Nature Biomedical Engineering最新文献_第3页

Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-12-04 DOI: 10.1038/s41551-024-01278-4

Jiang-An Yin, Lukas Frick, Manuel C. Scheidmann, Tingting Liu, Chiara Trevisan, Ashutosh Dhingra, Anna Spinelli, Yancheng Wu, Longping Yao, Dalila Laura Vena, Britta Knapp, Jingjing Guo, Elena De Cecco, Kathi Ging, Andrea Armani, Edward J. Oakeley, Florian Nigsch, Joel Jenzer, Jasmin Haegele, Michal Pikusa, Joachim Täger, Salvador Rodriguez-Nieto, Vangelis Bouris, Rafaela Ribeiro, Federico Baroni, Manmeet Sakshi Bedi, Scott Berry, Marco Losa, Simone Hornemann, Martin Kampmann, Lucas Pelkmans, Dominic Hoepfner, Peter Heutink, Adriano Aguzzi

{"title":"Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes","authors":"Jiang-An Yin, Lukas Frick, Manuel C. Scheidmann, Tingting Liu, Chiara Trevisan, Ashutosh Dhingra, Anna Spinelli, Yancheng Wu, Longping Yao, Dalila Laura Vena, Britta Knapp, Jingjing Guo, Elena De Cecco, Kathi Ging, Andrea Armani, Edward J. Oakeley, Florian Nigsch, Joel Jenzer, Jasmin Haegele, Michal Pikusa, Joachim Täger, Salvador Rodriguez-Nieto, Vangelis Bouris, Rafaela Ribeiro, Federico Baroni, Manmeet Sakshi Bedi, Scott Berry, Marco Losa, Simone Hornemann, Martin Kampmann, Lucas Pelkmans, Dominic Hoepfner, Peter Heutink, Adriano Aguzzi","doi":"10.1038/s41551-024-01278-4","DOIUrl":"https://doi.org/10.1038/s41551-024-01278-4","url":null,"abstract":"Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75–99%) and silencing (76–92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrPC, screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and ‘post-pooling’ individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"12 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A multimodal machine learning model for the stratification of breast cancer risk

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-12-04 DOI: 10.1038/s41551-024-01302-7

Xuejun Qian, Jing Pei, Chunguang Han, Zhiying Liang, Gaosong Zhang, Na Chen, Weiwei Zheng, Fanlun Meng, Dongsheng Yu, Yixuan Chen, Yiqun Sun, Hanqi Zhang, Wei Qian, Xia Wang, Zhuoran Er, Chenglu Hu, Hui Zheng, Dinggang Shen

{"title":"A multimodal machine learning model for the stratification of breast cancer risk","authors":"Xuejun Qian, Jing Pei, Chunguang Han, Zhiying Liang, Gaosong Zhang, Na Chen, Weiwei Zheng, Fanlun Meng, Dongsheng Yu, Yixuan Chen, Yiqun Sun, Hanqi Zhang, Wei Qian, Xia Wang, Zhuoran Er, Chenglu Hu, Hui Zheng, Dinggang Shen","doi":"10.1038/s41551-024-01302-7","DOIUrl":"https://doi.org/10.1038/s41551-024-01302-7","url":null,"abstract":"Machine learning models for the diagnosis of breast cancer can facilitate the prediction of cancer risk and subsequent patient management among other clinical tasks. For the models to impact clinical practice, they ought to follow standard workflows, help interpret mammography and ultrasound data, evaluate clinical contextual information, handle incomplete data and be validated in prospective settings. Here we report the development and testing of a multimodal model leveraging mammography and ultrasound modules for the stratification of breast cancer risk based on clinical metadata, mammography and trimodal ultrasound (19,360 images of 5,216 breasts) from 5,025 patients with surgically confirmed pathology across medical centres and scanner manufacturers. Compared with the performance of experienced radiologists, the model performed similarly at classifying tumours as benign or malignant and was superior at pathology-level differential diagnosis. With a prospectively collected dataset of 191 breasts from 187 patients, the overall accuracies of the multimodal model and of preliminary pathologist-level assessments of biopsied breast specimens were similar (90.1% vs 92.7%, respectively). Multimodal models may assist diagnosis in oncology.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"21 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Patterned gastrointestinal monolayers with bilateral access as observable models of parasite gut infection

