Cell Death and Differentiation最新文献

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ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure ARHGAP26 缺乏会导致卵母细胞非整倍体和早期胚胎发育失败。

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-23 DOI: 10.1038/s41418-024-01384-5

Sen Li, Yu Zhang, Ruiying Yuan, Shuai Zhu, Jie Bai, Yilong Miao, Xianghong Ou, Qiang Wang, Bo Xiong

Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.

非整倍体（染色体异常）是导致人类自然流产和复发性妊娠流产的主要原因。然而，人们对其潜在的分子机制仍然知之甚少。在这里，我们报告了一个推定的肿瘤抑制基因 ARHGAP26，它是一个新发现的卵母细胞质量调控因子，能维持线粒体的完整性和染色体的非整倍体，从而确保胚胎的正常发育和生育能力。利用基因敲除小鼠模型，我们发现 Arhgap26 基因消减会导致卵母细胞在 GV 阶段因线粒体功能障碍引起的 ROS 积累而死亡。缺失 Arhgap26 还会影响存活卵母细胞的体外和体内成熟，导致成熟停滞和非整倍体，从而导致早期胚胎发育缺陷和不育。转录组分析进一步验证了这些观察结果。从机理上讲，我们发现 Arhgap26 与 Cofilin1 相互作用，通过调节 Drp1 的动态来维持线粒体的完整性，恢复 Arhgap26 蛋白水平可恢复 Arhgap26 缺失卵母细胞的质量。重要的是，我们通过染色体微阵列分析在一位有复发性流产病史的患者体内发现了 ARHGAP26 突变。总之，我们的研究结果揭示了 ARHGAP26 在卵母细胞质量控制和预防非整倍体方面的新功能，并为 ARHGAP26 突变导致的不孕妇女提供了一种潜在的治疗策略。

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引用次数: 0

The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction IDH1-R132H 突变通过破坏 NDUFA1 和 FSP1 的相互作用促进铁变态反应，从而加重顺铂诱导的急性肾损伤

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-22 DOI: 10.1038/s41418-024-01381-8

Kunmei Lai, Zhimin Chen, Siyi Lin, Keng Ye, Ying Yuan, Guoping Li, Yankun Song, Huabin Ma, Tak W. Mak, Yanfang Xu

The IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1’s interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.

IDH1-R132H 突变与多种肿瘤的发病有关。IDH1-R132H突变是否会导致顺铂（一种常见的化疗药物）对IDH1-R132H突变者的肾脏产生更严重的毒性，目前仍不清楚。在这项研究中，我们观察到 IDH1-R132H 突变会加剧线粒体脂质过氧化和肾小管功能障碍，使肾脏更容易受到顺铂诱导的铁中毒的影响。IDH1-R132H 突变增加了 Ndufa1 启动子的甲基化，从而抑制了 NDUFA1 的转录和翻译。这种抑制破坏了 NDUFA1 与 FSP1 的相互作用，降低了 NDUFA1 对顺铂诱导的肾小管上皮细胞死亡的抵抗力。因此，ROS 积累，脂质过氧化发生，铁变态反应被触发，从而促进急性肾损伤。总之，本研究阐明了顺铂诱导肾毒性的新机制，为携带 IDH1-R132H 突变的肿瘤患者制定个性化治疗策略提供了宝贵的见解。

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引用次数: 0

The long non-coding RNA ROSALIND protects the mitochondrial translational machinery from oxidative damage 长非编码 RNA ROSALIND 保护线粒体翻译机制免受氧化损伤

IF 12.4 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-18 DOI: 10.1038/s41418-024-01377-4

Vicky Katopodi, Alessandro Marino, Nikoleta Pateraki, Yvessa Verheyden, Sonia Cinque, Elena Lara Jimenez, Sara Adnane, Ewout Demesmaeker, Alice Scomparin, Rita Derua, Elisabetta Groaz, Eleonora Leucci

Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognising and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNA ROSALIND as an interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity both in vitro and ex vivo in preclinical humanised cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

