Pub Date : 2024-11-06DOI: 10.1038/s42003-024-07140-2
Habiballah Shojaeisaadi, Andrew Schoenrock, Matthew J Meier, Andrew Williams, Jill M Norris, Nicholette D Palmer, Carole L Yauk, Francesco Marchetti
Whole-genome sequencing studies of parent-offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.
对父母-后代三人组进行的全基因组测序研究为了解新发突变（DNMs）对人类健康和疾病的潜在影响提供了宝贵的信息。然而，驱动 DNMs 的分子机制尚不清楚。针对多子女家庭的研究可以为了解家庭间 DNM 变异率的原因提供重要见解，但这些研究非常有限。我们对 13 个墨西哥裔美国人多子女家庭中的 2479 个从头单核苷酸变异（SNV）进行了特征分析。我们观察到，父亲的年龄对已验证的从头单核苷酸变异有强烈的影响，而且家庭间的年增长率存在很大差异。与父亲年龄较小的孩子相比，父亲年龄较大的孩子在 CpG 位点上表现出更多的 C > T 转变。根据一个癌症（COSMIC）和两个非癌症（人类种系和 CRISPR-Cas 9 基因敲除人类 DNA 修复基因）突变特征数据库对经过验证的 SNV 进行了检查。这些分析表明，在修复启动和切除过程中不准确的DNA错配修复以及DNA损伤和复制错误是人类种系新生SNV的主要来源。我们的研究结果为了解人类种系新生SNV的潜在来源以及DNA错配修复在其发生过程中的关键作用提供了重要信息。
{"title":"Mutational signature analyses in multi-child families reveal sources of age-related increases in human germline mutations.","authors":"Habiballah Shojaeisaadi, Andrew Schoenrock, Matthew J Meier, Andrew Williams, Jill M Norris, Nicholette D Palmer, Carole L Yauk, Francesco Marchetti","doi":"10.1038/s42003-024-07140-2","DOIUrl":"10.1038/s42003-024-07140-2","url":null,"abstract":"<p><p>Whole-genome sequencing studies of parent-offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590147","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 : 2024-11-05DOI: 10.1038/s42003-024-07052-1
Qingbing Han, Hejiao Zhao, Meng Chen, Wenshuo Xue, Jun Li, Lei Sun, Yingli Shang
Autophagy is a highly conserved degradative process that has been linked to various functions, including defending host cells against pathogens. Although the involvement of autophagy in porcine circovirus 2 (PCV2) infection has become apparent, it remains unclear whether selective autophagy plays a critical role in PCV2 restriction. Here we show that retinol-binding protein 4 (RBP4), an adipokine for retinol carrier, initiates the autophagic degradation of PCV2 ORF1 protein. PCV2 infection increases RBP4 protein levels through MAPK-eIF4E axis in living cells. Ectopic expression of RBP4 or recombinant RBP4 treatment promotes the degradation of ORF1 protein. Mechanistically, RBP4 activates TRAF6 to induce K63-linked ubiquitination of ORF1, leading to SQSTM1/p62-mediated selective autophagy for degradation. Consequently, RBP4 deficiency increases viral loads and exacerbates the pathogenicity of PCV2 in vivo. Collectively, these results identify RBP4 as a key host restriction factor of PCV2 and reveal a previously undescribed antiviral mechanism against PCV2 in infected cells. Retinol binding protein 4 activates TRAF6 to induce K63-linked ubiquitination and degradation of PCV2 ORF1 protein through SQSTM1/p62-mediated selective autophagy to restrict PCV2 replication.
