Pub Date : 2024-11-06DOI: 10.1038/s42003-024-07128-y
Aarón Israel Muñiz-Castillo, Andrea Rivera-Sosa, Melanie McField, Iliana Chollett, C Mark Eakin, Susana Enríquez, Ana Giró, Ian Drysdale, Marisol Rueda, Mélina Soto, Nicole Craig, Jesús Ernesto Arias-González
Coral bleaching, a consequence of stressed symbiotic relationships between corals and algae, has escalated due to intensified heat stress events driven by climate change. Despite global efforts, current early warning systems lack local precision. Our study, spanning 2015-2017 in the Mesoamerican Reef, revealed prevalent intermediate bleaching, peaking in 2017. By scrutinizing 23 stress exposure and sensitivity metrics, we accurately predicted 75% of bleaching severity variation. Notably, distinct thermal patterns-particularly the climatological seasonal warming rate and various heat stress metrics-emerged as better predictors compared to conventional indices (such as Degree Heating Weeks). Surprisingly, deeper reefs with diverse coral communities showed heightened vulnerability. This study presents a framework for coral reef bleaching vulnerability assessment, leveraging accessible data (including historical and real-time sea surface temperature, habitat variables, and species composition). Its operational potential lies in seamless integration with existing monitoring systems, offering crucial insights for conservation and management.
{"title":"Underlying drivers of coral reef vulnerability to bleaching in the Mesoamerican Reef.","authors":"Aarón Israel Muñiz-Castillo, Andrea Rivera-Sosa, Melanie McField, Iliana Chollett, C Mark Eakin, Susana Enríquez, Ana Giró, Ian Drysdale, Marisol Rueda, Mélina Soto, Nicole Craig, Jesús Ernesto Arias-González","doi":"10.1038/s42003-024-07128-y","DOIUrl":"10.1038/s42003-024-07128-y","url":null,"abstract":"<p><p>Coral bleaching, a consequence of stressed symbiotic relationships between corals and algae, has escalated due to intensified heat stress events driven by climate change. Despite global efforts, current early warning systems lack local precision. Our study, spanning 2015-2017 in the Mesoamerican Reef, revealed prevalent intermediate bleaching, peaking in 2017. By scrutinizing 23 stress exposure and sensitivity metrics, we accurately predicted 75% of bleaching severity variation. Notably, distinct thermal patterns-particularly the climatological seasonal warming rate and various heat stress metrics-emerged as better predictors compared to conventional indices (such as Degree Heating Weeks). Surprisingly, deeper reefs with diverse coral communities showed heightened vulnerability. This study presents a framework for coral reef bleaching vulnerability assessment, leveraging accessible data (including historical and real-time sea surface temperature, habitat variables, and species composition). Its operational potential lies in seamless integration with existing monitoring systems, offering crucial insights for conservation and management.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1452"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590247","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}
A spatiotemporal understanding of gene function requires the precise control of gene expression in each cell. Here, we use an infrared laser-evoked gene operator (IR-LEGO) system to induce gene expression at the single-cell level in the moss Physcomitrium patens by heating a living cell with an IR laser and thereby activating the heat shock response. We identify the laser irradiation conditions that provide higher inducibility with lower invasiveness by changing the laser power and irradiation duration. Furthermore, we quantitatively characterize the induction profile of the heat shock response using a heat-induced fluorescence reporter system after the IR laser irradiation of single cells under different conditions. Our data indicate that IR laser irradiation with long duration leads to higher inducibility according to increase in the laser power but not vice versa, and that the higher laser power even without conferring apparent damage to the cells decelerates and/or delayed gene induction. We define the temporal shift in expression as a function of onset and duration according to laser power and irradiation duration. This study contributes to the versatile application of IR-LEGO in plants and improves our understanding of heat shock-induced gene expression.
