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Modulation of ATM enhances DNA repair in G2/M phase of cell cycle and averts senescence in Fuchs endothelial corneal dystrophy. 在福氏内皮角膜营养不良症患者中,调节ATM可增强细胞周期G2/M期的DNA修复并避免衰老。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-10 DOI: 10.1038/s42003-024-07179-1
Shazia Ashraf, Neha Deshpande, Queenie Cheung, Jeffrey Boakye Asabere, Raymond Jeff Wong, Alex G Gauthier, Mohit Parekh, Yadav Adhikari, Geetha Melangath, Ula V Jurkunas

Fuchs Endothelial Corneal Dystrophy (FECD) is an aging disorder characterized by expedited loss of corneal endothelial cells (CEnCs) and heightened DNA damage compared to normal CEnCs. We previously established that ultraviolet-A (UVA) light causes DNA damage and leads to FECD phenotype in a non-genetic mouse model. Here, we demonstrate that acute treatment with chemical stressor, menadione, or physiological stressors, UVA, and catechol estrogen (4-OHE2), results in an early and increased activation of ATM-mediated DNA damage response in FECD compared to normal CEnCs. Acute stress with UVA and 4OHE2 causes (i) greater cell-cycle arrest and DNA repair in G2/M phase, and (ii) greater cytoprotective senescence in NQO1-/- compared to NQO1+/+ cells, which was reversed upon ATM inhibition. Chronic stress with UVA and 4OHE2 results in ATM-driven cell-cycle arrest in G0/G1 phase, reduced DNA repair, and cytotoxic senescence, due to sustained damage. Likewise, UVA-induced cell-cycle reentry, gamma-H2AX foci, and senescence-associated heterochromatin were reduced in Atm-null mice. Remarkably, inhibiting ATM activation with KU-55933 restored DNA repair in G2/M phase and attenuated senescence in chronic cellular model of FECD lacking NQO1. This study provides insights into understanding the pivotal role of ATM in regulating cell-cycle, DNA repair, and senescence, in oxidative-stress disorders like FECD.

富克斯内皮性角膜营养不良症(FECD)是一种衰老性疾病,其特征是角膜内皮细胞(CEnCs)加速丧失,与正常的CEnCs相比,DNA损伤加剧。我们以前曾在一个非遗传小鼠模型中证实,紫外线 A(UVA)光会导致 DNA 损伤并导致 FECD 表型。在这里,我们证明了与正常 CEnCs 相比,用化学应激源 menadione 或生理应激源 UVA 和儿茶酚雌激素(4-OHE2)进行急性处理会导致 FECD 早期激活 ATM 介导的 DNA 损伤反应。与 NQO1+/+ 细胞相比,UVA 和 4-OHE2 的急性应激会导致 (i) 更大的细胞周期停滞和 G2/M 期的 DNA 修复,以及 (ii) 更大的细胞保护性衰老,这种衰老在抑制 ATM 后被逆转。UVA和4OHE2的慢性应激会导致ATM驱动的细胞周期停滞在G0/G1期,DNA修复能力降低,并由于持续损伤而导致细胞毒性衰老。同样,在Atm-null小鼠中,UVA诱导的细胞周期重入、γ-H2AX病灶和衰老相关异染色质也减少了。值得注意的是,在缺乏 NQO1 的 FECD 慢性细胞模型中,用 KU-55933 抑制 ATM 的活化可恢复 G2/M 期的 DNA 修复并减轻衰老。这项研究为了解ATM在氧化应激性疾病(如FECD)中调节细胞周期、DNA修复和衰老的关键作用提供了见解。
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引用次数: 0
The kinase NEK6 positively regulates LSD1 activity and accumulation in local chromatin sub-compartments. 激酶 NEK6 可正向调节 LSD1 的活性和在局部染色质亚区块中的积累。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-10 DOI: 10.1038/s42003-024-07199-x
Franziska Knodel, Jürgen Eirich, Sabine Pinter, Stephan A Eisler, Iris Finkemeier, Philipp Rathert