{"title":"Retinol binding protein 4 restricts PCV2 replication via selective autophagy degradation of viral ORF1 protein","authors":"Qingbing Han, Hejiao Zhao, Meng Chen, Wenshuo Xue, Jun Li, Lei Sun, Yingli Shang","doi":"10.1038/s42003-024-07052-1","DOIUrl":"10.1038/s42003-024-07052-1","url":null,"abstract":"Autophagy is a highly conserved degradative process that has been linked to various functions, including defending host cells against pathogens. Although the involvement of autophagy in porcine circovirus 2 (PCV2) infection has become apparent, it remains unclear whether selective autophagy plays a critical role in PCV2 restriction. Here we show that retinol-binding protein 4 (RBP4), an adipokine for retinol carrier, initiates the autophagic degradation of PCV2 ORF1 protein. PCV2 infection increases RBP4 protein levels through MAPK-eIF4E axis in living cells. Ectopic expression of RBP4 or recombinant RBP4 treatment promotes the degradation of ORF1 protein. Mechanistically, RBP4 activates TRAF6 to induce K63-linked ubiquitination of ORF1, leading to SQSTM1/p62-mediated selective autophagy for degradation. Consequently, RBP4 deficiency increases viral loads and exacerbates the pathogenicity of PCV2 in vivo. Collectively, these results identify RBP4 as a key host restriction factor of PCV2 and reveal a previously undescribed antiviral mechanism against PCV2 in infected cells. Retinol binding protein 4 activates TRAF6 to induce K63-linked ubiquitination and degradation of PCV2 ORF1 protein through SQSTM1/p62-mediated selective autophagy to restrict PCV2 replication.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07052-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579795","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 endothelium-dependent vascular injury, a primary pathological feature of angiotensin II (Ang II)-induced hypertension. This study aimed to explore the role and underlying mechanisms of G protein-coupled receptor 39 (GPR39) in the pathogenesis of Ang II-induced hypertension. For in vivo studies, GPR39 knockout (KO) mice (C57BL/6 J, male) were generated and administered Ang II for 4 weeks. GPR39 expression was upregulated in the aorta of hypertensive patients and mice. The ablation of GPR39 mitigated vascular fibrosis, augmented endothelium-dependent vasodilation, and inhibited endothelial inflammation, oxidative stress, and apoptosis in mice. Additionally, GPR39 KO decreased NOD-like receptor protein 3 (Nlrp3) gene expression in Ang II-stimulated endothelial cells. Notably, Nlrp3 activation counteracted the therapeutic benefits of GPR39 KO. We identified the potential ligand of GPR39 using structure-based high throughput virtual screening (HTVS) and validated its antihypertensive function in vitro and in vivo. The small molecule ligand Z1780628919 of GPR39 can also reduce Ang II-induced hypertension and improve vascular function. GPR39 KO and the small molecule ligand Z1780628919 potentially downregulates Nlrp3, thereby mitigating vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis. This effect contributes to the alleviation of Ang II-induced hypertension and the rectification of vascular dysfunctions. These findings suggest new avenues for therapeutic intervention. Knocking out GPR39 or using its small molecule inhibitors can alleviate vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis by downregulating Nlrp3. This effect helps alleviate Ang II-induced hypertension in mice.
血管内皮依赖性血管损伤是血管紧张素 II（Ang II）诱导的高血压的主要病理特征。本研究旨在探讨 G 蛋白偶联受体 39（GPR39）在 Ang II 诱导的高血压发病机制中的作用及其内在机制。为了进行体内研究，我们产生了GPR39基因敲除（KO）小鼠（C57BL/6 J，雄性），并给它们注射了4周的Ang II。高血压患者和小鼠的主动脉中 GPR39 表达上调。消融 GPR39 可减轻血管纤维化，增强内皮依赖性血管舒张，抑制小鼠内皮炎症、氧化应激和细胞凋亡。此外，GPR39 KO 会降低 Ang II 刺激的内皮细胞中 NOD 样受体蛋白 3（Nlrp3）基因的表达。值得注意的是，Nlrp3 的激活抵消了 GPR39 KO 的治疗效果。我们利用基于结构的高通量虚拟筛选（HTVS）确定了 GPR39 的潜在配体，并在体外和体内验证了其抗高血压功能。GPR39 的小分子配体 Z1780628919 也能降低 Ang II 诱导的高血压并改善血管功能。GPR39 KO 和小分子配体 Z1780628919 有可能下调 Nlrp3，从而减轻血管纤维化、内皮炎症、氧化应激和细胞凋亡。这种效应有助于缓解 Ang II 诱导的高血压和纠正血管功能障碍。这些发现为治疗干预提供了新的途径。敲除 GPR39 或使用其小分子抑制剂可以通过下调 Nlrp3 来缓解血管纤维化、内皮炎症、氧化应激和细胞凋亡。这种效应有助于缓解 Ang II 诱导的小鼠高血压。
