Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. We present BioPathNet, a graph neural network framework based on the neural Bellman-Ford network (NBFNet), addressing limitations of traditional representation-based learning methods through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns representations between node pairs by considering all relations along paths, enhancing prediction accuracy and interpretability, and allowing visualization of influential paths and biological validation. BioPathNet leverages a background regulatory graph for enhanced message passing and uses stringent negative sampling to improve precision and scalability. BioPathNet outperforms or matches existing methods across diverse tasks including gene function annotation, drug-disease indication, synthetic lethality and lncRNA-target interaction prediction. Our study identifies promising additional drug indications for diseases such as acute lymphoblastic leukaemia and Alzheimer's disease, validated by medical experts and clinical trials. In addition, we prioritize putative synthetic lethal gene pairs and regulatory lncRNA-target interactions. BioPathNet's interpretability will enable researchers to trace prediction paths and gain molecular insights.
{"title":"Enhancing link prediction in biomedical knowledge graphs with BioPathNet.","authors":"Emy Yue Hu,Svitlana Oleshko,Samuele Firmani,Hui Cheng,Zhaocheng Zhu,Maria Ulmer,Matthias Arnold,Maria Colomé-Tatché,Jian Tang,Sophie Xhonneux,Annalisa Marsico","doi":"10.1038/s41551-025-01598-z","DOIUrl":"https://doi.org/10.1038/s41551-025-01598-z","url":null,"abstract":"Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. We present BioPathNet, a graph neural network framework based on the neural Bellman-Ford network (NBFNet), addressing limitations of traditional representation-based learning methods through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns representations between node pairs by considering all relations along paths, enhancing prediction accuracy and interpretability, and allowing visualization of influential paths and biological validation. BioPathNet leverages a background regulatory graph for enhanced message passing and uses stringent negative sampling to improve precision and scalability. BioPathNet outperforms or matches existing methods across diverse tasks including gene function annotation, drug-disease indication, synthetic lethality and lncRNA-target interaction prediction. Our study identifies promising additional drug indications for diseases such as acute lymphoblastic leukaemia and Alzheimer's disease, validated by medical experts and clinical trials. In addition, we prioritize putative synthetic lethal gene pairs and regulatory lncRNA-target interactions. BioPathNet's interpretability will enable researchers to trace prediction paths and gain molecular insights.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"276 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005413","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 : 2026-01-19DOI: 10.1038/s41551-025-01604-4
Han Ouyang, Dongjie Jiang, Yiran Hu, Sijing Cheng, Zhengmin Zhang, Bojing Shi, Engui Wang, Jiangtao Xue, Yizhu Shan, Lingling Xu, Yang Zou, Sixian Weng, Hui Li, Hongxia Niu, Min Gu, Lin Luo, Shengyu Chao, Puchuan Tan, Yan Yao, Ningning Wang, Yubo Fan, Zhong Lin Wang, Wei Hua, Zhou Li
Lifelong pacing is one of the ultimate goals of cardiac pacemakers. However, meeting the critical energy condition for lifelong service is a tremendous challenge. Here we report a symbiotic transcatheter pacemaker that regenerates electric energy from heart motion via electromagnetic induction and surpasses the critical energy condition for lifelong service. The pacemaker can be closely integrated with the body owing to favourable biocompatibility and hemocompatibility, and its small size enables interventional delivery. To minimize energy loss and eliminate mechanical collision and friction, we propose a straightforward magnetic levitation energy cache structure. The energy regeneration module has a near-zero boot threshold, high kinetic energy conversion efficiency and intracardiac root mean square output power. We show the energy regeneration and therapeutic function of the symbiotic transcatheter pacemaker over a month-long autonomous operation in a porcine model of brady-arrhythmia. These advances may provide a potential path to extend the service life of pacemakers to the level of the natural heart.