LSD1 plays a crucial role in mammalian biology, regulated through interactions with coregulators and post-translational modifications. Here we show that the kinase NEK6 stimulates LSD1 activity in cells and observe a strong colocalization of NEK6 and LSD1 at distinct chromatin sub-compartments (CSCs). We demonstrate that LSD1 is a substrate for NEK6 phosphorylation at the N-terminal intrinsically disordered region (IDR) of LSD1, which shows phase separation behavior in vitro and in cells. The LSD1-IDR is important for LSD1 activity and functions to co-compartmentalize NEK6, histone peptides and DNA. The subsequent phosphorylation of LSD1 by NEK6 supports the concentration of LSD1 at these distinct CSCs, which is imperative for dynamic control of transcription. This suggest that phase separation is crucial for the regulatory function of LSD1 and our findings highlight the role of NEK6 in modulating LSD1 activity and phase separation, expanding our understanding of LSD1 regulation and its implications in cellular processes.

LSD1 在哺乳动物生物学中发挥着至关重要的作用,通过与核心调控因子的相互作用和翻译后修饰进行调控。在这里,我们发现激酶 NEK6 可刺激细胞中 LSD1 的活性,并观察到 NEK6 和 LSD1 在不同染色质亚区(CSCs)中的强烈共定位。我们证明 LSD1 是 NEK6 在 LSD1 N 端本征无序区(IDR)磷酸化的底物,该区域在体外和细胞中表现出相分离行为。LSD1-IDR 对 LSD1 的活性非常重要,并具有将 NEK6、组蛋白肽和 DNA 共同分隔的功能。随后 NEK6 对 LSD1 的磷酸化支持了 LSD1 在这些不同的 CSC 上的浓度,这对于动态控制转录至关重要。这表明相分离对 LSD1 的调控功能至关重要,我们的研究结果突出了 NEK6 在调节 LSD1 活性和相分离中的作用,从而拓展了我们对 LSD1 调控及其在细胞过程中的意义的认识。
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引用次数: 0
Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness. 乌头脱羧酶 1 在神经炎症引起的丘脑室旁功能障碍和嗜睡中的保护作用
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-10 DOI: 10.1038/s42003-024-07215-0
Jianjun Chang, Zijie Li, Hui Yuan, Xuejiao Wang, Jingyi Xu, Pingting Yang, Ling Qin

Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep-wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. Our findings highlight PVT's role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.

嗜睡通常与神经炎症有关,但其潜在的神经调节机制仍不清楚。以前的研究表明,丘脑室旁区(PVT)在调节睡眠-觉醒动态中起着至关重要的作用;因此,丘脑室旁区的神经异常可能是神经炎症诱发嗜睡的原因之一。为了验证这一假设,我们对接受脂多糖(LPS)治疗的小鼠进行了脑电图记录,发现小鼠表现出持续 7 天的暂时性嗜睡。利用 Fos-TRAP 方法、纤维光度记录和免疫荧光染色,我们检测到了从 LPS 处理后第 1 天到第 7 天的暂时性 PVT 神经元低活化和小胶质细胞活化。结合大量和单细胞 RNA 测序的结果,我们发现 LPS 处理后 PVT 小胶质细胞中的丙酮脱羧酶 1(Acod1)上调。为了研究 Acod1 的作用,我们通过立体定向注射短发夹 RNA 腺病毒来操纵 Acod1 在 PVT 小胶质细胞中的基因表达。敲除 Acod1 会加剧炎症、神经元低活化和嗜睡。伊塔康酸是由 Acod1 编码的酶合成的代谢产物。最后,我们证实,外源性服用伊它康酸衍生物伊它康酸 4-辛酯可抑制小胶质细胞活化、缓解神经元功能障碍和嗜睡。我们的研究结果突显了PVT在炎症诱导的嗜睡中的作用,并建议将Acod1作为神经炎症的潜在治疗靶点。
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引用次数: 0
Single-cell transcriptomic and cross-species comparison analyses reveal distinct molecular changes of porcine testes during puberty. 单细胞转录组和跨种比较分析揭示了猪睾丸在青春期的独特分子变化。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07163-9
Xiaoyan Wang, Yang Wang, Yu Wang, Yifei Guo, Ruojun Zong, Shuaitao Hu, Jingwei Yue, Jing Yao, Chunsheng Han, Jingtao Guo, Jianguo Zhao

