Nature最新文献

{"title":"A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein","authors":"Ellen Van Damme, Pravien Abeywickrema, Yanting Yin, Jiexiong Xie, Sofie Jacobs, Mandeep Kaur Mann, Jordi Doijen, Robyn Miller, Madison Piassek, Simone Marsili, Murali Subramanian, Leah Gottlieb, Rana Abdelnabi, Michiel Van Gool, Nick Van den Broeck, Ines De Pauw, Annick Diels, Peter Vermeulen, Koen Temmerman, Trevor Scobey, Melissa Mattocks, Alexandra Schäfer, Dirk Jochmans, Steven De Jonghe, Pieter Leyssen, Winston Chiu, Mayra Diosa Toro, Marleen Zwaagstra, Anouk A. Leijs, Heidi L. M. De Gruyter, Christophe Buyck, Klaas Van Den Heede, Frank Jacobs, Christel Van den Eynde, Laura Thijs, Valerie Raeymaekers, Seth Miller, Amanda Del Rosario, Johan Neyts, Danielle Peeters, Ralph S. Baric, Frank J. M. van Kuppeveld, Eric J. Snijder, Martijn J. van Hemert, Mario Monshouwer, Sujata Sharma, Ruxandra Draghia-Akli, Anil Koul, Marnix Van Loock","doi":"10.1038/s41586-025-08651-6","DOIUrl":"https://doi.org/10.1038/s41586-025-08651-6","url":null,"abstract":"<p>The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly^1,2. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log₁₀-transformed RNA copies and 50% tissue culture infective dose (TCID₅₀) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"59 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713303","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}

{"title":"Track gender ratios in research to keep countries, institutions and publishers accountable","authors":"","doi":"10.1038/d41586-025-00891-w","DOIUrl":"10.1038/d41586-025-00891-w","url":null,"abstract":"Nature Index data reveal how countries and fields differ in gender equity in research. Nature Index data reveal how countries and fields differ in gender equity in research.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"639 8056","pages":"838-838"},"PeriodicalIF":50.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/d41586-025-00891-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why is there more matter than antimatter? CERN result offers tantalizing new clue","authors":"","doi":"10.1038/d41586-025-00955-x","DOIUrl":"https://doi.org/10.1038/d41586-025-00955-x","url":null,"abstract":"For the first time, physicists have spotted a difference in the way matter and antimatter baryons decay, which could help to explain a major cosmic mystery.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"21 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703089","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}

{"title":"New lasso-shaped antibiotic kills drug-resistant bacteria","authors":"","doi":"10.1038/d41586-025-00961-z","DOIUrl":"https://doi.org/10.1038/d41586-025-00961-z","url":null,"abstract":"Hear the biggest stories from the world of science | 26 March 2025","PeriodicalId":18787,"journal":{"name":"Nature","volume":"14 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713085","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}

