Pub Date : 2026-01-13DOI: 10.1038/s41551-025-01588-1
Jamie I. Scott, Zhiming Cheng, Emily J. Thompson, Utsa Karmakar, Verity Cowell, Maya David, Doireann Gordon, Lorena Mendive-Tapia, Alexander Le Saint-Grant, Pia Volkmer, Cher S. Chuah, Phoebe Lau, Adriano G. Rossi, Wouter B. Nagengast, Doron Shabat, Gwo-Tzer Ho, Marc Vendrell
The diagnosis and monitoring of inflammatory bowel disease (IBD) relies on histologic and endoscopic analysis, as well as measurements of generic markers of inflammation. However, there are no specific tests that report on T cell-mediated immune responses as a key driver of IBD pathogenesis. Here we detect increasing granzyme A (GzmA) in gut biopsies and confirm that CD8+ T cells secrete its active form to induce interleukin (IL)-8. We then rationally design a non-invasive chemiluminescence assay for measuring active GzmA in stool supernatants from patients with IBD. For our assay, we synthesize peptide-based GzmA-specific inhibitors and chemiluminescent reporters and use them to characterize biosamples from ~150 human patients with IBD and healthy controls. Our results demonstrate that GzmA activity is an indicator of gut inflammation that can enhance the identification of patients with IBD over existing tests and potentially act as a mechanistic biomarker for the dominance of T cell activity. We envision that the selectivity and sensitivity of our GzmA activity-based optical assay will accelerate the design of additional biomedical approaches to enhance precision medicine in IBD.
{"title":"A chemiluminescence assay targeting granzyme A activity for monitoring inflammatory bowel disease","authors":"Jamie I. Scott, Zhiming Cheng, Emily J. Thompson, Utsa Karmakar, Verity Cowell, Maya David, Doireann Gordon, Lorena Mendive-Tapia, Alexander Le Saint-Grant, Pia Volkmer, Cher S. Chuah, Phoebe Lau, Adriano G. Rossi, Wouter B. Nagengast, Doron Shabat, Gwo-Tzer Ho, Marc Vendrell","doi":"10.1038/s41551-025-01588-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01588-1","url":null,"abstract":"The diagnosis and monitoring of inflammatory bowel disease (IBD) relies on histologic and endoscopic analysis, as well as measurements of generic markers of inflammation. However, there are no specific tests that report on T cell-mediated immune responses as a key driver of IBD pathogenesis. Here we detect increasing granzyme A (GzmA) in gut biopsies and confirm that CD8+ T cells secrete its active form to induce interleukin (IL)-8. We then rationally design a non-invasive chemiluminescence assay for measuring active GzmA in stool supernatants from patients with IBD. For our assay, we synthesize peptide-based GzmA-specific inhibitors and chemiluminescent reporters and use them to characterize biosamples from ~150 human patients with IBD and healthy controls. Our results demonstrate that GzmA activity is an indicator of gut inflammation that can enhance the identification of patients with IBD over existing tests and potentially act as a mechanistic biomarker for the dominance of T cell activity. We envision that the selectivity and sensitivity of our GzmA activity-based optical assay will accelerate the design of additional biomedical approaches to enhance precision medicine in IBD.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"39 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956334","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}
Pub Date : 2026-01-13DOI: 10.1038/s41551-025-01596-1
Hui Zhang, Xinyue Yu, Fuhua Yang, Jinying An, Lin Su, Yuqing Liu, Mi Zhang, Ruiyan Fan, Hongli Yang, Xiaorong Li, Xiaomin Zhang
Small extracellular vesicles have been widely studied for their therapeutic properties and ability to deliver bioactive molecules. In addition to secretory vesicles, cells contain small intracellular vesicles involved in physiological and metabolic processes, whose therapeutic potential remains unexplored. Here we developed protocols to isolate small intracellular vesicles from multiple cell types and systematically compared their molecular and functional profiles to extracellular vesicles. Intracellular vesicles are smaller, yield higher quantities and demonstrate enhanced cellular uptake in both in vitro and in vivo models. Molecular profiling revealed that intracellular vesicles are enriched in proteins associated with the endoplasmic reticulum and Golgi apparatus, possess distinct microRNA signatures linked to intracellular membrane systems, and contain elevated levels of phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Vesicles derived from umbilical cord mesenchymal stem cells showed superior therapeutic efficacy in a model of retinal degeneration by reducing endoplasmic reticulum stress and delivering neuroprotective factors. In addition, intracellular vesicles exhibited enhanced drug-loading capacity and efficient delivery of lipophilic compounds to the retina. These findings position intracellular vesicles as promising candidates for therapeutic applications.
