Nature biotechnology最新文献

{"title":"Computationally designed enzymes show potent catalytic activity","authors":"Iris Marchal","doi":"10.1038/s41587-025-02751-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02751-4","url":null,"abstract":"<p>Computationally designing enzymes with activity levels matching those seen in nature remains a formidable challenge that often requires extensive laboratory optimization. Writing in <i>Nature</i>, Listov et al. now overcome this issue, describing a method that uses atomistic modeling to computationally design highly efficient de novo enzymes.</p><p>The authors applied their approach to design a catalyst for Kemp elimination (KE), a non-natural proton abstraction reaction that serves as a model for de novo enzyme design. The workflow uses natural protein backbone fragments to assemble and stabilize backbone variations that are likely to put the resulting enzyme in a catalytically competent constellation. Then geometric matching and Rosetta atomistic calculations are used to position the KE enzyme in each of these structures and to optimize the active site through mutations. Seventy-three designs were selected for experimental testing, of which three showed KE activity. Low-throughput screening further increased their catalytic efficiency. The best-performing design contained more than 140 mutations and an active site constellation different from natural scaffolds.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"109 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630242","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":"Transitive prediction of small-molecule function through alignment of high-content screening resources","authors":"Feng Bao, Li Li, Heinz Hammerlindl, Susan Q. Shen, Sabrina Hammerlindl, Steven J. Altschuler, Lani F. Wu","doi":"10.1038/s41587-025-02729-2","DOIUrl":"https://doi.org/10.1038/s41587-025-02729-2","url":null,"abstract":"<p>High-content image-based phenotypic screens (HCSs) provide a scalable approach to characterize biological functions of compounds. The widespread adoption of HCS has led to a growing body of available profile datasets. However, study-specific experimental and computational choices lead to profile datasets that cannot be directly combined. A critical, long-standing challenge is how to integrate these rich but currently isolated HCS dataset resources. Here we introduce a contrastive, deep-learning framework that leverages sparse sets of overlapping profiles as fiducials to align heterogeneous HCS profile datasets in a shared latent space. We demonstrate that this alignment facilitates accurate ‘transitive’ predictions, whereby the function of an uncharacterized compound screened in one dataset can be predicted through comparison with characterized compounds already profiled in other datasets. In silico alignment of HCS resources provides a path to unify fast-growing HCS resources and accelerate early drug discovery efforts.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"22 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603431","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":"Tracking microbiome-derived cell-free RNA modifications detects colorectal cancer","authors":"","doi":"10.1038/s41587-025-02735-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02735-4","url":null,"abstract":"We developed low-input multiple methylation sequencing (LIME-seq) to detect RNA modifications in plasma cell-free RNA (cfRNA) and identified microbiome-derived RNA modification signatures that can distinguish people with colorectal cancer from those without. We suggest that monitoring the modification levels on cfRNA or other RNA species could aid disease diagnosis and prognosis.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"21 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593863","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":"Modifications of microbiome-derived cell-free RNA in plasma discriminates colorectal cancer samples","authors":"Cheng-Wei Ju, Ruitu Lyu, Han Li, Jiangbo Wei, Alberto J. Parra Vitela, Urszula Dougherty, Akushika Kwesi, Alexander Luna, Xuanhao Zhu, Shenghai Shen, Yunzheng Liu, Liangliang Wang, Xiaolong Cui, Yuzhi Xu, Bochen Jiang, Yiyi Ji, Peng Xia, Diana C. West-Szymanski, Chenxi Sun, Yuhao Zhong, Chang Ye, Angelica Moran, Christopher Lehmann, Eric Pamer, Wei Zhang, Marc Bissonnette, Li-Sheng Zhang, Chuan He","doi":"10.1038/s41587-025-02731-8","DOIUrl":"https://doi.org/10.1038/s41587-025-02731-8","url":null,"abstract":"<p>Circulating cell-free RNA (cfRNA) in plasma represents a promising avenue for cancer detection. We report low-input multiple methylation sequencing, a method for profiling modification patterns in cfRNA, enabling the detection of diverse transfer RNAs and small noncoding RNAs derived from both the human genome and the microbiome. RNA modification patterns in microbiome-derived cfRNA accurately reflect host microbiota activity and hold potential for the early detection of colorectal cancer.