Pub Date : 2024-07-11DOI: 10.1038/d41586-024-02200-3
Records on the quality of the grape harvest sheds light on 600 years of weather.
有关葡萄收成质量的记录揭示了 600 年来的气候特征。
{"title":"Wine grapes’ sweetness reveals Europe’s climate history","authors":"","doi":"10.1038/d41586-024-02200-3","DOIUrl":"https://doi.org/10.1038/d41586-024-02200-3","url":null,"abstract":"Records on the quality of the grape harvest sheds light on 600 years of weather.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":64.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1038/d41586-024-02284-x
Single-cell RNA sequencing of endothelial and perivascular cells provides a detailed picture of the human brain vasculature.
内皮细胞和血管周围细胞的单细胞 RNA 测序提供了人类脑血管的详细图谱。
{"title":"High-resolution atlas of the developing, adult and diseased human brain vasculature","authors":"","doi":"10.1038/d41586-024-02284-x","DOIUrl":"https://doi.org/10.1038/d41586-024-02284-x","url":null,"abstract":"Single-cell RNA sequencing of endothelial and perivascular cells provides a detailed picture of the human brain vasculature.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":64.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/s41586-024-07658-9
Nerea Abrego, Brendan Furneaux, Bess Hardwick, Panu Somervuo, Isabella Palorinne, Carlos A Aguilar-Trigueros, Nigel R Andrew, Ulyana V Babiy, Tan Bao, Gisela Bazzano, Svetlana N Bondarchuk, Timothy C Bonebrake, Georgina L Brennan, Syndonia Bret-Harte, Claus Bässler, Luciano Cagnolo, Erin K Cameron, Elodie Chapurlat, Simon Creer, Luigi P D'Acqui, Natasha de Vere, Marie-Laure Desprez-Loustau, Michel A K Dongmo, Ida B Dyrholm Jacobsen, Brian L Fisher, Miguel Flores de Jesus, Gregory S Gilbert, Gareth W Griffith, Anna A Gritsuk, Andrin Gross, Håkan Grudd, Panu Halme, Rachid Hanna, Jannik Hansen, Lars Holst Hansen, Apollon D M T Hegbe, Sarah Hill, Ian D Hogg, Jenni Hultman, Kevin D Hyde, Nicole A Hynson, Natalia Ivanova, Petteri Karisto, Deirdre Kerdraon, Anastasia Knorre, Irmgard Krisai-Greilhuber, Juri Kurhinen, Masha Kuzmina, Nicolas Lecomte, Erin Lecomte, Viviana Loaiza, Erik Lundin, Alexander Meire, Armin Mešić, Otto Miettinen, Norman Monkhouse, Peter Mortimer, Jörg Müller, R Henrik Nilsson, Puani Yannick C Nonti, Jenni Nordén, Björn Nordén, Veera Norros, Claudia Paz, Petri Pellikka, Danilo Pereira, Geoff Petch, Juha-Matti Pitkänen, Flavius Popa, Caitlin Potter, Jenna Purhonen, Sanna Pätsi, Abdullah Rafiq, Dimby Raharinjanahary, Niklas Rakos, Achala R Rathnayaka, Katrine Raundrup, Yury A Rebriev, Jouko Rikkinen, Hanna M K Rogers, Andrey Rogovsky, Yuri Rozhkov, Kadri Runnel, Annika Saarto, Anton Savchenko, Markus Schlegel, Niels Martin Schmidt, Sebastian Seibold, Carsten Skjøth, Elisa Stengel, Svetlana V Sutyrina, Ilkka Syvänperä, Leho Tedersoo, Jebidiah Timm, Laura Tipton, Hirokazu Toju, Maria Uscka-Perzanowska, Michelle van der Bank, F Herman van der Bank, Bryan Vandenbrink, Stefano Ventura, Solvi R Vignisson, Xiaoyang Wang, Wolfgang W Weisser, Subodini N Wijesinghe, S Joseph Wright, Chunyan Yang, Nourou S Yorou, Amanda Young, Douglas W Yu, Evgeny V Zakharov, Paul D N Hebert, Tomas Roslin, Otso Ovaskainen
Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions1,2. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores3. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms4,5.
