{"title":"Deep-learning-based virtual screening of antibacterial compounds.","authors":"Gabriele Scalia,Steven T Rutherford,Ziqing Lu,Kerry R Buchholz,Nicholas Skelton,Kangway Chuang,Nathaniel Diamant,Jan-Christian Hütter,Jerome-Maxim Luescher,Anh Miu,Jeff Blaney,Leo Gendelev,Elizabeth Skippington,Greg Zynda,Nia Dickson,Micha Koziarski,Yoshua Bengio,Aviv Regev,Man-Wah Tan,Tommaso Biancalani","doi":"10.1038/s41587-025-02814-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02814-6","url":null,"abstract":"The increase in multidrug-resistant bacteria underscores an urgent need for additional antibiotics. Here, we integrate small-molecule high-throughput screening with a deep-learning-based virtual screening approach to uncover new antibacterial compounds. We screen ~2 million small molecules against a sensitized Escherichia coli strain, yielding thousands of hits. We use these data to train a deep learning model, GNEprop, to predict antibacterial activity, retrospectively validating robustness with respect to out-of-distribution generalization and activity cliff prediction. Virtual screening of over 1.4 billion synthetically accessible compounds identifies potential candidates, of which 82 exhibit antibacterial activity on the same strain, illustrating a 90-fold improved hit rate over the high-throughput screening experiment used for training. Many newly identified compounds exhibit high dissimilarity to known antibiotics, potency beyond the training bacterial strain and selectivity. Biological characterization identifies specific, validated targets, indicating promising avenues for further exploration in antibiotic discovery.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"77 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357634","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}
Yumeng Zhang,Jiangning Song,Cesar de la Fuente-Nunez
{"title":"Deep learning speeds the search for new antibiotic scaffolds.","authors":"Yumeng Zhang,Jiangning Song,Cesar de la Fuente-Nunez","doi":"10.1038/s41587-025-02806-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02806-6","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"68 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357636","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":"Democratizing protein language model training, sharing and collaboration.","authors":"Jin Su,Zhikai Li,Tianli Tao,Chenchen Han,Yan He,Fengyuan Dai,Qingyan Yuan,Yuan Gao,Tong Si,Xuting Zhang,Yuyang Zhou,Junjie Shan,Xibin Zhou,Xing Chang,Shiyu Jiang,Dacheng Ma, ,Martin Steinegger,Sergey Ovchinnikov,Fajie Yuan","doi":"10.1038/s41587-025-02859-7","DOIUrl":"https://doi.org/10.1038/s41587-025-02859-7","url":null,"abstract":"Training and deploying large-scale protein language models typically requires deep machine learning expertise-a barrier for researchers outside this field. SaprotHub overcomes this challenge by offering an intuitive platform that facilitates training and prediction as well as storage and sharing of models. Here we provide the ColabSaprot framework built on Google Colab, which potentially powers hundreds of protein training and prediction applications, enabling researchers to collaboratively build and share customized models.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"160 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357635","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":"Long-term imaging of cell divisions in human preimplantation embryos.","authors":"Corentin Mollier,Jean-Léon Maître","doi":"10.1038/s41587-025-02841-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02841-3","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"2 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351562","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}
Jesse D Buffington, Hung-Che Kuo, Kuang Hu, You-Chiun Chang, Kamyab Javanmardi, Brittney Voigt, Yi-Ru Li, Mary E Little, Sravan K Devanathan, Blerta Xhemalçe, Ryan S Gray, Ilya J Finkelstein