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"2 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577931","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":"High-precision cytosine base editors by evolving nucleic-acid-recognition hotspots in deaminase","authors":"Yuan Wu, Yu-Lan Xiao, Weixin Tang","doi":"10.1038/s41587-025-02678-w","DOIUrl":"https://doi.org/10.1038/s41587-025-02678-w","url":null,"abstract":"<p>Base editors (BEs), covalent fusions of a cytosine or adenine deaminase with a nuclease-impaired CRISPR protein, mediate site-specific conversion of C:G to T:A (CBEs) or A:T to G:C (ABEs) in the genome. Existing BEs modify all cytosines or adenines within the editing window, which limits their precision. Here we engineer nucleotide and context specificity of the <i>Escherichia coli</i> transfer RNA-specific adenosine deaminase (TadA) to pinpoint cytosine editing. Strategically sampling multiple nucleic-acid-recognition hotspots through directed evolution, we develop 16 TadA-derived N<u>C</u>N-specific deaminases that cover every possible −1 and +1 context for a target cytosine, providing on-demand deaminase choices for editor customization. We apply these variants to (1) correct disease-associated T:A-to-C:G transitions documented by ClinVar, achieving greater accuracy than conventional CBEs in 81.5% of cases, and (2) model two cancer-driver mutations—<i>KRAS</i>^G12D (A<u>C</u>C) and <i>TP53</i>^R248Q (C<u>C</u>G)—in vitro. Our approach offers a general strategy to access precise base editors for potential clinical applications.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"21 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577975","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":"Senolytics under scrutiny in the quest to slow aging","authors":"João Pedro de Magalhães","doi":"10.1038/s41587-025-02740-7","DOIUrl":"https://doi.org/10.1038/s41587-025-02740-7","url":null,"abstract":"<p>As the world’s population continues to age, the ability to slow human aging pharmacologically would bring enormous health and medical benefits. It would also offer extraordinary financial rewards to any enterprise that was capable of delivering longevity in a pill. Because the major causes of mortality worldwide are age-related diseases (such as cancer, cardiovascular disease, type 2 diabetes and neurodegenerative disorders), delaying the onset of aging and age-related diseases is a dream as old as time. The discovery that aging can be delayed in animal models (including in mice) using genetic, dietary and pharmacological interventions has given rise to a growing longevity biotechnology industry¹, which is keen to translate these preclinical discoveries into human applications.</p><p>The longevity biotechnology sector has been expanding rapidly in recent years and attracting high-profile investors. Approaches range from decades-old antioxidants to more recent approaches, such as those pursued by Altos Labs (which focuses on partial reprogramming and cellular rejuvenation). One of the major anti-aging strategies involves targeting senescent cells. In the 1960s, Hayflick and Moorhead discovered that human cells in culture have a limited proliferative potential before becoming senescent owing to telomere shortening. In addition, cellular senescence can be triggered by oncogenes or various forms of stress². This state is marked by irreversible growth arrest as well as other markers, including expression of cell cycle inhibitors (such as p21 and p16) and secretion of pro-inflammatory cytokines, termed the senescence-associated secretory phenotype (SASP). For decades, researchers have hypothesized that although cellular senescence can act as an anti-tumor mechanism, it may also contribute to aging and age-related degeneration. Senescent cells have been shown to accumulate in some aged tissues in both mice and humans, and their role in driving aging has been long and widely debated. Following earlier promising work on cellular senescence in prematurely aged mice, a groundbreaking 2016 study in the laboratory of van Deursen at the Mayo Clinic showed that genetic ablation of p16-expressing senescent cells in normal mice extends both lifespan (by 24–27%) and healthspan³. It demonstrated that eliminating senescent cells could have therapeutic benefits in normally aged mammals, which sparked interest in pharmacologically targeting senescent cells — especially with senolytic compounds that aim to selectively eliminate them.