{"title":"Airborne DNA reveals predictable spatial and seasonal dynamics of fungi.","authors":"Nerea Abrego, Brendan Furneaux, Bess Hardwick, Panu Somervuo, Isabella Palorinne, Carlos A Aguilar-Trigueros, Nigel R Andrew, Ulyana V Babiy, Tan Bao, Gisela Bazzano, Svetlana N Bondarchuk, Timothy C Bonebrake, Georgina L Brennan, Syndonia Bret-Harte, Claus Bässler, Luciano Cagnolo, Erin K Cameron, Elodie Chapurlat, Simon Creer, Luigi P D'Acqui, Natasha de Vere, Marie-Laure Desprez-Loustau, Michel A K Dongmo, Ida B Dyrholm Jacobsen, Brian L Fisher, Miguel Flores de Jesus, Gregory S Gilbert, Gareth W Griffith, Anna A Gritsuk, Andrin Gross, Håkan Grudd, Panu Halme, Rachid Hanna, Jannik Hansen, Lars Holst Hansen, Apollon D M T Hegbe, Sarah Hill, Ian D Hogg, Jenni Hultman, Kevin D Hyde, Nicole A Hynson, Natalia Ivanova, Petteri Karisto, Deirdre Kerdraon, Anastasia Knorre, Irmgard Krisai-Greilhuber, Juri Kurhinen, Masha Kuzmina, Nicolas Lecomte, Erin Lecomte, Viviana Loaiza, Erik Lundin, Alexander Meire, Armin Mešić, Otto Miettinen, Norman Monkhouse, Peter Mortimer, Jörg Müller, R Henrik Nilsson, Puani Yannick C Nonti, Jenni Nordén, Björn Nordén, Veera Norros, Claudia Paz, Petri Pellikka, Danilo Pereira, Geoff Petch, Juha-Matti Pitkänen, Flavius Popa, Caitlin Potter, Jenna Purhonen, Sanna Pätsi, Abdullah Rafiq, Dimby Raharinjanahary, Niklas Rakos, Achala R Rathnayaka, Katrine Raundrup, Yury A Rebriev, Jouko Rikkinen, Hanna M K Rogers, Andrey Rogovsky, Yuri Rozhkov, Kadri Runnel, Annika Saarto, Anton Savchenko, Markus Schlegel, Niels Martin Schmidt, Sebastian Seibold, Carsten Skjøth, Elisa Stengel, Svetlana V Sutyrina, Ilkka Syvänperä, Leho Tedersoo, Jebidiah Timm, Laura Tipton, Hirokazu Toju, Maria Uscka-Perzanowska, Michelle van der Bank, F Herman van der Bank, Bryan Vandenbrink, Stefano Ventura, Solvi R Vignisson, Xiaoyang Wang, Wolfgang W Weisser, Subodini N Wijesinghe, S Joseph Wright, Chunyan Yang, Nourou S Yorou, Amanda Young, Douglas W Yu, Evgeny V Zakharov, Paul D N Hebert, Tomas Roslin, Otso Ovaskainen","doi":"10.1038/s41586-024-07658-9","DOIUrl":"https://doi.org/10.1038/s41586-024-07658-9","url":null,"abstract":"<p><p>Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions<sup>1,2</sup>. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores<sup>3</sup>. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms<sup>4,5</sup>.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The fermionic Hubbard model (FHM)1 describes a wide range of physical phenomena resulting from strong electron-electron correlations, including conjectured mechanisms for unconventional superconductivity. Resolving its low-temperature physics is, however, challenging theoretically or numerically. Ultracold fermions in optical lattices2,3 provide a clean and well-controlled platform offering a path to simulate the FHM. Doping the antiferromagnetic ground state of a FHM simulator at half-filling is expected to yield various exotic phases, including stripe order4, pseudogap5, and d-wave superfluid6, offering valuable insights into high-temperature superconductivity7-9. Although the observation of antiferromagnetic correlations over short10 and extended distances11 has been obtained, the antiferromagnetic phase has yet to be realized as it requires sufficiently low temperatures in a large and uniform quantum simulator. Here we report the observation of the antiferromagnetic phase transition in a three-dimensional fermionic Hubbard system comprising lithium-6 atoms in a uniform optical lattice with approximately 800,000 sites. When the interaction strength, temperature and doping concentration are finely tuned to approach their respective critical values, a sharp increase in the spin structure factor is observed. These observations can be well described by a power-law divergence, with a critical exponent of 1.396 from the Heisenberg universality class12. At half-filling and with optimal interaction strength, the measured spin structure factor reaches 123(8), signifying the establishment of an antiferromagnetic phase. Our results provide opportunities for exploring the low-temperature phase diagram of the FHM.