The pig is an important model for studying human diseases and is also a significant livestock species, yet its testicular development remains underexplored. Here, we employ single-cell RNA sequencing to characterize the transcriptomic landscapes across multiple developmental stages of Bama pig testes from fetal stage through infancy, puberty to adulthood, and made comparisons with those of humans and mice. We reveal an exceptionally early onset of porcine meiosis shortly after birth, and identify a distinct subtype of porcine spermatogonia resembling transcriptome state 0 spermatogonial stem cells identified in humans, which were previously thought to be primate specific. We also discover the persistent presence of proliferating progenitors for myoid cells in postnatal testes. The regulatory roles of Leydig cell steroidogenesis and estrogen synthesis in supporting cell lineages are also explored, including the potential impact of estrogen on Sertoli cell maturation and spermatogenesis. Overall, this study offers valuable insights into porcine testicular development, paving the way for future research in reproductive biology, advancements in agricultural breeding, and potential applications in translational medicine.

猪是研究人类疾病的重要模型,也是重要的家畜物种,但对其睾丸发育的研究仍然不足。在这里,我们采用单细胞 RNA 测序技术描述了巴马猪睾丸从胎儿期、婴儿期、青春期到成年期多个发育阶段的转录组图谱,并与人类和小鼠的转录组图谱进行了比较。我们发现猪的减数分裂在出生后不久就开始了,而且猪精原细胞的亚型与人类精原干细胞的转录组状态0相似,以前认为这是灵长类动物特有的亚型。我们还发现产后睾丸中持续存在增殖的肌样细胞祖细胞。我们还探讨了Leydig细胞类固醇生成和雌激素合成在支持细胞系中的调节作用,包括雌激素对Sertoli细胞成熟和精子发生的潜在影响。总之,这项研究为猪的睾丸发育提供了宝贵的见解,为未来的生殖生物学研究、农业育种的进步以及转化医学的潜在应用铺平了道路。
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引用次数: 0
Helicobacter pylori outer membrane vesicles directly promote Aβ aggregation and enhance Aβ toxicity in APP/PS1 mice. 幽门螺杆菌外膜囊泡可直接促进 APP/PS1 小鼠体内 Aβ 的聚集并增强 Aβ 的毒性。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07125-1
Dongli Meng, Yiwen Lai, Lun Zhang, Wenting Hu, Hui Wei, Cuiping Guo, Xiaopeng Jing, Huan Zhou, Rui Xiao, Liping Zhu, Shengquan Luo, Zhendong Xu, Yu Chen, Xiaochuan Wang, Rong Liu, Ji Zeng

Helicobacter pylori (H. pylori) infection has been found associated with Alzheimer's disease (AD) with unclear mechanisms. Outer Membrane Vesicles (OMVs) are spherical particles secreted by Gram-negative bacteria. Here we explore the effect of H. pylori OMVs on Aβ aggregation and toxicity. We show intraperitoneally-injected H. pylori OMVs enter the brain and co-localize with Aβ plaques in APP/PS1 mice, accompanied by aggravated Aβ pathology, exacerbated cognitive deficits and synaptic impairment, indicating that H. pylori OMVs promote β-amyloidosis and AD development. The in vitro results further identify that H. pylori OMVs significantly accelerate Aβ aggregation and increase Aβ-induced neurotoxicity. Through lipidomic analysis, we reveal that lipid components, particularly LPC 18:0 in H. pylori OMVs accelerate Aβ aggregation and enhance Aβ neurotoxicity. Moreover, H. pylori OMVs-enhanced Aβ neurotoxicity is mediated by Ca2+. These findings reveal a mechanism of H. pylori OMVs in accelerating AD development in which the bacterial OMVs-originated lipid components play a key role in promoting Aβ aggregation and neurotoxicity.