线粒体呼吸的上调与高 ROS 清除能力是几种癌症耐药细胞的共同特征。由于翻译保真度对细胞健康至关重要，因此保护线粒体和细胞质核糖体免受氧化损伤至关重要。通过进行针对线粒体基质的抗坏血酸聚氧乙烯醚酶（APEX）-邻近连接测定，然后分离与线粒体蛋白相关的 RNA 并进行测序，我们确定了核编码的 lncRNA ROSALIND 是核糖体的相互作用伙伴。ROSALIND在复发性肿瘤中上调，它的表达可以区分黑色素瘤患者队列中对免疫检查点阻断有反应和无反应者。ROSALIND 的 G 含量异常高，是一种氧化底物。因此，抑制 ROSALIND 会导致 ROS 和蛋白质氧化增加，造成严重的线粒体呼吸缺陷。这反过来又损害了黑色素瘤细胞的活力，并增加了临床前人源化癌症模型体外和体内的免疫原性。这些发现强调了 ROSALIND 作为一种新型 ROS 缓冲系统的作用，它能保护线粒体翻译免受氧化应激，并揭示了克服癌症治疗耐药性的潜在治疗策略。

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引用次数: 0

Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3tm1Flv mice 保留 ES 细胞衍生的 129S 基因组会导致 Nlrp3tm1Flv 小鼠 NLRP1 超敏和转录失调

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-17 DOI: 10.1038/s41418-024-01379-2

Felix D. Weiss, Yubell Alvarez, Farhad Shakeri, Anshupa Sahu, Petro Leka, Alesja Dernst, Jessika Rollheiser, Matilde Vasconcelos, Adriana Geraci, Fraser Duthie, Rainer Stahl, Hye Eun Lee, Anne-Kathrin Gellner, Andreas Buness, Eicke Latz, Felix Meissner

Immune response genes are highly polymorphic in humans and mice, with heterogeneity amongst loci driving strain-specific host defence responses. The inadvertent retention of polymorphic loci can introduce confounding phenotypes, leading to erroneous conclusions, and impeding scientific advancement. In this study, we employ a combination of RNAseq and variant calling analyses to identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus, proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency (Nlrp3tm1Flv). We show that the presence of the Nlrp1129S locus leads to an increase in NLRP1B protein expression, and a sensitising of Nlrp3tm1Flv macrophages to NLRP1 inflammasome activation, independent of NLRP3 deficiency. Retention of 129S genome further leads to protein sequence differences and altered gene regulation across multiple cell types, including of the key tissue-resident macrophage marker, TIM4. Using alternative models of NLRP3 deficiency, including a previously undescribed conditional Nlrp3 allele enabling precise temporal and cell-type specific control over Nlrp3 deletion, we further show that NLRP3 contributes to Talabostat-driven IL-1β release. Our study also establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice using RNAseq data. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defence responses.

人类和小鼠的免疫反应基因具有高度的多态性，不同基因座之间的异质性驱动着菌株特异性的宿主防御反应。无意中保留的多态性位点会带来混杂的表型，导致错误的结论，阻碍科学进步。在这项研究中，我们结合使用了 RNAseq 和变异调用分析，在最常用的 NLRP3 缺乏症小鼠模型之一（Nlrp3tm1Flv）中鉴定了 129S 基因组的一个重要区域，包括 Nlrp3 近端高度多态的 Nlrp1 基因座。我们的研究表明，Nlrp1129S 基因座的存在导致 NLRP1B 蛋白表达增加，并使 Nlrp3tm1Flv 巨噬细胞对 NLRP1 炎症小体的激活敏感，而与 NLRP3 缺乏无关。129S 基因组的保留进一步导致蛋白质序列差异和多种细胞类型基因调控的改变，包括关键的组织驻留巨噬细胞标记物 TIM4。利用 NLRP3 缺乏症的替代模型，包括以前未曾描述过的条件性 Nlrp3 等位基因，对 Nlrp3 缺失进行精确的时间和细胞类型特异性控制，我们进一步表明 NLRP3 对 Talabostat 驱动的 IL-1β 释放做出了贡献。我们的研究还建立了一个通用框架，利用 RNAseq 数据鉴定功能相关的 SNPs 并评估转基因小鼠的基因组污染。这样就能将表型明确归因于目标基因，提高宿主防御反应领域研究的精确性和可靠性。

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引用次数: 0

Feeding cancer to death - a triad of aromatic acids reduces tumor growth 喂死癌症--三重芳香酸可减少肿瘤生长

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-12 DOI: 10.1038/s41418-024-01372-9

Audrey Xavier, Ivan Dikic

引用次数: 0

The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation E3连接酶ASB3通过靶向泛素-蛋白酶体降解MAVS来下调抗病毒先天免疫能力

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-12 DOI: 10.1038/s41418-024-01376-5

Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Dongqin Yang, Chunfeng Wang, Yan Zeng

E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-β and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.