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-12-04 DOI: 10.1038/s41551-024-01313-4

Moritz Hofer, Maria A. Duque-Correa, Matthias P. Lutolf

引用次数: 0

A two-phase point-of-care diagnostic device for bladder cancer

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-12-02 DOI: 10.1038/s41551-024-01301-8

引用次数: 0

Concurrent intratumoural Treg cell depletion and CD8+ T cell expansion via a cleavable anti-4-1BB–interleukin-15 fusion protein

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-12-02 DOI: 10.1038/s41551-024-01303-6

Yueqi Cai, Zilong Han, Jiao Shen, Zhuangzhi Zou, Jingya Guo, Yong Liang, Shijie Li, Huiping Liao, Zhenhua Ren, Hua Peng, Yang-Xin Fu

{"title":"Concurrent intratumoural Treg cell depletion and CD8+ T cell expansion via a cleavable anti-4-1BB–interleukin-15 fusion protein","authors":"Yueqi Cai, Zilong Han, Jiao Shen, Zhuangzhi Zou, Jingya Guo, Yong Liang, Shijie Li, Huiping Liao, Zhenhua Ren, Hua Peng, Yang-Xin Fu","doi":"10.1038/s41551-024-01303-6","DOIUrl":"https://doi.org/10.1038/s41551-024-01303-6","url":null,"abstract":"Potent agonists of the inducible co-stimulatory receptor 4-1BB are too toxic for patients with advanced cancer. Here, on the basis of observations of a weak agonist of 4-1BB depleting regulatory T (Treg) cells within the tumour microenvironment without leading to substantial restoration of dysfunctional cytotoxic T cells (CTLs), we show that effective tumour control can be achieved via concurrent Treg cell depletion and CTL expansion through an anti-4-1BB antibody fused to interleukin-15 (IL-15) via a peptide sensitive to tumour proteases. In mouse models of advanced cancers, intraperitoneal injection of the bifunctional protein attenuated the activity of the interleukin mostly in the periphery of the primary tumour while allowing for the expansion of CTLs within the tumour microenvironment, led to more effective tumour inhibition and to lower systemic toxicity than treating the cancers with combinatorial treatment with unlinked anti-4-1BB antibody and IL-15, and reduced the resistance of tumours to checkpoint blockade. Concurrent eradication of Treg cells and activation of tumour-infiltrating lymphocytes may represent a general strategy for the effective control of advanced metastatic tumours.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"74 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Magnetic-susceptibility-dependent ratiometric probes for enhancing quantitative MRI

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-11-29 DOI: 10.1038/s41551-024-01286-4

Cheng Zhang, Bin Nan, Juntao Xu, Tengxiang Yang, Li Xu, Chang Lu, Xiao-Bing Zhang, Jianghong Rao, Guosheng Song

{"title":"Magnetic-susceptibility-dependent ratiometric probes for enhancing quantitative MRI","authors":"Cheng Zhang, Bin Nan, Juntao Xu, Tengxiang Yang, Li Xu, Chang Lu, Xiao-Bing Zhang, Jianghong Rao, Guosheng Song","doi":"10.1038/s41551-024-01286-4","DOIUrl":"https://doi.org/10.1038/s41551-024-01286-4","url":null,"abstract":"In magnetic resonance imaging (MRI), quantitative measurements of analytes are hindered by difficulties in distinguishing the MRI signals of activation of the probe by the analyte from those of the accumulation of the intact probe. Here we show that imaging sensitivity and quantitation can be enhanced by ratiometric MRI probes with a high relaxivity-ratio change (more than 2.5-fold at 7 T) via magnetic-susceptibility-dependent magnetic resonance tuning. Specifically, polymeric probes that incorporate paramagnetic Mn-porphyrin and superparamagnetic iron oxide nanoparticles inducing opposite changes in the longitudinal and transverse magnetic relaxivities responded to analyte concentration independently of probe concentration. In mice, the probes allowed for quantitative real-time dynamic imaging of H2O2, H2S or pH in subcutaneous tumours, in livers with drug-induced injury and in orthotropic gliomas. The ratiometric MRI probes may be advantageously used to obtain molecular insight into pathological processes and to circumvent interference from dynamic changes in probe concentration within the body while providing anatomical information.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antibiotic-driven boosting of oncolytic virotherapy 抗生素推动溶瘤病毒疗法的发展