{"title":"Small intracellular vesicles outperform small extracellular vesicles in uptake, drug delivery and retinal neuroprotection","authors":"Hui Zhang, Xinyue Yu, Fuhua Yang, Jinying An, Lin Su, Yuqing Liu, Mi Zhang, Ruiyan Fan, Hongli Yang, Xiaorong Li, Xiaomin Zhang","doi":"10.1038/s41551-025-01596-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01596-1","url":null,"abstract":"Small extracellular vesicles have been widely studied for their therapeutic properties and ability to deliver bioactive molecules. In addition to secretory vesicles, cells contain small intracellular vesicles involved in physiological and metabolic processes, whose therapeutic potential remains unexplored. Here we developed protocols to isolate small intracellular vesicles from multiple cell types and systematically compared their molecular and functional profiles to extracellular vesicles. Intracellular vesicles are smaller, yield higher quantities and demonstrate enhanced cellular uptake in both in vitro and in vivo models. Molecular profiling revealed that intracellular vesicles are enriched in proteins associated with the endoplasmic reticulum and Golgi apparatus, possess distinct microRNA signatures linked to intracellular membrane systems, and contain elevated levels of phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Vesicles derived from umbilical cord mesenchymal stem cells showed superior therapeutic efficacy in a model of retinal degeneration by reducing endoplasmic reticulum stress and delivering neuroprotective factors. In addition, intracellular vesicles exhibited enhanced drug-loading capacity and efficient delivery of lipophilic compounds to the retina. These findings position intracellular vesicles as promising candidates for therapeutic applications.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"4 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956333","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}
Adoptive T cell transfer therapy remains limited by the inability to monitor live tumour cell dynamics during treatment. Here we introduce a real-time, label-free phenotyping system that integrates electrical impedance spectroscopy, Raman spectroscopy and microscopy to analyse live tumour cells undergoing therapy. This system enables simultaneous tracking of metabolic activity, membrane integrity and cytoplasmic properties at single-cell resolution. First, analysis of glycolysis reveals that tumour-infiltrating lymphocytes suppress lactate production early, reducing tumour aggressiveness, while chimaeric antigen receptor T cells trigger tumour silent escape early and delay metabolic inhibition until later stages, culminating in cell death. Second, membrane profiling shows early phospholipid and cholesterol depletion under tumour-infiltrating lymphocyte treatment, with partial recovery, whereas chimaeric antigen receptor T cells cause progressive and irreversible membrane damage. Third, cytoplasmic analysis identifies early protein structural disruption and ionic imbalance under tumour-infiltrating lymphocyte therapy, while chimaeric antigen receptor T cells trigger delayed metabolic collapse and cytoplasmic contraction. These findings uncover distinct immune killing mechanisms and escape phases, offering mechanistic insights into tumour-immune interactions and informing the design of personalized therapeutic strategies.
{"title":"Real-time multimodal phenotyping reveals distinct tumour cell dynamics and immune escape mechanisms in T cell therapies.","authors":"Shengjie Chen,Kunru Yu,Shengsen Zhang,Xiaoliang Guo,Rong Zhu","doi":"10.1038/s41551-025-01582-7","DOIUrl":"https://doi.org/10.1038/s41551-025-01582-7","url":null,"abstract":"Adoptive T cell transfer therapy remains limited by the inability to monitor live tumour cell dynamics during treatment. Here we introduce a real-time, label-free phenotyping system that integrates electrical impedance spectroscopy, Raman spectroscopy and microscopy to analyse live tumour cells undergoing therapy. This system enables simultaneous tracking of metabolic activity, membrane integrity and cytoplasmic properties at single-cell resolution. First, analysis of glycolysis reveals that tumour-infiltrating lymphocytes suppress lactate production early, reducing tumour aggressiveness, while chimaeric antigen receptor T cells trigger tumour silent escape early and delay metabolic inhibition until later stages, culminating in cell death. Second, membrane profiling shows early phospholipid and cholesterol depletion under tumour-infiltrating lymphocyte treatment, with partial recovery, whereas chimaeric antigen receptor T cells cause progressive and irreversible membrane damage. Third, cytoplasmic analysis identifies early protein structural disruption and ionic imbalance under tumour-infiltrating lymphocyte therapy, while chimaeric antigen receptor T cells trigger delayed metabolic collapse and cytoplasmic contraction. These findings uncover distinct immune killing mechanisms and escape phases, offering mechanistic insights into tumour-immune interactions and informing the design of personalized therapeutic strategies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"23 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956023","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}
Amidst the chronic issue of opioid misuse, finding an alternative to pharmaceutical pain control following surgical interventions stands as a major hurdle. Conventional non-pharmacological pain control technologies often rely on rigid stimulators linking internal and external body components, thereby imposing nerve burden and additional interventions for the removal. Here we introduce a bioresorbable triboelectric nerve cuff activated via ultrasounds for pain control. The targeted nerves are enveloped around polymers with opposite triboelectric properties that vibrate upon ultrasound stimulation, generating an alternating triboelectric field parallel to the nerve for pain modulation. In vivo testing in rat and porcine models demonstrates that the fully implanted neurostimulator exerts no discernible impact on gait and yields immediate pain relief. Application of the implant until full resorbing caused no adverse effects in the nerve or surrounding muscle tissue, and behavioural analysis confirmed its effective pain control. The implantable pain control system might offer a drug-free alternative to pain management strategies, helping prevent drug abuse.
