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A trimodal protein language model enables advanced protein searches. 三模态蛋白质语言模型使高级蛋白质搜索成为可能。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-10-02 DOI: 10.1038/s41587-025-02836-0
Jin Su,Yan He,Shiyang You,Shiyu Jiang,Xibin Zhou,Xuting Zhang,Yuxuan Wang,Xining Su,Igor Tolstoy,Xing Chang,Hongyuan Lu,Fajie Yuan
{"title":"A trimodal protein language model enables advanced protein searches.","authors":"Jin Su,Yan He,Shiyang You,Shiyu Jiang,Xibin Zhou,Xuting Zhang,Yuxuan Wang,Xining Su,Igor Tolstoy,Xing Chang,Hongyuan Lu,Fajie Yuan","doi":"10.1038/s41587-025-02836-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02836-0","url":null,"abstract":"ProTrek unifies protein sequence, structure and natural language function in a trimodal language model through contrastive learning, enabling comprehensive searches between any two modalities, including within modality. ProTrek surpasses current alignment tools (for example, Foldseek and MMseqs2) in speed and accuracy for identifying functionally related proteins. Computational and wet-lab experimental validations show that the ProTrek server ( www.search-protrek.com ), with precomputed embeddings for over 5 billion proteins, efficiently processes and analyzes large-scale protein repositories.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"23 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209180","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}
引用次数: 0
Discovery and protein language model-guided design of hyperactive transposases. 多活性转座酶的发现和蛋白质语言模型引导的设计。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-10-02 DOI: 10.1038/s41587-025-02816-4
Dimitrije Ivančić,Alejandro Agudelo,Jonathan Lindstrom-Vautrin,Jessica Jaraba-Wallace,Maria Gallo,Ravi Das,Alejandro Ragel,Jorge Herrero-Vicente,Irene Higueras,Federico Billeci,Marta Sanvicente-García,Paolo Petazzi,Noelia Ferruz,Avencia Sánchez-Mejías,Marc Güell
{"title":"Discovery and protein language model-guided design of hyperactive transposases.","authors":"Dimitrije Ivančić,Alejandro Agudelo,Jonathan Lindstrom-Vautrin,Jessica Jaraba-Wallace,Maria Gallo,Ravi Das,Alejandro Ragel,Jorge Herrero-Vicente,Irene Higueras,Federico Billeci,Marta Sanvicente-García,Paolo Petazzi,Noelia Ferruz,Avencia Sánchez-Mejías,Marc Güell","doi":"10.1038/s41587-025-02816-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02816-4","url":null,"abstract":"The diversity and biochemical potential of the PiggyBac transposase gene insertion system remains largely unexplored. Using a eukaryotic transposon mining pipeline, we expand the explored diversity by two orders of magnitude and experimentally validate a subset of highly divergent PiggyBac sequences. Fine-tuning a protein language model to further expand PiggyBac sequence space discovers transposases with improved activity and that are compatible with T cell engineering and Cas9-directed transposase-assisted integration.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"98 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209106","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}
引用次数: 0
Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates. 非人类灵长类动物PCSK9持久基因沉默的优化表观遗传调控设计。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-10-01 DOI: 10.1038/s41587-025-02838-y
Shaoshuai Mao,Wenbo Peng,Zhengyan Feng,Yang Chen,Jing Sun,Haiting Chen,Pengcheng Wang,Pinzheng Huang,Junzheng Zhao,Leilei Wu,Yifan Wang,Junjian Liu,Hao Luo,Ying Zang,Changqing Yang,Xue Qiao,Zhiwei Lu,Hongjun Wu,Mingjie Chen,Di Sun,Jun Xie,Yidi Sun,Changyang Zhou
{"title":"Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.","authors":"Shaoshuai Mao,Wenbo Peng,Zhengyan Feng,Yang Chen,Jing Sun,Haiting Chen,Pengcheng Wang,Pinzheng Huang,Junzheng Zhao,Leilei Wu,Yifan Wang,Junjian Liu,Hao Luo,Ying Zang,Changqing Yang,Xue Qiao,Zhiwei Lu,Hongjun Wu,Mingjie Chen,Di Sun,Jun Xie,Yidi Sun,Changyang Zhou","doi":"10.1038/s41587-025-02838-y","DOIUrl":"https://doi.org/10.1038/s41587-025-02838-y","url":null,"abstract":"Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"9 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203452","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}
