Nature MethodsPub Date : 2025-07-31DOI: 10.1038/s41592-025-02725-z
{"title":"Learning the language of biological interactions.","authors":"","doi":"10.1038/s41592-025-02725-z","DOIUrl":"https://doi.org/10.1038/s41592-025-02725-z","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":32.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760539","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}
Nature MethodsPub Date : 2025-07-28DOI: 10.1038/s41592-025-02748-6
Zhizheng Wang, Qiao Jin, Chih-Hsuan Wei, Shubo Tian, Po-Ting Lai, Qingqing Zhu, Chi-Ping Day, Christina Ross, Robert Leaman, Zhiyong Lu
{"title":"GeneAgent: self-verification language agent for gene-set analysis using domain databases.","authors":"Zhizheng Wang, Qiao Jin, Chih-Hsuan Wei, Shubo Tian, Po-Ting Lai, Qingqing Zhu, Chi-Ping Day, Christina Ross, Robert Leaman, Zhiyong Lu","doi":"10.1038/s41592-025-02748-6","DOIUrl":"https://doi.org/10.1038/s41592-025-02748-6","url":null,"abstract":"<p><p>Gene-set analysis seeks to identify the biological mechanisms underlying groups of genes with shared functions. Large language models (LLMs) have recently shown promise in generating functional descriptions for input gene sets but may produce factually incorrect statements, commonly referred to as hallucinations in LLMs. Here we present GeneAgent, an LLM-based AI agent for gene-set analysis that reduces hallucinations by autonomously interacting with biological databases to verify its own output. Evaluation of 1,106 gene sets collected from different sources demonstrates that GeneAgent is consistently more accurate than GPT-4 by a significant margin. We further applied GeneAgent to seven novel gene sets derived from mouse B2905 melanoma cell lines. Expert review confirmed that GeneAgent produces more relevant and comprehensive functional descriptions than GPT-4, providing valuable insights into gene functions and expediting knowledge discovery.</p>","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":32.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732393","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}
Nature MethodsPub Date : 2025-07-28DOI: 10.1038/s41592-025-02723-1
Jane C Siwek, Alisa A Omelchenko, Prabal Chhibbar, Sanya Arshad, AnnaElaine Rosengart, Iliyan Nazarali, Akash Patel, Kiran Nazarali, Javad Rahimikollu, Jeremy S Tilstra, Mark J Shlomchik, David R Koes, Alok V Joglekar, Jishnu Das
{"title":"Sliding Window Interaction Grammar (SWING): a generalized interaction language model for peptide and protein interactions.","authors":"Jane C Siwek, Alisa A Omelchenko, Prabal Chhibbar, Sanya Arshad, AnnaElaine Rosengart, Iliyan Nazarali, Akash Patel, Kiran Nazarali, Javad Rahimikollu, Jeremy S Tilstra, Mark J Shlomchik, David R Koes, Alok V Joglekar, Jishnu Das","doi":"10.1038/s41592-025-02723-1","DOIUrl":"10.1038/s41592-025-02723-1","url":null,"abstract":"<p><p>Protein language models embed protein sequences for different tasks. However, these are suboptimal at learning the language of protein interactions. We developed an interaction language model (iLM), Sliding Window Interaction Grammar (SWING) that leverages differences in amino-acid properties to generate an interaction vocabulary. SWING successfully predicted both class I and class II peptide-major histocompatibility complex interactions. Furthermore, the class I SWING model could uniquely cross-predict class II interactions, a complex prediction task not attempted by existing methods. Using human class I and II data, SWING accurately predicted murine class II peptide-major histocompatibility interactions involving risk alleles in systemic lupus erythematosus and type 1 diabetes. SWING accurately predicted how variants can disrupt specific protein-protein interactions, based on sequence information alone. SWING outperformed passive uses of protein language model embeddings, demonstrating the value of the unique iLM architecture. Overall, SWING is a generalizable zero-shot iLM that learns the language of protein-protein interactions.</p>","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":32.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732394","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}
Nature MethodsPub Date : 2025-07-25DOI: 10.1038/s41592-025-02769-1
Gat Rauner, Piyush B Gupta, Charlotte Kuperwasser
