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A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM. 冷冻电镜揭示人类巨细胞病毒的同源三聚体 GPCR 结构。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-16 DOI: 10.1038/s41421-024-00684-x
Yanyan Chen, Yang Li, Qingtong Zhou, Zhaotong Cong, Shi Lin, Jiahui Yan, Xianyue Chen, Dehua Yang, Tianlei Ying, Ming-Wei Wang
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引用次数: 0
Author Correction: Identification of an intraocular microbiota. 作者更正:眼内微生物群的鉴定。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-15 DOI: 10.1038/s41421-024-00675-y
Yuhua Deng, Xiaofei Ge, Yan Li, Bin Zou, Xiaofeng Wen, Weirong Chen, Lin Lu, Meifen Zhang, Xiaomin Zhang, Chunmei Li, Chan Zhao, Xiaofeng Lin, Xiulan Zhang, Xinhua Huang, Xiaorong Li, Ming Jin, Guang-Hua Peng, Dongni Wang, Xun Wang, Weiyi Lai, Juanran Liang, Jing Jing Li, Qiaoxing Liang, Liu Yang, Qinfen Zhang, Yinyin Li, Ping Lu, Xiao Hu, Xifang Li, Xiuli Deng, Yu Liu, Yanli Zou, Shixin Guo, Tingting Chen, Yali Qin, Fuhua Yang, Li Miao, Wei Chen, Chi-Chao Chan, Haotian Lin, Yizhi Liu, Richard W J Lee, Lai Wei
{"title":"Author Correction: Identification of an intraocular microbiota.","authors":"Yuhua Deng, Xiaofei Ge, Yan Li, Bin Zou, Xiaofeng Wen, Weirong Chen, Lin Lu, Meifen Zhang, Xiaomin Zhang, Chunmei Li, Chan Zhao, Xiaofeng Lin, Xiulan Zhang, Xinhua Huang, Xiaorong Li, Ming Jin, Guang-Hua Peng, Dongni Wang, Xun Wang, Weiyi Lai, Juanran Liang, Jing Jing Li, Qiaoxing Liang, Liu Yang, Qinfen Zhang, Yinyin Li, Ping Lu, Xiao Hu, Xifang Li, Xiuli Deng, Yu Liu, Yanli Zou, Shixin Guo, Tingting Chen, Yali Qin, Fuhua Yang, Li Miao, Wei Chen, Chi-Chao Chan, Haotian Lin, Yizhi Liu, Richard W J Lee, Lai Wei","doi":"10.1038/s41421-024-00675-y","DOIUrl":"10.1038/s41421-024-00675-y","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11096321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944120","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}
引用次数: 0
Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study. 新型多功能 M10 CAR-T 细胞对 HIV-1 感染者的疗效和安全性:一项 I 期、多中心、单臂、开放标签研究。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-14 DOI: 10.1038/s41421-024-00658-z
Yunyu Mao, Qibin Liao, Youwei Zhu, Mingyuan Bi, Jun Zou, Nairong Zheng, Lingyan Zhu, Chen Zhao, Qing Liu, Li Liu, Jun Chen, Ling Gu, Zhuoqun Liu, Xinghao Pan, Ying Xue, Meiqi Feng, Tianlei Ying, Pingyu Zhou, Zhanshuai Wu, Jian Xiao, Renfang Zhang, Jing Leng, Yongtao Sun, Xiaoyan Zhang, Jianqing Xu

Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

有人提出用嵌合抗原受体 T(CAR-T)细胞治疗 HIV-1,但尚未显示出理想的疗效。在这里,我们报告了新开发的抗HIV-1 CAR-T细胞,它们带有内源性广谱中和抗体(bNAbs)和滤泡归巢受体CXCR5,被称为M10细胞。M10 细胞旨在发挥三重生物功能,包括对 HIV 感染细胞的广泛细胞毒性作用、中和潜伏期逆转后产生的无细胞病毒以及 B 细胞滤泡归巢。在证明了这三方面的生物活性后,M10 细胞通过两次间隔 30 天的异源 M10 细胞输注方案治疗了 18 名 HIV-1 患者,每次输注 M10 细胞后都进行了两次用于激活 HIV-1 储库的利多酰胺刺激。结果,74.3%的M10细胞输注显著抑制了病毒反弹,病毒载量平均下降了67.1%,有10名患者在150天的观察期内细胞相关的HIV-1 RNA水平持续下降(平均下降1.15 log10)。研究还发现,M10 细胞对潜伏病毒库产生了选择性压力。没有观察到与治疗相关的明显不良反应。总之,我们的研究证明了 M10 CAR-T 细胞作为一种新型、安全、有效的治疗方案,在功能性治愈 HIV-1/AIDS 方面的潜力。
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引用次数: 0
A Tau PET tracer PBB3 binds to TMEM106B amyloid fibril in brain. 一种 Tau PET 示踪剂 PBB3 与大脑中的 TMEM106B 淀粉样纤维结合。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-14 DOI: 10.1038/s41421-024-00674-z
Qinyue Zhao, Yun Fan, Wanbing Zhao, You Ni, Youqi Tao, Jiang Bian, Wencheng Xia, Wenbo Yu, Zhen Fan, Cong Liu, Bo Sun, Weidong Le, Wensheng Li, Jian Wang, Dan Li
{"title":"A Tau PET tracer PBB3 binds to TMEM106B amyloid fibril in brain.","authors":"Qinyue Zhao, Yun Fan, Wanbing Zhao, You Ni, Youqi Tao, Jiang Bian, Wencheng Xia, Wenbo Yu, Zhen Fan, Cong Liu, Bo Sun, Weidong Le, Wensheng Li, Jian Wang, Dan Li","doi":"10.1038/s41421-024-00674-z","DOIUrl":"10.1038/s41421-024-00674-z","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921095","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}
引用次数: 0
Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors. 配体识别和激活黑色素浓缩激素受体的机制。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-07 DOI: 10.1038/s41421-024-00679-8
Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, Gi/o, and MCHR2 can only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.

黑色素浓缩激素(MCH)是一种环状神经肽,通过刺激 MCHR1 和 MCHR2 受体来调节食物摄入量、能量平衡和其他生理功能,这两种受体都是 A 类 G 蛋白偶联受体。MCHR1 主要与抑制性 G 蛋白 Gi/o 结合,而 MCHR2 只能与 Gq/11 结合。这里我们展示了 MCH 激活的 MCHR1 与 Gi 和 MCH 激活的 MCHR2 与 Gq 的冷冻电镜结构,其全局分辨率分别为 3.01 Å 和 2.40 Å。这些结构显示,当 MCH 与这两种受体结合时,其半胱氨酸介导的发夹环构型是一致的。在 MCH 的两个半胱氨酸之间,来自 LGRVY 核心基团的中央精氨酸深入跨膜袋,引发受体活化。结合突变和功能方面的见解,我们的发现阐明了配体识别和 MCH 受体激活的分子基础,并为靶向药物设计提供了结构基础。
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引用次数: 0
Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet’s uveitis 性别特异性循环非常规中性粒细胞决定自身炎性贝赫切特葡萄膜炎的免疫结局
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-04 DOI: 10.1038/s41421-024-00671-2
Qingfeng Wang, Junfeng Ma, Yuxing Gong, Lifu Zhu, Huanyu Tang, Xingsheng Ye, Guannan Su, Fanfan Huang, Shiyao Tan, Xianbo Zuo, Yuan Gao, Peizeng Yang

Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet’s uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.