引用次数: 0
Scaling DNA synthesis with a microchip-based massively parallel synthesis system. 基于微芯片的大规模并行合成系统的DNA合成缩放。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-10-01 DOI: 10.1038/s41587-025-02844-0
Xiandi Zhang,Xiang'er Jiang,Yun Wang,Qinzhen Chen,Hao Jiang,Hu Zhang,Antoni Beltran,Weiya Yang,Tai Chen,Chenglong Liang,Ning Cheng,Yun Huang,Guqiao Ding,Chengwang Xie,Nanfeng Gao,Juntao Liu,Wei Xu,Jinlei Huang,Dong Cai,Lihao Zhu,Songjin Mo,Mengzhe Shen,Wenwei Zhang,Ben Lehner,Ming Ni,Jian Wang,Xun Xu,Yue Shen
{"title":"Scaling DNA synthesis with a microchip-based massively parallel synthesis system.","authors":"Xiandi Zhang,Xiang'er Jiang,Yun Wang,Qinzhen Chen,Hao Jiang,Hu Zhang,Antoni Beltran,Weiya Yang,Tai Chen,Chenglong Liang,Ning Cheng,Yun Huang,Guqiao Ding,Chengwang Xie,Nanfeng Gao,Juntao Liu,Wei Xu,Jinlei Huang,Dong Cai,Lihao Zhu,Songjin Mo,Mengzhe Shen,Wenwei Zhang,Ben Lehner,Ming Ni,Jian Wang,Xun Xu,Yue Shen","doi":"10.1038/s41587-025-02844-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02844-0","url":null,"abstract":"Current high-throughput DNA synthesis technologies use intricate chip and microfluidic systems to produce large-scale synthetic oligonucleotides but with low concentration and limited compatibility for long DNA assembly. Here we report a massive-in-parallel synthesis system, with an 'identification-sorting-synthesis-recycling' iteration mechanism applied to microchips for high-throughput DNA synthesis. This approach increases DNA product concentration by four to six orders of magnitude and simplifies downstream processes for large-scale gene synthesis.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"21 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203454","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}
引用次数: 0
Detecting and quantifying circular RNAs in terabyte-scale RNA-seq datasets with CIRI3. 利用CIRI3在太字节规模的RNA-seq数据集中检测和定量环状rna。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-10-01 DOI: 10.1038/s41587-025-02835-1
Xin Zheng,Jinyang Zhang,Lipu Song,Xiang Jennie Li,Fangqing Zhao,Yuan Gao
{"title":"Detecting and quantifying circular RNAs in terabyte-scale RNA-seq datasets with CIRI3.","authors":"Xin Zheng,Jinyang Zhang,Lipu Song,Xiang Jennie Li,Fangqing Zhao,Yuan Gao","doi":"10.1038/s41587-025-02835-1","DOIUrl":"https://doi.org/10.1038/s41587-025-02835-1","url":null,"abstract":"To address recent challenges in circular RNA (circRNA) analysis, we present CIRI3, a tool for circRNA detection and quantification in terabyte-scale RNA-sequencing datasets. Using dynamic multithreaded task partitioning and a blocking search strategy for junction reads, CIRI3 is an order of magnitude faster than existing tools, while providing increased accuracy. We identified differentially spliced circRNAs across 2,535 cancer-related samples, and constructed a pretraining model and a biomarker network provided as the CIRIonco database.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"5 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203453","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}
引用次数: 0
Derivation of embryonic stem cells across avian species. 禽类胚胎干细胞的衍生。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-09-30 DOI: 10.1038/s41587-025-02833-3
Xi Chen,Zheng Guo,Xinyi Tong,Xizi Wang,Xugeng Liu,Hiroki Nagai,Ping Wu,Jiayi Lu,David Huss,Martin Tran,Carol Readhead,Christina Wu,Lin Cao,Yixin Huang,Zhaohan Zeng,Fan Feng,Nima Adhami,Sirjan Mor,Rusty Lansford,Cheng-Ming Chuong,Guojun Sheng,Carlos Lois,Qi-Long Ying
