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Hypoxia signaling in the adipose tissue. 脂肪组织中的缺氧信号传导
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-03 DOI: 10.1093/jmcb/mjae039
Phu M Huynh, Fenfen Wang, Yu A An

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

肥胖症本身正在全球范围内迅速蔓延,并进一步导致许多其他危及生命的疾病,如糖尿病、心血管疾病和癌症。脂肪组织中氧气供应减少或相对耗氧量增加导致脂肪组织缺氧,这是肥胖症的一个特征。本综述旨在提供有关脂肪组织缺氧信号传导的最新概述。首先,我们总结了文献证据,证明在人类和啮齿类动物肥胖模型中脂肪组织重塑过程中经常观察到缺氧现象。接下来,我们讨论了缺氧诱导因子(HIFs)是如何被调控的,以及脂肪组织是如何对缺氧做出反应的。然后,我们强调了脂肪 HIF-1α 和 HIF-2α 在脂肪组织生物学和肥胖病理学中的不同作用。最后,综述强调了调节脂肪缺氧作为一种治疗途径的重要性,以帮助脂肪组织在功能上适应缺氧条件,最终促进脂肪健康并改善肥胖症的预后。
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引用次数: 0
HIV-1 inhibits IFITM3 expression to promote the infection of megakaryocytes. HIV-1 可抑制 IFITM3 的表达,从而促进巨核细胞的感染。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 DOI: 10.1093/jmcb/mjae042
Cyrine Bentaleb, Souad Adrouche, Jade Finkelstein, Christelle Devisme, Nathalie Callens, Claude Capron, Morgane Bomsel, Fernando Real

Despite an undetectable plasma viral load as a result of antiretroviral therapy, HIV-1-infected individuals with poor immune reconstitution harbor infectious HIV-1 within their platelets. Megakaryocytes, as platelet precursors, are the likely cellular origin of these HIV-1-containing platelets. To investigate the mechanisms that allow megakaryocytes to support HIV-1 infection, we established in vitro models of viral infection using hematopoietic stem cell-derived megakaryocytes and the megakaryocytic MEG-01 cell line. We observed HIV-1 DNA provirus integration into the megakaryocyte cell genome, self-limiting virus production, and HIV-1 protein and RNA compartmentalization, which are hallmarks of HIV-1 infection in myeloid cells. In addition, following HIV-1 infection of megakaryocyte precursors, the expression of interferon-induced transmembrane protein 3 (IFITM3), an antiviral factor constitutively expressed in megakaryocytes, was inhibited in terminally differentiated HIV-1-infected megakaryocytes. IFITM3 knockdown in MEG-01 cells prior to infection led to enhanced HIV-1 infection, indicating that IFITM3 acts as an HIV-1 restriction factor in megakaryocytes. Together, these findings indicate that megakaryocyte precursors are susceptible to HIV-1 infection, leading to terminally differentiated megakaryocytes harboring virus in a process regulated by IFITM3. Megakaryocytes may thus constitute a neglected HIV-1 reservoir that warrants further study in order to develop improved antiretroviral therapies and to facilitate HIV-1 eradication.

尽管抗逆转录病毒疗法可检测到血浆病毒载量,但免疫重建不良的 HIV-1 感染者的血小板中仍潜藏着可感染的 HIV-1。作为血小板前体的巨核细胞可能是这些含有 HIV-1 的血小板的细胞来源。为了研究巨核细胞支持HIV-1感染的机制,我们利用造血干细胞衍生的巨核细胞和巨核细胞MEG-01细胞系建立了病毒感染的体外模型。我们观察到 HIV-1 DNA 前病毒整合到巨核细胞基因组、自限性病毒产生以及 HIV-1 蛋白质和 RNA 区隔化,这些都是 HIV-1 感染骨髓细胞的特征。此外,HIV-1 感染巨核细胞前体后,终末分化的 HIV-1 感染巨核细胞中干扰素诱导跨膜蛋白 3(IFITM3)(一种在巨核细胞中组成表达的抗病毒因子)的表达受到抑制。在感染前敲除 MEG-01 细胞中的 IFITM3 会导致 HIV-1 感染增强,这表明 IFITM3 在巨核细胞中充当 HIV-1 限制因子。这些发现共同表明,巨核细胞前体易受 HIV-1 感染,在 IFITM3 的调控过程中导致终末分化的巨核细胞携带病毒。因此,巨核细胞可能是一个被忽视的 HIV-1 储库,值得进一步研究,以便开发出更好的抗逆转录病毒疗法,促进根除 HIV-1。
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引用次数: 0
ATP promotes protein coacervation through conformational compaction. ATP 通过构象压实促进蛋白质共轭。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 DOI: 10.1093/jmcb/mjae038
Yueling Zhu, Shiyan Lin, Lingshen Meng, Min Sun, Maili Liu, Jingyuan Li, Chun Tang, Zhou Gong

