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Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-24 DOI: 10.1038/s41587-025-02569-0
Mikael G. Pezet, Juan A. Torres, Tania A. Thimraj, Ivana Matkovic, Nadine Schrode, John W. Murray, Anjali Saqi, Kristin G. Beaumont, Hans-Willem Snoeck
{"title":"Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis","authors":"Mikael G. Pezet, Juan A. Torres, Tania A. Thimraj, Ivana Matkovic, Nadine Schrode, John W. Murray, Anjali Saqi, Kristin G. Beaumont, Hans-Willem Snoeck","doi":"10.1038/s41587-025-02569-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02569-0","url":null,"abstract":"<p>Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons with lung injury and idiopathic pulmonary fibrosis (IPF), a lethal lung disease. As these populations are absent in rodents, deeper understanding requires a human in vitro model. Here we convert human pluripotent stem cells (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 10<sup>10</sup> iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Heřmanský–Pudlák Syndrome 1 (HPS1), which causes pulmonary fibrosis in humans, replicate the aberrant differentiation and recruitment of profibrotic fibroblasts observed in IPF, indicating that intrinsic dysfunction of RA/TRB-associated alveolar progenitors contributes to HPS1-related IPF. iRAPs may provide a system suitable for IPF drug discovery and validation.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"30 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477389","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
Internal cap-initiated translation for efficient protein production from circular mRNA
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-19 DOI: 10.1038/s41587-025-02561-8
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
{"title":"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/s41587-025-02561-8","DOIUrl":"https://doi.org/10.1038/s41587-025-02561-8","url":null,"abstract":"<p>Circular mRNA faces challenges in enhancing its translation potential as an RNA therapeutic. Here we introduce two molecular designs that bolster circular mRNA translation through an internal cap-initiated mechanism. The first consists of a circular mRNA with a covalently attached <i>N</i><sup>7</sup>-methylguanosine (m<sup>7</sup>G) cap through a branching structure (cap-circ mRNA). This modification allows circular mRNA to recruit translation machinery and produce proteins more efficiently than internal ribosome entry site (IRES)-containing circular mRNAs. Combining with an <i>N</i><sup>1</sup>-methylpseudouridine (m<sup>1</sup>Ψ) modification, cap-circ mRNA exhibits a lower acute immunostimulatory effect, maintaining high translation in mice. The second design features the non-covalent attachment of an m<sup>7</sup>G cap to a circular mRNA through hybridization with an m<sup>7</sup>G cap-containing oligonucleotide, enhancing translation by more than 50-fold. This setup allows circular mRNAs to synthesize reporter proteins upon hybridizing with capped mRNAs or long non-coding RNAs and to undergo rolling circle-type translation. These advancements broaden the therapeutic applications of circular mRNAs by minimizing their molecular size, elevating translation efficiency and facilitating cell-type-selective translation.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"14 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443716","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
Covalently or non-covalently attached m7G cap enhances protein production from circular mRNA
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-19 DOI: 10.1038/s41587-025-02580-5
{"title":"Covalently or non-covalently attached m7G cap enhances protein production from circular mRNA","authors":"","doi":"10.1038/s41587-025-02580-5","DOIUrl":"https://doi.org/10.1038/s41587-025-02580-5","url":null,"abstract":"The mechanism of translation initiation in linear and circular mRNAs influences translation efficiency. Covalent attachment of an N7-methylguanosine (m7G) cap increases protein production from circular mRNAs in mice. Hybridization with capped endogenous RNAs also promotes protein production in cells, suggesting that this interaction might also occur between endogenous RNAs.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"20 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452029","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
Sustained in situ protein production and release in the mammalian gut by an engineered bacteriophage
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-18 DOI: 10.1038/s41587-025-02570-7
Zachary R. Baker, Yao Zhang, Haiyan Zhang, Hollyn C. Franklin, Priscila B. S. Serpa, Teresa Southard, Liwu Li, Bryan B. Hsu
{"title":"Sustained in situ protein production and release in the mammalian gut by an engineered bacteriophage","authors":"Zachary R. Baker, Yao Zhang, Haiyan Zhang, Hollyn C. Franklin, Priscila B. S. Serpa, Teresa Southard, Liwu Li, Bryan B. Hsu","doi":"10.1038/s41587-025-02570-7","DOIUrl":"https://doi.org/10.1038/s41587-025-02570-7","url":null,"abstract":"<p>Oral administration of biologic drugs is challenging because of the degradative activity of the upper gastrointestinal tract. Strategies that use engineered microbes to produce biologics in the lower gastrointestinal tract are limited by competition with resident commensal bacteria. Here we demonstrate the engineering of bacteriophage (phage) that infect resident commensals to express heterologous proteins released during cell lysis. Working with the virulent T4 phage, which targets resident, nonpathogenic <i>Escherichia coli</i>, we first identify T4-specific promoters with maximal protein expression and minimal impact on T4 phage titers. We engineer T4 phage to express a serine protease inhibitor of a pro-inflammatory enzyme with increased activity in ulcerative colitis and observe reduced enzyme activity in a mouse model of colitis. We also apply the approach to reduce weight gain and inflammation in mouse models of diet-induced obesity. This work highlights an application of virulent phages in the mammalian gut as engineerable vectors to release therapeutics from resident gut bacteria.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"30 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435127","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