E3 泛素连接酶在病毒感染期间对调节抗病毒免疫非常重要。在这里，我们发现在 RNA 病毒（尤其是甲型流感病毒（IAV））存在的情况下，E3 连接酶 Ankyrin repeat and SOCS box-containing protein 3 (ASB3) 会上调。值得注意的是，过表达 ASB3 会抑制仙台病毒（SeV）和 IAV 诱导的 I 型 IFN（IFN-I）反应，而消减 ASB3 则会恢复 SeV 和 H9N2 感染介导的 IFN-β 及其下游干扰素刺激基因（ISGs）的转录。有趣的是，缺乏 ASB3 的动物对 H9N2 和 H1N1 感染的易感性降低。从机理上讲，ASB3 与 MAVS 相互作用，直接介导 K48 链接的多泛素化和 MAVS 在 K297 处的降解，从而抑制 TBK1 和 IRF3 的磷酸化并下调下游抗病毒信号。这些发现确立了 ASB3 作为控制抗病毒信号激活的关键负调控因子的地位，并描述了 ASB3 以前未曾报道过的一种新功能。

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引用次数: 0

Inhibition of nucleo-cytoplasmic proteasome translocation by the aromatic amino acids or silencing Sestrin3—their sensing mediator—is tumor suppressive 通过芳香族氨基酸抑制核-细胞质蛋白酶体转运或沉默Sestrin3--它们的感应介质--具有抑瘤作用

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-12 DOI: 10.1038/s41418-024-01370-x

Ido Livneh, Bertrand Fabre, Gilad Goldhirsh, Chen Lulu, Adar Zinger, Yael Shammai Vainer, Maya Kaduri, Aviva Dahan, Tamar Ziv, Avi Schroeder, Yinon Ben-Neriah, Yaniv Zohar, Victoria Cohen-Kaplan, Aaron Ciechanover

The proteasome, the catalytic arm of the ubiquitin system, is regulated via its dynamic compartmentation between the nucleus and the cytoplasm, among other mechanisms. Under amino acid shortage, the proteolytic complex is translocated to the cytoplasm, where it stimulates proteolysis to supplement recycled amino acids for essential protein synthesis. This response is mediated via the mTOR pathway and the lack of the three aromatic amino acids Tyr, Trp, and Phe (YWF). mTOR activation by supplementation of the triad inhibits proteasome translocation, leading to cell death. We now show that tumoral inherent stress conditions result in translocation of the proteasome from the nucleus to the cytosol. We further show that the modulation of the signaling cascade governed by YWF is applicable also to non-starved cells by using higher concentration of the triad to achieve a surplus relative to all other amino acids. Based on these two phenomena, we found that the modulation of stress signals via the administration of YWF leads to nuclear proteasome sequestration and inhibition of growth of xenograft, spontaneous, and metastatic mouse tumor models. In correlation with the observed effect of YWF on tumors, we found – using transcriptomic and proteomic analyses – that the triad affects various cellular processes related to cell proliferation, migration, and death. In addition, Sestrin3—a mediator of YWF sensing upstream of mTOR—is essential for proteasome translocation, and therefore plays a pro-tumorigenic role, positioning it as a potential oncogene. This newly identified approach for hijacking the cellular “satiety center” carries therefore potential therapeutic implications for cancer.

蛋白酶体是泛素系统的催化臂，通过其在细胞核和细胞质之间的动态分区等机制进行调节。在氨基酸短缺的情况下，蛋白水解复合物会转运到细胞质中，在那里刺激蛋白水解，以补充用于合成必需蛋白质的再生氨基酸。这种反应是通过 mTOR 途径和三种芳香族氨基酸 Tyr、Trp 和 Phe（YWF）的缺乏来介导的。通过补充三元组来激活 mTOR 可抑制蛋白酶体的转运，从而导致细胞死亡。我们现在证明，肿瘤固有的应激条件会导致蛋白酶体从细胞核转位到细胞质。我们还进一步证明，通过使用更高浓度的三聚氰胺来实现相对于所有其他氨基酸的过剩，YWF 对信号级联的调节也适用于非饥饿细胞。基于这两种现象，我们发现通过服用 YWF 调节应激信号可导致核蛋白酶体螯合，并抑制异种移植、自发性和转移性小鼠肿瘤模型的生长。与观察到的 YWF 对肿瘤的影响相关，我们通过转录组和蛋白质组分析发现，三联体影响了与细胞增殖、迁移和死亡相关的各种细胞过程。此外，Sestrin3--mTOR上游YWF感应的介质--对蛋白酶体转运至关重要，因此起着促癌作用，被定位为潜在的致癌基因。因此，这种新发现的劫持细胞 "饱食中心 "的方法对癌症具有潜在的治疗意义。

