faas, Maria;  Pfeifle, Rene;  Ackermann, Jochen A.;  Pachowsky, Milena;  Renner, Nina;  Simon, David;  Haseloff, Reiner F.;  Ekici, Arif B.;  Baeuerle, Tobias;  Blasig, Ingolf E.;  Vera, Julio;  Voehringer, David;  Kleyer, Arnd;  Paulsen, Friedrich;  Schett, Georg;  Hidalgo, Andres;  Kroenke, Gerhard
收藏  |  浏览/下载:11/0  |  提交时间:2019/11/27