ATP has been recognized as a hydrotrope in the phase separation process of intrinsically disordered proteins (IDPs). Surprisingly, when using the disordered RG/RGG-rich motif from HNRNPG protein as a model system, we discover a biphasic relationship between the ATP concentration and IDP phase separation. We show that at a relatively low ATP concentration, ATP dynamically interacts with the IDP, which neutralizes protein surface charges, promotes intermolecular interactions, and consequently promotes phase separation. We further demonstrate that ATP induces a compact conformation of the IDP, accounting for the reduced solvent exchange rate and lower compression ratio during phase separation. As ATP concentration increases, its hydrotropic properties emerge, leading to the dissolution of the phase-separated droplets. Our finding uncovers a complex mechanism by which ATP molecules modulate the structure, interaction, and phase separation of IDPs, and accounts for the distinct phase separation behaviors for the charge-rich RGG motif and other low-complexity IDPs.

ATP 被认为是本征无序蛋白(IDPs)相分离过程中的一种催化剂。令人惊奇的是,当使用 HNRNPG 蛋白中富含 RG/RGG 的无序结构作为模型系统时,我们发现 ATP 浓度与 IDP 相分离之间存在双相关系。我们发现,在 ATP 浓度相对较低时,ATP 会与 IDP 发生动态相互作用,从而中和蛋白质表面电荷,促进分子间相互作用,进而促进相分离。我们进一步证明,ATP 会诱导 IDP 形成紧凑的构象,这也是相分离过程中溶剂交换率降低和压缩率降低的原因。随着 ATP 浓度的增加,它的趋水特性逐渐显现,从而导致相分离液滴的溶解。我们的发现揭示了 ATP 分子调节 IDP 的结构、相互作用和相分离的复杂机制,并解释了富电荷 RGG 主题和其他低复杂度 IDP 的不同相分离行为。
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引用次数: 0
The FAcilitates Chromatin Transcription complex regulates the ratio of glycolysis to oxidative phosphorylation in neural stem cells. FAcilitates 染色质转录复合物调节神经干细胞中糖酵解与氧化磷酸化的比例。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 DOI: 10.1093/jmcb/mjae017
Yuhan Lou, Litao Wu, Wanlin Cai, Huan Deng, Rong Sang, Shanshan Xie, Xiao Xu, Xin Yuan, Cheng Wu, Man Xu, Wanzhong Ge, Yongmei Xi, Xiaohang Yang

Defects in the FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone composed of SSRP1 and SUPT16H, are implicated in intellectual disability. Here, we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain. We show that the FACT complex binds to the promoter region of the estrogen-related receptor (ERR) gene and positively regulates ERR expression. ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis. Dysfunction of the FACT complex leads to the downregulation of ERR transcription, resulting in a decreased ratio of glycolysis to oxidative phosphorylation (G/O) in neuroblasts. Consequently, neuroblasts exhibit smaller cell sizes, lower proliferation potential, and altered cell fates. Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex. Thus, the G/O ratio, mediated by the FACT complex, plays a crucial role in neuroblast cell fate maintenance. Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.