{"title":"Targeting GPR39 in structure-based drug discovery reduces Ang II-induced hypertension","authors":"Dongxu Hua, Wanlin Huang, Qiyang Xie, Wenna Xu, Lu Tang, Mingwei Liu, Xiaoguang Wu, Qiaodong Zhang, Xu Cao, Peng Li, Yanhui Sheng","doi":"10.1038/s42003-024-07132-2","DOIUrl":"10.1038/s42003-024-07132-2","url":null,"abstract":"The endothelium-dependent vascular injury, a primary pathological feature of angiotensin II (Ang II)-induced hypertension. This study aimed to explore the role and underlying mechanisms of G protein-coupled receptor 39 (GPR39) in the pathogenesis of Ang II-induced hypertension. For in vivo studies, GPR39 knockout (KO) mice (C57BL/6 J, male) were generated and administered Ang II for 4 weeks. GPR39 expression was upregulated in the aorta of hypertensive patients and mice. The ablation of GPR39 mitigated vascular fibrosis, augmented endothelium-dependent vasodilation, and inhibited endothelial inflammation, oxidative stress, and apoptosis in mice. Additionally, GPR39 KO decreased NOD-like receptor protein 3 (Nlrp3) gene expression in Ang II-stimulated endothelial cells. Notably, Nlrp3 activation counteracted the therapeutic benefits of GPR39 KO. We identified the potential ligand of GPR39 using structure-based high throughput virtual screening (HTVS) and validated its antihypertensive function in vitro and in vivo. The small molecule ligand Z1780628919 of GPR39 can also reduce Ang II-induced hypertension and improve vascular function. GPR39 KO and the small molecule ligand Z1780628919 potentially downregulates Nlrp3, thereby mitigating vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis. This effect contributes to the alleviation of Ang II-induced hypertension and the rectification of vascular dysfunctions. These findings suggest new avenues for therapeutic intervention. Knocking out GPR39 or using its small molecule inhibitors can alleviate vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis by downregulating Nlrp3. This effect helps alleviate Ang II-induced hypertension in mice.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07132-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579814","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 : 2024-11-05DOI: 10.1038/s42003-024-07054-z
Erik Saberski, Tom Lorimer, Delia Carpenter, Ethan Deyle, Ewa Merz, Joseph Park, Gerald M. Pao, George Sugihara
While it is commonly accepted that ecosystem dynamics are nonlinear, what is often not acknowledged is that nonlinearity implies scale-dependence. With the increasing availability of high-resolution ecological time series, there is a growing need to understand how scale and resolution in the data affect the construction and interpretation of causal networks—specifically, networks mapping how changes in one variable drive changes in others as part of a shared dynamic system (“dynamic causation”). We use Convergent Cross Mapping (CCM), a method specifically designed to measure dynamic causation, to study the effects of varying temporal and taxonomic/functional resolution in data when constructing ecological causal networks. As the system is viewed at different scales relationships will appear and disappear. The relationship between data resolution and interaction presence is not random: the temporal scale at which a relationship is uncovered identifies a biologically relevant scale that drives changes in population abundance. Further, causal relationships between taxonomic aggregates (low-resolution) are shown to be influenced by the number of interactions between their component species (high-resolution). Because no single level of resolution captures all the causal links in a system, a more complete understanding requires multiple levels when constructing causal networks. This paper examines how data resolution affects dynamic causal inference in ecological networks. Using Convergent Cross Mapping (CCM), we show that different temporal and taxonomic scales reveal varying causal links, important for ecosystem management.
