Nature Biomedical Engineering最新文献

{"title":"A foundation model for enhancing magnetic resonance images and downstream segmentation, registration and diagnostic tasks","authors":"Yue Sun, Limei Wang, Gang Li, Weili Lin, Li Wang","doi":"10.1038/s41551-024-01283-7","DOIUrl":"https://doi.org/10.1038/s41551-024-01283-7","url":null,"abstract":"<p>In structural magnetic resonance (MR) imaging, motion artefacts, low resolution, imaging noise and variability in acquisition protocols frequently degrade image quality and confound downstream analyses. Here we report a foundation model for the motion correction, resolution enhancement, denoising and harmonization of MR images. Specifically, we trained a tissue-classification neural network to predict tissue labels, which are then leveraged by a ‘tissue-aware’ enhancement network to generate high-quality MR images. We validated the model’s effectiveness on a large and diverse dataset comprising 2,448 deliberately corrupted images and 10,963 images spanning a wide age range (from foetuses to elderly individuals) acquired using a variety of clinical scanners across 19 public datasets. The model consistently outperformed state-of-the-art algorithms in improving the quality of MR images, handling pathological brains with multiple sclerosis or gliomas, generating 7-T-like images from 3 T scans and harmonizing images acquired from different scanners. The high-quality, high-resolution and harmonized images generated by the model can be used to enhance the performance of models for tissue segmentation, registration, diagnosis and other downstream tasks.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"53 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776905","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}

{"title":"In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor","authors":"Andi Pan,&nbsp;Charles C. Bailey,&nbsp;Tianling Ou,&nbsp;Jinge Xu,&nbsp;Tonia Aristotelous,&nbsp;Xin Liu,&nbsp;Baodan Hu,&nbsp;Gogce Crynen,&nbsp;Nickolas Skamangas,&nbsp;Naomi Bronkema,&nbsp;Mai H. Tran,&nbsp;Huihui Mou,&nbsp;Xia Zhang,&nbsp;Michael D. Alpert,&nbsp;Yiming Yin,&nbsp;Michael Farzan,&nbsp;Wenhui He","doi":"10.1038/s41551-024-01289-1","DOIUrl":"10.1038/s41551-024-01289-1","url":null,"abstract":"Human proteins repurposed as biologics for clinical use have been engineered through in vitro techniques that improve the affinity of the biologics for their ligands. However, the techniques do not select against properties, such as protease sensitivity or self-reactivity, that impair the biologics’ clinical efficacy. Here we show that the B-cell receptors of primary murine B cells can be engineered to affinity mature in vivo the human CD4 domains of the HIV-1-entry inhibitor CD4 immunoadhesin (CD4-Ig). Specifically, we introduced genes encoding the CD4 domains 1 and 2 (D1D2) of a half-life-enhanced form of CD4-Ig (CD4-Ig-v0) into the heavy-chain loci of murine B cells and adoptively transferred these cells into wild-type mice. After immunization, the B cells proliferated, class switched, affinity matured and produced D1D2-presenting antibodies. Somatic hypermutations in the D1D2-encoding region of the engrafted cells improved the binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein and the inhibitor’s ability to neutralize a panel of HIV-1 isolates without impairing its pharmacokinetic properties. In vivo affinity maturation of non-antibody protein biologics may guide the development of more effective therapeutics. The B-cell receptor of primary mouse B cells can be engineered to affinity mature an HIV-1-entry inhibitor in vivo.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1715-1729"},"PeriodicalIF":26.8,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776906","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}