由 SSRP1 和 SUPT16H 组成的组蛋白伴侣--FAcilitates Chromatin Transcription (FACT) 复合物的缺陷与智力残疾有关。在这里,我们揭示了 FACT 复合物能促进糖酵解,并维持果蝇三龄幼虫中枢大脑神经干细胞/神经母细胞正确的细胞命运。我们发现,FACT复合体与雌激素相关受体(ERR)基因的启动子区域结合,并正向调节ERR的表达。众所周知,ERR 通过上调糖酵解所需的酶,起到有氧糖酵解开关的作用。FACT 复合物功能失调会导致ERR转录下调,从而导致神经母细胞中糖酵解与氧化磷酸化(G/O)的比例下降。因此,神经母细胞表现出细胞体积变小、增殖潜力降低和细胞命运改变。在神经母细胞中过表达ERR或抑制线粒体氧化磷酸化可提高相对G/O比率,并挽救因FACT复合体功能障碍而导致的缺陷表型。因此,由FACT复合体介导的G/O比率在神经母细胞命运维持中起着至关重要的作用。我们的研究可能揭示了FACT复合体突变导致人类智力障碍的机制。
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引用次数: 0
Synergistic regulation of fusion pore opening and dilation by SNARE and synaptotagmin-1. SNARE 和 synaptotagmin-1 对融合孔开放和扩张的协同调控。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 DOI: 10.1093/jmcb/mjae011
Kaiju Li, Kaiyu Li, Jiaqi Fan, Xing Zhang, Chengyan Tao, Yijuan Xiang, Lele Cui, Hao Li, Minghan Li, Yanjing Zhang, Jia Geng, Ying Lai

Fusion pore opening is a transient intermediate state of synaptic vesicle exocytosis, which is highly dynamic and precisely regulated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and synaptotagmin-1 (Syt1). Yet, the regulatory mechanism is not fully understood. In this work, using single-channel membrane fusion electrophysiology, we determined that SNAREpins are important for driving fusion pore opening and dilation but incapable of regulating the dynamics. When Syt1 was added, the closing frequency of fusion pores significantly increased, while the radius of fusion pores mildly decreased. In response to Ca2+, SNARE/Syt1 greatly increased the radius of fusion pores and reduced their closing frequency. Moreover, the residue F349 in the C2B domain of Syt1, which mediates Syt1 oligomerization, was required for clamping fusion pore opening in the absence of Ca2+, probably by extending the distance between the two membranes. Finally, in Ca2+-triggered fusion, the primary interface between SNARE and Syt1 plays a critical role in stabilizing and dilating the fusion pore, while the polybasic region of Syt1 C2B domain has a mild effect on increasing the radius of the fusion pore. In summary, our results suggest that Syt1, SNARE, and the anionic membrane synergically orchestrate the dynamics of fusion pore opening in synaptic vesicle exocytosis.

融合孔开放是突触小泡外渗过程中的一个短暂中间状态,它是高度动态的,并受到可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合物和突触标记蛋白-1(Syt1)的精确调控。然而,其调控机制尚不完全清楚。在这项工作中,我们使用单通道膜融合电生理学方法确定了 SNAREpins 对于驱动融合孔的打开和扩张非常重要,但却无法调节其动态。加入 Syt1 后,融合孔的关闭频率显著增加,而融合孔的半径则轻度减小。在 Ca2+ 的作用下,SNARE/Syt1 大大增加了融合孔的半径,降低了其关闭频率。此外,Syt1 C2B结构域中介导Syt1寡聚化的残基F349是在无Ca2+情况下钳制融合孔开放所必需的,这可能是通过延长两膜之间的距离实现的。最后,在 Ca2+ 触发的融合过程中,SNARE 和 Syt1 之间的主界面在稳定和扩张融合孔方面起着关键作用,而 Syt1 C2B 结构域的多基区对增加融合孔半径有轻微影响。总之,我们的研究结果表明,Syt1、SNARE和阴离子膜协同协调了突触小泡外排过程中融合孔开放的动力学。
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引用次数: 0
Chromothripsis: an emerging crossroad from aberrant mitosis to therapeutic opportunities. 染色体三分裂:从异常有丝分裂到治疗机会的新兴十字路口。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 DOI: 10.1093/jmcb/mjae016
Umer Ejaz, Zhen Dou, Phil Y Yao, Zhikai Wang, Xing Liu, Xuebiao Yao