{"title":"The impact of data resolution on dynamic causal inference in multiscale ecological networks","authors":"Erik Saberski, Tom Lorimer, Delia Carpenter, Ethan Deyle, Ewa Merz, Joseph Park, Gerald M. Pao, George Sugihara","doi":"10.1038/s42003-024-07054-z","DOIUrl":"10.1038/s42003-024-07054-z","url":null,"abstract":"While it is commonly accepted that ecosystem dynamics are nonlinear, what is often not acknowledged is that nonlinearity implies scale-dependence. With the increasing availability of high-resolution ecological time series, there is a growing need to understand how scale and resolution in the data affect the construction and interpretation of causal networks—specifically, networks mapping how changes in one variable drive changes in others as part of a shared dynamic system (“dynamic causation”). We use Convergent Cross Mapping (CCM), a method specifically designed to measure dynamic causation, to study the effects of varying temporal and taxonomic/functional resolution in data when constructing ecological causal networks. As the system is viewed at different scales relationships will appear and disappear. The relationship between data resolution and interaction presence is not random: the temporal scale at which a relationship is uncovered identifies a biologically relevant scale that drives changes in population abundance. Further, causal relationships between taxonomic aggregates (low-resolution) are shown to be influenced by the number of interactions between their component species (high-resolution). Because no single level of resolution captures all the causal links in a system, a more complete understanding requires multiple levels when constructing causal networks. This paper examines how data resolution affects dynamic causal inference in ecological networks. Using Convergent Cross Mapping (CCM), we show that different temporal and taxonomic scales reveal varying causal links, important for ecosystem management.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07054-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579793","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}
Measurement techniques often result in domain gaps among batches of cellular data from a specific modality. The effectiveness of cross-batch annotation methods is influenced by inductive bias, which refers to a set of assumptions that describe the behavior of model predictions. Different annotation methods possess distinct inductive biases, leading to varying degrees of generalizability and interpretability. Given that certain cell types exhibit unique functional patterns, we hypothesize that the inductive biases of cell annotation methods should align with these biological patterns to produce meaningful predictions. In this study, we propose KIDA, Knowledge-based Inductive bias and Domain Adaptation. The knowledge-based inductive bias constrains the prediction rules learned from the reference dataset, composed of multiple batches, to functional patterns relevant to biology, thereby enhancing the generalization of the model to unseen batches. Since the query dataset also contains gaps from multiple batches, KIDA’s domain adaptation employs pseudo labels for self-knowledge distillation, effectively narrowing the distribution gap between model predictions and the query dataset. Benchmark experiments demonstrate that KIDA is capable of achieving accurate cross-batch cell type annotation. Knowledge-based inductive bias and domain adaptation can enhance the cell type annotation accuracy of deep learning models.
{"title":"Knowledge-based inductive bias and domain adaptation for cell type annotation","authors":"Zhenchao Tang, Guanxing Chen, Shouzhi Chen, Haohuai He, Linlin You, Calvin Yu-Chian Chen","doi":"10.1038/s42003-024-07171-9","DOIUrl":"10.1038/s42003-024-07171-9","url":null,"abstract":"Measurement techniques often result in domain gaps among batches of cellular data from a specific modality. The effectiveness of cross-batch annotation methods is influenced by inductive bias, which refers to a set of assumptions that describe the behavior of model predictions. Different annotation methods possess distinct inductive biases, leading to varying degrees of generalizability and interpretability. Given that certain cell types exhibit unique functional patterns, we hypothesize that the inductive biases of cell annotation methods should align with these biological patterns to produce meaningful predictions. In this study, we propose KIDA, Knowledge-based Inductive bias and Domain Adaptation. The knowledge-based inductive bias constrains the prediction rules learned from the reference dataset, composed of multiple batches, to functional patterns relevant to biology, thereby enhancing the generalization of the model to unseen batches. Since the query dataset also contains gaps from multiple batches, KIDA’s domain adaptation employs pseudo labels for self-knowledge distillation, effectively narrowing the distribution gap between model predictions and the query dataset. Benchmark experiments demonstrate that KIDA is capable of achieving accurate cross-batch cell type annotation. Knowledge-based inductive bias and domain adaptation can enhance the cell type annotation accuracy of deep learning models.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07171-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579790","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 : 2024-11-05DOI: 10.1038/s42003-024-07166-6