{"title":"Genome-wide CRISPR screen in human T cells reveals regulators of FOXP3","authors":"Kelvin Y. Chen, Tatsuya Kibayashi, Ambre Giguelay, Mayu Hata, Shunsuke Nakajima, Norihisa Mikami, Yusuke Takeshima, Kenji Ichiyama, Ryusuke Omiya, Leif S. Ludwig, Kunihiro Hattori, Shimon Sakaguchi","doi":"10.1038/s41586-025-08795-5","DOIUrl":"https://doi.org/10.1038/s41586-025-08795-5","url":null,"abstract":"<p>Regulatory T (T_reg) cells, which specifically express the master transcription factor FOXP3, have a pivotal role in maintaining immunological tolerance and homeostasis and have the potential to revolutionize cell therapies for autoimmune diseases^1,2,3. Although stimulation of naive CD4⁺ T cells in the presence of TGFβ and IL-2 can induce FOXP3⁺ T_reg cells in vitro (iT_reg cells), the resulting cells are often unstable and have thus far hampered translational efforts^4,5,6. A systematic approach towards understanding the regulatory networks that dictate T_reg differentiation could lead to more effective iT_reg cell-based therapies. Here we performed a genome-wide CRISPR loss-of-function screen to catalogue gene regulatory determinants of FOXP3 induction in primary human T cells and characterized their effects at single-cell resolution using Perturb-icCITE-seq. We identify the RBPJ–NCOR repressor complex as a novel, context-specific negative regulator of FOXP3 expression. RBPJ-targeted knockout enhanced iT_reg differentiation and function, independent of canonical Notch signalling. Repeated cytokine and T cell receptor signalling stimulation in vitro revealed that RBPJ-deficient iT_reg cells exhibit increased phenotypic stability compared with control cells through DNA demethylation of the <i>FOXP3</i> enhancer CNS2, reinforcing FOXP3 expression. Conversely, overexpression of RBPJ potently suppressed FOXP3 induction through direct modulation of <i>FOXP3</i> histone acetylation by HDAC3. Finally, RBPJ-ablated human iT_reg cells more effectively suppressed xenogeneic graft-versus-host disease than control iT_reg cells in a humanized mouse model. Together, our findings reveal novel regulators of FOXP3 and point towards new avenues to improve the efficacy of adoptive cell therapy for autoimmune disease.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"12 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713189","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}

{"title":"Empower families to lead the design of their ageing loved ones’ health care","authors":"Shahmir H. Ali","doi":"10.1038/d41586-025-00893-8","DOIUrl":"10.1038/d41586-025-00893-8","url":null,"abstract":"Rather than assuming that relatives of older people will step up to fill systemic gaps in health care, communities need research and policies that align with families’ existing routines. Rather than assuming that relatives of older people will step up to fill systemic gaps in health care, communities need research and policies that align with families’ existing routines.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"639 8056","pages":"840-840"},"PeriodicalIF":50.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/d41586-025-00893-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalytic allylation of native hexoses and pentoses in water with indium","authors":"Tapas Adak,&nbsp;Travis Menard,&nbsp;Matthew Albritton,&nbsp;Federico Florit,&nbsp;Martin D. Burke,&nbsp;Klavs F. Jensen,&nbsp;Scott E. Denmark","doi":"10.1038/s41586-025-08690-z","DOIUrl":"10.1038/s41586-025-08690-z","url":null,"abstract":"Carbohydrates are an abundant, inexpensive and renewable biomass feedstock that could be a cornerstone for sustainable chemical manufacturing, but scalable and environmentally friendly methods that leverage these feedstocks are lacking. For example, 1-allyl sorbitol is the foundational building block for the polypropylene clarifying agent Millad NX 8000, which is produced on the&nbsp;multi-metric&nbsp;ton scale annually, but the manufacturing process at present requires superstoichiometric amounts of tin1,2. The NX 8000 additives dominate about 80% of the global clarified polypropylene market3 and are used in concentrations of 0.01–1% during polypropylene production to improve its transparency and resistance to high temperatures, translating&nbsp;to 300–30,000 metric&nbsp;tons annually. The market volume of polypropylene in 2022 was approximately 79.01 million metric tons (MMT), with demand expected to rise by nearly 33% to 105 MMT by 2030 (ref. 4). The cost and sustainability benefits of clarified polypropylene are driving this demand, necessitating more clarifying agents5. Here we report a high-yielding allylation of unprotected carbohydrates in water using a catalytic amount of indium metal and either allylboronic acid or the pinacol ester (allylBpin) as donors. Aldohexoses, aminohexoses, ketohexoses and aldopentoses are all allylated in high yield under mild conditions and the indium metal is recoverable and reusable with no loss of catalytic activity. Leveraging these features, this process was translated to a scalable continuous synthesis of 1-allyl sorbitol in flow6 with high yield and productivity through Bayesian optimization of reaction parameters. A longstanding challenge in organic synthesis—the catalytic allylation of unprotected saccharides in an aqueous medium, a key step for the synthesis of Millad NX 8000—is achieved through a simple and efficient indium-catalysed nucleophilic allylation using a three-carbon-unit allylboronic acid or its pinacol ester.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"640 8057","pages":"94-99"},"PeriodicalIF":50.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713185","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}