Chromothripsis, a type of complex chromosomal rearrangement originally known as chromoanagenesis, has been a subject of extensive investigation due to its potential role in various diseases, particularly cancer. Chromothripsis involves the rapid acquisition of tens to hundreds of structural rearrangements within a short period, leading to complex alterations in one or a few chromosomes. This phenomenon is triggered by chromosome mis-segregation during mitosis. Errors in accurate chromosome segregation lead to formation of aberrant structural entities such as micronuclei or chromatin bridges. The association between chromothripsis and cancer has attracted significant interest, with potential implications for tumorigenesis and disease prognosis. This review aims to explore the intricate mechanisms and consequences of chromothripsis, with a specific focus on its association with mitotic perturbations. Herein, we discuss a comprehensive analysis of crucial molecular entities and pathways, exploring the intricate roles of the CIP2A-TOPBP1 complex, micronuclei formation, chromatin bridge processing, DNA damage repair, and mitotic checkpoints. Moreover, the review will highlight recent advancements in identifying potential therapeutic targets and the underlying molecular mechanisms associated with chromothripsis, paving the way for future therapeutic interventions in various diseases.

染色体三分裂(Chromothripsis)是一种复杂的染色体重排,最初被称为染色体基因突变(chromoanagenesis),由于其在各种疾病(尤其是癌症)中的潜在作用,一直是广泛研究的主题。染色体三分裂是指在短时间内迅速获得数十至数百个结构重排,导致一条或几条染色体发生复杂的改变。这种现象是由有丝分裂过程中染色体的错误分离引发的。染色体准确分离的错误会导致微核或染色质桥等异常结构实体的形成。染色质三分裂与癌症之间的关联引起了人们的极大兴趣,并对肿瘤发生和疾病预后产生了潜在影响。本综述旨在探讨染色质三分裂的复杂机制和后果,特别关注染色质三分裂与有丝分裂扰动的关联。在此,我们将讨论对关键分子实体和途径的全面分析,探讨 CIP2A-TOPBP1 复合物、微核形成、染色质桥处理、DNA 损伤修复和有丝分裂检查点的复杂作用。此外,该综述还将重点介绍在确定潜在治疗靶点和与染色质三分裂相关的潜在分子机制方面取得的最新进展,从而为未来对各种疾病的治疗干预铺平道路。
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引用次数: 0
Phase separation of hnRNPA1 and TERRA regulates telomeric stability. hnRNPA1 和 TERRA 的相分离调节端粒的稳定性。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-23 DOI: 10.1093/jmcb/mjae037
Ziyan Xu, Yongrui Liu, Fudong Li, Yi Yang, Hong Zhang, Xing Liu, Xin Xie, Xianjun Chen, Yunyu Shi, Liang Zhang

Telomeres are repetitive DNA sequences and associated protein complexes located at the end of chromatin. As a result of the DNA replication ending issue, telomeric DNA shortens during each cell cycle. The shelterin protein complex caps telomeric ends and forms a high-order protein-DNA structure to protect telomeric DNA. The stability of telomeres is critical for cellular function and is related to the progression of many human diseases. Telomeric repeat-containing RNA (TERRA) is a noncoding RNA transcribed from telomeric DNA regions. TERRA plays an essential role in regulating and maintaining the stability of telomeres. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes. HnRNPA1 can recognize both TERRA and telomeric DNA. Previous research reported that hnRNPA1, TERRA, and POT1, a component of the shelterin complex, worked coordinately and displaced replication protein A from telomeric ssDNA after DNA replication, promoting telomere capping to preserve genomic integrity. However, the detailed molecular mechanism has remained unclear for over twenty years. Our study revealed the molecular structure through which the hnRNPA1 UP1 domain interacts with TERRA. Through structural analysis, we identified critical residues on the interacting surface between UP1 and TERRA. Furthermore, we proved that nucleic acids significantly increase the phase separation ability of hnRNPA1 and disrupting the UP1-TERRA interaction extraordinarily affects hnRNPA1 droplet formation both in vitro and in vivo. Taken together, these data revealed the molecular mechanism of the droplet formation of hnRNPA1 and TERRA and the possible function of the droplets for maintaining genomic stability.

