Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Sébastien Monette, Dana Goerzen, Nicole Aguirre, Rüdiger M. Exner, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Darren Veach, Daniel A. Heller, Jan Grimm
{"title":"A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging","authors":"Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Sébastien Monette, Dana Goerzen, Nicole Aguirre, Rüdiger M. Exner, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Darren Veach, Daniel A. Heller, Jan Grimm","doi":"10.1038/s41551-024-01248-w","DOIUrl":"10.1038/s41551-024-01248-w","url":null,"abstract":"The efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215—a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650–900 nm) and shortwave infrared (SWIR) fluorescence imaging (900–1,700 nm)—can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing. In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs. At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions. A commercial near-infrared dye that is sensitive to apoptosis and that provides high tumour-to-muscle and tumour-to-liver contrast ratios facilitates fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 9","pages":"1092-1108"},"PeriodicalIF":26.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158748","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}
Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu
{"title":"Virally delivered CMYA5 enhances the assembly of cardiac dyads","authors":"Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu","doi":"10.1038/s41551-024-01253-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01253-z","url":null,"abstract":"<p>Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) lack nanoscale structures essential for efficient excitation–contraction coupling. Such nanostructures, known as dyads, are frequently disrupted in heart failure. Here we show that the reduced expression of cardiomyopathy-associated 5 (CMYA5), a master protein that establishes dyads, contributes to dyad disorganization in heart failure and to impaired dyad assembly in hiPSC-CMs, and that a miniaturized form of CMYA5 suitable for delivery via an adeno-associated virus substantially improved dyad architecture and normalized cardiac function under pressure overload. In hiPSC-CMs, the miniaturized form of CMYA5 increased contractile forces, improved Ca<sup>2+</sup> handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca<sup>2+</sup>. Our findings clarify the mechanisms responsible for impaired dyad structure in diseased cardiomyocytes, and suggest strategies for promoting dyad assembly and stability in heart disease and during the derivation of hiPSC-CMs.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"51 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137988","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":"Engineering signalling pathways in mammalian cells","authors":"Anna V. Leopold, Vladislav V. Verkhusha","doi":"10.1038/s41551-024-01237-z","DOIUrl":"10.1038/s41551-024-01237-z","url":null,"abstract":"In mammalian cells, signalling pathways orchestrate cellular growth, differentiation and survival, as well as many other processes that are essential for the proper functioning of cells. Here we describe cutting-edge genetic-engineering technologies for the rewiring of signalling networks in mammalian cells. Specifically, we describe the recombination of native pathway components, cross-kingdom pathway transplantation, and the development of de novo signalling within cells and organelles. We also discuss how, by designing signalling pathways, mammalian cells can acquire new properties, such as the capacity for photosynthesis, the ability to detect cancer and senescent cell markers or to synthesize hormones or metabolites in response to chemical or physical stimuli. We also review the applications of mammalian cells in biocomputing. Technologies for engineering signalling pathways in mammalian cells are advancing basic cellular biology, biomedical research and drug discovery. This Review discusses genetic-engineering technologies for the rewiring of signalling networks in mammalian cells, including the recombination of native pathway components, cross-kingdom pathway transplantation and the development of de novo signalling.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1523-1539"},"PeriodicalIF":26.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137990","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}
Yannan Chen, Shradha Chauhan, Cheng Gong, Hannah Dayton, Cong Xu, Estanislao Daniel De La Cruz, Yu-Young Wesley Tsai, Malika S. Datta, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Maura Boldrini, Kam W. Leong, Lars E. P. Dietrich, Raju Tomer