{"title":"Wireless and bioresorbable triboelectric nerve block system for postoperative pain control.","authors":"Young-Jun Kim,So-Hee Kim,Byung-Joon Park,Jinyoung Jeon,Donghyeon Kang,Youngwook Chung,Joon-Ha Hwang,Hong-Joon Yoon,Kyu Hyoung Lee,Byung-Ok Choi,Sang-Woo Kim","doi":"10.1038/s41551-025-01579-2","DOIUrl":"https://doi.org/10.1038/s41551-025-01579-2","url":null,"abstract":"Amidst the chronic issue of opioid misuse, finding an alternative to pharmaceutical pain control following surgical interventions stands as a major hurdle. Conventional non-pharmacological pain control technologies often rely on rigid stimulators linking internal and external body components, thereby imposing nerve burden and additional interventions for the removal. Here we introduce a bioresorbable triboelectric nerve cuff activated via ultrasounds for pain control. The targeted nerves are enveloped around polymers with opposite triboelectric properties that vibrate upon ultrasound stimulation, generating an alternating triboelectric field parallel to the nerve for pain modulation. In vivo testing in rat and porcine models demonstrates that the fully implanted neurostimulator exerts no discernible impact on gait and yields immediate pain relief. Application of the implant until full resorbing caused no adverse effects in the nerve or surrounding muscle tissue, and behavioural analysis confirmed its effective pain control. The implantable pain control system might offer a drug-free alternative to pain management strategies, helping prevent drug abuse.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937761","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}
Pub Date : 2026-01-08DOI: 10.1038/s41551-025-01576-5
Dachao Tang, Chi Zhang, Weizhi Zhang, Funian Lu, Leming Xiao, Xinhe Huang, Jiangyi Shao, Dan Liu, Shanshan Fu, Miaoying Zhao, Luoying Zhang, Da Jia, Han-Ming Shen, Chaoyang Sun, Gang Chen, Bin Liu, Di Peng, Yu Xue
Profiling molecular panorama from massive omics data identifies regulatory networks in cells but requires mechanistic interpretation and experimental follow up. Here we combine deep learning and large language model reasoning to develop a hybrid workflow for omics interpretation, called LyMOI. LyMOI incorporates GPT-3.5 for biological knowledge reasoning and a large graph model with graph convolutional networks (GCNs). The large graph model integrates evolutionarily conserved protein interactions and uses hierarchical fine-tuning to predict context-specific molecular regulators from multi-omics data. GPT-3.5 then generates machine chain-of-thought (CoT) to mechanistically interpret their roles in biological systems. Focusing on autophagy, LyMOI mechanistically interprets 1.3 TB transcriptomic, proteomic and phosphoproteomic data and expands the knowledge of autophagy regulators. We also show that LyMOI highlights two human oncoproteins, CTSL and FAM98A, for enhancing autophagy upon treatment with disulfiram (DSF), an antitumour agent. Silencing these genes in vitro attenuates DSF-mediated autophagy and suppresses cancer cell proliferation. Strikingly, DSF treatment with Z-FY-CHO, a CTSL-specific inhibitor previously used for preventing SARS-CoV-2 infection, potently inhibits tumour growth in vivo.