端粒是位于染色质末端的重复 DNA 序列和相关蛋白质复合物。由于DNA复制结束的问题,端粒DNA在每个细胞周期中都会缩短。庇护蛋白复合物覆盖端粒末端,形成高阶蛋白-DNA 结构,保护端粒 DNA。端粒的稳定性对细胞功能至关重要,并与许多人类疾病的进展有关。含端粒重复序列的RNA(TERRA)是一种从端粒DNA区域转录的非编码RNA。TERRA 在调节和维持端粒稳定性方面发挥着重要作用。异质核核糖核蛋白(hnRNPs)是与复杂多样的生物过程相关的 RNA 结合蛋白。HnRNPA1 可识别 TERRA 和端粒 DNA。以前的研究报告称,hnRNPA1、TERRA 和庇护蛋白复合物的一个成分 POT1 协同工作,在 DNA 复制后将复制蛋白 A 从端粒 ssDNA 中移除,促进端粒封顶以保持基因组完整性。然而,详细的分子机制二十多年来一直不清楚。我们的研究揭示了 hnRNPA1 UP1 结构域与 TERRA 相互作用的分子结构。通过结构分析,我们确定了 UP1 与 TERRA 相互作用表面上的关键残基。此外,我们还证明了核酸能显著提高 hnRNPA1 的相分离能力,而破坏 UP1 与 TERRA 的相互作用会极大地影响 hnRNPA1 在体外和体内的液滴形成。综上所述,这些数据揭示了 hnRNPA1 和 TERRA 形成液滴的分子机制以及液滴在维持基因组稳定性方面的可能功能。
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引用次数: 0
Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression. Temsirolimus 可抑制 FSP1 酶的活性,从而诱导铁变态反应,抑制肝癌的进展。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-23 DOI: 10.1093/jmcb/mjae036
Rui-Lin Tian, Tian-Xiang Wang, Zi-Xuan Huang, Zhen Yang, Kun-Liang Guan, Yue Xiong, Pu Wang, Dan Ye

Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation. While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an anti-tumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and FDA-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mTOR inhibitor, its ferroptosis-inducing effect is primarily attributed to its inhibition of FSP1 rather than mTOR activity. By performing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multi-target ferroptosis-inducing agents to circumvent resistance to ferroptosis in liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.

铁凋亡是一种非凋亡性细胞死亡模式,其特点是铁依赖性脂质过氧化物的积累。由谷胱甘肽过氧化物酶 4(GPX4)催化的脂质自由基消除反应是一种主要的抗铁细胞凋亡机制,通过药物抑制这一途径有望成为一种抗肿瘤策略。然而,某些肿瘤细胞在脂质自由基消除途径上表现出冗余性,导致它们对 GPX4 抑制剂无反应。在这项研究中,我们对不同的癌细胞系和美国食品与药物管理局(FDA)批准的药物进行了筛选,最终发现替米考星(temsirolimus)与 GPX4 抑制剂 RSL3 联用可有效诱导肝癌细胞中的铁变态反应。从机理上讲,替米考星通过直接结合和抑制铁氧化抑制蛋白1(FSP1)酶,使肝癌细胞对铁氧化敏感。值得注意的是,虽然替莫司被认为是一种强效的mTOR抑制剂,但其诱导铁变态反应的作用主要归因于对FSP1的抑制,而不是mTOR活性。通过体外集落形成试验和体内肿瘤异种移植模型,我们证明了替西罗莫司和 RSL3 的组合能有效抑制肝脏肿瘤的进展。这种杀瘤作用与脂质过氧化反应的增加和铁变态反应的诱导有关。总之,我们的研究结果强调了结合多靶点铁蛋白沉降诱导剂来规避肝癌细胞对铁蛋白沉降的耐药性的潜力,并突出了替西罗莫司作为一种有前景的FSP1抑制剂和铁蛋白沉降诱导剂,在转化医学中也值得进一步研究。
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引用次数: 0
Unleashing the power of antigen-presenting neutrophils. 释放抗原递呈中性粒细胞的力量
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-16 DOI: 10.1093/jmcb/mjae034
Yingcheng Wu, Jiaqiang Ma, Qiang Gao
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引用次数: 0
Probing centromere-kinetochore core complex CENP-L/M assembly using cenpemlin. 使用 cenpemlin 探测中心粒-着丝点核心复合体 CENP-L/M 的组装。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-06 DOI: 10.1093/jmcb/mjae035
Olanrewaju Ayodeji Durojaye, Fengrui Yang, Xinjiao Gao, Felix Aikhionbare, Liangyu Zhang, Xing Liu, Xuebiao Yao
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引用次数: 0
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Journal of Molecular Cell Biology
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