Nature Methods最新文献

{"title":"Precise DNA base editing using ContactSeek","authors":"Arunima Singh","doi":"10.1038/s41592-026-03230-7","DOIUrl":"10.1038/s41592-026-03230-7","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1679-1679"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein nanocages empower RNA profiling","authors":"Aparna Anantharaman","doi":"10.1038/s41592-026-03232-5","DOIUrl":"10.1038/s41592-026-03232-5","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1680-1680"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale single-molecule analysis of tau proteoforms","authors":"James Joly, Vivekananda Budamagunta, Zhengjian Zhang, Brittany Nortman, Maryam Jouzi, Rajat Bhatnagar, Jarrett D. Egertson, Michael E. Flaster, Rob Grothe, Sanjib Guha, Kota Kaneshige, Kevin McVey, Nicholas Nelson, Rukshan T. Perera, Steven J. Tan, Tuan Trinh, David Arnott, Joanna Lipka, Nikhil J. Pandya, Lionel Rougé, Timothy J. Wendorff, Donald S. Kirkpatrick, Alexis Rohou, David C. Butler, Steven Lotz, Ana Forton, Emily R. Sartori, Jessica E. Schwarz, Phillip S. Brereton, Kevin Chen, Michael A. Darcy, Hamid R. Golnabi, Ross Hartley, Pierre F. Indermuhl, Christina E. Inman, Kevin M. Jin, Stanislav Katsyuk, Rajesh Kota, Bryant Lowry, Jonathan C. Menger, Denise A. Miller, Maureen R. Newman, Adedeji Ogunyemi, Julia K. Robinson, Noah Steiner, Juanfeng Sun, Scott M. Tabakman, Lisen Wang, Zhiqiang Wang, Sheri K. Wilcox, Nautilus Biotechnology, Gregory T. Kapp, Sujal Patel, Sally Temple, Taylor Bertucci, Joel Blanchard, Andreas F. R. Huhmer, Subramanian V. Sankar, Kara Juneau, Parag Mallick","doi":"10.1038/s41592-026-03188-6","DOIUrl":"10.1038/s41592-026-03188-6","url":null,"abstract":"Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key protein in neurodegenerative diseases, using 12 site-specific antibodies. The tau proteoform assay demonstrates high sensitivity (detecting proteoforms at 0.1% abundance), high reproducibility (median coefficient of variation <5.5%) and broad dynamic range (>3 orders of magnitude), outperforming conventional techniques in resolving closely related proteoform groups. Analysis of relevant biological samples, including organoids, mouse brains and human Alzheimer’s disease samples, revealed 130 distinct tau proteoform groups with as many as six phosphorylation events. The nonrandom distribution of these phosphorylation events suggests ordered and site-specific modification processes rather than random, stochastic accumulation. Iterative Mapping provides insights into proteoform complexity at the single-molecule level, with implications for understanding protein regulation in neurodegenerative diseases and beyond. Iterative Mapping of proteoforms enables large-scale measurement of intact proteoforms with single-molecule resolution. The approach is demonstrated here by quantifying tau proteoform groups across control samples of known composition, model systems used in tauopathy research, and human-derived brain tissue samples.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1786-1797"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capturing protein communication","authors":"Madhura Mukhopadhyay","doi":"10.1038/s41592-026-03229-0","DOIUrl":"10.1038/s41592-026-03229-0","url":null,"abstract":"Sprox-seq enables simultaneous in situ measurement of protein and mRNA abundance.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1678-1678"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embedding AI in biology — part 2","authors":"","doi":"10.1038/s41592-026-03234-3","DOIUrl":"10.1038/s41592-026-03234-3","url":null,"abstract":"Artificial intelligence is rapidly changing the landscape of how biological data are acquired and analyzed. Almost no corner of biological research has been left untouched.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1659-1659"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41592-026-03234-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Designer binding for multiplexed molecular imaging","authors":"Rosie Bunton-Stasyshyn","doi":"10.1038/s41592-026-03233-4","DOIUrl":"10.1038/s41592-026-03233-4","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1680-1680"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial isoform sequencing at single-cell resolution reveals cell-type-specific spatial isoform variability in multiple brain cell types","authors":"Lieke Michielsen, Andrey D. Prjibelski, Careen Foord, Yelizaveta Spiegelman, Taewoo Kim, Wen Hu, Julien Jarroux, Justine Hsu, Rebecca Pfeil, Xinyi Zhang, Li Gan, Alexandru I. Tomescu, Iman Hajirasouliha, Hagen U. Tilgner","doi":"10.1038/s41592-026-03211-w","DOIUrl":"10.1038/s41592-026-03211-w","url":null,"abstract":"Spatial long-read technologies are increasingly common but usually lack single-cell resolution. This leaves unanswered whether spatially variable isoforms reflect variability within one cell type or differences in region-specific cell-type composition. Here, we developed Spl-ISO-Seq2 (500-nm resolution) and accompanying software, Spl-IsoQuant-2 and Spl-IsoFind, enabling long-read sequencing of >450 million barcodes versus 80,000 previously. Applying this to the adult mouse brain, we compared differential isoform abundance between known regions and spatial isoform patterns independent of predefined regions. Both identified overlapping hits, for example, Rps24 in oligodendrocytes. For known Snap25 spatial isoform variation, we show that it occurs in excitatory neurons. The region-agnostic approach also uncovered patterns missed by region-based comparisons, for example, for Ighm. Notably, many spatial isoform signals are not driven by cell-type composition alone. Finally, our software is applicable to many spatial and single-cell protocols, demonstrating reproducibility between platforms (for example, Visium HD/Stereo-seq). Overall, our experimental/analytical methods enable a submicron-resolution-isoform view and open avenues for spatial isoform disease research. Spl-ISO-Seq2, Spl-IsoQuant-2 and Spl-IsoFind enable isoform sequencing, barcode calling of >450 million barcodes, and spatially variable isoform detection with high spatial resolution as demonstrated on mouse brain slices.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1869-1881"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41592-026-03211-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing distinctive traits of individual proteins","authors":"Albert J. R. Heck","doi":"10.1038/s41592-026-03209-4","DOIUrl":"10.1038/s41592-026-03209-4","url":null,"abstract":"Tau: distinguishing the good, the bad and the ugly.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 9","pages":"1686-1688"},"PeriodicalIF":28.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards high-quality large-scale T cell receptor antigen specificity data: challenges and promises","authors":"Mikhail Shugay, Daniil V. Luppov, Elizaveta K. Vlasova, Dmitry M. Chudakov","doi":"10.1038/s41592-026-03227-2","DOIUrl":"10.1038/s41592-026-03227-2","url":null,"abstract":"Antigen recognition by T cells through their highly diverse T cell receptors (TCRs) is central to adaptive immunity, and recent high‑throughput methods and databases have greatly expanded the availability of TCR–antigen specificity data. However, much of this information is noisy or weakly validated. We explore the field’s main bottlenecks, which are data quality rather than quantity, motivating rigorous experimental validation, statistical filtering and multimodal AI approaches to derive high-confidence TCR specificity records.","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":"23 10","pages":"1932-1937"},"PeriodicalIF":28.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human stewardship in the age of organoids.","authors":"Pradipta Ghosh, Sara Gianella, Courtney Tindle, Karine Dubé","doi":"10.1038/s41592-026-03228-1","DOIUrl":"10.1038/s41592-026-03228-1","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":28.3,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}