{"title":"A deep learning and large language hybrid workflow for omics interpretation","authors":"Dachao Tang, Chi Zhang, Weizhi Zhang, Funian Lu, Leming Xiao, Xinhe Huang, Jiangyi Shao, Dan Liu, Shanshan Fu, Miaoying Zhao, Luoying Zhang, Da Jia, Han-Ming Shen, Chaoyang Sun, Gang Chen, Bin Liu, Di Peng, Yu Xue","doi":"10.1038/s41551-025-01576-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01576-5","url":null,"abstract":"Profiling molecular panorama from massive omics data identifies regulatory networks in cells but requires mechanistic interpretation and experimental follow up. Here we combine deep learning and large language model reasoning to develop a hybrid workflow for omics interpretation, called LyMOI. LyMOI incorporates GPT-3.5 for biological knowledge reasoning and a large graph model with graph convolutional networks (GCNs). The large graph model integrates evolutionarily conserved protein interactions and uses hierarchical fine-tuning to predict context-specific molecular regulators from multi-omics data. GPT-3.5 then generates machine chain-of-thought (CoT) to mechanistically interpret their roles in biological systems. Focusing on autophagy, LyMOI mechanistically interprets 1.3 TB transcriptomic, proteomic and phosphoproteomic data and expands the knowledge of autophagy regulators. We also show that LyMOI highlights two human oncoproteins, CTSL and FAM98A, for enhancing autophagy upon treatment with disulfiram (DSF), an antitumour agent. Silencing these genes in vitro attenuates DSF-mediated autophagy and suppresses cancer cell proliferation. Strikingly, DSF treatment with Z-FY-CHO, a CTSL-specific inhibitor previously used for preventing SARS-CoV-2 infection, potently inhibits tumour growth in vivo.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"43 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919983","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}
Pub Date : 2026-01-05DOI: 10.1038/s41551-025-01565-8
Tian Tan, Tom Van Wouwe, Keenon F. Werling, C. Karen Liu, Scott L. Delp, Jennifer L. Hicks, Akshay S. Chaudhari
{"title":"GaitDynamics: a generative foundation model for analyzing human walking and running","authors":"Tian Tan, Tom Van Wouwe, Keenon F. Werling, C. Karen Liu, Scott L. Delp, Jennifer L. Hicks, Akshay S. Chaudhari","doi":"10.1038/s41551-025-01565-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01565-8","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"381 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902706","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}
Pub Date : 2026-01-05DOI: 10.1038/s41551-025-01581-8
Marie-Madeleine Nzila, Ulrike Koehl, Zoltán Ivics
{"title":"Non-viral vectors as beacons of hope for reducing genotoxic risks of gene therapy","authors":"Marie-Madeleine Nzila, Ulrike Koehl, Zoltán Ivics","doi":"10.1038/s41551-025-01581-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01581-8","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"41 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902705","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}
Pub Date : 2026-01-02DOI: 10.1038/s41551-025-01573-8
Lisa R Volpatti, Salvador Norton de Matos, Gustavo Borjas, Taryn N Beckman, Joseph W Reda, Elyse A Watkins, Zhengjie Zhou, Mindy Nguyen, Ani Solanki, Yun Fang, Jeffrey A Hubbell
Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here we engineer IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we construct Fab-IL-10 by fusing IL-10 to the antibody fragment (Fab) of four different oxidized LDL-binding antibodies. We show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques in atherosclerosis mouse models. Among them, 2D03-IL-10 significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This modular technology may be applied to a variety of protein therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.
{"title":"LDL-binding IL-10 reduces vascular inflammation in atherosclerotic mice.","authors":"Lisa R Volpatti, Salvador Norton de Matos, Gustavo Borjas, Taryn N Beckman, Joseph W Reda, Elyse A Watkins, Zhengjie Zhou, Mindy Nguyen, Ani Solanki, Yun Fang, Jeffrey A Hubbell","doi":"10.1038/s41551-025-01573-8","DOIUrl":"10.1038/s41551-025-01573-8","url":null,"abstract":"<p><p>Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here we engineer IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we construct Fab-IL-10 by fusing IL-10 to the antibody fragment (Fab) of four different oxidized LDL-binding antibodies. We show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques in atherosclerosis mouse models. Among them, 2D03-IL-10 significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This modular technology may be applied to a variety of protein therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892787","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}
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