{"title":"Symbiotic transcatheter pacemaker for lifelong energy regeneration and therapeutic function in porcine disease model.","authors":"Han Ouyang, Dongjie Jiang, Yiran Hu, Sijing Cheng, Zhengmin Zhang, Bojing Shi, Engui Wang, Jiangtao Xue, Yizhu Shan, Lingling Xu, Yang Zou, Sixian Weng, Hui Li, Hongxia Niu, Min Gu, Lin Luo, Shengyu Chao, Puchuan Tan, Yan Yao, Ningning Wang, Yubo Fan, Zhong Lin Wang, Wei Hua, Zhou Li","doi":"10.1038/s41551-025-01604-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01604-4","url":null,"abstract":"<p><p>Lifelong pacing is one of the ultimate goals of cardiac pacemakers. However, meeting the critical energy condition for lifelong service is a tremendous challenge. Here we report a symbiotic transcatheter pacemaker that regenerates electric energy from heart motion via electromagnetic induction and surpasses the critical energy condition for lifelong service. The pacemaker can be closely integrated with the body owing to favourable biocompatibility and hemocompatibility, and its small size enables interventional delivery. To minimize energy loss and eliminate mechanical collision and friction, we propose a straightforward magnetic levitation energy cache structure. The energy regeneration module has a near-zero boot threshold, high kinetic energy conversion efficiency and intracardiac root mean square output power. We show the energy regeneration and therapeutic function of the symbiotic transcatheter pacemaker over a month-long autonomous operation in a porcine model of brady-arrhythmia. These advances may provide a potential path to extend the service life of pacemakers to the level of the natural heart.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003922","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 : 2026-01-16DOI: 10.1038/s41551-025-01603-5
Yang Zhang, Shuai Na, Jonathan J Russin, Karteekeya Sastry, Li Lin, Junfu Zheng, Yilin Luo, Xin Tong, Yujin An, Peng Hu, Konstantin Maslov, Tze-Woei Tan, Charles Y Liu, Lihong V Wang
Imaging the human body's morphological and angiographic information is essential for diagnosing, monitoring and treating medical conditions. Here we combine the power of ultrasonography for morphological assessment of soft tissue with photoacoustic tomography (PAT) for visualizing blood vessels to enable three-dimensional (3D) panoramic imaging. Specifically, fast panoramic rotational ultrasound tomography and PAT are integrated for hybrid rotational ultrasound and photoacoustic tomography (RUS-PAT), which obtains 3D ultrasound structural and PAT angiographic images of the human body quasi-simultaneously. The rotational ultrasound tomography functionality is achieved using a single-element ultrasonic transducer for ultrasound transmission and rotating arc-shaped arrays for 3D panoramic detection. By switching the acoustic source to a light source, the system is conveniently converted to PAT mode to acquire angiographic images in the same region. Using RUS-PAT, we successfully imaged the human head, breast, hand and foot with a 10-cm-diameter field of view, submillimetre isotropic resolution and 10 s imaging time for each modality. 3D RUS-PAT is a powerful tool for high-speed, dual-contrast imaging of the human body with potential for rapid clinical translation.
{"title":"Rotational ultrasound and photoacoustic tomography of the human body.","authors":"Yang Zhang, Shuai Na, Jonathan J Russin, Karteekeya Sastry, Li Lin, Junfu Zheng, Yilin Luo, Xin Tong, Yujin An, Peng Hu, Konstantin Maslov, Tze-Woei Tan, Charles Y Liu, Lihong V Wang","doi":"10.1038/s41551-025-01603-5","DOIUrl":"10.1038/s41551-025-01603-5","url":null,"abstract":"<p><p>Imaging the human body's morphological and angiographic information is essential for diagnosing, monitoring and treating medical conditions. Here we combine the power of ultrasonography for morphological assessment of soft tissue with photoacoustic tomography (PAT) for visualizing blood vessels to enable three-dimensional (3D) panoramic imaging. Specifically, fast panoramic rotational ultrasound tomography and PAT are integrated for hybrid rotational ultrasound and photoacoustic tomography (RUS-PAT), which obtains 3D ultrasound structural and PAT angiographic images of the human body quasi-simultaneously. The rotational ultrasound tomography functionality is achieved using a single-element ultrasonic transducer for ultrasound transmission and rotating arc-shaped arrays for 3D panoramic detection. By switching the acoustic source to a light source, the system is conveniently converted to PAT mode to acquire angiographic images in the same region. Using RUS-PAT, we successfully imaged the human head, breast, hand and foot with a 10-cm-diameter field of view, submillimetre isotropic resolution and 10 s imaging time for each modality. 3D RUS-PAT is a powerful tool for high-speed, dual-contrast imaging of the human body with potential for rapid clinical translation.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990053","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}
Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.