A ‘CRISPR’ way to visualize RNA in live cells
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-18 DOI: 10.1038/s41587-025-02560-9
{"title":"A ‘CRISPR’ way to visualize RNA in live cells","authors":"","doi":"10.1038/s41587-025-02560-9","DOIUrl":"https://doi.org/10.1038/s41587-025-02560-9","url":null,"abstract":"Visualizing RNA molecules in live cells remains a challenge, and existing methods require genetic manipulation or have limited resolution. Our study overcomes these limitations by using the programmable CRISPR–Csm tool to bind and track individual transcripts in their native state.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"49 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435125","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
Single-molecule live-cell RNA imaging with CRISPR–Csm
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-18 DOI: 10.1038/s41587-024-02540-5
Chenglong Xia, David Colognori, Xueyang Stephen Jiang, Ke Xu, Jennifer A. Doudna
{"title":"Single-molecule live-cell RNA imaging with CRISPR–Csm","authors":"Chenglong Xia, David Colognori, Xueyang Stephen Jiang, Ke Xu, Jennifer A. Doudna","doi":"10.1038/s41587-024-02540-5","DOIUrl":"https://doi.org/10.1038/s41587-024-02540-5","url":null,"abstract":"<p>Understanding the diverse dynamic behaviors of individual RNA molecules in single cells requires visualizing them at high resolution in real time. However, single-molecule live-cell imaging of unmodified endogenous RNA has not yet been achieved in a generalizable manner. Here, we present single-molecule live-cell fluorescence in situ hybridization (smLiveFISH), a robust approach that combines the programmable RNA-guided, RNA-targeting CRISPR–Csm complex with multiplexed guide RNAs for direct and efficient visualization of single RNA molecules in a range of cell types, including primary cells. Using smLiveFISH, we track individual native <i>NOTCH2</i> and <i>MAP1B</i> transcripts in living cells and identify two distinct localization mechanisms including the cotranslational translocation of <i>NOTCH2</i> mRNA at the endoplasmic reticulum and directional transport of <i>MAP1B</i> mRNA toward the cell periphery. This method has the potential to unlock principles governing the spatiotemporal organization of native transcripts in health and disease.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"24 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435126","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
Vertex’s opioid-free drug for acute pain wins FDA approval
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-17 DOI: 10.1038/s41587-025-02590-3
{"title":"Vertex’s opioid-free drug for acute pain wins FDA approval","authors":"","doi":"10.1038/s41587-025-02590-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02590-3","url":null,"abstract":"Society, patients and clinicians welcome a much-needed non-opioid pain medication. Vertex’s first-in-class analgesic Journavx could soon be followed by a new generation of addiction-free pain drugs acting at NaV1.8 sodium channels.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"208 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427161","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
The reverse transcriptase domain of prime editors contributes to DNA repair in mammalian cells
IF 46.9 1区 生物学
Nature biotechnology Pub Date : 2025-02-17 DOI: 10.1038/s41587-025-02568-1
Chunwei Zheng, Gangming Zhang, Lilia J. Dean, Erik J. Sontheimer, Wen Xue
{"title":"The reverse transcriptase domain of prime editors contributes to DNA repair in mammalian cells","authors":"Chunwei Zheng, Gangming Zhang, Lilia J. Dean, Erik J. Sontheimer, Wen Xue","doi":"10.1038/s41587-025-02568-1","DOIUrl":"https://doi.org/10.1038/s41587-025-02568-1","url":null,"abstract":"<p>Reverse transcriptase (RT) has been shown to play a role in double-strand break repair in bacteria, yet the impact of the RT component of prime editors (PEs) on normal mammalian cellular functions is unclear. Here we show that overexpressed RT or PE increases short insertions and diminishes homology-directed repair following Cas9 cleavage at multiple loci in multiple cell lines. Live-cell imaging shows that RT and PEs are rapidly recruited to laser-induced DNA damage sites and promote endogenous repair, independent of known DNA damage sensors. Interestingly, RT–mCherry partially impairs green fluorescent protein–PARP1 recruitment. A compact PE without an RNase H domain shows reduced DNA repair activity and may therefore be more suitable for clinical application. These data reveal a role for untethered RT or the RT domain of PEs in the repair of chromosomal breaks, calling for evaluation of the long-term effect of PEs and retroviral RT in mammalian cells.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"3 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427077","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
Gene and cell therapies for Parkinson’s make headway 帕金森病基因和细胞疗法取得进展
IF 33.1 1区 生物学
Nature biotechnology Pub Date : 2025-02-14 DOI: 10.1038/s41587-025-02581-4
{"title":"Gene and cell therapies for Parkinson’s make headway","authors":"","doi":"10.1038/s41587-025-02581-4","DOIUrl":"10.1038/s41587-025-02581-4","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"43 2","pages":"156-156"},"PeriodicalIF":33.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417943","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
A chromatin-based model for deciphering gene interactions 基于染色质的基因相互作用解密模型
IF 33.1 1区 生物学
Nature biotechnology Pub Date : 2025-02-14 DOI: 10.1038/s41587-025-02573-4
Rong Li
{"title":"A chromatin-based model for deciphering gene interactions","authors":"Rong Li","doi":"10.1038/s41587-025-02573-4","DOIUrl":"10.1038/s41587-025-02573-4","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"43 2","pages":"176-176"},"PeriodicalIF":33.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417946","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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