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Mast cells: a double-edged sword in inflammation and fibrosis 肥大细胞:炎症和纤维化的双刃剑
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1466491
Xufang Wang, Peipei Zhang, Yuxin Tang, Yanlin Chen, Enchao Zhou, Kun Gao
As one of the key components of the immune system, mast cells are well known for their role in allergic reactions. However, they are also involved in inflammatory and fibrotic processes. Mast cells participate in all the stages of acute inflammatory responses, playing an immunomodulatory role in both innate and adaptive immunity. Mast cell-derived histamine, TNF-α, and IL-6 contribute to the inflammatory processes, while IL-10 mediates the suppression of inflammation. Crosstalk between mast cells and other immune cells is also involved in the development of inflammation. The cell–cell adhesion of mast cells and fibroblasts is crucial for fibrosis. Mast cell mediators, including cytokines and proteases, play contradictory roles in the fibrotic process. Here, we review the double-edged role of mast cells in inflammation and fibrosis.
作为免疫系统的重要组成部分之一,肥大细胞在过敏反应中的作用众所周知。不过,它们也参与炎症和纤维化过程。肥大细胞参与急性炎症反应的所有阶段,在先天性免疫和适应性免疫中发挥免疫调节作用。肥大细胞衍生的组胺、TNF-α和IL-6有助于炎症过程,而IL-10则介导炎症的抑制。肥大细胞与其他免疫细胞之间的相互影响也参与了炎症的发展。肥大细胞和成纤维细胞的细胞间粘附对纤维化至关重要。肥大细胞介质,包括细胞因子和蛋白酶,在纤维化过程中发挥着相互矛盾的作用。在此,我们回顾了肥大细胞在炎症和纤维化中的双刃作用。
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引用次数: 0
An interpretable deep learning framework identifies proteomic drivers of Alzheimer’s disease 可解释的深度学习框架可识别阿尔茨海默病的蛋白质组驱动因素
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1379984
Elena Panizza, Richard A. Cerione
Alzheimer’s disease (AD) is the leading neurodegenerative pathology in aged individuals, but many questions remain on its pathogenesis, and a cure is still not available. Recent research efforts have generated measurements of multiple omics in individuals that were healthy or diagnosed with AD. Although machine learning approaches are well-suited to handle the complexity of omics data, the models typically lack interpretability. Additionally, while the genetic landscape of AD is somewhat more established, the proteomic landscape of the diseased brain is less well-understood. Here, we establish a deep learning method that takes advantage of an ensemble of autoencoders (AEs) — EnsembleOmicsAE–to reduce the complexity of proteomics data into a reduced space containing a small number of latent features. We combine brain proteomic data from 559 individuals across three AD cohorts and demonstrate that the ensemble autoencoder models generate stable latent features which are well-suited for downstream biological interpretation. We present an algorithm to calculate feature importance scores based on the iterative scrambling of individual input features (i.e., proteins) and show that the algorithm identifies signaling modules (AE signaling modules) that are significantly enriched in protein–protein interactions. The molecular drivers of AD identified within the AE signaling modules derived with EnsembleOmicsAE were missed by linear methods, including integrin signaling and cell adhesion. Finally, we characterize the relationship between the AE signaling modules and the age of death of the patients and identify a differential regulation of vimentin and MAPK signaling in younger compared with older AD patients.