Yingying Liu, Yang Geng, Man Si, Dan Zhu, Zhenglanyi Huang, Hanli Yin, Hao Zeng, Jiang Feng, Tinglei Jiang
Predation reduces the population density of prey, affecting its fitness and population dynamics. Few studies have connected trait changes with fitness consequences in prey and the molecular basis and metabolic mechanisms of such changes in bat-insect systems. This study focuses on the responses of Helicoverpa armigera to different predation risks, focusing on echolocating bats and their calls. Substantial modifications were observed in the nocturnal and diurnal activities of H. armigera under predation risk, with enhanced evasion behaviors. Accelerated development and decreased fitness were observed under predation risks. Transcriptomic and metabolomic analyses indicated that exposure to bats induced the upregulation of amino acid metabolism- and antioxidant pathway-related genes, reflecting shifts in resource utilization in response to oxidative stress. Exposure to bat predation risks enhanced the activity of DNA damage repair pathways and suppressed energy metabolism, contributing to the observed trait changes and fitness decreases. The current results underscore the complex adaptive strategies that prey species evolve in response to predation risk, enhancing our understanding of the predator–prey dynamic and offering valuable insights for innovative and ecologically informed pest management strategies. Helicoverpa armigera shows adaptive trait changes under bat predation risk, with increased evasion, accelerated development, and fitness decreases. Molecular analyses reveal shifts in metabolism and stress response pathways linked to these changes.
{"title":"Trait responses, nonconsumptive effects, and the physiological basis of Helicoverpa armigera to bat predation risk","authors":"Yingying Liu, Yang Geng, Man Si, Dan Zhu, Zhenglanyi Huang, Hanli Yin, Hao Zeng, Jiang Feng, Tinglei Jiang","doi":"10.1038/s42003-024-07166-6","DOIUrl":"10.1038/s42003-024-07166-6","url":null,"abstract":"Predation reduces the population density of prey, affecting its fitness and population dynamics. Few studies have connected trait changes with fitness consequences in prey and the molecular basis and metabolic mechanisms of such changes in bat-insect systems. This study focuses on the responses of Helicoverpa armigera to different predation risks, focusing on echolocating bats and their calls. Substantial modifications were observed in the nocturnal and diurnal activities of H. armigera under predation risk, with enhanced evasion behaviors. Accelerated development and decreased fitness were observed under predation risks. Transcriptomic and metabolomic analyses indicated that exposure to bats induced the upregulation of amino acid metabolism- and antioxidant pathway-related genes, reflecting shifts in resource utilization in response to oxidative stress. Exposure to bat predation risks enhanced the activity of DNA damage repair pathways and suppressed energy metabolism, contributing to the observed trait changes and fitness decreases. The current results underscore the complex adaptive strategies that prey species evolve in response to predation risk, enhancing our understanding of the predator–prey dynamic and offering valuable insights for innovative and ecologically informed pest management strategies. Helicoverpa armigera shows adaptive trait changes under bat predation risk, with increased evasion, accelerated development, and fitness decreases. Molecular analyses reveal shifts in metabolism and stress response pathways linked to these changes.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07166-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579807","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 : 2024-11-05DOI: 10.1038/s42003-024-07155-9
Praneeth Karempudi, Konrad Gras, Elias Amselem, Spartak Zikrin, Dvir Schirman, Johan Elf
The intracellular position of genes may impact their expression, but it has not been possible to accurately measure the 3D position of chromosomal loci. In 2D, loci can be tracked using arrays of DNA-binding sites for transcription factors (TFs) fused with fluorescent proteins. However, the same 2D data can result from different 3D trajectories. Here, we have developed a deep learning method for super-resolved astigmatism-based 3D localization of chromosomal loci in live E. coli cells which enables a precision better than 61 nm at a signal-to-background ratio of ~4 on a heterogeneous cell background. Determining the spatial localization of chromosomal loci, we find that some loci are at the periphery of the nucleoid for large parts of the cell cycle. Analyses of individual trajectories reveal that these loci are subdiffusive both longitudinally (x) and radially (r), but that individual loci explore the full radial width on a minute time scale.
