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Intercellular genetic tracing by alternative synthetic Notch signaling. 通过替代合成 Notch 信号进行细胞间基因追踪。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.1038/s41421-024-00721-9
Kuo Liu, Shaohua Zhang, Xinfeng Meng, Hongxin Li, Jingting Zhu, Enci Wang, Muxue Tang, Mingjun Zhang, Bin Zhou, Lixin Wang
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引用次数: 0
Pathogenic BALB/c mice infection model for evaluation of mpox countermeasures. 用于评估 mpox 对策的致病性 BALB/c 小鼠感染模型。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-13 DOI: 10.1038/s41421-024-00739-z
Lin Cheng, Wenqi Huang, Meimei Duan, Zhuohuan Li, Qi Chen, Mingxia Zhang, Zheng Zhang
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引用次数: 0
Programmable broad-spectrum resistance to bacterial blight using targeted insertion in rice. 利用水稻中的靶向插入技术对细菌性枯萎病产生可编程的广谱抗性。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-08 DOI: 10.1038/s41421-024-00714-8
Xuening Zhang, Minglei Song, Yingying Wang, Qi Yao, Rundong Shen, Yifu Tian, Yuming Lu, Jian-Kang Zhu
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引用次数: 0
Developing an erythrocyte‒MHC-I conjugate for cancer treatment. 开发用于癌症治疗的红细胞-MHC-I 结合物。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-01 DOI: 10.1038/s41421-024-00713-9
Yuehua Liu, Xiaoqian Nie, Xingyun Yao, Huafeng Shou, Yang Yuan, Yun Ge, Xiangmin Tong, Hsiang-Ying Lee, Xiaofei Gao

Mature erythrocytes are known to lack major histocompatibility complex (MHC) proteins. However, the presence of MHC molecules on erythrocytes has been occasionally reported, though without a defined function. In this study, we designed erythrocyte conjugated solely with a fusion protein consisting of an antigenic peptide linked to MHC class I (MHC-I) protein, termed MHC-I‒Ery. The modified erythrocyte, decorated with the peptide derived from human papillomavirus (HPV) 16 oncoprotein E6/E7, effectively activated antigen-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from HPV16+ cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8+ T cells and reduced suppressive myeloid cells in the spleen, leading to systemic anti-tumor activity. Safety and tolerability evaluations of MHC-I‒Ery in non-human primates further supported its clinical potential. Our results first demonstrated that erythrocytes equipped solely with antigen peptide‒MHC-I complexes can robustly stimulate the immune system, suggesting a novel and promising approach for advancing cancer immunotherapy.

众所周知,成熟的红细胞缺乏主要组织相容性复合体(MHC)蛋白。不过,偶尔也有报道称红细胞上存在 MHC 分子,但没有明确的功能。在这项研究中,我们设计了仅与一种融合蛋白结合的红细胞,这种融合蛋白由与 MHC I 类蛋白质(MHC-I)相连的抗原肽组成,被称为 MHC-I-Ery。经修饰的红细胞上装饰有来自人类乳头瘤病毒(HPV)16 肿瘤蛋白 E6/E7 的多肽,能有效激活 HPV16+ 宫颈癌患者外周血单核细胞(PBMC)中的抗原特异性 CD8+ T 细胞。此外,MHC-I-Ery 单药疗法还能抑制抗原阳性肿瘤在小鼠体内的生长。这种疗法能立即激活 CD8+ T 细胞,减少脾脏中的抑制性髓细胞,从而产生全身抗肿瘤活性。MHC-I-Ery在非人灵长类动物中的安全性和耐受性评估进一步证实了它的临床潜力。我们的研究结果首次证明了红细胞仅配备抗原肽-MHC-I 复合物就能强有力地刺激免疫系统,为推进癌症免疫疗法提供了一种新颖而有前景的方法。
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引用次数: 0
Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development. 人类胚胎在早期发育过程中存在复杂的嵌合现象,非整倍体细胞广泛存在。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-24 DOI: 10.1038/s41421-024-00719-3
Fan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan, Jie Qiao