{"title":"Discovery and engineering of retrons for precise genome editing.","authors":"Jesse D Buffington, Hung-Che Kuo, Kuang Hu, You-Chiun Chang, Kamyab Javanmardi, Brittney Voigt, Yi-Ru Li, Mary E Little, Sravan K Devanathan, Blerta Xhemalçe, Ryan S Gray, Ilya J Finkelstein","doi":"10.1038/s41587-025-02879-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02879-3","url":null,"abstract":"<p><p>Retrons can produce multicopy single-stranded DNA in cells through self-primed reverse transcription. However, their potential for inserting genetic cargos in eukaryotes remains largely unexplored. Here we report the discovery and engineering of highly efficient retron-based gene editors for mammalian cells and vertebrates. Through bioinformatic analysis of metagenomic data and functional screening, we identify retron reverse transcriptases that are highly active in mammalian cells. Rational design further improves the editing efficiency to levels comparable with conventional single-stranded oligodeoxynucleotide donors but from a genetically encoded cassette. Retron editors exhibit robust activity with Cas12a nuclease and Cas9 nickase, expanding the genomic target scope and bypassing the need for a DNA double-stranded break. Using a rationally engineered retron editor, we incorporate a split GFP epitope tag for live-cell imaging. Lastly, we develop an all-RNA delivery strategy to enable DNA-free gene editing in cells and vertebrate embryos. This work establishes retron editors as a versatile and efficient tool for precise gene editing.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":41.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355372","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}
Fang Xie,Bingkang Zhao,Songxiang Xu,Zehua Wang,James J Moon,Lana X Garmire
{"title":"Overcoming barriers to the wide adoption of single-cell large language models in biomedical research.","authors":"Fang Xie,Bingkang Zhao,Songxiang Xu,Zehua Wang,James J Moon,Lana X Garmire","doi":"10.1038/s41587-025-02846-y","DOIUrl":"https://doi.org/10.1038/s41587-025-02846-y","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"109 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351561","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}
Benjamin B Larsen, Ofer Kimchi, Owen R S Dunkley, Maaike S Grimm, Jurre Y Siegers, Yujia Huang, Venu G Vandavasi, Long T Nguyen, Caitlin H Lamb, Irina Aranovich, Dirk Eggink, Adam Meijer, Hamid Jalal, Daniel A Notterman, Erik A Karlsson, Aartjan J W Te Velthuis, Cameron Myhrvold
{"title":"RNA structure modulates Cas13 activity and enables mismatch detection.","authors":"Benjamin B Larsen, Ofer Kimchi, Owen R S Dunkley, Maaike S Grimm, Jurre Y Siegers, Yujia Huang, Venu G Vandavasi, Long T Nguyen, Caitlin H Lamb, Irina Aranovich, Dirk Eggink, Adam Meijer, Hamid Jalal, Daniel A Notterman, Erik A Karlsson, Aartjan J W Te Velthuis, Cameron Myhrvold","doi":"10.1038/s41587-025-02868-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02868-6","url":null,"abstract":"<p><p>Cas13 is activated by the hybridization of a CRISPR RNA to a complementary single-stranded RNA protospacer in a target RNA. While Cas13 is not activated by double-stranded RNA in vitro, it robustly targets RNA in cellular environments where RNAs are highly structured. The mechanism by which Cas13 targets structured RNAs remains unknown. Here, we systematically probe the effects of secondary structure on Cas13. We find that secondary structure in the protospacer and 3' to it inhibits Cas13 activity and quantitatively explains the former effect through a strand displacement framework. We then harness strand displacement to generate an 'occluded' Cas13, which enhances mismatch discrimination up to 50-fold and enables sequence-agnostic mutation identification at low (<1%) allele frequencies. Using occluded Cas13, we identify human-adaptive mutations in SARS-CoV-2 and human and avian influenza A viruses, as well as oncogenic mutations in KRAS. Our work leverages improved mechanistic understanding of Cas13 to expand the scope of RNA diagnostics and enable structure-informed Cas13 approaches.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":41.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355328","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}
Marshall S Padilla,Sarah J Shepherd,Andrew R Hanna,Martin Kurnik,Xujun Zhang,Michelle Chen,James Byrnes,Ryann A Joseph,Hannah M Yamagata,Adele S Ricciardi,Kaitlin Mrksich,David Issadore,Kushol Gupta,Michael J Mitchell
{"title":"Elucidating lipid nanoparticle properties and structure through biophysical analyses.","authors":"Marshall S Padilla,Sarah J Shepherd,Andrew R Hanna,Martin Kurnik,Xujun Zhang,Michelle Chen,James Byrnes,Ryann A Joseph,Hannah M Yamagata,Adele S Ricciardi,Kaitlin Mrksich,David Issadore,Kushol Gupta,Michael J Mitchell","doi":"10.1038/s41587-025-02855-x","DOIUrl":"https://doi.org/10.1038/s41587-025-02855-x","url":null,"abstract":"Designing lipid nanoparticle (LNP) delivery systems with specific targeting, potency and minimal side effects is crucial for their clinical use. However, traditional characterization methods, such as dynamic light scattering, cannot accurately quantify physicochemical properties of LNPs and how these are influenced by the lipid composition and mixing method. Here, we structurally characterize