Cell ResearchPub Date : 2025-03-25DOI: 10.1038/s41422-025-01101-y
Liujia Qian, Zhen Dong, Tiannan Guo
{"title":"Grow AI virtual cells: three data pillars and closed-loop learning","authors":"Liujia Qian, Zhen Dong, Tiannan Guo","doi":"10.1038/s41422-025-01101-y","DOIUrl":"10.1038/s41422-025-01101-y","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"319-321"},"PeriodicalIF":25.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699788","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}
Cell ResearchPub Date : 2025-03-25DOI: 10.1038/s41422-025-01105-8
Panyu Fei, Michael L. Dustin
{"title":"Mechano-pharmacology of T cell receptor specificity","authors":"Panyu Fei, Michael L. Dustin","doi":"10.1038/s41422-025-01105-8","DOIUrl":"10.1038/s41422-025-01105-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"324-325"},"PeriodicalIF":25.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699798","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}
Cell ResearchPub Date : 2025-03-25DOI: 10.1038/s41422-025-01102-x
Biyun Zhu, Shao Wei Hu, Yilai Shu
{"title":"Identification of a GPCR as a tip link-independent equilibrioceptor","authors":"Biyun Zhu, Shao Wei Hu, Yilai Shu","doi":"10.1038/s41422-025-01102-x","DOIUrl":"10.1038/s41422-025-01102-x","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"326-327"},"PeriodicalIF":25.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699790","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}
Cell ResearchPub Date : 2025-03-25DOI: 10.1038/s41422-025-01106-7
Benjamin A. Plog, Leon C. D. Smyth, Jonathan Kipnis
{"title":"The night shift: norepinephrine drives glymphatics","authors":"Benjamin A. Plog, Leon C. D. Smyth, Jonathan Kipnis","doi":"10.1038/s41422-025-01106-7","DOIUrl":"10.1038/s41422-025-01106-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 9","pages":"621-622"},"PeriodicalIF":25.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699802","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}
{"title":"Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells","authors":"Kaiyuan Wang, Bo Ni, Yongjie Xie, Zekun Li, Limei Yuan, Chenyang Meng, Tiansuo Zhao, Song Gao, Chongbiao Huang, Hongwei Wang, Ying Ma, Tianxing Zhou, Yukuan Feng, Antao Chang, Chao Yang, Jun Yu, Wenwen Yu, Fenglin Zang, Yanhui Zhang, Ru-Rong Ji, Xiuchao Wang, Jihui Hao","doi":"10.1038/s41422-025-01098-4","DOIUrl":"10.1038/s41422-025-01098-4","url":null,"abstract":"The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"362-380"},"PeriodicalIF":25.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677992","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}
Cell ResearchPub Date : 2025-03-24DOI: 10.1038/s41422-025-01100-z
Feng Wang, Haijiang Xu, Chendi Zhang, Jialin Xue, Zhuang Li
{"title":"Target DNA-induced filament formation and nuclease activation of SPARDA complex","authors":"Feng Wang, Haijiang Xu, Chendi Zhang, Jialin Xue, Zhuang Li","doi":"10.1038/s41422-025-01100-z","DOIUrl":"10.1038/s41422-025-01100-z","url":null,"abstract":"The short Argonaute-based bacterial defense system, SPARDA (Short Prokaryotic Argonaute and DNase/RNase-APAZ), utilizes guide RNA to target invading complementary DNA and exhibits collateral nuclease activity, leading to cell death or dormancy. However, its detailed mechanisms remain poorly understood. In this study, we investigated the SPARDA system from Novosphingopyxis baekryungensis (NbaSPARDA) and discovered an unexpected filament configuration upon target DNA binding, which strongly correlated with collateral nuclease activity. Filament formation and nuclease activation require a guide–target heteroduplex of sufficient length with perfect complementarity at the central region. A series of cryo-EM structures of NbaSPARDA complexes, loaded with guide RNA, target DNA of varying lengths, and substrate ssDNA, were determined at ~3.0 Å resolution. Structural analyses indicated that guide RNA binding induces dimerization of the NbaSPARDA complex, while target DNA engagement disrupts this dimerization. Further propagation of the guide–target heteroduplex triggers filament formation through a checkpoint mechanism. The NbaSPARDA filament consists of a backbone formed by interlocking short Argonaute proteins, with an inner layer composed of DREN nuclease domains. Filament formation leads to tetramerization of the monomeric DREN nuclease domain, activating its collateral nuclease activity against environmental nucleic acids — a feature leveraged for molecular diagnostics. For bacteria heterologously expressing the NbaSPARDA system, defense against invading bacteriophages and plasmids relies on filament formation. Collectively, these findings illustrate the detailed working mechanism of the NbaSPARDA complex and highlight the importance of its filament formation in host defense.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 7","pages":"510-519"},"PeriodicalIF":25.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01100-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143678022","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}
Cell ResearchPub Date : 2025-03-21DOI: 10.1038/s41422-025-01095-7
Demeng Sun, Xiang Li, Qingning Yuan, Yuanxia Wang, Pan Shi, Huanhuan Zhang, Tao Wang, Wenjing Sun, Shenglong Ling, Yuanchun Liu, Jinglin Lai, Wenqin Xie, Wanchao Yin, Lei Liu, H. Eric Xu, Changlin Tian
{"title":"Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator","authors":"Demeng Sun, Xiang Li, Qingning Yuan, Yuanxia Wang, Pan Shi, Huanhuan Zhang, Tao Wang, Wenjing Sun, Shenglong Ling, Yuanchun Liu, Jinglin Lai, Wenqin Xie, Wanchao Yin, Lei Liu, H. Eric Xu, Changlin Tian","doi":"10.1038/s41422-025-01095-7","DOIUrl":"10.1038/s41422-025-01095-7","url":null,"abstract":"Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures of GPCRs in complex with G protein or GRK in a BAM-bound state have recently been resolved, revealing that BAM can induce biased signaling by directly modulating interactions between GPCRs and these two transducers, no BAM-bound GPCR–arrestin complex structure has yet been determined, limiting our understanding of the full pharmacological profile of BAMs. Herein, we developed a chemical protein synthesis strategy to generate neurotensin receptor 1 (NTSR1) with defined hexa-phosphorylation at its C-terminus and resolved high-resolution cryo-EM structures (2.65–2.88 Å) of NTSR1 in complex with both β-arrestin1 and the BAM SBI-553. These structures revealed a unique “loop engagement” configuration of β-arrestin1 coupling to NTSR1 in the presence of SBI-553, markedly different from the typical “core engagement” configuration observed in the absence of BAMs. This configuration is characterized by the engagement of the intracellular loop 3 of NTSR1 with a cavity in the central crest of β-arrestin1, representing a previously unobserved, arrestin-selective conformation of GPCR. Our findings fill the critical knowledge gap regarding the regulation of GPCR–arrestin interactions and biased signaling by BAMs, which would advance the development of safer and more efficacious GPCR-targeted therapeutics.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 4","pages":"284-295"},"PeriodicalIF":28.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-025-01095-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672367","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}
Cell ResearchPub Date : 2025-03-20DOI: 10.1038/s41422-025-01090-y
Heng Zhang, Nana Cui, Xiong Ma, H. Eric Xu
{"title":"Structural basis of augmenting taurine uptake by the taurine transporter in alleviating cellular senescence","authors":"Heng Zhang, Nana Cui, Xiong Ma, H. Eric Xu","doi":"10.1038/s41422-025-01090-y","DOIUrl":"10.1038/s41422-025-01090-y","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"385-388"},"PeriodicalIF":25.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662892","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}