{"title":"From 2D to 3D and beyond: the evolution and impact of in vitro tumor models in cancer research.","authors":"Gat Rauner, Piyush B Gupta, Charlotte Kuperwasser","doi":"10.1038/s41592-025-02769-1","DOIUrl":"https://doi.org/10.1038/s41592-025-02769-1","url":null,"abstract":"<p><p>In vitro tumor models are essential tools for cancer research, offering key insights into not only tumor biology but also therapeutic responses. The transition from traditional two-dimensional to three-dimensional organoid systems marks a paradigm shift in cancer modeling. Although two-dimensional models have been instrumental in elucidating fundamental molecular and genetic mechanisms, they fail to accurately replicate the intricate three-dimensional architecture and dynamic microenvironment characteristic of human tumors. Here we outline how advanced organoid technologies now enable more faithful recapitulation of tumor heterogeneity that better mimic native tissue mechanics and biochemistry. We discuss emerging methods, including air-liquid interface cultures, microfluidic tumor-on-a-chip devices and high-content imaging integrated with machine learning, which collectively address longstanding challenges such as matrix variability and the limited incorporation of immune and vascular elements. These innovations promise to enhance reproducibility and scalability while providing unprecedented insights into tumor biology, cancer progression and therapeutic strategies.</p>","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":36.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718214","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}
Nature MethodsPub Date : 2025-07-24DOI: 10.1038/s41592-025-02762-8
Fang-Cheng Yeh
{"title":"DSI Studio: an integrated tractography platform and fiber data hub for accelerating brain research.","authors":"Fang-Cheng Yeh","doi":"10.1038/s41592-025-02762-8","DOIUrl":"https://doi.org/10.1038/s41592-025-02762-8","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":36.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708294","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}
Nature MethodsPub Date : 2025-07-23DOI: 10.1038/s41592-025-02760-w
Luca Greco, George Luta, Martin Krzywinski, Naomi Altman
{"title":"Symmetric alternatives to the ordinary least squares regression.","authors":"Luca Greco, George Luta, Martin Krzywinski, Naomi Altman","doi":"10.1038/s41592-025-02760-w","DOIUrl":"https://doi.org/10.1038/s41592-025-02760-w","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":36.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699098","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}
Nature MethodsPub Date : 2025-07-21DOI: 10.1038/s41592-025-02768-2
Vivien Marx
{"title":"To do a PhD these days.","authors":"Vivien Marx","doi":"10.1038/s41592-025-02768-2","DOIUrl":"https://doi.org/10.1038/s41592-025-02768-2","url":null,"abstract":"","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":36.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682804","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":"Genetically encoded biosensor for monitoring spatiotemporal dynamics of CCR2 ligands in culture and in vivo.","authors":"Xian Xiao, Chenyu Wang, Xun Guo, Fengxue Xi, Qiuling Qian, Guoteng Liang, Ming Chen, Xiaoting Sun, Balint Szabo, Miao Jing, Kiryl D Piatkevich","doi":"10.1038/s41592-025-02742-y","DOIUrl":"https://doi.org/10.1038/s41592-025-02742-y","url":null,"abstract":"<p><p>Chemokines regulate immune cell migration in development, homeostasis and inflammation, but the precise spatiotemporal pattern of chemokine release in vivo remains elusive due to the constraints of existing detection methodologies. Here, we report the engineering and characterization of a genetically encoded green fluorescent chemokine sensor, named CRAFi-CCR2, which utilizes the CCR2 receptor as a sensing moiety. In astrocytes, hCRAFi-CCR2, derived from the human CCR2B receptor, exhibited ~300% increase in fluorescence in response to mCCL2, with nanomolar affinity (2.5 nM). Activation of hCRAFi-CCR2 did not affect downstream signaling pathways, such as calcium mobilization and receptor internalization. Using this sensor, we performed 17-20 h of real-time imaging to observe endogenous mCCL2 release under inflammatory conditions, both in cell culture and in mice. In mouse brain, we observed spatial heterogeneity of CCL2 signal response on a scale of about 20-50 µm, highlighting the complexity of the immune system's spatiotemporal signaling.</p>","PeriodicalId":18981,"journal":{"name":"Nature Methods","volume":" ","pages":""},"PeriodicalIF":36.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642984","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}