{"title":"Antiferromagnetic phase transition in a 3D fermionic Hubbard model.","authors":"Hou-Ji Shao, Yu-Xuan Wang, De-Zhi Zhu, Yan-Song Zhu, Hao-Nan Sun, Si-Yuan Chen, Chi Zhang, Zhi-Jie Fan, Youjin Deng, Xing-Can Yao, Yu-Ao Chen, Jian-Wei Pan","doi":"10.1038/s41586-024-07689-2","DOIUrl":"https://doi.org/10.1038/s41586-024-07689-2","url":null,"abstract":"<p><p>The fermionic Hubbard model (FHM)<sup>1</sup> describes a wide range of physical phenomena resulting from strong electron-electron correlations, including conjectured mechanisms for unconventional superconductivity. Resolving its low-temperature physics is, however, challenging theoretically or numerically. Ultracold fermions in optical lattices<sup>2,3</sup> provide a clean and well-controlled platform offering a path to simulate the FHM. Doping the antiferromagnetic ground state of a FHM simulator at half-filling is expected to yield various exotic phases, including stripe order<sup>4</sup>, pseudogap<sup>5</sup>, and d-wave superfluid<sup>6</sup>, offering valuable insights into high-temperature superconductivity<sup>7-9</sup>. Although the observation of antiferromagnetic correlations over short<sup>10</sup> and extended distances<sup>11</sup> has been obtained, the antiferromagnetic phase has yet to be realized as it requires sufficiently low temperatures in a large and uniform quantum simulator. Here we report the observation of the antiferromagnetic phase transition in a three-dimensional fermionic Hubbard system comprising lithium-6 atoms in a uniform optical lattice with approximately 800,000 sites. When the interaction strength, temperature and doping concentration are finely tuned to approach their respective critical values, a sharp increase in the spin structure factor is observed. These observations can be well described by a power-law divergence, with a critical exponent of 1.396 from the Heisenberg universality class<sup>12</sup>. At half-filling and with optimal interaction strength, the measured spin structure factor reaches 123(8), signifying the establishment of an antiferromagnetic phase. Our results provide opportunities for exploring the low-temperature phase diagram of the FHM.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/s41586-024-07644-1
Nils Birkholz, Kotaro Kamata, Maximilian Feussner, Max E Wilkinson, Christian Cuba Samaniego, Angela Migur, Dari Kimanius, Marijn Ceelen, Sam C Went, Ben Usher, Tim R Blower, Chris M Brown, Chase L Beisel, Zasha Weinberg, Robert D Fagerlund, Simon A Jackson, Peter C Fineran
In all organisms, regulation of gene expression must be adjusted to meet cellular requirements and frequently involves helix-turn-helix (HTH) domain proteins1. For instance, in the arms race between bacteria and bacteriophages, rapid expression of phage anti-CRISPR (acr) genes upon infection enables evasion from CRISPR-Cas defence; transcription is then repressed by an HTH-domain-containing anti-CRISPR-associated (Aca) protein, probably to reduce fitness costs from excessive expression2-5. However, how a single HTH regulator adjusts anti-CRISPR production to cope with increasing phage genome copies and accumulating acr mRNA is unknown. Here we show that the HTH domain of the regulator Aca2, in addition to repressing Acr synthesis transcriptionally through DNA binding, inhibits translation of mRNAs by binding conserved RNA stem-loops and blocking ribosome access. The cryo-electron microscopy structure of the approximately 40 kDa Aca2-RNA complex demonstrates how the versatile HTH domain specifically discriminates RNA from DNA binding sites. These combined regulatory modes are widespread in the Aca2 family and facilitate CRISPR-Cas inhibition in the face of rapid phage DNA replication without toxic acr overexpression. Given the ubiquity of HTH-domain-containing proteins, it is anticipated that many more of them elicit regulatory control by dual DNA and RNA binding.