阿尔茨海默病(AD)是老年人最主要的神经退行性病变,但其发病机制仍存在许多问题,而且至今仍无法治愈。最近的研究工作已经对健康或确诊为阿尔茨海默病的个体进行了多种全息测量。虽然机器学习方法非常适合处理复杂的全息数据,但这些模型通常缺乏可解释性。此外,虽然多发性硬化症的遗传学特征已基本确定,但对患病大脑的蛋白质组特征却不甚了解。在这里,我们建立了一种深度学习方法,利用自动编码器集合(AE)--EnsembleOmicsAE--将蛋白质组学数据的复杂性降低到包含少量潜在特征的精简空间。我们结合了来自三个注意力缺失症队列 559 个个体的大脑蛋白质组学数据,证明了集合自动编码器模型能生成稳定的潜在特征,非常适合下游生物学解释。我们提出了一种基于单个输入特征(即蛋白质)的迭代扰乱来计算特征重要性得分的算法,并证明该算法能识别在蛋白质-蛋白质相互作用中显著富集的信号模块(AE 信号模块)。在用EnsembleOmicsAE得出的AE信号模块中,发现了线性方法所遗漏的AD分子驱动因素,包括整合素信号转导和细胞粘附。最后,我们描述了AE信号模块与患者死亡年龄之间的关系,并发现年轻AD患者与老年AD患者的波形蛋白和MAPK信号调节存在差异。
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引用次数: 0
Aurora B and Aurora C pools at two chromosomal regions collaboratively maintain chromosome alignment and prevent aneuploidy at the second meiotic division in mammalian oocytes 位于两个染色体区域的极光 B 和极光 C 池在哺乳动物卵母细胞减数第二次分裂中协同维持染色体排列并防止非整倍体的发生
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1470981
Anna Kouznetsova, Sonata Valentiniene, Jian-Guo Liu, Tomoya S. Kitajima, Hjalmar Brismar, Christer Höög
Correct chromosome segregation is essential to preserve genetic integrity. The two protein kinases, Aurora B and its meiotic homolog Aurora C, regulate attachments between chromosomal kinetochores and microtubules, thereby contributing to the accuracy of the chromosome segregation process. Here we performed a detailed examination of the localization and activity of Aurora B/C kinases, their partner Incenp and the kinetochore target Hec1, during the second meiotic division in mouse oocytes. We found that a majority of Aurora B and C changed their localization from the outer kinetochore region of chromosomes at prometaphase II to an inner central region localized between sister centromeres at metaphase II. Depletion of the Aurora B/C pool at the inner central region using the haspin kinase inhibitor 5-iodotubercidin resulted in chromosome misalignments at the metaphase II stage. To further understand the role of the Aurora B/C pool at the central region, we examined the behaviour of single chromatids, that lack a central Aurora B/C pool but retain Aurora B/C at the outer kinetochores. We found that kinetochore-microtubule attachments at single chromatids were corrected at both prometaphase II and metaphase II stages, but that single chromatids compared to paired chromatids were more prone to misalignments following treatment of oocytes with the Aurora B/C inhibitory drugs AZD1152 and GSK1070916. We conclude that the Aurora B/C pool at the inner central region stabilizes chromosome alignment during metaphase II arrest, while Aurora B/C localized at the kinetochore assist in re-establishing chromosome positioning at the metaphase plate if alignment is lost. Collaboratively these two pools prevent missegregation and aneuploidy at the second meiotic division in mammalian oocytes.
正确的染色体分离对保持遗传完整性至关重要。极光 B 及其减数分裂同源物极光 C 这两种蛋白激酶调节染色体动点与微管之间的连接,从而有助于染色体分离过程的准确性。在这里,我们详细研究了小鼠卵母细胞减数第二次分裂过程中极光 B/C 激酶、它们的伙伴 Incenp 和着丝点靶标 Hec1 的定位和活性。我们发现,大多数极光 B 和 C 的定位发生了变化,从原分裂后期染色体的外侧着丝点区域变为分裂后期姐妹中心粒之间的内侧中心区域。使用哈氏激酶抑制剂 5-iodotubercidin 清除内中心区的极光 B/C 池,会导致染色体在分裂后期 II 阶段错位。为了进一步了解中央区极光 B/C 池的作用,我们研究了缺乏中央极光 B/C 池但在外部动点处保留极光 B/C 的单染色单体的行为。我们发现,单染色单体上的动点核-微管附着在原核期 II 和移行期 II 阶段都得到了纠正,但在用极光 B/C 抑制药物 AZD1152 和 GSK1070916 处理卵母细胞后,与成对染色单体相比,单染色单体更容易发生错位。我们得出的结论是,内中心区的极光 B/C 池能在移相Ⅱ停滞期间稳定染色体排列,而定位在着丝点的极光 B/C 则能在排列丢失时帮助染色体在移相板上重新定位。在哺乳动物卵母细胞的第二次减数分裂过程中,这两个库共同防止了染色体的错误分离和非整倍体。
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引用次数: 0
A new microscopy pipeline for studying the initial stages of nuclear and micronuclear rupture and repair 用于研究核和微核破裂与修复初始阶段的新型显微镜管道
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1475095
Melody Di Bona, Samuel F. Bakhoum
Nuclear envelope repair is a fundamental cellular response to stress, especially for cells experiencing frequent nuclear ruptures, such as cancer cells. Moreover, for chromosomally unstable cancer cells, characterized by the presence of micronuclei, the irreversible rupture of these structures constitutes a fundamental step toward cancer progression and therapy resistance. For these reasons, the study of nuclear envelope rupture and repair is of paramount importance. Nonetheless, due to the constraint imposed by the stochastic nature of rupture events, a precise characterization of the initial stage of nuclear repair remains elusive. In this study, we overcame this limitation by developing a new imaging pipeline that deterministically induces rupture while simultaneously imaging fluorescently tagged repair proteins. We provide a detailed step-by-step protocol to implement this method on any confocal microscope and applied it to study the major nuclear repair protein, barrier-to-autointegration factor (BAF). As a proof of principle, we demonstrated two different downstream analysis methods and showed how BAF is differentially recruited at sites of primary and micronuclear rupture. Additionally, we applied this method to study the recruitment at primary nuclei of the inner nuclear membrane protein LEM-domain 2 (LEMD2) and Charged Multivesicular Protein 7 (CHMP7), the scaffolding protein of the endosomal sorting complex required for transport III (ESCRT-III) membrane remodeling complex. The CHMP7-LEMD2 binding is the fundamental step allowing the recruitment of ESCRT-III, which represents the other major nuclear repair mechanism. This demonstrates the method’s applicability for investigating protein dynamics at sites of nuclear and micronuclear envelope rupture and paves the way to more time-resolved studies of nuclear envelope repair.