{"title":"Chemically modified and inactivated bacteria enable intra-biofilm drug delivery and long-term immunity against implant infections.","authors":"Chuang Yang,Qimanguli Saiding,Wei Chen,Soohwan An,Senfeng Zhao,Muhammad Muzamil Khan,Na Kong,Min Ge,Jianlin Shi,Han Lin,Wei Tao","doi":"10.1038/s41551-025-01600-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01600-8","url":null,"abstract":"Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"36 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986524","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 : 2026-01-15DOI: 10.1038/s41551-025-01583-6
Christopher Hughes,Xing Chen,Warren Grill,Takashi D Y Kozai
Sensation plays a pivotal role in the orchestration of our daily lives. Intracortical microstimulation (ICMS) can elicit artificial sensations in persons who have lost sensation due to neurological injury or disease. Despite ongoing clinical studies to assess the safety and efficacy of ICMS, the mechanisms underlying neural activation by ICMS and their implications for perception are not well understood. This Review delves into the current understanding of ICMS mechanisms, drawing parallels with physiological sensory processing in the cortex. We explore emerging approaches and note challenges to current technologies, including resolution and the tissue response to electrode insertion. We conclude by highlighting the basic principles of ICMS, lingering questions and important focus areas for continued development.
{"title":"Neural mechanisms underlying intracortical microstimulation for sensory restoration.","authors":"Christopher Hughes,Xing Chen,Warren Grill,Takashi D Y Kozai","doi":"10.1038/s41551-025-01583-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01583-6","url":null,"abstract":"Sensation plays a pivotal role in the orchestration of our daily lives. Intracortical microstimulation (ICMS) can elicit artificial sensations in persons who have lost sensation due to neurological injury or disease. Despite ongoing clinical studies to assess the safety and efficacy of ICMS, the mechanisms underlying neural activation by ICMS and their implications for perception are not well understood. This Review delves into the current understanding of ICMS mechanisms, drawing parallels with physiological sensory processing in the cortex. We explore emerging approaches and note challenges to current technologies, including resolution and the tissue response to electrode insertion. We conclude by highlighting the basic principles of ICMS, lingering questions and important focus areas for continued development.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"3 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971966","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 : 2026-01-15DOI: 10.1038/s41551-025-01578-3
Xiaoqing Guo, Mohammad Alsharid, He Zhao, Yipei Wang, Jayne Lander, Aris T. Papageorghiou, J. Alison Noble
Freehand fetal ultrasound examinations require substantial clinical skill. Here we propose Sonomate (mate of a sonographer), an AI assistant to a user during fetal ultrasound examinations. Sonomate is based on aligning video features and text features derived from transcribed audio to facilitate real-time interactions between an ultrasound machine and a user. Our approach combines coarse-grained video–text alignment with fine-grained image–sentence alignment to build a robust visually grounded language model capable of understanding fetal ultrasound videos. To tackle the challenges associated with heterogeneous language and asynchronous content in real-world video–audio pairs, we design the anatomy-aware alignment and context label correction in the fine-grained alignment. Sonomate is effective at anatomy detection in fetal ultrasound images without the need for retraining on manually annotated data. Furthermore, Sonomate shows promising performance in visual question answering for both fetal ultrasound images and videos. Guardrails are built to ensure the safety of Sonomate during deployment. This advancement paves the way towards AI-assistive technology being used to support sonography training and enhanced diagnostic capabilities.
{"title":"A visually grounded language model for fetal ultrasound understanding","authors":"Xiaoqing Guo, Mohammad Alsharid, He Zhao, Yipei Wang, Jayne Lander, Aris T. Papageorghiou, J. Alison Noble","doi":"10.1038/s41551-025-01578-3","DOIUrl":"https://doi.org/10.1038/s41551-025-01578-3","url":null,"abstract":"Freehand fetal ultrasound examinations require substantial clinical skill. Here we propose Sonomate (mate of a sonographer), an AI assistant to a user during fetal ultrasound examinations. Sonomate is based on aligning video features and text features derived from transcribed audio to facilitate real-time interactions between an ultrasound machine and a user. Our approach combines coarse-grained video–text alignment with fine-grained image–sentence alignment to build a robust visually grounded language model capable of understanding fetal ultrasound videos. To tackle the challenges associated with heterogeneous language and asynchronous content in real-world video–audio pairs, we design the anatomy-aware alignment and context label correction in the fine-grained alignment. Sonomate is effective at anatomy detection in fetal ultrasound images without the need for retraining on manually annotated data. Furthermore, Sonomate shows promising performance in visual question answering for both fetal ultrasound images and videos. Guardrails are built to ensure the safety of Sonomate during deployment. This advancement paves the way towards AI-assistive technology being used to support sonography training and enhanced diagnostic capabilities.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"266 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968788","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}
Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca2+ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.