{"title":"Three-dimensional localization and tracking of chromosomal loci throughout the Escherichia coli cell cycle.","authors":"Praneeth Karempudi, Konrad Gras, Elias Amselem, Spartak Zikrin, Dvir Schirman, Johan Elf","doi":"10.1038/s42003-024-07155-9","DOIUrl":"10.1038/s42003-024-07155-9","url":null,"abstract":"<p><p>The intracellular position of genes may impact their expression, but it has not been possible to accurately measure the 3D position of chromosomal loci. In 2D, loci can be tracked using arrays of DNA-binding sites for transcription factors (TFs) fused with fluorescent proteins. However, the same 2D data can result from different 3D trajectories. Here, we have developed a deep learning method for super-resolved astigmatism-based 3D localization of chromosomal loci in live E. coli cells which enables a precision better than 61 nm at a signal-to-background ratio of ~4 on a heterogeneous cell background. Determining the spatial localization of chromosomal loci, we find that some loci are at the periphery of the nucleoid for large parts of the cell cycle. Analyses of individual trajectories reveal that these loci are subdiffusive both longitudinally (x) and radially (r), but that individual loci explore the full radial width on a minute time scale.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582617","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 : 2024-11-05DOI: 10.1038/s42003-024-07127-z
Laigang Zhao, HanLin Yang, Yuanmei Wang, Shuang Yang, Qisi Jiang, Jun Tan, Xing Zhao, Dan Zi
Paclitaxel (PTX) is a first-line drug for ovarian cancer (OC) treatment. However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear. Genes and proteins levels were evaluated by RT-qPCR, western blot and IHC. Cell viability and proliferation were measured by CCK-8 and clone formation. The changes of mitochondrial morphology were observed under a transmission electron microscope (TEM). Reactive oxygen species (ROS), iron, malondialdehyde (MDA) and glutathione (GSH) were measured using suitable kits. The interactions among STUB1, HOXB3 and PARK7 were validated using Co-IP, and dual luciferase reporter assay. Our study found that STUB1 was decreased and PARK7 was increased in tumor tissue, especially from chemotherapy resistant ovarian cancer tissue and resistant OC cells. STUB1 overexpression or PARK7 silencing suppressed cell growth and promoted ferroptosis in PTX-resistant OC cells, which was reversed by HOXB3 overexpression. Mechanistically, STUB1 mediated ubiquitination of HOXB3 to inhibit HOXB3 expression, and HOXB3 promoted the transcription of PARK7 by binding to the promoter region of PARK7. Furthermore, STUB1 overexpression or PARK7 silencing suppressed tumor formation in nude mice. In short, STUB1 promoted ferroptosis through regulating HOXB3/PARK7 axis, thereby suppressing chemotherapy resistance in OC. STUB1 mediates the degradation of HOXB3 through ubiquitin, and the decrease of HOXB3 inhibits the level of PARK7, thereby promoting ferroptosis in drug-resistant ovarian cancer cells.
