Pub Date : 2024-11-10DOI: 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。
{"title":"Modulation of ATM enhances DNA repair in G2/M phase of cell cycle and averts senescence in Fuchs endothelial corneal dystrophy.","authors":"Shazia Ashraf, Neha Deshpande, Queenie Cheung, Jeffrey Boakye Asabere, Raymond Jeff Wong, Alex G Gauthier, Mohit Parekh, Yadav Adhikari, Geetha Melangath, Ula V Jurkunas","doi":"10.1038/s42003-024-07179-1","DOIUrl":"10.1038/s42003-024-07179-1","url":null,"abstract":"<p><p>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-OHE<sub>2</sub>), results in an early and increased activation of ATM-mediated DNA damage response in FECD compared to normal CEnCs. Acute stress with UVA and 4OHE<sub>2</sub> causes (i) greater cell-cycle arrest and DNA repair in G2/M phase, and (ii) greater cytoprotective senescence in NQO1<sup>-/-</sup> compared to NQO1<sup>+/+</sup> cells, which was reversed upon ATM inhibition. Chronic stress with UVA and 4OHE<sub>2</sub> 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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1482"},"PeriodicalIF":5.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11551145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616254","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}
Pub Date : 2024-11-10DOI: 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.
{"title":"The kinase NEK6 positively regulates LSD1 activity and accumulation in local chromatin sub-compartments.","authors":"Franziska Knodel, Jürgen Eirich, Sabine Pinter, Stephan A Eisler, Iris Finkemeier, Philipp Rathert","doi":"10.1038/s42003-024-07199-x","DOIUrl":"10.1038/s42003-024-07199-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1483"},"PeriodicalIF":5.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11551153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616312","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}
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.
{"title":"Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness.","authors":"Jianjun Chang, Zijie Li, Hui Yuan, Xuejiao Wang, Jingyi Xu, Pingting Yang, Ling Qin","doi":"10.1038/s42003-024-07215-0","DOIUrl":"10.1038/s42003-024-07215-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1484"},"PeriodicalIF":5.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11551151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616296","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}
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.
{"title":"Single-cell transcriptomic and cross-species comparison analyses reveal distinct molecular changes of porcine testes during puberty.","authors":"Xiaoyan Wang, Yang Wang, Yu Wang, Yifei Guo, Ruojun Zong, Shuaitao Hu, Jingwei Yue, Jing Yao, Chunsheng Han, Jingtao Guo, Jianguo Zhao","doi":"10.1038/s42003-024-07163-9","DOIUrl":"10.1038/s42003-024-07163-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1478"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616302","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}
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.
{"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}
Pub Date : 2024-11-09DOI: 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.
{"title":"The brain's first \"traffic map\" through Unified Structural and Functional Connectivity (USFC) modeling.","authors":"Arzu C Has Silemek, Haitao Chen, Pascal Sati, Wei Gao","doi":"10.1038/s42003-024-07160-y","DOIUrl":"10.1038/s42003-024-07160-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1477"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616309","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}
Pub Date : 2024-11-09DOI: 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}
Pub Date : 2024-11-09DOI: 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.
{"title":"Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production.","authors":"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","doi":"10.1038/s42003-024-07070-z","DOIUrl":"10.1038/s42003-024-07070-z","url":null,"abstract":"<p><p>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 <sup>13</sup>C 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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1479"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616283","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}
Pub Date : 2024-11-09DOI: 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.
{"title":"Self-priming of Plk1 binding to BubR1 ensures accurate mitotic progression.","authors":"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","doi":"10.1038/s42003-024-07205-2","DOIUrl":"10.1038/s42003-024-07205-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1473"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616300","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}
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.
{"title":"Neurexin facilitates glycosylation of Dystroglycan to sustain muscle architecture and function in Drosophila.","authors":"Yu Zhao, Junhua Geng, Zhu Meng, Yichen Sun, Mengzhu Ou, Lizhong Xu, Moyi Li, Guangming Gan, Menglong Rui, Junhai Han, Wei Xie","doi":"10.1038/s42003-024-07191-5","DOIUrl":"10.1038/s42003-024-07191-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1481"},"PeriodicalIF":5.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616273","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}