综合性期刊最新文献

{"title":"Nickase fidelity drives EvolvR-mediated diversification in mammalian cells","authors":"Juan E. Hurtado, Adam J. Schieferecke, Shakked O. Halperin, John Guan, Dylan Aidlen, David V. Schaffer, John E. Dueber","doi":"10.1038/s41467-025-58414-0","DOIUrl":"https://doi.org/10.1038/s41467-025-58414-0","url":null,"abstract":"<p>In vivo genetic diversifiers have previously enabled efficient searches of genetic variant fitness landscapes for continuous directed evolution. However, existing genomic diversification modalities for mammalian genomic loci exclusively rely on deaminases to generate transition mutations within target loci, forfeiting access to most missense mutations. Here, we engineer CRISPR-guided error-prone DNA polymerases (EvolvR) to diversify all four nucleotides within genomic loci in mammalian cells. We demonstrate that EvolvR generates both transition and transversion mutations throughout a mutation window of at least 40 bp and implement EvolvR to evolve previously unreported drug-resistant <i>MAP2K1</i> variants via substitutions not achievable with deaminases. Moreover, we discover that the nickase’s mismatch tolerance limits EvolvR’s mutation window and substitution biases in a gRNA-specific fashion. To compensate for gRNA-to-gRNA variability in mutagenesis, we maximize the number of gRNA target sequences by incorporating a PAM-flexible nickase into EvolvR. Finally, we find a strong correlation between predicted free energy changes underlying R-loop formation and EvolvR’s performance using a given gRNA. The EvolvR system diversifies all four nucleotides to enable the evolution of mammalian cells, while nuclease and gRNA-specific properties underlying nickase fidelity can be engineered to further enhance EvolvR’s mutation rates.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"48 5 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849720","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":"Multivariate covalent organic frameworks with tailored electrostatic potential promote nitrate electroreduction to ammonia in acid","authors":"Qiyang Cheng, Sisi Liu, Yanzheng He, Mengfan Wang, Haoqing Ji, Yunfei Huan, Tao Qian, Chenglin Yan, Jianmei Lu","doi":"10.1038/s41467-025-59052-2","DOIUrl":"https://doi.org/10.1038/s41467-025-59052-2","url":null,"abstract":"<p>The direct synthesis of ammonia from nitrate (NO₃^–) reduction in acid is a promising approach for industrialization. However, the difficulty arises from the intense competition with the inevitable hydrogen evolution reaction, which is favoured due to the overwhelming protons (H⁺). Here, we systematically explore and rationally optimize the microenvironment using multivariate covalent organic frameworks (COFs) as catalyst adlayers to promote the nitrate-to-ammonia conversion in acid. With the application of tailored positive electrostatic potential generated over the multivariate COFs, both the mass transfer of NO₃^– and H⁺ are regulated via appropriate electrostatic interactions, thus realizing the priority of NO₃RR with respect to HER or NO₃^–-to-NO₂^–. As a result, an NH₃ yield rate of 11.01 mmol h^–1 mg^–1 and a corresponding Faradaic efficiency of 91.0% are attained, and solid NH₄Cl with a high purity of 96.2% is directly collected in acid; therefore, this method provides a practical approach for economically valorising wastewater into valuable ammonia.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"49 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849351","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":"Anion intercalation enables efficient and stable carboxylate upgrading via aqueous non-Kolbe electrolysis","authors":"Xinyan Zhang, Laihao Luo, Chunxiao Liu, Weiqing Xue, Yuan Ji, Donghao Zhao, Pengbo Liu, Xinran Feng, Jun Luo, Qiu Jiang, Tingting Zheng, Xu Li, Chuan Xia, Jie Zeng","doi":"10.1038/s41467-025-58924-x","DOIUrl":"https://doi.org/10.1038/s41467-025-58924-x","url":null,"abstract":"<p>Next-generation techniques for sustainable carboxylate production generate carboxylate salts as the primary outcome. To circumvent the costly conversion of carboxylate salts to acids, we demonstrate the aqueous (non-)Kolbe electrolysis process as an alternative strategy to generate downstream value-added chemicals. Upon revealing the irreversible oxidation-induced charge transfer inhibition on the graphite anode, we propose an anion intercalation strategy to mitigate the stability problem induced by the ever-increasing overpotential. In acetate decarboxylation, we observe a high Faradaic efficiency of ~95% for non-Kolbe products (methanol and methyl acetate) at wide current densities ranging from 0.05 to 1 A cm⁻² and long-term stability at current densities of 0.15 and 0.6 A cm⁻² for 130 and 35 h, respectively. We also extended this strategy for the upgrading of long-chain carboxylates such as propionate, butyrate, and succinate. Our work provides valuable guidance for carboxylate upgrading and extendable strategy for overcoming passivation challenges in catalysis.