核包膜修复是细胞对压力的一种基本反应,尤其是对于经常发生核破裂的细胞,如癌细胞。此外,对于以出现微核为特征的染色体不稳定癌细胞来说,这些结构的不可逆破裂是癌症进展和耐药性的基本步骤。因此,对核包膜破裂和修复的研究至关重要。然而,由于破裂事件的随机性所带来的限制,核修复初始阶段的精确特征描述仍然难以捉摸。在本研究中,我们通过开发一种新的成像管道克服了这一限制,该管道可确定性地诱导破裂,同时对荧光标记的修复蛋白进行成像。我们提供了在任何共聚焦显微镜上实施这种方法的详细步骤,并将其用于研究主要的核修复蛋白--屏障-自整合因子(BAF)。作为原理验证,我们演示了两种不同的下游分析方法,并展示了 BAF 在原发性和微核破裂部位的不同招募方式。此外,我们还应用这种方法研究了核内膜蛋白 LEM-domain 2 (LEMD2) 和带电多囊蛋白 7 (CHMP7)在原核的招募情况,LEMD2 和 CHMP7 是运输所需的内体分选复合物 III(ESCRT-III)膜重塑复合物的支架蛋白。CHMP7-LEMD2 的结合是 ESCRT-III 招募的基本步骤,而 ESCRT-III 是另一种主要的核修复机制。这表明该方法适用于研究核和微核包膜破裂部位的蛋白质动态,并为更多时间分辨的核包膜修复研究铺平了道路。
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引用次数: 0
Mechanical force promotes tissue and molecular changes in adipose tissue regeneration post-transplantation 机械力促进移植后脂肪组织再生的组织和分子变化
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1472575
Yuan Ye, Jian Ma, Bing-yang Guo, Xiong-jie Li, Kui-kui Hu, Mei-jun Tan, Liang Zhang
IntroductionFat grafting often yields inconsistent and suboptimal results, necessitating improved fat processing techniques. A stromal vascular fraction (SVF) gel created using mechanical emulsification demonstrates superior retention rates to conventional Coleman fat grafts.MethodsThis study investigated the mechanisms at play by transplanting fat aspirates from liposuction patients—either processed as Coleman fat grafts or further refined into an SVF gel via mechanical shear force—onto the backs of nude mice.ResultsThe retention rate of the SVF gel after transplantation surpassed that observed for Coleman fat. Hematoxylin and eosin (HE) staining and immunofluorescence results demonstrated that the SVF gel group could form new adipose tissue characterized by well-organized mature fat structures. Mechanical shear force application induced increased mesenchymal stem cell abundance. Rather than merely surviving regeneration, fat was regenerated after transplantation, and the regenerated cells were mainly from mice, which was supported by microarray analysis. RNA-seq highlighted 601 genes expressed between SVF gel and Coleman fat groups, with 164 genes upregulated (cell cycle processes), and 437 genes downregulated (lipid metabolism).DiscussionThe application of mechanical shear force reduces the risk of complications and fosters cell proliferation and division, thereby enhancing the retention and regeneration of transplanted fat.