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-11-28 DOI: 10.1038/s41551-024-01269-5

Himanshu Soni, E. Antonio Chiocca, Joshua D. Bernstock

引用次数: 0

Antibiotic-mediated selection of randomly mutagenized and cytokine-expressing oncolytic viruses 抗生素介导的随机诱变和细胞因子表达溶瘤病毒的选择

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-11-28 DOI: 10.1038/s41551-024-01259-7

Reza Rezaei, Stephen Boulton, Mahsa Ahmadi, Julia Petryk, Miles Da Silva, Nika Kooshki Zamani, Ragunath Singaravelu, Gabriel St-Laurent, Lauren Daniel, Arezoo Sadeghipour, Adrian Pelin, Joanna Poutou, Abril Ixchel Munoz Zuniga, Clarence Choy, Victoria H. Gilchrist, Zumama Khalid, Bradley Austin, Kemal Alper Onsu, Ricardo Marius, Zahra Ameli, Fazel Mohammadi, Valeria Mancinelli, Emily Wang, Abolfazl Nik-Akhtar, Akram Alwithenani, Fatemeh Panahi Arasi, Stephen S. G. Ferguson, Tom C. Hobman, Tommy Alain, Lee-Hwa Tai, Carolina S. Ilkow, Jean-Simon Diallo, John C. Bell, Taha Azad

{"title":"Antibiotic-mediated selection of randomly mutagenized and cytokine-expressing oncolytic viruses","authors":"Reza Rezaei, Stephen Boulton, Mahsa Ahmadi, Julia Petryk, Miles Da Silva, Nika Kooshki Zamani, Ragunath Singaravelu, Gabriel St-Laurent, Lauren Daniel, Arezoo Sadeghipour, Adrian Pelin, Joanna Poutou, Abril Ixchel Munoz Zuniga, Clarence Choy, Victoria H. Gilchrist, Zumama Khalid, Bradley Austin, Kemal Alper Onsu, Ricardo Marius, Zahra Ameli, Fazel Mohammadi, Valeria Mancinelli, Emily Wang, Abolfazl Nik-Akhtar, Akram Alwithenani, Fatemeh Panahi Arasi, Stephen S. G. Ferguson, Tom C. Hobman, Tommy Alain, Lee-Hwa Tai, Carolina S. Ilkow, Jean-Simon Diallo, John C. Bell, Taha Azad","doi":"10.1038/s41551-024-01259-7","DOIUrl":"https://doi.org/10.1038/s41551-024-01259-7","url":null,"abstract":"Optimization of oncolytic viruses for therapeutic applications requires the strategic removal or mutagenesis of virulence genes alongside the insertion of transgenes that enhance viral replication, spread and immunogenicity. However, the complexity of many viral genomes and the labour-intensive nature of methods for the generation and isolation of recombinant viruses have hindered the development of therapeutic oncolytic viruses. Here we report an iterative strategy that exploits the preferential susceptibility of viruses to certain antibiotics to accelerate the engineering of the genomes of oncolytic viruses for the insertion of immunomodulatory cytokine transgenes, and the identification of dispensable genes with regard to replication of the recombinant oncolytic viruses in tumour cells. We applied the strategy by leveraging insertional mutagenesis via the Sleeping Beauty transposon system, combined with long-read nanopore sequencing, to generate libraries of herpes simplex virus type 1 and vaccinia virus, identifying stable transgene insertion sites and gene deletions that enhance the safety and efficacy of the viruses.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"22 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates 通过对从肿瘤裂解物中分离出来的抗原进行靶向蛋白水解来接种抗肿瘤疫苗

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-11-28 DOI: 10.1038/s41551-024-01285-5

Yu Zhao, Donghui Song, Zeyu Wang, Qingqing Huang, Fan Huang, Zhongfeng Ye, Douglas Wich, Mengting Chen, Jennifer Khirallah, Shuliang Gao, Yang Liu, Qiaobing Xu