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"17 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849714","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":"A hollow TFG condensate spatially compartmentalizes the early secretory pathway","authors":"Savannah M. Bogus, William R. Wegeng, Miguel Ruiz, Sindy R. Chavez, Samantha N. Cheung, Khalid S. M. Noori, Ingrid R. Niesman, Andreas M. Ernst","doi":"10.1038/s41467-025-59118-1","DOIUrl":"https://doi.org/10.1038/s41467-025-59118-1","url":null,"abstract":"<p>In the early secretory pathway, endoplasmic reticulum (ER) and Golgi membranes form a nearly spherical interface. In this ribosome-excluding zone, bidirectional transport of cargo coincides with a spatial segregation of anterograde and retrograde carriers by an unknown mechanism. We show that at physiological conditions, the Trk-fused gene (TFG) self-organizes to form a hollow, anisotropic condensate that matches the dimensions of the ER–Golgi interface and is dynamically regulated across the cell cycle. Regularly spaced hydrophobic residues in TFG control the condensation mechanism and result in a porous condensate surface. We find that TFG condensates act as a molecular sieve capable of allowing access of anterograde coats (COPII) to the condensate interior while restricting retrograde coats (COPI). We propose that a hollow TFG condensate structures the ER–Golgi interface to create a diffusion-limited space for anterograde transport. We further propose that TFG condensates optimize membrane flux by insulating secretory carriers in their lumen from retrograde carriers outside TFG cages.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"64 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849344","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":"Mechanosensing antagonizes ethylene signaling to promote root gravitropism in rice","authors":"Han-Qing Wang, Xing-Yu Zhao, Zhong Tang, Xin-Yuan Huang, Peng Wang, Wenhua Zhang, Yunhui Zhang, Sheng Luan, Fang-Jie Zhao","doi":"10.1038/s41467-025-59047-z","DOIUrl":"https://doi.org/10.1038/s41467-025-59047-z","url":null,"abstract":"<p>Root gravitropism relies on gravity perception by the root cap and requires tightly regulated phytohormone signaling. Here, we isolate a rice mutant that displays root coiling in hydroponics but normal gravitropic growth in soil. We identify <i>COILING ROOT IN WATER 1</i> (<i>CRW1</i>) encoding an ETHYLENE-INSENSITIVE3 (EIN3)-BINDING F-BOX PROTEIN (OsEBF1) as the causative gene for the mutant phenotype. We show that the OsCRW1-EIN3 LIKE 1 and 2 (OsEIL1/2)-ETHYLENE RESPONSE FACTOR 82 (OsERF82) module controls the production of reactive oxygen species in the root tip, subsequently impacting root cap stability, polar localization of PIN-FORMED 2 (OsPIN2), symmetric distribution of auxin, and ultimately gravitropic growth of roots. The OsEIL1/2-OsERF82 ethylene signaling module is effectively impeded by applying gentle mechanical resistance to root tips, including growing in water-saturated paddy soil. We further show that mechanosensing-induced calcium signaling is required and sufficient for antagonizing the ethylene signaling pathway. This study has revealed previously unanticipated interplay among ethylene, auxin, and mechanosensing in the control of plant gravitropism.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"68 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849345","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":"Epithelial cell competition is promoted by signaling from immune cells","authors":"Yilun Zhu, Zeba Wunderlich, Arthur D. Lander","doi":"10.1038/s41467-025-59130-5","DOIUrl":"https://doi.org/10.1038/s41467-025-59130-5","url":null,"abstract":"<p>In epithelial tissues, juxtaposition of cells of different phenotypes can trigger cell competition, a process whereby one type of cell drives death and extrusion of another. During growth and homeostasis, cell competition is thought to serve a quality control function, eliminating cells that are “less fit”. Tissues may also attack and eliminate newly arising tumor cells, exploiting mechanisms shared with other instances of cell competition, but that differ, reportedly, in the involvement of the immune system. Whereas immune cells have been shown to play a direct role in killing tumor cells, this has not been observed in other cases of cell competition, suggesting that tissues recognize and handle cancer cells differently. Here, we challenge this view, showing that, in the fruit fly <i>Drosophila</i>, innate immune cells play similar roles in cell killing during classical cell competition as in eliminating tumors. These findings suggest that immune suppression of cancer may exploit the same mechanisms as are involved in promoting phenotypic uniformity among epithelial cells.