导言脂肪移植往往会产生不一致和不理想的效果,因此需要改进脂肪处理技术。方法本研究通过将吸脂患者抽出的脂肪移植到裸鼠背上,研究其作用机制--这些脂肪既可以作为科尔曼脂肪移植物处理,也可以通过机械剪切力进一步提炼成 SVF 凝胶。结果移植后 SVF 凝胶的保留率超过了科尔曼脂肪的保留率。血红素和伊红(HE)染色和免疫荧光结果表明,SVF凝胶组能形成以组织良好的成熟脂肪结构为特征的新脂肪组织。机械剪切力的应用增加了间充质干细胞的数量。微阵列分析证实,移植后的脂肪不仅没有存活,反而再生了,而且再生细胞主要来自小鼠。RNA-seq突显了SVF凝胶组和科尔曼脂肪组之间有601个基因表达,其中164个基因上调(细胞周期过程),437个基因下调(脂质代谢)。
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引用次数: 0
Editorial: Stem cells and extracellular vesicles in aging-related diseases. 社论:衰老相关疾病中的干细胞和细胞外囊泡。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1467532
Bin Jiang, Li Duan, Junjun Li, Li Yan
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引用次数: 0
The signal that stimulates mammalian embryo development 刺激哺乳动物胚胎发育的信号
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-18 DOI: 10.3389/fcell.2024.1474009
Zoltan Machaty
Embryo development is stimulated by calcium (Ca2+) signals that are generated in the egg cytoplasm by the fertilizing sperm. Eggs are formed via oogenesis. They go through a cell division known as meiosis, during which their diploid chromosome number is halved and new genetic combinations are created by crossing over. During formation the eggs also acquire cellular components that are necessary to produce the Ca2+ signal and also, to support development of the newly formed embryo. Ionized calcium is a universal second messenger used by cells in a plethora of biological processes and the eggs develop a “toolkit”, a set of molecules needed for signaling. Meiosis stops twice and these arrests are controlled by a complex interaction of regulatory proteins. The first meiotic arrest lasts until after puberty, when a luteinizing hormone surge stimulates meiotic resumption. The cell cycle proceeds to stop again in the middle of the second meiotic division, right before ovulation. The union of the female and male gametes takes place in the oviduct. Following gamete fusion, the sperm triggers the release of Ca2+ from the egg’s intracellular stores which in mammals is followed by repetitive Ca2+ spikes known as Ca2+ oscillations in the cytosol that last for several hours. Downstream sensor proteins help decoding the signal and stimulate other molecules whose actions are required for proper development including those that help to prevent the fusion of additional sperm cells to the egg and those that assist in the release from the second meiotic arrest, completion of meiosis and entering the first mitotic cell division. Here I review the major steps of egg formation, discuss the signaling toolkit that is essential to generate the Ca2+ signal and describe the steps of the signal transduction mechanism that activates the egg’s developmental program and turns it into an embryo.
受精精子在卵细胞质中产生的钙(Ca2+)信号刺激胚胎发育。卵子通过卵子发生过程形成。在此过程中,卵子的二倍体染色体数目减半,并通过杂交产生新的基因组合。在形成过程中,卵子还会获得产生 Ca2+ 信号和支持新形成的胚胎发育所需的细胞成分。电离钙是一种通用的第二信使,细胞在大量的生物过程中都会用到它。减数分裂会停止两次,这些停止是由调节蛋白的复杂相互作用控制的。第一次减数分裂停止持续到青春期后,此时黄体生成素激增,刺激减数分裂恢复。在第二次减数分裂中期,即排卵前,细胞周期再次停止。雌配子和雄配子在输卵管中结合。配子融合后,精子引发卵子细胞内储存的 Ca2+ 释放,在哺乳动物中,随后细胞质中会出现重复的 Ca2+ 尖峰,即 Ca2+ 振荡,这种振荡会持续数小时。下游传感蛋白帮助解码信号并刺激其他分子,这些分子的作用是正常发育所必需的,其中包括帮助防止其他精子细胞与卵子融合的分子,以及帮助摆脱第二次减数分裂停滞、完成减数分裂并进入第一次有丝分裂的分子。在此,我将回顾卵子形成的主要步骤,讨论产生 Ca2+ 信号所必需的信号工具包,并描述激活卵子发育程序并将其转化为胚胎的信号转导机制的各个步骤。
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引用次数: 0
Editorial: Advances in translational and applied stem cell biology. 社论:转化和应用干细胞生物学的进展。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1489085
Fangfang Zhu, Yan-Ru Lou, Cheguo Cai, Jianjun Zhou
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引用次数: 0
Spatiotemporal regulation of MELK during mitosis. 有丝分裂过程中 MELK 的时空调控
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1406940
Sreemita Majumdar, Song-Tao Liu

Maternal Embryonic Leucine Zipper Kinase (MELK) has been studied intensively in recent years due to its overexpression in multiple cancers. However, the cell biology of MELK remains less characterized despite its well-documented association with mitosis. Here we report a distinctive pattern of human MELK that translocates from the cytoplasm to cell cortex within 3 min of anaphase onset. The cortex association lasts about 30 min till telophase. The spatiotemporal specific localization of MELK depends on the interaction between its Threonine-Proline (TP) rich domain and kinase associated 1 (KA1) domain, which is regulated by CDK1 kinase and PP4 protein phosphatase. KA1 domains are known to regulate kinase activities through various intramolecular interactions. Our results revealed a new role for KA1 domain to control subcellular localization of a protein kinase.