Pre-implantation genetic testing for aneuploidy (PGT-A) is used in approximately half of in vitro fertilization cycles. Given the limited understanding of the genetics of human embryos, the current use of PGT-A is based on biologically uncertain assumptions and unvalidated guidelines, leading to the possibility of disposing of embryos with pregnancy potential. We isolated and sequenced all single cells (1133) from in vitro cultured 20 human blastocysts. We found that all blastocysts exhibited mosaicism with mitotic-induced aneuploid cells and showed an ~25% aneuploidy rate per embryo. Moreover, 70% (14/20) of blastocysts contained 'chromosome-complementary' cells, suggesting genetic mosaicism is underestimated in routine PGT-A. Additionally, the analysis of 20,945 single cells from day 8-14 embryos (in vitro cultured) and embryonic/fetal organs showed that 97% of the analyzed embryos/organs were mosaic. Over 96% of their aneuploid cells harbored ≤ 2 chromosome errors. Our findings have revealed a high prevalence of mosaicism in human embryos.

约有一半的体外受精周期使用植入前非整倍体基因检测(PGT-A)。由于对人类胚胎遗传学的了解有限,目前 PGT-A 的使用是基于生物学上不确定的假设和未经验证的指导原则,从而可能导致具有妊娠潜能的胚胎被弃置。我们对体外培养的 20 个人类囊胚的所有单细胞(1133 个)进行了分离和测序。我们发现,所有囊胚都表现出与有丝分裂诱导的非整倍体细胞嵌合,每个胚胎的非整倍体率约为 25%。此外,70%(14/20)的囊胚含有 "染色体互补 "细胞,这表明在常规 PGT-A 中基因嵌合被低估了。此外,对来自第 8-14 天胚胎(体外培养)和胚胎/胎儿器官的 20,945 个单细胞进行的分析表明,97% 的受分析胚胎/器官是镶嵌的。96%以上的非整倍体细胞含有≤2条染色体错误。我们的研究结果表明,人类胚胎中镶嵌现象非常普遍。
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引用次数: 0
Epigenetic editing alleviates Angelman syndrome phenotype in mice by unsilencing paternal Ube3a 表观遗传编辑通过解除父系 Ube3a 的沉默减轻小鼠的安杰曼综合征表型
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00727-3
Yajing Liu, Sensen Lou, Jinhui Li, Yuanhua Liu, Shisheng Huang, Yu Wei, Jikai Liu, Ruimin Lv, Junjie Tang, Zhixin Shen, Yidi Sun, Xingxu Huang, Zhiqi Xiong, Hui Yang, Changyang Zhou
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引用次数: 0
Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer 以 SNRNP200 诱导的剪接失调为靶点,为糖代谢三阴性乳腺癌提供免疫疗法机会
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00715-7
Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.

代谢失调在三阴性乳腺癌(TNBC)中非常突出,但针对癌症代谢的治疗策略却很有限。在这里,我们利用 TNBC 队列(n = 465)的多组学数据,证明了在糖酵解 TNBC 亚型中广泛存在剪接失调和剪接体丰度增加的现象。我们发现 SNRNP200 是葡萄糖驱动的代谢重编程的关键介质。从机理上讲,葡萄糖会诱导 SNRNP200 K1610 处的乙酰化,阻止其蛋白酶体降解。增强的 SNRNP200 会促进关键代谢酶编码基因(GAPDH、ALDOA 和 GSS)的剪接,从而增加乳酸和谷胱甘肽的产生。以 SNRNP200 为靶点的反义寡核苷酸疗法会阻碍肿瘤的新陈代谢,并通过激活瘤内 CD8+ T 细胞同时抑制调节性 T 细胞来提高抗 PD-1 疗法的疗效。在临床上,SNRNP200水平越高,表明糖代谢性TNBC对免疫疗法的反应越差。总之,我们的研究揭示了RNA剪接与代谢失调之间错综复杂的相互作用,为糖代谢性TNBCs的免疫疗法提出了一种创新的组合策略。
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引用次数: 0
Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control 精氨酸-eIF5A 轴对通过翻译控制激活肌肉干细胞至关重要
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00712-w
Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li

Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

成人骨骼肌干细胞又称卫星细胞(SCs),具有静止状态,在受伤时会激活。然而,静止骨骼肌干细胞(QSCs)的活化机制在很大程度上仍不为人知。在这里,我们通过鉴定促进SC活化的调控代谢物,研究了SC活化的代谢调控。通过靶向代谢组学研究,我们发现亚精胺是促进小鼠SC活化和肌肉再生的调节代谢物。从机理上讲,亚精胺通过产生高浓度的 eIF5A 来激活 SC。通过使用 SC 特异性 eIF5A 基因敲除(KO)和 Myod-KO 小鼠,我们进一步发现 eIF5A 是通过控制 MyoD 翻译来实现亚精胺介导的 SC 激活的必要条件。更重要的是,消耗 SC 中的 eIF5A 会导致小鼠肌肉再生能力受损。总之,我们的研究结果确定了一种新的机制,它对 SC 的活化至关重要,并通过精胺-eIF5A 介导的 MyoD 翻译发挥作用。我们的研究结果表明,精胺-eIF5A 轴是激活内源性 SCs 治疗肌肉疾病的一个很有前景的药理靶点。
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引用次数: 0
A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity 条件蛋白质扩散模型可生成具有更强活性的人工可编程内切酶序列
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00728-2
Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong

Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) Kurthia massiliensis Ago (KmAgo) and Pyrococcus furiosus Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.

基于深度学习的功能蛋白质生成方法满足了对新型生物催化剂日益增长的需求,可精确定制功能以满足特定要求。这一进步促使人们开发出高效、特异的蛋白质,并在科学、技术和生物医学领域得到广泛应用。本研究利用条件蛋白质扩散模型(即 CPDiffusion)建立了蛋白质序列生成管道,以创建具有增强功能的多样化蛋白质序列。CPDiffusion 可满足蛋白质的特定条件,如二级结构和高度保守的氨基酸。CPDiffusion 无需依赖大量训练数据,就能有效捕捉特定蛋白质家族的高度保守残基和序列特征。我们根据野生型(WT)Kurthia massiliensis Ago(KmAgo)和Pyrococcus furiosus Ago(PfAgo)的骨架结构,应用CPDiffusion生成了Argonaute(Ago)蛋白的人工序列。生成的序列与它们的 WT 模板最多相差近 400 个氨基酸。实验测试表明,生成的大多数 KmAgo 和 PfAgo 蛋白在 DNA 切割方面都表现出明确的活性,其中许多蛋白的活性比 WT 蛋白更强。这些发现突出表明,CPDiffusion 在为具有复杂结构和功能的蛋白质生成新序列方面取得了显著的成功,从而提高了活性。这种方法有助于通过硅学生成和筛选设计具有多域分子结构和复杂功能的酶,而这一切都不需要标记数据的监督。
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引用次数: 0
Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer. 单细胞和空间蛋白质转录组特征分析揭示了与小细胞肺癌神经内分泌特征相关的免疫浸润异质性。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1038/s41421-024-00703-x
Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

小细胞肺癌(SCLC)是一种侵袭性肺神经内分泌恶性肿瘤,其特点是肿瘤免疫微环境(TIME)寒冷、免疫疗法获益有限且生存率低。目前尚未对 SCLC 中与抗肿瘤免疫显著相关的 TIME 空间异质性进行系统研究。我们对来自 44 例未接受治疗的局限期 SCLC 肿瘤的 132 个组织芯片核进行了超高倍数字空间谱分析。结合来自本地队列的单细胞 RNA 序列数据和已发表的 SCLC 数据,我们建立了一个空间蛋白质转录组图谱,涵盖了 18,000 多个基因和 60 个关键免疫肿瘤学蛋白,这些蛋白参与了影响肿瘤发生、免疫调节和癌症代谢的信号通路,横跨 3 个病理学定义的空间分区(pan-CK 阳性瘤巢;CD45/CD3 阳性肿瘤基质;瘤旁)。我们的研究描绘了SCLC的空间转录组和蛋白质组TIME结构,表明通过典型神经内分泌亚型标志物决定的肿瘤内异质性;揭示了先天性免疫细胞和功能受损的B细胞在肿瘤巢中的富集,并提出了单核细胞/巨噬细胞潜在的重要免疫调节作用。我们发现RE1沉默因子(REST)是SCLC的潜在生物标志物,它与低神经内分泌特征、更活跃的抗肿瘤免疫和生存期延长有关。
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引用次数: 0
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Cell Discovery
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