{"title":"Phage anti-CRISPR control by an RNA- and DNA-binding helix-turn-helix protein.","authors":"Nils Birkholz, Kotaro Kamata, Maximilian Feussner, Max E Wilkinson, Christian Cuba Samaniego, Angela Migur, Dari Kimanius, Marijn Ceelen, Sam C Went, Ben Usher, Tim R Blower, Chris M Brown, Chase L Beisel, Zasha Weinberg, Robert D Fagerlund, Simon A Jackson, Peter C Fineran","doi":"10.1038/s41586-024-07644-1","DOIUrl":"https://doi.org/10.1038/s41586-024-07644-1","url":null,"abstract":"<p><p>In all organisms, regulation of gene expression must be adjusted to meet cellular requirements and frequently involves helix-turn-helix (HTH) domain proteins<sup>1</sup>. For instance, in the arms race between bacteria and bacteriophages, rapid expression of phage anti-CRISPR (acr) genes upon infection enables evasion from CRISPR-Cas defence; transcription is then repressed by an HTH-domain-containing anti-CRISPR-associated (Aca) protein, probably to reduce fitness costs from excessive expression<sup>2-5</sup>. However, how a single HTH regulator adjusts anti-CRISPR production to cope with increasing phage genome copies and accumulating acr mRNA is unknown. Here we show that the HTH domain of the regulator Aca2, in addition to repressing Acr synthesis transcriptionally through DNA binding, inhibits translation of mRNAs by binding conserved RNA stem-loops and blocking ribosome access. The cryo-electron microscopy structure of the approximately 40 kDa Aca2-RNA complex demonstrates how the versatile HTH domain specifically discriminates RNA from DNA binding sites. These combined regulatory modes are widespread in the Aca2 family and facilitate CRISPR-Cas inhibition in the face of rapid phage DNA replication without toxic acr overexpression. Given the ubiquity of HTH-domain-containing proteins, it is anticipated that many more of them elicit regulatory control by dual DNA and RNA binding.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/d41586-024-02119-9
Sjors H W Scheres
{"title":"Alzheimer's plaques and tangles revealed by 3D microscopy.","authors":"Sjors H W Scheres","doi":"10.1038/d41586-024-02119-9","DOIUrl":"https://doi.org/10.1038/d41586-024-02119-9","url":null,"abstract":"","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/s41586-024-07630-7
Miriam Bosch, Nina Kallin, Sainitin Donakonda, Jitao David Zhang, Hannah Wintersteller, Silke Hegenbarth, Kathrin Heim, Carlos Ramirez, Anna Fürst, Elias Isaac Lattouf, Martin Feuerherd, Sutirtha Chattopadhyay, Nadine Kumpesa, Vera Griesser, Jean-Christophe Hoflack, Juliane Siebourg-Polster, Carolin Mogler, Leo Swadling, Laura J. Pallett, Philippa Meiser, Katrin Manske, Gustavo P. de Almeida, Anna D. Kosinska, Ioana Sandu, Annika Schneider, Vincent Steinbacher, Yan Teng, Julia Schnabel, Fabian Theis, Adam J. Gehring, Andre Boonstra, Harry L. A. Janssen, Michiel Vandenbosch, Eva Cuypers, Rupert Öllinger, Thomas Engleitner, Roland Rad, Katja Steiger, Annette Oxenius, Wan-Lin Lo, Victoria Klepsch, Gottfried Baier, Bernhard Holzmann, Mala K. Maini, Ron Heeren, Peter J. Murray, Robert Thimme, Carl Herrmann, Ulrike Protzer, Jan P. Böttcher, Dietmar Zehn, Dirk Wohlleber, Georg M. Lauer, Maike Hofmann, Souphalone Luangsay, Percy A. Knolle
Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3,4,5,6,7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12–22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP–PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase–cAMP–PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase–cAMP–PKA axis in an immune rheostat-like fashion.