近年来,由于母体胚胎亮氨酸拉链激酶(MELK)在多种癌症中的过度表达,人们对它进行了深入研究。然而,尽管MELK与有丝分裂的关系已被充分证明,但其细胞生物学特征仍然较少。在这里,我们报告了人类 MELK 的一种独特模式,即在无丝分裂开始后 3 分钟内从细胞质转位到细胞皮层。与皮层的结合持续约 30 分钟,直至端期。MELK 的时空特异性定位取决于其富含苏氨酸-脯氨酸(TP)的结构域与激酶相关 1(KA1)结构域之间的相互作用,这种相互作用受 CDK1 激酶和 PP4 蛋白磷酸酶的调控。已知 KA1 结构域可通过各种分子内相互作用调节激酶活性。我们的研究结果揭示了 KA1 结构域在控制蛋白激酶亚细胞定位方面的新作用。
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引用次数: 0
Identification and validation of ferroptosis-related biomarkers in intervertebral disc degeneration. 椎间盘退行性变中铁质沉积相关生物标记物的鉴定和验证。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1416345
Chenglong Li, Chengshuo Fei, Shiyong Le, Zhongming Lai, Bo Yan, Liang Wang, Zhongmin Zhang

Introduction: Ferroptosis plays a significant role in intervertebral disc degeneration (IDD). Understanding the key genes regulating ferroptosis in IDD could reveal fundamental mechanisms of the disease, potentially leading to new diagnostic and therapeutic targets.

Methods: Public datasets (GSE23130 and GSE70362) and the FerrDb database were analyzed to identify ferroptosis-related genes (DE-FRGs) involved in IDD. Single-cell RNA sequencing data (GSE199866) was used to validate the specific roles and expression patterns of these genes. Immunohistochemistry and Western blot analyses were subsequently conducted in both clinical samples and mouse models to assess protein expression levels across different tissues.

Results: The analysis identified seven DE-FRGs, including MT1G, CA9, AKR1C1, AKR1C2, DUSP1, CIRBP, and KLHL24, with their expression patterns confirmed by single-cell RNA sequencing. Immunohistochemistry and Western blot analysis further revealed that MT1G, CA9, AKR1C1, AKR1C2, DUSP1, and KLHL24 exhibited differential expression during the progression of IDD. Additionally, the study highlighted the potential immune-modulatory functions of these genes within the IDD microenvironment.

Discussion: Our study elucidates the critical role of ferroptosis in IDD and identifies specific genes, such as MT1G and CA9, as potential targets for diagnosis and therapy. These findings offer new insights into the molecular mechanisms underlying IDD and present promising avenues for future research and clinical applications.

简介铁突变在椎间盘退变(IDD)中起着重要作用。了解调控 IDD 中铁细胞减少的关键基因可以揭示该疾病的基本机制,从而有可能找到新的诊断和治疗靶点:方法:分析了公共数据集(GSE23130和GSE70362)和FerrDb数据库,以确定参与IDD的铁突变相关基因(DE-FRGs)。单细胞 RNA 测序数据(GSE199866)用于验证这些基因的特定作用和表达模式。随后对临床样本和小鼠模型进行了免疫组化和 Western 印迹分析,以评估不同组织的蛋白质表达水平:结果:分析发现了7个DE-FRGs,包括MT1G、CA9、AKR1C1、AKR1C2、DUSP1、CIRBP和KLHL24,单细胞RNA测序证实了它们的表达模式。免疫组化和 Western 印迹分析进一步显示,MT1G、CA9、AKR1C1、AKR1C2、DUSP1 和 KLHL24 在 IDD 的进展过程中表现出不同的表达。此外,该研究还强调了这些基因在 IDD 微环境中的潜在免疫调节功能:我们的研究阐明了IDD中铁蛋白沉积的关键作用,并确定了MT1G和CA9等特定基因作为诊断和治疗的潜在靶点。这些发现为了解 IDD 的分子机制提供了新的视角,并为未来的研究和临床应用提供了广阔的前景。
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引用次数: 0
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