Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.10.014
Anina N. Lund, Brian H. Kopell, Negar Golestani, Eric Vornholt, Ryan C. Thompson, Lora E. Liharska, Yuyang Luo, Esther Cheng, You Jeong Park, Brian Fennessy, Lilian Wilkins, Deepak A. Kaji, Hannah Silk, Kimia Ziafat, Alice Hashemi, Emily Moya, Claudia Feng, Lisa M. Linares, Ariela Buxbaum Grice, Sabrina Xie, Marysia-Kolbe Rieder, Joseph Scarpa, Prashant Kota, Vanessa Cohen, Brendan Sullivan, Punit Shah, Weiping Ma, Jessica S. Johnson, Gregory M. Miller, Richard Searfoss, Nischal Mahaveer Chand, Pei Wang, Girish N. Nadkarni, Niven R. Narain, Eric J. Nestler, Michael A. Kiebish, Eric E. Schadt, Alexander W. Charney, Noam D. Beckmann
{"title":"Establishing the relationship between brain cellular senescence and brain structure","authors":"Anina N. Lund, Brian H. Kopell, Negar Golestani, Eric Vornholt, Ryan C. Thompson, Lora E. Liharska, Yuyang Luo, Esther Cheng, You Jeong Park, Brian Fennessy, Lilian Wilkins, Deepak A. Kaji, Hannah Silk, Kimia Ziafat, Alice Hashemi, Emily Moya, Claudia Feng, Lisa M. Linares, Ariela Buxbaum Grice, Sabrina Xie, Marysia-Kolbe Rieder, Joseph Scarpa, Prashant Kota, Vanessa Cohen, Brendan Sullivan, Punit Shah, Weiping Ma, Jessica S. Johnson, Gregory M. Miller, Richard Searfoss, Nischal Mahaveer Chand, Pei Wang, Girish N. Nadkarni, Niven R. Narain, Eric J. Nestler, Michael A. Kiebish, Eric E. Schadt, Alexander W. Charney, Noam D. Beckmann","doi":"10.1016/j.cell.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.10.014","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22Epub Date: 2025-12-31DOI: 10.1016/j.cell.2025.11.036
Xuefei Chen, H Diessel Duan, Michael J Hoy, Kalinka Koteva, Michaela Spitzer, Allison K Guitor, Emily Puumala, Aline A Fiebig, Guanggan Hu, Bonnie Yiu, Sommer Chou, Zhuyun Bian, Yeseul Choi, Amelia Bing Ya Guo, Wenliang Wang, Sheng Sun, Nicole Robbins, Anna Floyd Averette, Michael A Cook, Ray Truant, Lesley T MacNeil, Eric D Brown, James W Kronstad, Brian K Coombes, Leah E Cowen, Joseph Heitman, Huilin Li, Gerard D Wright
Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode-of-action studies reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.
{"title":"Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi.","authors":"Xuefei Chen, H Diessel Duan, Michael J Hoy, Kalinka Koteva, Michaela Spitzer, Allison K Guitor, Emily Puumala, Aline A Fiebig, Guanggan Hu, Bonnie Yiu, Sommer Chou, Zhuyun Bian, Yeseul Choi, Amelia Bing Ya Guo, Wenliang Wang, Sheng Sun, Nicole Robbins, Anna Floyd Averette, Michael A Cook, Ray Truant, Lesley T MacNeil, Eric D Brown, James W Kronstad, Brian K Coombes, Leah E Cowen, Joseph Heitman, Huilin Li, Gerard D Wright","doi":"10.1016/j.cell.2025.11.036","DOIUrl":"10.1016/j.cell.2025.11.036","url":null,"abstract":"<p><p>Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode-of-action studies reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"620-639.e28"},"PeriodicalIF":42.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12774453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.022
Linjin Fan, Yulong Wang, Yinghao Wang, Zequn Wang, Xiaofeng Yang, Chudan Liang, Chongguang Yang, Nan Liu, Jun Zheng, Weifang Kang, Pengfei Ye, Pei Sun, Wendi Shi, Xinyi Guo, Weijian Wu, Jian-Rong Yang, Quan Liu, Linna Liu, Jun Qian
The 2018–2020 Ebola virus disease (EVD) epidemic facilitated the emergence of viral mutations, enhancing the potential for host adaptation during sustained human transmission. Here, we identified the Ebola virus (EBOV) glycoprotein V75A (GP-V75A) substitution as a dominant variant during the epidemic. This substitution, located within the receptor-binding domain, emerged early in the outbreak and rapidly reached high prevalence. GP-V75A demonstrated enhanced infectivity in multiple cell lines and murine models. Mechanistically, GP-V75A increased viral GP binding affinity to the host receptor Niemann-Pick C1 (NPC1) and reduced the dependency on endosomal cysteine proteases for entry. Notably, GP-V75A also significantly reduced the efficacy of NPC1-targeting compounds and neutralizing antibodies. Epidemiological analysis indicated that the rise in GP-V75A prevalence coincided with the increase in case number during the outbreak. These findings provide crucial insights into the evolutionary adaptation of EBOV during large-scale outbreaks and underscore the importance of real-time genomic surveillance for improving epidemic preparedness.