幽门螺杆菌(H. pylori)感染与阿尔茨海默病(AD)有关,其机制尚不清楚。外膜小泡(OMVs)是革兰氏阴性细菌分泌的球形颗粒。在此,我们探讨了幽门螺杆菌 OMVs 对 Aβ 聚合和毒性的影响。我们的研究表明,腹腔注射幽门螺杆菌OMV进入APP/PS1小鼠的大脑并与Aβ斑块共定位,伴随着Aβ病理学的加重、认知障碍的加剧和突触损伤,表明幽门螺杆菌OMV促进了β淀粉样变性和AD的发展。体外研究结果进一步确定,幽门螺杆菌 OMVs 显著加速了 Aβ 的聚集,并增加了 Aβ 诱导的神经毒性。通过脂质体分析,我们发现幽门螺杆菌 OMVs 中的脂质成分,尤其是 LPC 18:0 可加速 Aβ 的聚集并增强 Aβ 的神经毒性。此外,幽门螺杆菌 OMVs 增强 Aβ 神经毒性是由 Ca2+ 介导的。这些发现揭示了幽门螺杆菌OMVs加速AD发展的机制,其中细菌OMVs产生的脂质成分在促进Aβ聚集和神经毒性方面发挥了关键作用。
{"title":"Helicobacter pylori outer membrane vesicles directly promote Aβ aggregation and enhance Aβ toxicity in APP/PS1 mice.","authors":"Dongli Meng, Yiwen Lai, Lun Zhang, Wenting Hu, Hui Wei, Cuiping Guo, Xiaopeng Jing, Huan Zhou, Rui Xiao, Liping Zhu, Shengquan Luo, Zhendong Xu, Yu Chen, Xiaochuan Wang, Rong Liu, Ji Zeng","doi":"10.1038/s42003-024-07125-1","DOIUrl":"10.1038/s42003-024-07125-1","url":null,"abstract":"<p><p>Helicobacter pylori (H. pylori) infection has been found associated with Alzheimer's disease (AD) with unclear mechanisms. Outer Membrane Vesicles (OMVs) are spherical particles secreted by Gram-negative bacteria. Here we explore the effect of H. pylori OMVs on Aβ aggregation and toxicity. We show intraperitoneally-injected H. pylori OMVs enter the brain and co-localize with Aβ plaques in APP/PS1 mice, accompanied by aggravated Aβ pathology, exacerbated cognitive deficits and synaptic impairment, indicating that H. pylori OMVs promote β-amyloidosis and AD development. The in vitro results further identify that H. pylori OMVs significantly accelerate Aβ aggregation and increase Aβ-induced neurotoxicity. Through lipidomic analysis, we reveal that lipid components, particularly LPC 18:0 in H. pylori OMVs accelerate Aβ aggregation and enhance Aβ neurotoxicity. Moreover, H. pylori OMVs-enhanced Aβ neurotoxicity is mediated by Ca<sup>2+</sup>. These findings reveal a mechanism of H. pylori OMVs in accelerating AD development in which the bacterial OMVs-originated lipid components play a key role in promoting Aβ aggregation and neurotoxicity.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1474"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616230","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
The brain's first "traffic map" through Unified Structural and Functional Connectivity (USFC) modeling. 通过统一结构和功能连接(USFC)建模,绘制出大脑的第一张 "交通图"。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07160-y
Arzu C Has Silemek, Haitao Chen, Pascal Sati, Wei Gao

The brain's white matter connections are thought to provide the structural basis for its functional connections between distant brain regions but how our brain selects the best structural routes for functional communications remains poorly understood. In this study, we propose a Unified Structural and Functional Connectivity (USFC) model and use an "economical assumption" to create the brain's first "traffic map" reflecting how frequently each segment of the brain structural connection is used to achieve the global functional communication system. The resulting USFC map highlights regions in the subcortical, default-mode, and salience networks as the most heavily traversed nodes and a midline frontal-caudate-thalamus-posterior cingulate-visual cortex corridor as the backbone of the whole brain connectivity system. Our results further revealed a striking negative association between structural and functional connectivity strengths in routes supporting negative functional connections, as well as significantly higher efficiency metrics and better predictive performance for cognition in the USFC connectome when compared to structural and functional ones alone. Overall, the proposed USFC model opens up a new window for integrated brain connectome modeling and provides a major leap forward in brain mapping efforts for a better understanding of the brain's fundamental communication mechanisms.