慢性乙型肝炎病毒(HBV)感染影响着全球 3 亿患者1,2,在这些患者中,病毒特异性 CD8 T 细胞因机制尚不明确而丧失功能,无法清除受 HBV 感染的肝细胞3,4,5,6,7。在这里,我们证明了肝脏免疫流变抑制剂会使病毒特异性 CD8 T 细胞难于激活,并导致其丧失效应功能。在持续感染 HBV 等致肝病毒的临床前模型中,功能失调的病毒特异性 CXCR6+ CD8 T 细胞在肝脏中聚集,其特征是 cAMP 反应元件调节器(CREM)的转录活性增强,与 T 细胞衰竭截然不同。在慢性乙型肝炎患者中,循环和肝内 HBV 特异性 CXCR6+ CD8 T 细胞的 CREM 表达和转录活性增强,在 HBV 特异性 CD8 T 细胞中的检测频率为 12-22%。然而,敲除T细胞中的抑制性CREM/ICER异构体并不能挽救T细胞免疫。这表明 CREM 活性是 T 细胞功能丧失的结果,而不是原因,而 CREM 上游蛋白激酶 A(PKA)磷酸化增强的观察结果进一步证实了这一点。事实上,我们发现,T细胞腺苷酸环化酶活性增强所产生的cAMP-PKA信号增强了CREM的活性,并抑制了T细胞的活化和在持续肝感染中的效应功能。从机理上讲,CD8 T 细胞识别肝细胞上的抗原后,与肝窦状内皮细胞建立了密切而广泛的接触,从而增强了 T 细胞腺苷酸环化酶-CAMP-PKA 信号。在这些肝脏 CD8 T 细胞中,它们能识别肝细胞上的抗原,但 T 细胞受体信号通路的关键信号激酶的磷酸化受到了影响,从而使它们难以被激活。因此,与肝窦状内皮细胞的密切接触会抑制 HBV 特异性 CD8 T 细胞的激活和效应功能,这些细胞通过腺苷酸环化酶-CAMP-PKA 轴以类似免疫流变的方式靶向表达病毒抗原的肝细胞。
{"title":"A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection","authors":"Miriam Bosch, Nina Kallin, Sainitin Donakonda, Jitao David Zhang, Hannah Wintersteller, Silke Hegenbarth, Kathrin Heim, Carlos Ramirez, Anna Fürst, Elias Isaac Lattouf, Martin Feuerherd, Sutirtha Chattopadhyay, Nadine Kumpesa, Vera Griesser, Jean-Christophe Hoflack, Juliane Siebourg-Polster, Carolin Mogler, Leo Swadling, Laura J. Pallett, Philippa Meiser, Katrin Manske, Gustavo P. de Almeida, Anna D. Kosinska, Ioana Sandu, Annika Schneider, Vincent Steinbacher, Yan Teng, Julia Schnabel, Fabian Theis, Adam J. Gehring, Andre Boonstra, Harry L. A. Janssen, Michiel Vandenbosch, Eva Cuypers, Rupert Öllinger, Thomas Engleitner, Roland Rad, Katja Steiger, Annette Oxenius, Wan-Lin Lo, Victoria Klepsch, Gottfried Baier, Bernhard Holzmann, Mala K. Maini, Ron Heeren, Peter J. Murray, Robert Thimme, Carl Herrmann, Ulrike Protzer, Jan P. Böttcher, Dietmar Zehn, Dirk Wohlleber, Georg M. Lauer, Maike Hofmann, Souphalone Luangsay, Percy A. Knolle","doi":"10.1038/s41586-024-07630-7","DOIUrl":"https://doi.org/10.1038/s41586-024-07630-7","url":null,"abstract":"<p>Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide<sup>1,2</sup>, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes<sup>3,4,5,6,7</sup>. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6<sup>+</sup> CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6<sup>+</sup> CD8 T cells with enhanced <i>CREM</i> expression and transcriptional activity were detected at a frequency of 12–22% of HBV-specific CD8 T cells. Knocking out the inhibitory <i>CREM</i>/<i>ICER</i> isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP–PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase–cAMP–PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase–cAMP–PKA axis in an immune rheostat-like fashion.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":64.8,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.
{"title":"Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.","authors":"Ke Lai, Iva Pritišanac, Zhen-Qi Liu, Han-Wei Liu, Li-Na Gong, Ming-Xian Li, Jian-Fei Lu, Xin Qi, Tian-Le Xu, Julie Forman-Kay, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin","doi":"10.1038/s41586-024-07684-7","DOIUrl":"https://doi.org/10.1038/s41586-024-07684-7","url":null,"abstract":"<p><p>Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke<sup>1,2</sup>, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms<sup>3-7</sup>. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke<sup>4</sup>. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels<sup>4-7</sup>. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/d41586-024-02285-w
Space scientist who took humanity on a tour of the Solar System and beyond, in a journey of discovery like no other.
他是一位太空科学家,他带领人类在太阳系内外进行了一次无与伦比的探索之旅。
{"title":"Edward C. Stone obituary: physicist who guided Voyager probes to interstellar space","authors":"","doi":"10.1038/d41586-024-02285-w","DOIUrl":"https://doi.org/10.1038/d41586-024-02285-w","url":null,"abstract":"Space scientist who took humanity on a tour of the Solar System and beyond, in a journey of discovery like no other.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":64.8,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1038/d41586-024-02125-x
Judith Goncalves, Scott J Dixon
{"title":"Waves of ferroptotic cell death sculpt embryonic tissue.","authors":"Judith Goncalves, Scott J Dixon","doi":"10.1038/d41586-024-02125-x","DOIUrl":"https://doi.org/10.1038/d41586-024-02125-x","url":null,"abstract":"","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}