{"title":"Molecular characterization of Ebola virus glycoprotein V75A substitution in the 2018–2020 epidemic","authors":"Linjin Fan, Yulong Wang, Yinghao Wang, Zequn Wang, Xiaofeng Yang, Chudan Liang, Chongguang Yang, Nan Liu, Jun Zheng, Weifang Kang, Pengfei Ye, Pei Sun, Wendi Shi, Xinyi Guo, Weijian Wu, Jian-Rong Yang, Quan Liu, Linna Liu, Jun Qian","doi":"10.1016/j.cell.2025.12.022","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.022","url":null,"abstract":"The 2018–2020 Ebola virus disease (EVD) epidemic facilitated the emergence of viral mutations, enhancing the potential for host adaptation during sustained human transmission. Here, we identified the Ebola virus (EBOV) glycoprotein V75A (GP-V75A) substitution as a dominant variant during the epidemic. This substitution, located within the receptor-binding domain, emerged early in the outbreak and rapidly reached high prevalence. GP-V75A demonstrated enhanced infectivity in multiple cell lines and murine models. Mechanistically, GP-V75A increased viral GP binding affinity to the host receptor Niemann-Pick C1 (NPC1) and reduced the dependency on endosomal cysteine proteases for entry. Notably, GP-V75A also significantly reduced the efficacy of NPC1-targeting compounds and neutralizing antibodies. Epidemiological analysis indicated that the rise in GP-V75A prevalence coincided with the increase in case number during the outbreak. These findings provide crucial insights into the evolutionary adaptation of EBOV during large-scale outbreaks and underscore the importance of real-time genomic surveillance for improving epidemic preparedness.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"70 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.034
Sudarshan Pinglay, John T. Atwater, Ran Brosh, Jay Shendure, Matthew T. Maurano, Jef D. Boeke
{"title":"Mammalian genome writing: Unlocking new length scales for genome engineering","authors":"Sudarshan Pinglay, John T. Atwater, Ran Brosh, Jay Shendure, Matthew T. Maurano, Jef D. Boeke","doi":"10.1016/j.cell.2025.12.034","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.034","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"38 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22Epub Date: 2025-12-16DOI: 10.1016/j.cell.2025.11.017
Zhen Long, Yongzhen Yu, Chenyi He, Linhe Xu, Yiming Yan, Zhuoru Li, Zengcai V Guo, Da Mi
The mammalian brain contains diverse neuronal and immune cell types that exhibit dynamic motions in response to distinct extracellular environments. However, technical limitations make it difficult to investigate complex cellular motions in the developing brain in vivo. Here, we establish the intravital imaging of externally immobilized embryos (IMEE) method for long-term, large-field, and deep-depth imaging of mouse embryos, excelling in viewing angle flexibility, procedural simplicity, and functional applicability. Through combining IMEE with in utero retro-orbital injection and topological analysis of vector fields, we characterize distinct neuronal migration patterns and illustrate interactions among neurons, immune cells, and vasculature under physiological conditions and environmental stress during brain development. Our results suggest that neuronal migration guidance and immune surveillance depend on cellular adaptation to the local environment through distinct motion patterns of somata or processes. Our findings provide critical insight into the environmentally adaptive nature of neural cells in the developmental landscape.