中性粒细胞是最丰富的免疫细胞,它们首先对血液循环中的损伤做出反应。尽管有关联证据表明,中性粒细胞的差异可能与炎症性疾病的性别特异性易感性有关,但机理上的联系仍然难以捉摸。在这里,我们以单细胞分辨率鉴定了正常和自身炎症条件下中性粒细胞组成的广泛性别特异性异质性。通过结合使用单细胞 RNA 测序分析、中性粒细胞特异性基因敲除和转移实验,我们发现了两种非常规(干扰素-α 反应性和 T 细胞调节性)中性粒细胞亚群的失调,这导致了自身炎症性白塞氏葡萄膜炎的男性偏向发病率、严重程度和不良预后。全基因组关联研究(GWAS)和外泌体研究显示,遗传因素和循环外泌体对非常规中性粒细胞亚群的负面影响导致男性易患病。总之,我们的研究结果确定了具有性别特异性的中性粒细胞亚群,并强调非常规中性粒细胞亚群是限制炎症性疾病的性别特异性治疗目标。
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引用次数: 0
Author Correction: Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy. 作者更正:生酮饮食产生的β-羟丁酸可积聚脑内GABA并增加GABA/谷氨酸比率,从而抑制癫痫。
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-30 DOI: 10.1038/s41421-024-00669-w
Ya-Nan Qiao, Lei Li, Song-Hua Hu, Yuan-Xin Yang, Zhen-Zhen Ma, Lin Huang, Yan-Peng An, Yi-Yuan Yuan, Yan Lin, Wei Xu, Yao Li, Peng-Cheng Lin, Jing Cao, Jian-Yuan Zhao, Shi-Min Zhao
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引用次数: 0
Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue 通过个性化内胚层干细胞衍生胰岛组织治疗胰岛功能受损的 2 型糖尿病患者
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-30 DOI: 10.1038/s41421-024-00662-3
Jiaying Wu, Tuo Li, Meng Guo, Junsong Ji, Xiaoxi Meng, Tianlong Fu, Tengfei Nie, Tongkun Wei, Ying Zhou, Weihua Dong, Ming Zhang, Yongquan Shi, Xin Cheng, Hao Yin
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引用次数: 0
Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism 现实世界中 PM2.5 暴露对男性特异性原发性性腺功能减退症的跨代和跨代影响
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-23 DOI: 10.1038/s41421-024-00657-0
Xiaoyu Wei, Zhonghao Zhang, Yayun Gu, Rong Zhang, Jie Huang, Feng Li, Yuanlin He, Shuai Lu, Yifei Wu, Wentao Zeng, Xiaorui Liu, Chenzi Liu, Jin-Yi Liu, L. Ao, Fuquan Shi, Qing Chen, Yuan Lin, Jiangbo Du, G. Jin, Yankai Xia, Hongxia Ma, Yuxin Zheng, Ran Huo, Jia Cao, Hongbing Shen, Zhibin Hu
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引用次数: 0
ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores ANKFY1 是 ATG2A 介导的脂质从内体转移到吞噬细胞的桥梁
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-16 DOI: 10.1038/s41421-024-00659-y
Bin Wei, Yuhui Fu, Xiuzhi Li, Fang Chen, Yiqing Zhang, Hanmo Chen, Mindan Tong, Linsen Li, Yi Pan, Shen Zhang, She Chen, Xiaoxia Liu, Qing Zhong

Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.

大自噬是细胞通过自噬体吞噬细胞质并将其运送到溶酶体进行降解的过程。自噬体的生物生成需要作为脂质转移蛋白的 ATG2 将脂质从现有的膜转移到吞噬体。一般认为,内质网是自噬体形成过程中脂质供应的主要来源;ATG2能否将其他细胞器中的脂质转运到噬菌体中,目前尚无定论。在这项研究中,我们发现了一种新的 ATG2A 结合蛋白 ANKFY1。消耗这种定位在内质体的蛋白会导致自噬体生长受阻和自噬通量降低,这在很大程度上表征了ATG2A/B的消耗。ANKFY1与ATG2A共定位在内质体和吞噬细胞之间,消耗UVRAG、ANKFY1或ATG2A/B会导致PI3P在吞噬细胞上的分布减少。纯化的重组 ANKFY1 通过其 FYVE 结构域与膜上的 PI3P 结合,并增强了 ATG2A 介导的含 PI3P 脂质体之间的脂质转移。因此,我们认为 ANKFY1 将 ATG2A 募集到富含 PI3P 的内体上,并促进 ATG2A 介导的脂质从内体转移到吞噬细胞。这一发现为 ATG2A 介导的吞噬细胞扩张提供了新的脂质来源,即内体通过脂质转移将 PI3P 和其他脂质捐赠给吞噬细胞。
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引用次数: 0
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Cell Discovery
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