{"title":"Derivation of embryonic stem cells across avian species.","authors":"Xi Chen,Zheng Guo,Xinyi Tong,Xizi Wang,Xugeng Liu,Hiroki Nagai,Ping Wu,Jiayi Lu,David Huss,Martin Tran,Carol Readhead,Christina Wu,Lin Cao,Yixin Huang,Zhaohan Zeng,Fan Feng,Nima Adhami,Sirjan Mor,Rusty Lansford,Cheng-Ming Chuong,Guojun Sheng,Carlos Lois,Qi-Long Ying","doi":"10.1038/s41587-025-02833-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02833-3","url":null,"abstract":"Germline-competent embryonic stem (ES) cells have been successfully derived from mice and rats, but not from other species. Here we report the development of culture conditions for deriving ES cells from chickens and seven other avian species. Chicken ES cells express core pluripotency markers and can differentiate into cells of all embryonic germ layers, as well as extra-embryonic lineages. Notably, chicken ES cells contribute to high rates of chimerism when injected into chicken embryos and give rise to germ cells both in vitro and in ovo, confirming their germline competence. In addition, we demonstrated that ES cell self-renewal pathways are conserved among avian species, allowing ES cells from multiple avian species to be established using optimized chicken ES cell culture conditions. The establishment of authentic avian ES cells lays the groundwork for future applications in genetic engineering and the conservation of avian biodiversity.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"69 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194876","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}
引用次数: 0
Embryonic stem cells across bird species. 鸟类的胚胎干细胞。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-09-30 DOI: 10.1038/s41587-025-02807-5
Yangqing Lu,Long Xie
{"title":"Embryonic stem cells across bird species.","authors":"Yangqing Lu,Long Xie","doi":"10.1038/s41587-025-02807-5","DOIUrl":"https://doi.org/10.1038/s41587-025-02807-5","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"24 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194793","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}
引用次数: 0
Long-read sequencing and chemical synthesis access previously hidden antibiotics. 长读测序和化学合成可以获得以前隐藏的抗生素。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-09-23 DOI: 10.1038/s41587-025-02861-z
{"title":"Long-read sequencing and chemical synthesis access previously hidden antibiotics.","authors":"","doi":"10.1038/s41587-025-02861-z","DOIUrl":"https://doi.org/10.1038/s41587-025-02861-z","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"40 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127271","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}
引用次数: 0
Editor's Pick: City Therapeutics. 编辑推荐：City Therapeutics。
IF 41.7 1区 生物学
Nature biotechnology Pub Date : 2025-09-18 DOI: 10.1038/s41587-025-02834-2
Charles Schmidt
{"title":"Editor's Pick: City Therapeutics.","authors":"Charles Schmidt","doi":"10.1038/s41587-025-02834-2","DOIUrl":"10.1038/s41587-025-02834-2","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":41.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086656","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}
引用次数: 0
From frameworks to finance: how sharing benefits from the use of digital sequence information can evolve to contribute to biodiversity conservation. 从框架到资金：如何通过分享数字序列信息的惠益来促进生物多样性保护。
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-09-18 DOI: 10.1038/s41587-025-02820-8
Charlotte Blom,Marcel Jaspars,Jasmina Muminovic Rilak,Amber Hartman Scholz
{"title":"From frameworks to finance: how sharing benefits from the use of digital sequence information can evolve to contribute to biodiversity conservation.","authors":"Charlotte Blom,Marcel Jaspars,Jasmina Muminovic Rilak,Amber Hartman Scholz","doi":"10.1038/s41587-025-02820-8","DOIUrl":"https://doi.org/10.1038/s41587-025-02820-8","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"53 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083546","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}
引用次数: 0
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