{"title":"Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates","authors":"Yu Zhao, Donghui Song, Zeyu Wang, Qingqing Huang, Fan Huang, Zhongfeng Ye, Douglas Wich, Mengting Chen, Jennifer Khirallah, Shuliang Gao, Yang Liu, Qiaobing Xu","doi":"10.1038/s41551-024-01285-5","DOIUrl":"https://doi.org/10.1038/s41551-024-01285-5","url":null,"abstract":"The activation of cytotoxic T cells against tumour cells typically requires the cross-presentation, by antigen-presenting cells (and via major histocompatibility complex class I molecules), of an epitope derived from a tumour antigen. A critical step in antigen processing is the proteolysis of tumour antigens mediated by the ubiquitin–proteasome pathway. Here we describe a tumour vaccine leveraging targeted antigen degradation to augment antigen processing and cross-presentation. Analogous to proteolysis-targeting chimaeras, the vaccine consists of lymph-node-targeting lipid nanoparticles encapsulated with tumour antigens pre-conjugated with ligands that can bind to E3 ubiquitin ligases. In mice with subcutaneous human melanoma or triple-negative breast cancer, or with orthotopic mouse Lewis lung carcinoma or clinically inoperable mouse ovarian cancer, subcutaneously delivered vaccines prepared using tumour lysate proteins elicited antigen-specific adaptive immunity and immunological memory, and inhibited tumour growth, metastasis and recurrence, particularly when combined with immune checkpoint inhibition.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"258 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations 通过优化的脂质纳米颗粒配方输送核糖核蛋白，实现更安全高效的碱基编辑和基质编辑

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2024-11-28 DOI: 10.1038/s41551-024-01296-2

Rafał Hołubowicz, Samuel W. Du, Jiin Felgner, Roman Smidak, Elliot H. Choi, Grazyna Palczewska, Carolline Rodrigues Menezes, Zhiqian Dong, Fangyuan Gao, Omar Medani, Alexander L. Yan, Maria W. Hołubowicz, Paul Z. Chen, Marco Bassetto, Eleonora Risaliti, David Salom, J. Noah Workman, Philip D. Kiser, Andrzej T. Foik, David C. Lyon, Gregory A. Newby, David R. Liu, Philip L. Felgner, Krzysztof Palczewski

{"title":"Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations","authors":"Rafał Hołubowicz, Samuel W. Du, Jiin Felgner, Roman Smidak, Elliot H. Choi, Grazyna Palczewska, Carolline Rodrigues Menezes, Zhiqian Dong, Fangyuan Gao, Omar Medani, Alexander L. Yan, Maria W. Hołubowicz, Paul Z. Chen, Marco Bassetto, Eleonora Risaliti, David Salom, J. Noah Workman, Philip D. Kiser, Andrzej T. Foik, David C. Lyon, Gregory A. Newby, David R. Liu, Philip L. Felgner, Krzysztof Palczewski","doi":"10.1038/s41551-024-01296-2","DOIUrl":"https://doi.org/10.1038/s41551-024-01296-2","url":null,"abstract":"Delivering ribonucleoproteins (RNPs) for in vivo genome editing is safer than using viruses encoding for Cas9 and its respective guide RNA. However, transient RNP activity does not typically lead to optimal editing outcomes. Here we show that the efficiency of delivering RNPs can be enhanced by cell-penetrating peptides (covalently fused to the protein or as excipients) and that lipid nanoparticles (LNPs) encapsulating RNPs can be optimized for enhanced RNP stability, delivery efficiency and editing potency. Specifically, after screening for suitable ionizable cationic lipids and by optimizing the concentration of the synthetic lipid DMG-PEG 2000, we show that the encapsulation, via microfluidic mixing, of adenine base editor and prime editor RNPs within LNPs using the ionizable lipid SM102 can result in in vivo editing-efficiency enhancements larger than 300-fold (with respect to the delivery of the naked RNP) without detectable off-target edits. We believe that chemically defined LNP formulations optimized for RNP-encapsulation stability and delivery efficiency will lead to safer genome editing.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"65 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0