大脑白质连接被认为是远处脑区之间功能连接的结构基础,但人们对大脑如何为功能通信选择最佳结构路线仍然知之甚少。在这项研究中,我们提出了一个统一结构和功能连接(USFC)模型,并利用 "经济假设 "绘制了大脑的第一张 "交通图",反映了大脑结构连接的每个部分在实现全局功能通信系统中的使用频率。由此绘制的 USFC 地图显示,皮层下、默认模式和显著性网络中的区域是被穿越次数最多的节点,而中线额叶-尾状-丘脑-后扣带回-视觉皮层走廊则是整个大脑连接系统的主干。我们的研究结果进一步表明,在支持负功能连接的路径中,结构连接强度和功能连接强度之间存在显著的负相关,而且与单独的结构连接强度和功能连接强度相比,USFC连接组的效率指标明显更高,对认知的预测性能也更好。总之,所提出的 USFC 模型为综合大脑连接组建模打开了一扇新窗口,为大脑绘图工作提供了一次重大飞跃,有助于更好地理解大脑的基本通信机制。
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引用次数: 0
Genomic diversity and transmission patterns of Yersinia pestis in Inner Mongolia Autonomous Region, China. 中国内蒙古自治区鼠疫耶尔森菌的基因组多样性和传播模式。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07190-6
Xiujuan Zuo, Fang Liu, Yanhong Hu, Xuezhi Huang, Yan Guo, Mengnan Cui, Hang Fan, Xianglilan Zhang, Zhenghua Wu, Wenrui Wang, Ruifu Yang, Yarong Wu, Jianyun Li, Yujun Cui

According to WHO, plague, caused by Yersinia pestis, has resurged since 2000. Inner Mongolia, harboring a quarter of China's plague foci, has accounted for 80% of national plague cases in the past five years. Despite its pivotal role in Chinese plague epidemiology, the genetic diversity and transmission dynamics of Y. pestis in this region remain under-investigated. Our analysis of 585 Y. pestis strains from Inner Mongolia (1948-2021) revealed three primary lineages, with 2.MED3 being predominant. We further delineated seven sub-phylogroups in 2.MED3, with 2.MED3.1.2 and 2.MED3.1.4 showing recent dominance. These two subgroups reveal dual transmission patterns: localized short-distance spread and long-distance dispersals over 300 km. Xilingol League is highlighted as a key source and reservoir for Y. pestis, predominantly spreading from central-eastern to southwestern Inner Mongolia, including occasional reverse transmissions. These findings enhance understanding of Y. pestis diversity and transmission in Inner Mongolia, aiding in enhanced surveillance and control measures.

据世界卫生组织称,由鼠疫耶尔森氏菌引起的鼠疫自 2000 年以来再次爆发。内蒙古占中国鼠疫疫点的四分之一,在过去五年中,内蒙古鼠疫病例占全国鼠疫病例的80%。尽管内蒙古在中国鼠疫流行病学中占有举足轻重的地位,但对该地区鼠疫 Y. pestis 的遗传多样性和传播动态的研究仍然不足。我们对来自内蒙古(1948-2021年)的585株鼠疫耶氏菌进行了分析,发现了三个主要的品系,其中以2.MED3为主。我们进一步划分了2.MED3中的七个亚系统群,其中2.MED3.1.2和2.MED3.1.4在近期占主导地位。这两个亚群显示了双重传播模式:局部短距离传播和 300 公里以上的长距离传播。锡林郭勒盟是鼠疫 Y. 的主要来源和贮藏地,主要从内蒙古中东部向西南部传播,包括偶尔的反向传播。这些发现加深了人们对内蒙古鼠疫耶氏菌多样性和传播的了解,有助于加强监测和控制措施。
{"title":"Genomic diversity and transmission patterns of Yersinia pestis in Inner Mongolia Autonomous Region, China.","authors":"Xiujuan Zuo, Fang Liu, Yanhong Hu, Xuezhi Huang, Yan Guo, Mengnan Cui, Hang Fan, Xianglilan Zhang, Zhenghua Wu, Wenrui Wang, Ruifu Yang, Yarong Wu, Jianyun Li, Yujun Cui","doi":"10.1038/s42003-024-07190-6","DOIUrl":"10.1038/s42003-024-07190-6","url":null,"abstract":"<p><p>According to WHO, plague, caused by Yersinia pestis, has resurged since 2000. Inner Mongolia, harboring a quarter of China's plague foci, has accounted for 80% of national plague cases in the past five years. Despite its pivotal role in Chinese plague epidemiology, the genetic diversity and transmission dynamics of Y. pestis in this region remain under-investigated. Our analysis of 585 Y. pestis strains from Inner Mongolia (1948-2021) revealed three primary lineages, with 2.MED3 being predominant. We further delineated seven sub-phylogroups in 2.MED3, with 2.MED3.1.2 and 2.MED3.1.4 showing recent dominance. These two subgroups reveal dual transmission patterns: localized short-distance spread and long-distance dispersals over 300 km. Xilingol League is highlighted as a key source and reservoir for Y. pestis, predominantly spreading from central-eastern to southwestern Inner Mongolia, including occasional reverse transmissions. These findings enhance understanding of Y. pestis diversity and transmission in Inner Mongolia, aiding in enhanced surveillance and control measures.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1480"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616228","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
Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production. 将精确切割的肝脏切片作为体内外模型来评估受损的肝糖生成。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07070-z
Ligia Akemi Kiyuna, Kishore Alagere Krishnamurthy, Esther B Homan, Miriam Langelaar-Makkinje, Albert Gerding, Trijnie Bos, Dorenda Oosterhuis, Ruben J Overduin, Andrea B Schreuder, Vincent E de Meijer, Peter Olinga, Terry G J Derks, Karen van Eunen, Barbara M Bakker, Maaike H Oosterveer

Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using 13C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond.

空腹低血糖症是各种先天性代谢错误(IEM)的一种严重症状,但人们对这种症状的了解并不全面。精密切片肝脏(PCLS)是研究体内葡萄糖生成的一种很有前景的模型。本研究量化了人和小鼠 PCLS 在不同生糖前体存在下的净葡萄糖生成量。添加了二羟丙酮的喂养小鼠切片产糖率最高,并受到了福斯克林和二丁烯酰-cAMP 的进一步刺激。此外,我们还利用 13C 同位素追踪技术评估了糖原分解和糖元生成对净葡萄糖产生的贡献。药物抑制葡萄糖-6-磷酸转运体 SLC37A4 可显著减少净葡萄糖生成,增加乳酸分泌和糖原贮存,而糖原贮积症 Ia 型和 Ib 型患者 PCLS 的葡萄糖生成完全消失。总之,本研究发现 PCLS 是研究肝糖生成的有效体外模型,为其未来在 IEM 研究及其他领域的应用提供了机会。
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引用次数: 0
Self-priming of Plk1 binding to BubR1 ensures accurate mitotic progression. Plk1 与 BubR1 结合的自吸作用确保了有丝分裂的准确进行。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07205-2
Chunlin Song, Mingzhe Zhang, Thomas Kruse, Mads Harder Møller, Blanca López-Méndez, Yuqing Zhang, Yujing Zhai, Ying Wang, Tingting Lei, Arminja N Kettenbach, Jakob Nilsson, Gang Zhang

Plk1 is a key mitotic kinase that localizes to distinct subcellular structures to promote accurate mitotic progression. Plk1 recruitment depends on direct interaction between polo-box domain (PBD) on Plk1 and PBD binding motif (PBD BM) on the interactors. However, recent study showed that PBD BM alone is not enough for stable binding between CENP-U and Plk1 highlighting the complexity of the interaction which warrants further investigation. An important interactor for Plk1 during mitosis is the checkpoint protein BubR1. Plk1 bound to BubR1 via PBD interaction with pT620 phosphorylates BubR1 S676/T680 to promote BubR1-PP2A/B56 interaction. The BubR1-PP2A/B56 complex counteracts the destablizing effect on kinetochore-microtubule attachments by mitotic kinases to promote mitotic progression. Here we show that Plk1 phosphorylates T600/T608 on BubR1 and the double phosphorylation is critical for BubR1-Plk1 interaction. A similar mechanism for Plk1-Bub1 interaction also exists indicating a general principle for Plk1 kinetochore recruitment through self-priming. Mechanistically preventing BubR1 T600/T608 phosphorylation impairs chromosome congression and checkpoint silencing by reducing Plk1 and PP2A/B56 binding to BubR1. Increasing the binding affinity towards Plk1 and PP2A/B56 in BubR1 through protein engineering bypasses the requirement of T600/T608 phosphorylation for mitotic progression. These results reveal a new layer of regulation for accurate mitotic progression.