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"26 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547300","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":"Unlocking gene regulatory networks for crop resilience and sustainable agriculture","authors":"Richalynn Leong, Xin He, Bob Sebastiaan Beijen, Toshiyuki Sakai, Jorge Goncalves, Pingtao Ding","doi":"10.1038/s41587-025-02727-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02727-4","url":null,"abstract":"<p>Understanding the complex mechanisms of gene regulatory networks (GRNs) has emerged as a transformative approach in agricultural research. By deciphering the regulatory mechanisms underlying key traits, GRN studies offer opportunities to enhance crop resilience to environmental challenges, improve yield and ensure sustainable food production. In this Review, we highlight the importance of GRN research in agriculture and explore how cutting-edge biotechnology, interdisciplinary approaches and computational modeling techniques are addressing the challenges in the field. We discuss how integrating diverse datasets at different resolutions empowers us to unravel the complex genetic networks governing crop responses to climate change, pests and diseases. By harnessing the power of GRNs, we have the potential to transform crop improvement strategies, develop stress-tolerant varieties and ensure global food security. We provide insights into the current opportunities and challenges of GRN research in agriculture, bridging the gap between scientific advancements and the pressing need for sustainable agricultural practices.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"19 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533189","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":"Publisher Correction: Internal cap-initiated translation for efficient protein production from circular mRNA","authors":"Kosuke Fukuchi, Yuko Nakashima, Naoko Abe, Seigo Kimura, Fumitaka Hashiya, Yuichi Shichino, Yiwei Liu, Ryoko Ogisu, Satomi Sugiyama, Daisuke Kawaguchi, Masahito Inagaki, Zheyu Meng, Shiryu Kajihara, Mizuki Tada, Satoshi Uchida, Ting-Ting Li, Ramkrishna Maity, Tairin Kawasaki, Yasuaki Kimura, Shintaro Iwasaki, Hiroshi Abe","doi":"10.1038/s41587-025-02758-x","DOIUrl":"https://doi.org/10.1038/s41587-025-02758-x","url":null,"abstract":"<p>Correction to: <i>Nature Biotechnology</i> https://doi.org/10.1038/s41587-025-02561-8, published online 19 February 2025.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"150 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533168","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":"Probing the proteome","authors":"","doi":"10.1038/s41587-025-02737-2","DOIUrl":"https://doi.org/10.1038/s41587-025-02737-2","url":null,"abstract":"Chemical proteomics has brought rigor to covalent drug discovery and drugs to the clinic. Can it deliver a new generation of drug targets?","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"18 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520435","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":"Defining and benchmarking open problems in single-cell analysis","authors":"Malte D. Luecken, Scott Gigante, Daniel B. Burkhardt, Robrecht Cannoodt, Daniel C. Strobl, Nikolay S. Markov, Luke Zappia, Giovanni Palla, Wesley Lewis, Daniel Dimitrov, Michael E. Vinyard, D. S. Magruder, Michaela F. Mueller, Alma Andersson, Emma Dann, Qian Qin, Dominik J. Otto, Michal Klein, Olga Borisovna Botvinnik, Louise Deconinck, Kai Waldrant, Sai Nirmayi Yasa, Artur Szałata, Andrew Benz, Zhijian Li, Jonathan M. Bloom, Angela Oliveira Pisco, Julio Saez-Rodriguez, Drausin Wulsin, Luca Pinello, Yvan Saeys, Fabian J. Theis, Smita Krishnaswamy","doi":"10.1038/s41587-025-02694-w","DOIUrl":"https://doi.org/10.1038/s41587-025-02694-w","url":null,"abstract":"<p>Single-cell genomics has enabled the study of biological processes at an unprecedented scale and resolution. These studies were enabled by innovative data generation technologies coupled with emerging computational tools specialized for single-cell data. As single-cell technologies have become more prevalent, so has the development of new analysis tools, which has resulted in over 1,700 published algorithms¹ (as of February 2024). Thus, there is an increasing need to continually evaluate which algorithm performs best in which context to inform best practices^2,3 that evolve with the field.</p><p>In many fields of quantitative science, public competitions and benchmarks address this need by evaluating state-of-the-art methods against known criteria, following the concept of a common task framework⁴. Here, we present Open Problems, a living, extensive, community-guided platform including 12 current single-cell tasks that we envisage raising standards for the selection, evaluation and development of methods in single-cell analysis.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"47 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520436","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}