{"title":"Intermittent hypobaric pressure induces selective senescent cell death and alleviates age-related osteoporosis.","authors":"Bowen Meng,Yan Qu,Benyi Yang,Chaoran Fu,Yifan He,Jing Li,Rentao Wan,Xin Li,Zhulin Xue,Zeyuan Cao,Meng Hao,Xiao Zhang,Zhe An,Fen Chen,Ruibao Ren,Xueli Mao,Yang Cao,Songtao Shi","doi":"10.1038/s41551-025-01584-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01584-5","url":null,"abstract":"Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca2+ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"15 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968531","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 : 2026-01-14DOI: 10.1038/s41551-025-01597-0
Justin C Rolando,Anton Thieme,Nicole E Weckman,Nayoung Kim,Helena de Puig,Xiao Tan,Emily Cotnoir,Vishnu Chaturvedi,James J Collins,David R Walt
Candida auris, an increasingly prevalent fungal pathogen, requires both rapid identification and antifungal susceptibility testing to enable proper treatment. This study introduces digital SHERLOCK (dSHERLOCK), a platform that combines CRISPR/Cas nucleic acid detection, single-template quantification and real-time kinetics monitoring. Assays implemented on this platform display excellent sensitivity to C. auris from major clades 1-4, while maintaining specificity when challenged with common environmental and pathogenic fungi. dSHERLOCK detects C. auris within 20 min in minimally processed swab samples and achieves sensitive quantification (1 c.f.u. µl-1) within 40 min. To address antifungal susceptibility testing, we develop assays that detect mutations that are commonly associated with azole and echinocandin multidrug resistance. We use machine learning and real-time monitoring of reaction kinetics to achieve highly accurate simultaneous quantification of mutant and wild-type FKS1 SNP alleles in fungal populations with mixed antifungal susceptibility, which would be misdiagnosed as completely susceptible or resistant under standard reaction conditions. Our platform's use of commercially available materials and common laboratory equipment makes C. auris diagnostics widely deployable in global healthcare settings.
{"title":"Digital CRISPR-based diagnostics for quantification of Candida auris and resistance mutations.","authors":"Justin C Rolando,Anton Thieme,Nicole E Weckman,Nayoung Kim,Helena de Puig,Xiao Tan,Emily Cotnoir,Vishnu Chaturvedi,James J Collins,David R Walt","doi":"10.1038/s41551-025-01597-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01597-0","url":null,"abstract":"Candida auris, an increasingly prevalent fungal pathogen, requires both rapid identification and antifungal susceptibility testing to enable proper treatment. This study introduces digital SHERLOCK (dSHERLOCK), a platform that combines CRISPR/Cas nucleic acid detection, single-template quantification and real-time kinetics monitoring. Assays implemented on this platform display excellent sensitivity to C. auris from major clades 1-4, while maintaining specificity when challenged with common environmental and pathogenic fungi. dSHERLOCK detects C. auris within 20 min in minimally processed swab samples and achieves sensitive quantification (1 c.f.u. µl-1) within 40 min. To address antifungal susceptibility testing, we develop assays that detect mutations that are commonly associated with azole and echinocandin multidrug resistance. We use machine learning and real-time monitoring of reaction kinetics to achieve highly accurate simultaneous quantification of mutant and wild-type FKS1 SNP alleles in fungal populations with mixed antifungal susceptibility, which would be misdiagnosed as completely susceptible or resistant under standard reaction conditions. Our platform's use of commercially available materials and common laboratory equipment makes C. auris diagnostics widely deployable in global healthcare settings.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"17 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968532","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/s41551-025-01588-1
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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：