{"title":"Intravital observation of neuronal and immune cell dynamics in the developing mammalian brain.","authors":"Zhen Long, Yongzhen Yu, Chenyi He, Linhe Xu, Yiming Yan, Zhuoru Li, Zengcai V Guo, Da Mi","doi":"10.1016/j.cell.2025.11.017","DOIUrl":"10.1016/j.cell.2025.11.017","url":null,"abstract":"<p><p>The mammalian brain contains diverse neuronal and immune cell types that exhibit dynamic motions in response to distinct extracellular environments. However, technical limitations make it difficult to investigate complex cellular motions in the developing brain in vivo. Here, we establish the intravital imaging of externally immobilized embryos (IMEE) method for long-term, large-field, and deep-depth imaging of mouse embryos, excelling in viewing angle flexibility, procedural simplicity, and functional applicability. Through combining IMEE with in utero retro-orbital injection and topological analysis of vector fields, we characterize distinct neuronal migration patterns and illustrate interactions among neurons, immune cells, and vasculature under physiological conditions and environmental stress during brain development. Our results suggest that neuronal migration guidance and immune surveillance depend on cellular adaptation to the local environment through distinct motion patterns of somata or processes. Our findings provide critical insight into the environmentally adaptive nature of neural cells in the developmental landscape.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"528-547.e25"},"PeriodicalIF":42.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.028
Aaron Kilgallon, Rafael Tubelleza, Arutha Kulasinghe
{"title":"Large-scale spatial profiling of the tumor microenvironment","authors":"Aaron Kilgallon, Rafael Tubelleza, Arutha Kulasinghe","doi":"10.1016/j.cell.2025.12.028","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.028","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"178 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.cell.2025.12.016
Xiao-Yan Ge, Jie Cheng, Li-Jun Zhang, Lu-Lu Guo, Rui Xiang, Yan Lu, Shang-Lei Ning, Kai-Yu Wang, Kong-Kai Zhu, Ming-Xin Gao, Yue Li, Yu-Song Zhang, Nai-Kang Rong, Xiang Han, Ming-Hui Zhang, Le Fang, Yun-Fei Xu, Su-Wen Zhao, Qian Li, Fan Yang, Jin-Peng Sun
Oxylipins are important metabolic messengers for normal life activities, and olfactory receptors (ORs) are known for their low affinity for odor and are not considered oxylipin receptors. By developing the “anonymous receptor identification by reverse-G-protein pull-down” (ARIG) method, we identify orphan OR Or5v1/Olfr110 as an oxylipin 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE) receptor. The serum from obese patients with increased BMI showed lower Or5v1/Olfr110-Gs activation compared with normal people. Systemic Or5v1/Olfr110 deficiency or liver-specific Or5v1/Olfr110 deficiency impaired glucose homeostasis, even after stimulation with 12(S)-HEPE. Engagement of 12(S)-HEPE with Olfr110 activated Gs-PKA-pATF2-Cpt1α signaling to reduce obesity through promotion of fatty acid oxidation in liver. Structural aided development of synthetic agonist HOR1-C59 improved glucose homeostasis, which is dependent on Or5v1/Olfr110 expression. Overall, we revealed that a high-affinity oxylipin-sensing OR plays key roles in metabolism. The beneficial effects of HOR1-C59 underscore the therapeutic value of small synthetic compounds that target ORs for disease treatment.