{"title":"STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression","authors":"Laigang Zhao, HanLin Yang, Yuanmei Wang, Shuang Yang, Qisi Jiang, Jun Tan, Xing Zhao, Dan Zi","doi":"10.1038/s42003-024-07127-z","DOIUrl":"10.1038/s42003-024-07127-z","url":null,"abstract":"Paclitaxel (PTX) is a first-line drug for ovarian cancer (OC) treatment. However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear. Genes and proteins levels were evaluated by RT-qPCR, western blot and IHC. Cell viability and proliferation were measured by CCK-8 and clone formation. The changes of mitochondrial morphology were observed under a transmission electron microscope (TEM). Reactive oxygen species (ROS), iron, malondialdehyde (MDA) and glutathione (GSH) were measured using suitable kits. The interactions among STUB1, HOXB3 and PARK7 were validated using Co-IP, and dual luciferase reporter assay. Our study found that STUB1 was decreased and PARK7 was increased in tumor tissue, especially from chemotherapy resistant ovarian cancer tissue and resistant OC cells. STUB1 overexpression or PARK7 silencing suppressed cell growth and promoted ferroptosis in PTX-resistant OC cells, which was reversed by HOXB3 overexpression. Mechanistically, STUB1 mediated ubiquitination of HOXB3 to inhibit HOXB3 expression, and HOXB3 promoted the transcription of PARK7 by binding to the promoter region of PARK7. Furthermore, STUB1 overexpression or PARK7 silencing suppressed tumor formation in nude mice. In short, STUB1 promoted ferroptosis through regulating HOXB3/PARK7 axis, thereby suppressing chemotherapy resistance in OC. STUB1 mediates the degradation of HOXB3 through ubiquitin, and the decrease of HOXB3 inhibits the level of PARK7, thereby promoting ferroptosis in drug-resistant ovarian cancer cells.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07127-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579825","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 : 2024-11-04DOI: 10.1038/s42003-024-07167-5
Wenzhi Xue, Juken Hong, Teng Wang
The balance between chromosomal and plasmid DNAs determines the genomic plasticity of prokaryotes. Natural selections, acting on the level of organisms or plasmids, shape the abundances of plasmid DNAs in prokaryotic genomes. Despite the importance of plasmids in health and engineering, there have been rare systematic attempts to quantitatively model and predict the determinants underlying the strength of different selection forces. Here, we develop a metabolic flux model that describes the intracellular resource competition between chromosomal and plasmid-encoded reactions. By coarse graining, this model predicts a landscape of natural selections on chromosome/plasmid balance, which is featured by the tradeoff between phenotypic and non-phenotypic selection pressures. This landscape is further validated by the observed pattern of plasmid distributions in the vast collection of prokaryotic genomes retrieved from the NCBI database. Our results establish a universal paradigm to understand the prokaryotic chromosome/plasmid interplay and provide insights into the evolutionary origin of plasmid diversity. An intracellular resource competition model sheds light on the evolutionary forces that govern the balance between chromosomal and plasmid DNAs in prokaryotic genomes.
染色体和质粒 DNA 之间的平衡决定了原核生物基因组的可塑性。作用于生物体或质粒层面的自然选择决定了原核生物基因组中质粒 DNA 的丰度。尽管质粒在健康和工程学中非常重要，但很少有人系统地尝试对不同选择力强度的决定因素进行定量建模和预测。在这里，我们建立了一个代谢通量模型，用于描述染色体和质粒编码反应之间的细胞内资源竞争。通过粗粒度分析，该模型预测了染色体/质粒平衡的自然选择景观，其特点是表型和非表型选择压力之间的权衡。从 NCBI 数据库检索到的大量原核生物基因组中观察到的质粒分布模式进一步验证了这一格局。我们的研究结果为理解原核生物染色体/质粒之间的相互作用建立了一个通用范式，并为质粒多样性的进化起源提供了见解。
{"title":"The evolutionary landscape of prokaryotic chromosome/plasmid balance","authors":"Wenzhi Xue, Juken Hong, Teng Wang","doi":"10.1038/s42003-024-07167-5","DOIUrl":"10.1038/s42003-024-07167-5","url":null,"abstract":"The balance between chromosomal and plasmid DNAs determines the genomic plasticity of prokaryotes. Natural selections, acting on the level of organisms or plasmids, shape the abundances of plasmid DNAs in prokaryotic genomes. Despite the importance of plasmids in health and engineering, there have been rare systematic attempts to quantitatively model and predict the determinants underlying the strength of different selection forces. Here, we develop a metabolic flux model that describes the intracellular resource competition between chromosomal and plasmid-encoded reactions. By coarse graining, this model predicts a landscape of natural selections on chromosome/plasmid balance, which is featured by the tradeoff between phenotypic and non-phenotypic selection pressures. This landscape is further validated by the observed pattern of plasmid distributions in the vast collection of prokaryotic genomes retrieved from the NCBI database. Our results establish a universal paradigm to understand the prokaryotic chromosome/plasmid interplay and provide insights into the evolutionary origin of plasmid diversity. An intracellular resource competition model sheds light on the evolutionary forces that govern the balance between chromosomal and plasmid DNAs in prokaryotic genomes.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07167-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574991","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 : 2024-11-04DOI: 10.1038/s42003-024-07148-8