Plk1 是一种关键的有丝分裂激酶,可定位到不同的亚细胞结构,以促进有丝分裂的准确进行。Plk1的招募依赖于Plk1上的polo-box结构域(PBD)与相互作用体上的PBD结合基团(PBD BM)之间的直接相互作用。然而,最近的研究表明,仅靠 PBD BM 并不足以使 CENP-U 和 Plk1 稳定结合,这凸显了相互作用的复杂性,值得进一步研究。有丝分裂过程中 Plk1 的一个重要互作因子是检查点蛋白 BubR1。Plk1 通过 PBD 与 pT620 的相互作用与 BubR1 结合,使 BubR1 S676/T680 磷酸化,从而促进 BubR1-PP2A/B56 的相互作用。BubR1-PP2A/B56 复合物可抵消有丝分裂激酶对有丝分裂中动子轴-微管连接的破坏作用,从而促进有丝分裂的进行。在这里,我们发现 Plk1 会使 BubR1 上的 T600/T608 发生磷酸化,这种双重磷酸化对 BubR1-Plk1 的相互作用至关重要。Plk1 与 Bub1 的相互作用也存在类似的机制,这表明 Plk1 通过自吸作用招募动点的一般原理。通过减少 Plk1 和 PP2A/B56 与 BubR1 的结合,从机理上防止 BubR1 T600/T608 磷酸化,从而损害染色体连接和检查点沉默。通过蛋白质工程增加BubR1与Plk1和PP2A/B56的结合亲和力,可绕过有丝分裂进程对T600/T608磷酸化的要求。这些结果揭示了有丝分裂精确进行的一个新的调控层。
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引用次数: 0
Neurexin facilitates glycosylation of Dystroglycan to sustain muscle architecture and function in Drosophila. Neurexin 可促进 Dystroglycan 的糖基化,从而维持果蝇的肌肉结构和功能。
IF 5.2 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-09 DOI: 10.1038/s42003-024-07191-5
Yu Zhao, Junhua Geng, Zhu Meng, Yichen Sun, Mengzhu Ou, Lizhong Xu, Moyi Li, Guangming Gan, Menglong Rui, Junhai Han, Wei Xie

Neurexin, a molecule associated with autism spectrum disorders, is thought to function mainly in neurons. Recently, it was reported that Neurexin is also present in muscle, but the role of Neurexin in muscle is still poorly understood. Here, we demonstrate that the overexpression of Neurexin in muscles effectively restored the locomotor function of Drosophila neurexin mutants, while rescuing effects are observed within the nervous. Notably, the defects in muscle structure and function caused by Neurexin deficiency were similar to those caused by mutations in dystroglycan, a gene associated with progressive muscular dystrophy. The absence of Neurexin leads to muscle attachment defects, emphasizing the essential role of Neurexin in muscle integrity. Furthermore, Neurexin deficiency reduces Dystroglycan glycosylation on the cell surface, which is crucial for maintaining proper muscle structure and function. Finally, Neurexin guides Dystroglycan to the glycosyltransferase complex through interactions with Rotated Abdomen, a homolog of mammalian POMT1. Our findings reveal that Neurexin mediates muscle development and function through Dystroglycan glycosylation, suggesting a potential association between autism spectrum disorders and muscular dystrophy.

Neurexin 是一种与自闭症谱系障碍有关的分子,人们认为它主要在神经元中发挥作用。最近有报道称,Neurexin 也存在于肌肉中,但人们对 Neurexin 在肌肉中的作用仍知之甚少。在这里,我们证明了在肌肉中过表达 Neurexin 能有效恢复果蝇 neurexin 突变体的运动功能,同时在神经系统中也观察到了拯救作用。值得注意的是,Neurexin缺乏导致的肌肉结构和功能缺陷与进行性肌营养不良症相关基因dystroglycan突变导致的缺陷相似。Neurexin 的缺失导致肌肉附着缺陷,强调了 Neurexin 在肌肉完整性中的重要作用。此外,Neurexin 缺乏还会减少细胞表面的 Dystroglycan 糖基化,而这对于维持肌肉的正常结构和功能至关重要。最后,Neurexin通过与哺乳动物POMT1的同源物Rotated Abdomen相互作用,引导Dystroglycan进入糖基转移酶复合物。我们的研究结果表明,Neurexin 通过 Dystroglycan 糖基化介导肌肉发育和功能,这表明自闭症谱系障碍和肌肉萎缩症之间可能存在关联。
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Communications Biology
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