{"title":"Low-cost and scalable projected light-sheet microscopy for the high-resolution imaging of cleared tissue and living samples","authors":"Yannan Chen, Shradha Chauhan, Cheng Gong, Hannah Dayton, Cong Xu, Estanislao Daniel De La Cruz, Yu-Young Wesley Tsai, Malika S. Datta, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Maura Boldrini, Kam W. Leong, Lars E. P. Dietrich, Raju Tomer","doi":"10.1038/s41551-024-01249-9","DOIUrl":"10.1038/s41551-024-01249-9","url":null,"abstract":"Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named ‘projected light-sheet microscopy’ (pLSM), with high imaging performance and small device and computational footprints. We characterized the capabilities of pLSM, which repurposes readily available consumer-grade components, optimized optics, over-network control architecture and software-driven light-sheet modulation, by performing high-resolution mapping of cleared mouse brains and of post-mortem pathological human brain samples, and via the molecular phenotyping of brain and blood-vessel organoids derived from human induced pluripotent stem cells. We also report a method that leverages pLSM for the live imaging of the dynamics of sparsely labelled multi-layered bacterial pellicle biofilms at an air–liquid interface. pLSM can make high-resolution LSFM for biomedical applications more accessible, affordable and scalable. A light-sheet fluorescence microscope leveraging consumer-grade components as well as optimized optics and software facilitates the high-resolution imaging of cleared and living samples at scale with lower costs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 9","pages":"1109-1123"},"PeriodicalIF":26.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090115","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}
Michael Tong, Nathan Palmer, Amir Dailamy, Aditya Kumar, Hammza Khaliq, Sangwoo Han, Emma Finburgh, Madeleine Wing, Camilla Hong, Yichen Xiang, Katelyn Miyasaki, Andrew Portell, Joseph Rainaldi, Amanda Suhardjo, Sami Nourreddine, Wei Leong Chew, Ester J. Kwon, Prashant Mali
{"title":"Robust genome and cell engineering via in vitro and in situ circularized RNAs","authors":"Michael Tong, Nathan Palmer, Amir Dailamy, Aditya Kumar, Hammza Khaliq, Sangwoo Han, Emma Finburgh, Madeleine Wing, Camilla Hong, Yichen Xiang, Katelyn Miyasaki, Andrew Portell, Joseph Rainaldi, Amanda Suhardjo, Sami Nourreddine, Wei Leong Chew, Ester J. Kwon, Prashant Mali","doi":"10.1038/s41551-024-01245-z","DOIUrl":"10.1038/s41551-024-01245-z","url":null,"abstract":"Circularization can improve RNA persistence, yet simple and scalable approaches to achieve this are lacking. Here we report two methods that facilitate the pursuit of circular RNAs (cRNAs): cRNAs developed via in vitro circularization using group II introns, and cRNAs developed via in-cell circularization by the ubiquitously expressed RtcB protein. We also report simple purification protocols that enable high cRNA yields (40–75%) while maintaining low immune responses. These methods and protocols facilitate a broad range of applications in stem cell engineering as well as robust genome and epigenome targeting via zinc finger proteins and CRISPR–Cas9. Notably, cRNAs bearing the encephalomyocarditis internal ribosome entry enabled robust expression and persistence compared with linear capped RNAs in cardiomyocytes and neurons, which highlights the utility of cRNAs in these non-dividing cells. We also describe genome targeting via deimmunized Cas9 delivered as cRNA and a long-range multiplexed protein engineering methodology for the combinatorial screening of deimmunized protein variants that enables compatibility between persistence of expression and immunogenicity in cRNA-delivered proteins. The cRNA toolset will aid research and the development of therapeutics. Two simple and efficient methods for RNA circularization and a complementary Cas9 deimmunization method enhance a broad range of applications in genome and cell engineering.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":"109-126"},"PeriodicalIF":26.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073377","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}
Dennis M. Nahon, Renée Moerkens, Hande Aydogmus, Bas Lendemeijer, Adriana Martínez-Silgado, Jeroen M. Stein, Milica Dostanić, Jean-Philippe Frimat, Cristina Gontan, Mees N. S. de Graaf, Michel Hu, Dhanesh G. Kasi, Lena S. Koch, Kieu T. T. Le, Sangho Lim, Heleen H. T. Middelkamp, Joram Mooiweer, Paul Motreuil-Ragot, Eva Niggl, Cayetano Pleguezuelos-Manzano, Jens Puschhof, Nele Revyn, José M. Rivera-Arbelaez, Jelle Slager, Laura M. Windt, Mariia Zakharova, Berend J. van Meer, Valeria V. Orlova, Femke M. S. de Vrij, Sebo Withoff, Massimo Mastrangeli, Andries D. van der Meer, Christine L. Mummery
{"title":"Standardizing designed and emergent quantitative features in microphysiological systems","authors":"Dennis M. Nahon, Renée Moerkens, Hande Aydogmus, Bas Lendemeijer, Adriana Martínez-Silgado, Jeroen M. Stein, Milica Dostanić, Jean-Philippe Frimat, Cristina Gontan, Mees N. S. de Graaf, Michel Hu, Dhanesh G. Kasi, Lena S. Koch, Kieu T. T. Le, Sangho Lim, Heleen H. T. Middelkamp, Joram Mooiweer, Paul Motreuil-Ragot, Eva Niggl, Cayetano Pleguezuelos-Manzano, Jens Puschhof, Nele Revyn, José M. Rivera-Arbelaez, Jelle Slager, Laura M. Windt, Mariia Zakharova, Berend J. van Meer, Valeria V. Orlova, Femke M. S. de Vrij, Sebo Withoff, Massimo Mastrangeli, Andries D. van der Meer, Christine L. Mummery","doi":"10.1038/s41551-024-01236-0","DOIUrl":"10.1038/s41551-024-01236-0","url":null,"abstract":"Microphysiological systems (MPSs) are cellular models that replicate aspects of organ and tissue functions in vitro. In contrast with conventional cell cultures, MPSs often provide physiological mechanical cues to cells, include fluid flow and can be interlinked (hence, they are often referred to as microfluidic tissue chips or organs-on-chips). Here, by means of examples of MPSs of the vascular system, intestine, brain and heart, we advocate for the development of standards that allow for comparisons of quantitative physiological