M. D. Burns, D. R. Satterfield, N. Peoples, H. Chan, A. J. Barley, M. L. Yuan, A. S. Roberts-Hugghis, K. T. Russell, M. Hess, S. L. Williamson, K. A. Corn, M. Mihalitsis, D. K. Wainwright, P. C. Wainwright
Major trade-offs often manifest as axes of diversity in organismal functional systems. Overarching trade-offs may result in high trait integration and restrict the trajectory of diversification to be along a single axis. Here, we explore the diversification of the feeding mechanism in coral reef fishes to establish the role of trade-offs and complexity in a spectacular ecological radiation. We show that the primary axis of variation in the measured musculo-skeletal traits is aligned with a trade-off between mobility and force transmission, spanning species that capture prey with suction and those that bite attached prey. We found weak or no covariation between about half the traits, reflecting deviations from the trade-off axis. The dramatic trophic range found among reef fishes occurs along the primary trade-off axis, with numerous departures that use a mosaic of trait combinations to adapt the feeding mechanism to diverse challenges. We suggest that morphological evolution both along and independent of a major axis of variation is a widespread mechanism of diversification in complex systems where a global trade-off shapes major patterns of diversity. Significant additional diversity emerges as systems use weak integration and complexity to assemble functional units with many trait combinations that meet varying ecological demands. The diversity of coral reef fishes’ feeding apparatus aligns with the trade-off between mobility and force transmission, but weak trait covariation and complexity allow jaw traits to evolve independently to adapt to diverse ecological challenges.
{"title":"Complexity and weak integration promote the diversity of reef fish oral jaws","authors":"M. D. Burns, D. R. Satterfield, N. Peoples, H. Chan, A. J. Barley, M. L. Yuan, A. S. Roberts-Hugghis, K. T. Russell, M. Hess, S. L. Williamson, K. A. Corn, M. Mihalitsis, D. K. Wainwright, P. C. Wainwright","doi":"10.1038/s42003-024-07148-8","DOIUrl":"10.1038/s42003-024-07148-8","url":null,"abstract":"Major trade-offs often manifest as axes of diversity in organismal functional systems. Overarching trade-offs may result in high trait integration and restrict the trajectory of diversification to be along a single axis. Here, we explore the diversification of the feeding mechanism in coral reef fishes to establish the role of trade-offs and complexity in a spectacular ecological radiation. We show that the primary axis of variation in the measured musculo-skeletal traits is aligned with a trade-off between mobility and force transmission, spanning species that capture prey with suction and those that bite attached prey. We found weak or no covariation between about half the traits, reflecting deviations from the trade-off axis. The dramatic trophic range found among reef fishes occurs along the primary trade-off axis, with numerous departures that use a mosaic of trait combinations to adapt the feeding mechanism to diverse challenges. We suggest that morphological evolution both along and independent of a major axis of variation is a widespread mechanism of diversification in complex systems where a global trade-off shapes major patterns of diversity. Significant additional diversity emerges as systems use weak integration and complexity to assemble functional units with many trait combinations that meet varying ecological demands. The diversity of coral reef fishes’ feeding apparatus aligns with the trade-off between mobility and force transmission, but weak trait covariation and complexity allow jaw traits to evolve independently to adapt to diverse ecological challenges.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07148-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575538","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}
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