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引用次数: 0

Correction: John F. R. Kerr (1934–2024) 更正：约翰-科尔（1934-2024）

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-12 DOI: 10.1038/s41418-024-01373-8

Margaret C. Cummings, David L. Vaux, Andreas Strasser, Ruth Kluck

引用次数: 0

Intracellular zinc protects tumours from T cell-mediated cytotoxicity 细胞内锌可保护肿瘤免受 T 细胞介导的细胞毒性影响

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-11 DOI: 10.1038/s41418-024-01369-4

Emily J. Lelliott, Jonathan Naddaf, Katherine Ganio, Jessica Michie, Shelly Wang, Lin Liu, Natasha Silke, Antonio Ahn, Kelly M. Ramsbottom, Amelia J. Brennan, Andrew J. Freeman, Shom Goel, Stephin J. Vervoort, Conor J. Kearney, Paul A. Beavis, Christopher A. McDevitt, John Silke, Jane Oliaro

Tumour immune evasion presents a significant challenge to the effectiveness of cancer immunotherapies. Recent advances in high-throughput screening techniques have uncovered that loss of antigen presentation and cytokine signalling pathways are central mechanisms by which tumours evade T cell immunity. To uncover additional vulnerabilities in tumour cells beyond the well-recognized antigen presentation pathway, we conducted a genome-wide CRISPR/Cas9 screen to identify genes that mediate resistance to chimeric-antigen receptor (CAR)-T cells, which function independently of classical antigen presentation. Our study revealed that loss of core-binding factor subunit beta (CBFβ) enhances tumour cell resistance to T cell killing, mediated through T cell-derived TNF. Mechanistically, RNA-sequencing and elemental analyses revealed that deletion of CBFβ disrupts numerous pathways including those involved in zinc homoeostasis. Moreover, we demonstrated that modulation of cellular zinc, achieved by supplementation or chelation, significantly altered tumour cell susceptibility to TNF by regulating the levels of inhibitor of apoptosis proteins. Consistent with this, treatment of tumour cells with a membrane-permeable zinc chelator had no impact on tumour cell viability alone, but significantly increased tumour cell lysis by CD8+ T cells in a TNF-dependent but perforin-independent manner. These results underscore the crucial role of intracellular zinc in regulating tumour cell susceptibility to T cell-mediated killing, revealing a novel vulnerability in tumour cells that might be exploited for the development of future cancer immunotherapeutics.

肿瘤免疫逃避是对癌症免疫疗法有效性的重大挑战。高通量筛选技术的最新进展发现，抗原递呈和细胞因子信号通路的缺失是肿瘤逃避T细胞免疫的核心机制。为了揭示肿瘤细胞在公认的抗原递呈途径之外的其他弱点，我们进行了一次全基因组CRISPR/Cas9筛选，以确定介导对嵌合抗原受体（CAR）-T细胞产生抗性的基因。我们的研究发现，核心结合因子亚基β（CBFβ）的缺失会增强肿瘤细胞对T细胞杀伤的抵抗力，这种抵抗力是通过T细胞衍生的TNF介导的。从机理上讲，RNA 序列分析和元素分析表明，CBFβ 的缺失破坏了许多通路，包括那些参与锌平衡的通路。此外，我们还证明，通过补充或螯合来调节细胞锌，可通过调节细胞凋亡抑制蛋白的水平，显著改变肿瘤细胞对 TNF 的易感性。与此相一致的是，用一种膜渗透性锌螯合剂处理肿瘤细胞对肿瘤细胞的存活率没有影响，但却以一种依赖 TNF 但不依赖穿孔素的方式显著增加了 CD8+ T 细胞对肿瘤细胞的裂解。这些结果强调了细胞内锌在调节肿瘤细胞对T细胞介导的杀伤敏感性中的关键作用，揭示了肿瘤细胞的一种新的脆弱性，可用于开发未来的癌症免疫疗法。

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引用次数: 0

Correction to: Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis 更正：两种热点突变 p53 小鼠模型在肿瘤发生过程中显示出不同的功能增益。

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation

Pub Date : 2024-09-10 DOI: 10.1038/s41418-024-01366-7

W. Hanel, N. Marchenko, S. Xu, S. Xiaofeng Yu, W. Weng, U. Moll

引用次数: 0

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