{"title":"Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target","authors":"Xiao-Yan Ge, Jie Cheng, Li-Jun Zhang, Lu-Lu Guo, Rui Xiang, Yan Lu, Shang-Lei Ning, Kai-Yu Wang, Kong-Kai Zhu, Ming-Xin Gao, Yue Li, Yu-Song Zhang, Nai-Kang Rong, Xiang Han, Ming-Hui Zhang, Le Fang, Yun-Fei Xu, Su-Wen Zhao, Qian Li, Fan Yang, Jin-Peng Sun","doi":"10.1016/j.cell.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.016","url":null,"abstract":"Oxylipins are important metabolic messengers for normal life activities, and olfactory receptors (ORs) are known for their low affinity for odor and are not considered oxylipin receptors. By developing the “anonymous receptor identification by reverse-G-protein pull-down” (ARIG) method, we identify orphan OR Or5v1/Olfr110 as an oxylipin 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE) receptor. The serum from obese patients with increased BMI showed lower Or5v1/Olfr110-Gs activation compared with normal people. Systemic Or5v1/Olfr110 deficiency or liver-specific Or5v1/Olfr110 deficiency impaired glucose homeostasis, even after stimulation with 12(S)-HEPE. Engagement of 12(S)-HEPE with Olfr110 activated Gs-PKA-pATF2-Cpt1α signaling to reduce obesity through promotion of fatty acid oxidation in liver. Structural aided development of synthetic agonist HOR1-C59 improved glucose homeostasis, which is dependent on Or5v1/Olfr110 expression. Overall, we revealed that a high-affinity oxylipin-sensing OR plays key roles in metabolism. The beneficial effects of HOR1-C59 underscore the therapeutic value of small synthetic compounds that target ORs for disease treatment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"30 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olfactory receptors (ORs) are a diverse superfamily of G protein-coupled receptors responsible for odor detection that are also implicated in non-olfactory physiological functions. OR6A2, a class II OR, selectively senses medium-chain aldehydes and belongs to a cluster of ORs genetically associated with the “soapy” perception of cilantro. It also modulates macrophage-mediated inflammatory responses. Structural studies of ORs have long been challenging. Using a back-mutation strategy, we engineered a functional OR6A2 variant (bmOR6A2) from a consensus OR6 (consOR6). Structures of bmOR6A2 in complex with aldehydes reveal a novel ligand-recognition mechanism involving a reversible Schiff base linkage with residue K4.60, validated by mass spectrometry. By integrating structures of consOR6, molecular dynamics simulations, and functional assays, we identified a conserved D45.51Y6.55Y7.41 triad critical for activation in class II ORs. These findings establish a practical strategy for decoding odorant recognition, offering new insights into olfaction signaling and applications in fragrance and therapeutic development.
{"title":"Structural decoding of reversible covalent linkage of odorants in human olfactory receptor OR6A2","authors":"Tian Wang, Yiran Wu, Ling Wang, Shanshan Li, Fei Zhao, Lijie Wu, Yue Liu, Jingzi Qin, Qiwen Tan, Junlin Liu, Liting Zeng, Yilin Chen, Shenyuan Gao, Wenqing Shui, Suwen Zhao, Tian Hua, Zhi-Jie Liu","doi":"10.1016/j.cell.2025.12.017","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.017","url":null,"abstract":"Olfactory receptors (ORs) are a diverse superfamily of G protein-coupled receptors responsible for odor detection that are also implicated in non-olfactory physiological functions. OR6A2, a class II OR, selectively senses medium-chain aldehydes and belongs to a cluster of ORs genetically associated with the “soapy” perception of cilantro. It also modulates macrophage-mediated inflammatory responses. Structural studies of ORs have long been challenging. Using a back-mutation strategy, we engineered a functional OR6A2 variant (bmOR6A2) from a consensus OR6 (consOR6). Structures of bmOR6A2 in complex with aldehydes reveal a novel ligand-recognition mechanism involving a reversible Schiff base linkage with residue K<sup>4.60</sup>, validated by mass spectrometry. By integrating structures of consOR6, molecular dynamics simulations, and functional assays, we identified a conserved D<sup>45.51</sup>Y<sup>6.55</sup>Y<sup>7.41</sup> triad critical for activation in class II ORs. These findings establish a practical strategy for decoding odorant recognition, offering new insights into olfaction signaling and applications in fragrance and therapeutic development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"94 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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