features in MPSs and humans. Such standards should ensure that the in vivo relevance and predictive value of MPSs can be properly assessed as fit-for-purpose in specific applications, such as the assessment of drug toxicity, the identification of therapeutics or the understanding of human physiology or disease. Specifically, we distinguish designed features, which can be controlled via the design of the MPS, from emergent features, which describe cellular function, and propose methods for improving MPSs with readouts and sensors for the quantitative monitoring of complex physiology towards enabling wider end-user adoption and regulatory acceptance. This Perspective discusses the need for standards that allow for comparisons of quantitative physiological features in microphysiological systems and humans.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 8","pages":"941-962"},"PeriodicalIF":26.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073378","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}
Christian Bluethgen, Pierre Chambon, Jean-Benoit Delbrouck, Rogier van der Sluijs, Małgorzata Połacin, Juan Manuel Zambrano Chaves, Tanishq Mathew Abraham, Shivanshu Purohit, Curtis P Langlotz, Akshay S Chaudhari
{"title":"A vision-language foundation model for the generation of realistic chest X-ray images.","authors":"Christian Bluethgen, Pierre Chambon, Jean-Benoit Delbrouck, Rogier van der Sluijs, Małgorzata Połacin, Juan Manuel Zambrano Chaves, Tanishq Mathew Abraham, Shivanshu Purohit, Curtis P Langlotz, Akshay S Chaudhari","doi":"10.1038/s41551-024-01246-y","DOIUrl":"10.1038/s41551-024-01246-y","url":null,"abstract":"<p><p>The paucity of high-quality medical imaging datasets could be mitigated by machine learning models that generate compositionally diverse images that faithfully represent medical concepts and pathologies. However, large vision-language models are trained on natural images, and the diversity distribution of the generated images substantially differs from that of medical images. Moreover, medical language involves specific and semantically rich vocabulary. Here we describe a domain-adaptation strategy for large vision-language models that overcomes distributional shifts. Specifically, by leveraging publicly available datasets of chest X-ray images and the corresponding radiology reports, we adapted a latent diffusion model pre-trained on pairs of natural images and text descriptors to generate diverse and visually plausible synthetic chest X-ray images (as confirmed by board-certified radiologists) whose appearance can be controlled with free-form medical text prompts. The domain-adaptation strategy for the text-conditioned synthesis of medical images can be used to augment training datasets and is a viable alternative to the sharing of real medical images for model training and fine-tuning.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073376","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":"The formation and maintenance of peri-implant fibrosis requires skeletal cells expressing the leptin receptor","authors":"","doi":"10.1038/s41551-024-01244-0","DOIUrl":"10.1038/s41551-024-01244-0","url":null,"abstract":"The cellular composition of fibrous tissue around orthopaedic implants and the genetic pathways involved in its formation are unclear. We find that leptin-receptor-expressing cells activate the adhesion G-protein-coupled receptor F5 (ADGRF5) pathway to form peri-implant fibrous tissue. Inhibition of ADGRF5 in leptin-receptor-expressing cells can prevent and reverse peri-implant fibrosis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 10","pages":"1195-1196"},"PeriodicalIF":26.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980868","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}
Chong Cui, Shengyi Wang, Daqi Wang, Jingjing Zhao, Bowei Huang, Biyun Zhu, Yuxin Chen, Honghai Tang, Yu Han, Cheng Ye, Dan Mu, Chengdong Zhang, Yuan Yang, Yihan Bao, Jun Lv, Shuang Han, Geng-Lin Li, Huawei Li, Yilai Shu
{"title":"A base editor for the long-term restoration of auditory function in mice with recessive profound deafness","authors":"Chong Cui, Shengyi Wang, Daqi Wang, Jingjing Zhao, Bowei Huang, Biyun Zhu, Yuxin Chen, Honghai Tang, Yu Han, Cheng Ye, Dan Mu, Chengdong Zhang, Yuan Yang, Yihan Bao, Jun Lv, Shuang Han, Geng-Lin Li, Huawei Li, Yilai Shu","doi":"10.1038/s41551-024-01235-1","DOIUrl":"10.1038/s41551-024-01235-1","url":null,"abstract":"A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness. The hearing-loss phenotype can be corrected via the injection, into the inner ear, of a base editor packaged in an adeno-associated virus, as shown in mice harbouring a mutation homozygous to human OTOF and in humanized mice with the human mutation.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":"40-56"},"PeriodicalIF":26.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918827","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 base editor for correcting deafness","authors":"Bence György","doi":"10.1038/s41551-024-01234-2","DOIUrl":"10.1038/s41551-024-01234-2","url":null,"abstract":"Base editing can correct the hearing-loss phenotype in mice harbouring a common mutation in the otoferlin gene.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":"3-4"},"PeriodicalIF":26.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918826","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}