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"41 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849350","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":"Climate change is projected to shrink phylogenetic endemism of Neotropical frogs","authors":"Gabriela Alves-Ferreira, Neander M. Heming, Daniela Talora, Timothy H. Keitt, Mirco Solé, Kelly R. Zamudio","doi":"10.1038/s41467-025-59036-2","DOIUrl":"https://doi.org/10.1038/s41467-025-59036-2","url":null,"abstract":"<p>Climate change is widely recognized as one of the main threats to biodiversity¹ and predicting its consequences is critical to conservation efforts. A wide range of studies have evaluated the effects of future climate using taxon-based metrics^3,4, but few studies to date have applied a phylogenetic approach to forecast these impacts. Here, we show that future climate change is expected to significantly modify not only species richness, but also phylogenetic diversity and phylogenetic endemism of Neotropical frogs. Our results show that by 2050, the ranges of 42.20% (<i>n</i> = 213) of species are projected to shrink and the range of 1.71% of species (<i>n</i> = 9) are projected to disappear. Furthermore, we find that areas of high SR and PD are not always congruent with areas of high PE. Our study highlights the projected impacts of climate change on Neotropical frog diversity and identifies target areas for conservation efforts that consider not just species numbers, but also distinct evolutionary histories.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"5 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849348","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":"The ectodomain sheddase ADAM10 restricts HIV-1 propagation and is counteracted by Nef","authors":"Balaji Olety, Yoshiko Usami, Paul Peters, Yuanfei Wu, Heinrich Göttlinger","doi":"10.1126/sciadv.adt1836","DOIUrl":"https://doi.org/10.1126/sciadv.adt1836","url":null,"abstract":"HIV-1 Nef enhances virus propagation by down-regulating CD4 and SERINC5. However, recent evidence points to the existence of an additional Nef-sensitive restriction mechanism. We now show that Nef suppresses the aberrant cleavage of HIV-1 gp41 by ADAM10, a virion-associated cellular ectodomain sheddase, and thus increases the amount of HIV-1 envelope glycoprotein (Env) on virions. Additionally, Nef inhibits the shedding of at least some cellular ADAM10 substrates, resulting in their accumulation on HIV-1 virions. Whereas Nef <jats:sup>+</jats:sup> HIV-1 replicated only marginally better in the absence of ADAM10, the propagation of Nef <jats:sup>−</jats:sup> HIV-1 was notably rescued in ADAM10 <jats:sup>−</jats:sup> T cell lines. Crucially, Nef <jats:sup>−</jats:sup> HIV-1 also benefited from the absence of ADAM10 in primary CD4 <jats:sup>+</jats:sup> T cells. Collectively, our results indicate that ADAM10 negatively affects both laboratory-adapted and primary HIV-1 strains by shedding the ectodomains of viral and cellular transmembrane proteins from virions and that Nef rescues virus replication by counteracting ADAM10.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"6 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847142","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":"Earth system instability amplified biogeochemical oscillations following the end-Permian mass extinction","authors":"Zi-Heng Li, Timothy M. Lenton, Fei-Fei Zhang, Zhong-Qiang Chen, Stuart J. Daines","doi":"10.1038/s41467-025-59038-0","DOIUrl":"https://doi.org/10.1038/s41467-025-59038-0","url":null,"abstract":"<p>After the end-Permian mass extinction, the Earth system underwent extreme ecological and environmental fluctuations, including high temperatures, recurrent oceanic anoxia, and carbon cycle oscillations as demonstrated by the geochemical isotope proxy records. However, the underlying mechanism behind these oscillations remains poorly understood. Here we propose that they were produced by a coupled oscillation mode of marine phosphorus (<b><i>P</i></b>) and atmosphere–ocean carbon (<b><i>A</i></b>), driven by nonlinear redox controls on marine phosphorus burial. Our modeling demonstrates that the initial emplacement of the Siberian Traps and the mass extinction (on land and in the ocean) directly led to an early Triassic greenhouse. More importantly, it homogenized the ocean floor redox condition towards anoxia, activating amplifying feedbacks and destabilizing the system. The internal dynamics of an unstable system—rather than recurrent volcanic shocks—triggered the periodic oscillations (limit cycles) of serial excursions in carbonate carbon and uranium isotopes during the early Triassic.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"108 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846960","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":"The pentameric chloride channel BEST1 is activated by extracellular GABA","authors":"Swati Pant, Stephanie W. Tam, Stephen B. Long","doi":"10.1073/pnas.2424474122","DOIUrl":"https://doi.org/10.1073/pnas.2424474122","url":null,"abstract":"Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter <jats:italic>γ</jats:italic> -aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA <jats:sub>B</jats:sub> G-protein-coupled receptors and the pentameric GABA <jats:sub>A</jats:sub> chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel’s extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel’s central gate. This same gate, “the neck,” is activated by intracellular [Ca <jats:sup>2+</jats:sup> ], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA <jats:sub>A</jats:sub> receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"28 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849632","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}