{"title":"Phosphate-enabled mechanochemical PFAS destruction for fluoride reuse","authors":"Long Yang,&nbsp;Zijun Chen,&nbsp;Christopher A. Goult,&nbsp;Thomas Schlatzer,&nbsp;Robert S. Paton,&nbsp;Véronique Gouverneur","doi":"10.1038/s41586-025-08698-5","DOIUrl":"10.1038/s41586-025-08698-5","url":null,"abstract":"Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent, bioaccumulative and anthropogenic pollutants that have attracted the attention of the public and private sectors because of their adverse impact on human health1. Although various technologies have been deployed to degrade PFASs with a focus on non-polymeric functionalized compounds (perfluorooctanoic acid and perfluorooctanesulfonic acid)2–4, a general PFAS destruction method coupled with fluorine recovery for upcycling is highly desirable. Here we disclose a protocol that converts multiple classes of PFAS, including the fluoroplastics polytetrafluoroethylene and polyvinylidene fluoride, into high-value fluorochemicals. To achieve this, PFASs were reacted with potassium phosphate salts under solvent-free mechanochemical conditions, a mineralization process enabling fluorine recovery as KF and K2PO3F for fluorination chemistry. The phosphate salts can be recovered for reuse, implying no detrimental impact on the phosphorus cycle. Therefore, PFASs are not only destructible but can now contribute to a sustainable circular fluorine economy. This study highlights a protocol that converts various perfluoroalkyl and polyfluoroalkyl substances&nbsp;(PFASs), including fluoroplastics, into valuable fluorochemicals through a solvent-free mechanochemical process, thereby enabling fluorine recovery and contributing to a sustainable circular fluorine economy.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"640 8057","pages":"100-106"},"PeriodicalIF":50.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41586-025-08698-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STING agonist-based ER-targeting molecules boost antigen cross-presentation","authors":"Xiafeng Wang, Zhangping Huang, Lixiao Xing, Liru Shang, Juan Jiang, Caiguanxi Deng, Wei Yu, Lin Peng, Hao Yang, Xiaohong Zheng, Xinmin Liu, Haolan Yang, Yixin Chen, Yongyong Li, Jing Liu, Xi Xie, Wei Xu, Xiaojun Xia, Zezhong Liu, Wanli Liu, Shibo Jiang, Yingyue Zeng, Lu Lu, Ji Wang","doi":"10.1038/s41586-025-08758-w","DOIUrl":"https://doi.org/10.1038/s41586-025-08758-w","url":null,"abstract":"<p>CD8⁺ T cell immune responses are critical for combating infectious diseases and tumours^1,2,3. Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8⁺ T cell responses⁴. Current efforts have focused on antigen delivery at the tissue and cellular levels, whereas subcellular delivery has been limited to facilitating antigen escape from lysosomes into the cytosol. In the absence of a small-sized high-affinity ER-targeting molecule, the importance of the ‘last mile’ from the cytosol to the ER remains elusive. Here we developed stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), which effectively deliver antigens to the ER and cluster key machinery in cross-presentation to form microreactors by folding the ER membrane. Conjugation of SABER to various antigens substantially enhances the induction of CD8⁺ T cell immune responses to tumour neoantigens and conserved viral epitopes, far exceeding that achieved by mixtures of antigens with STING agonists or conventional adjuvants. SABER also retains a potent adjuvant effect, effectively enhancing the ability of a SARS-CoV-2 subunit vaccine to induce broadly neutralizing antibodies. This study provides a high-affinity ER-targeting delivery system and vaccine adjuvant, demonstrating that precise subcellular delivery targeting the last mile of cross-presentation can lead to a qualitative leap.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"183 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713304","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}

{"title":"Some assembly required","authors":"","doi":"10.1038/d41586-025-00922-6","DOIUrl":"https://doi.org/10.1038/d41586-025-00922-6","url":null,"abstract":"The personal touch.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"29 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703352","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}