polydisperse LNP formulations by applying emerging solution-based biophysical methods that have higher resolution and provide biophysical data beyond size and polydispersity. These techniques include sedimentation velocity analytical ultracentrifugation, field-flow fractionation followed by multiangle light scattering and size-exclusion chromatography in line with synchrotron small-angle X-ray scattering. We show that LNPs have intrinsic polydispersity in size, RNA loading and shape, which depend on both the formulation technique and the lipid composition. Lastly, we predict LNP transfection in vitro and in vivo by examining the relationship between mRNA translation and physicochemical characteristics. Solution-based biophysical methods will be essential for determining LNP structure-function relationships, facilitating the creation of new design rules for LNPs.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"105 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351559","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}
Ahmed Abdelbaki,Afshan McCarthy,Anita Karsa,Leila Muresan,Kay Elder,Athanasios Papathanasiou,Phil Snell,Leila Christie,Martin Wilding,Benjamin J Steventon,Kathy K Niakan
{"title":"Live imaging of late-stage preimplantation human embryos reveals de novo mitotic errors.","authors":"Ahmed Abdelbaki,Afshan McCarthy,Anita Karsa,Leila Muresan,Kay Elder,Athanasios Papathanasiou,Phil Snell,Leila Christie,Martin Wilding,Benjamin J Steventon,Kathy K Niakan","doi":"10.1038/s41587-025-02851-1","DOIUrl":"https://doi.org/10.1038/s41587-025-02851-1","url":null,"abstract":"Existing methods to image chromosome segregation errors are not suitable for studying human embryos at advanced preimplantation stages. As chromosomal errors are a leading cause of miscarriage and infertility, it remains unclear whether missegregation arises postfertilization. Here we optimize nuclear DNA labeling via messenger RNA electroporation and apply light-sheet live imaging to reveal chromosome segregation errors immediately before implantation. We show that embryos at advanced preimplantation stages display missegregation, including multipolar spindle formation, lagging chromosomes, misalignment and mitotic slippage. Most lagging chromosomes are passively inherited rather than reincorporated. To trace individual nuclei, we developed an open-source, semi-automated segmentation method using a customized deep learning model optimized for variability in embryo size, shape and signal. With this approach, we find most labeled cells remain externally positioned, consistent with placental rather than inner cell mass fate. Our findings raise questions about clinical uses of preimplantation genetic testing for aneuploidy, while providing broadly applicable imaging and segmentation methods for studying diverse cellular structures in human embryos.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"20 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351560","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}
Aidan C Daly, Francesco Cambuli, Tarmo Äijö, Britta Lötstedt, Nemanja Despot Marjanovic, Sara Fernandez, Olena Kuksenko, Matthew Smith-Erb, Daniel Domovic, Nicholas Van Wittenberghe, Eugene Drokhlyansky, Gabriel K Griffin, Hemali Phatnani, Richard Bonneau, Aviv Regev, Sanja Vickovic
{"title":"Tissue and cellular spatiotemporal dynamics in colon aging.","authors":"Aidan C Daly, Francesco Cambuli, Tarmo Äijö, Britta Lötstedt, Nemanja Despot Marjanovic, Sara Fernandez, Olena Kuksenko, Matthew Smith-Erb, Daniel Domovic, Nicholas Van Wittenberghe, Eugene Drokhlyansky, Gabriel K Griffin, Hemali Phatnani, Richard Bonneau, Aviv Regev, Sanja Vickovic","doi":"10.1038/s41587-025-02830-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02830-6","url":null,"abstract":"<p><p>Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects but many of the underlying molecular cues remain unclear. Here, we build a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing ~1,500 mouse gut tissues profiled by spatial transcriptomics and ~400,000 single nucleus RNA-sequencing profiles. We develop a computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region and sex by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identify cellular and molecular gradients along the adult colonic tract and across the main crypt axis and multicellular programs associated with aging in the large intestine. Our multimodal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":41.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346269","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}
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