{"title":"Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes","authors":"Jiang-An Yin,&nbsp;Lukas Frick,&nbsp;Manuel C. Scheidmann,&nbsp;Tingting Liu,&nbsp;Chiara Trevisan,&nbsp;Ashutosh Dhingra,&nbsp;Anna Spinelli,&nbsp;Yancheng Wu,&nbsp;Longping Yao,&nbsp;Dalila Laura Vena,&nbsp;Britta Knapp,&nbsp;Jingjing Guo,&nbsp;Elena De Cecco,&nbsp;Kathi Ging,&nbsp;Andrea Armani,&nbsp;Edward J. Oakeley,&nbsp;Florian Nigsch,&nbsp;Joel Jenzer,&nbsp;Jasmin Haegele,&nbsp;Michal Pikusa,&nbsp;Joachim Täger,&nbsp;Salvador Rodriguez-Nieto,&nbsp;Vangelis Bouris,&nbsp;Rafaela Ribeiro,&nbsp;Federico Baroni,&nbsp;Manmeet Sakshi Bedi,&nbsp;Scott Berry,&nbsp;Marco Losa,&nbsp;Simone Hornemann,&nbsp;Martin Kampmann,&nbsp;Lucas Pelkmans,&nbsp;Dominic Hoepfner,&nbsp;Peter Heutink,&nbsp;Adriano Aguzzi","doi":"10.1038/s41551-024-01278-4","DOIUrl":"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. Arrayed CRISPR libraries with each plasmid encoding an array of four non-overlapping single-guide RNAs allow for the efficient genome-wide ablation, activation and epigenetic silencing of human protein-coding genes.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":"127-148"},"PeriodicalIF":26.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01278-4.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multimodal machine learning model for the stratification of breast cancer risk","authors":"Xuejun Qian,&nbsp;Jing Pei,&nbsp;Chunguang Han,&nbsp;Zhiying Liang,&nbsp;Gaosong Zhang,&nbsp;Na Chen,&nbsp;Weiwei Zheng,&nbsp;Fanlun Meng,&nbsp;Dongsheng Yu,&nbsp;Yixuan Chen,&nbsp;Yiqun Sun,&nbsp;Hanqi Zhang,&nbsp;Wei Qian,&nbsp;Xia Wang,&nbsp;Zhuoran Er,&nbsp;Chenglu Hu,&nbsp;Hui Zheng,&nbsp;Dinggang Shen","doi":"10.1038/s41551-024-01302-7","DOIUrl":"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. A multimodal model for the stratification of breast cancer risk based on clinical metadata, mammography and trimodal ultrasound images performed as well as or better than radiologists at tumour classification and at differential diagnosis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 3","pages":"356-370"},"PeriodicalIF":26.8,"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}

{"title":"Patterned gastrointestinal monolayers with bilateral access as observable models of parasite gut infection","authors":"Moritz Hofer, Maria A. Duque-Correa, Matthias P. Lutolf","doi":"10.1038/s41551-024-01313-4","DOIUrl":"https://doi.org/10.1038/s41551-024-01313-4","url":null,"abstract":"<p>Organoids for modelling the physiology and pathology of gastrointestinal tissues are constrained by a poorly accessible lumen. Here we report the development and applicability of bilaterally accessible organoid-derived patterned epithelial monolayers that allow the independent manipulation of their apical and basal sides. We constructed gastric, small-intestinal, caecal and colonic epithelial models that faithfully reproduced their respective tissue geometries and that exhibited stem cell regionalization and transcriptional resemblance to in vivo epithelia. The models’ enhanced observability allowed single-cell tracking and studies of the motility of cells in immersion culture and at the air–liquid interface. Models mimicking infection of the caecal epithelium by the parasite <i>Trichuris muris</i> allowed us to live image syncytial tunnel formation. The enhanced observability of bilaterally accessible organoid-derived gastrointestinal tissue will facilitate the study of the dynamics of epithelial cells and their interactions with pathogens.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"82 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763175","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}

{"title":"A two-phase point-of-care diagnostic device for bladder cancer","authors":"","doi":"10.1038/s41551-024-01301-8","DOIUrl":"https://doi.org/10.1038/s41551-024-01301-8","url":null,"abstract":"Point-of-care diagnostic kits for detecting bladder cancer using urine enable screening and surveillance to be carried out at home. We demonstrate a point-of-care diagnostic device with a two-phase system that uses buoyant signal transducers to allow the direct use of untreated urine for screening, providing enhanced accuracy and ease of use over existing methods.","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":"142758370","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}

{"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":"<p>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 (T_reg) 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 T_reg 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 T_reg cells and activation of tumour-infiltrating lymphocytes may represent a general strategy for the effective control of advanced metastatic tumours.</p>","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}

{"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":"<p>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.</p>","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}

{"title":"Antibiotic-driven boosting of oncolytic virotherapy","authors":"Himanshu Soni, E. Antonio Chiocca, Joshua D. Bernstock","doi":"10.1038/s41551-024-01269-5","DOIUrl":"https://doi.org/10.1038/s41551-024-01269-5","url":null,"abstract":"Oncolytic viruses expressing transgenes for immunomodulatory cytokines can be produced at high throughput by exploiting the preferential susceptibility of the viruses to certain antibiotics.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"15 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735590","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}

{"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":"<p>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.</p>","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}