{"title":"Infrared laser-induced gene expression in single cells characterized by quantitative imaging in Physcomitrium patens.","authors":"Takumi Tomoi, Yuka Yoshida, Suguru Ohe, Yukiko Kabeya, Mitsuyasu Hasebe, Tomohiro Morohoshi, Takashi Murata, Joe Sakamoto, Yosuke Tamada, Yasuhiro Kamei","doi":"10.1038/s42003-024-07141-1","DOIUrl":"10.1038/s42003-024-07141-1","url":null,"abstract":"<p><p>A spatiotemporal understanding of gene function requires the precise control of gene expression in each cell. Here, we use an infrared laser-evoked gene operator (IR-LEGO) system to induce gene expression at the single-cell level in the moss Physcomitrium patens by heating a living cell with an IR laser and thereby activating the heat shock response. We identify the laser irradiation conditions that provide higher inducibility with lower invasiveness by changing the laser power and irradiation duration. Furthermore, we quantitatively characterize the induction profile of the heat shock response using a heat-induced fluorescence reporter system after the IR laser irradiation of single cells under different conditions. Our data indicate that IR laser irradiation with long duration leads to higher inducibility according to increase in the laser power but not vice versa, and that the higher laser power even without conferring apparent damage to the cells decelerates and/or delayed gene induction. We define the temporal shift in expression as a function of onset and duration according to laser power and irradiation duration. This study contributes to the versatile application of IR-LEGO in plants and improves our understanding of heat shock-induced gene expression.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1448"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590224","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 : 2024-11-06DOI: 10.1038/s42003-024-07146-w
Tereza Beránková, Jigyasa Arora, Johanna Romero Arias, Aleš Buček, Gaku Tokuda, Jan Šobotník, Simon Hellemans, Thomas Bourguignon
Termites digest wood using Carbohydrate-Active Enzymes (CAZymes) produced by gut bacteria with whom they have cospeciated at geological timescales. Whether CAZymes were encoded in the genomes of their ancestor's gut bacteria and transmitted to modern termites or acquired more recently from bacteria not associated with termites is unclear. We used gut metagenomes from 195 termites and one Cryptocercus, the sister group of termites, to investigate the evolution of termite gut bacterial CAZymes. We found 420 termite-specific clusters in 81 bacterial CAZyme gene trees, including 404 clusters showing strong cophylogenetic patterns with termites. Of the 420 clusters, 131 included at least one bacterial CAZyme sequence associated with Cryptocercus or Mastotermes, the sister group of all other termites. Our results suggest many bacterial CAZymes have been encoded in the genomes of termite gut bacteria since termite origin, indicating termites rely upon many bacterial CAZymes endemic to their guts to digest wood.
{"title":"Termites and subsocial roaches inherited many bacterial-borne carbohydrate-active enzymes (CAZymes) from their common ancestor.","authors":"Tereza Beránková, Jigyasa Arora, Johanna Romero Arias, Aleš Buček, Gaku Tokuda, Jan Šobotník, Simon Hellemans, Thomas Bourguignon","doi":"10.1038/s42003-024-07146-w","DOIUrl":"10.1038/s42003-024-07146-w","url":null,"abstract":"<p><p>Termites digest wood using Carbohydrate-Active Enzymes (CAZymes) produced by gut bacteria with whom they have cospeciated at geological timescales. Whether CAZymes were encoded in the genomes of their ancestor's gut bacteria and transmitted to modern termites or acquired more recently from bacteria not associated with termites is unclear. We used gut metagenomes from 195 termites and one Cryptocercus, the sister group of termites, to investigate the evolution of termite gut bacterial CAZymes. We found 420 termite-specific clusters in 81 bacterial CAZyme gene trees, including 404 clusters showing strong cophylogenetic patterns with termites. Of the 420 clusters, 131 included at least one bacterial CAZyme sequence associated with Cryptocercus or Mastotermes, the sister group of all other termites. Our results suggest many bacterial CAZymes have been encoded in the genomes of termite gut bacteria since termite origin, indicating termites rely upon many bacterial CAZymes endemic to their guts to digest wood.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1449"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590244","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 : 2024-11-06DOI: 10.1038/s42003-024-07152-y
Hiroaki Akasaka, Fumiya K Sano, Wataru Shihoya, Osamu Nureki
Lysophosphatidic acid receptor 1 (LPA1) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA1 is associated with a variety of diseases, and LPA1 agonists have potential therapeutic value for treating obesity and depression. Although potent nonlipid LPA1 agonists have recently been identified, the mechanisms of nonlipid molecule-mediated LPA1 activation remain unclear. Here, we report a cryo-electron microscopy structure of the human LPA1-Gi complex bound to a nonlipid basic agonist, CpY, which has 30-fold higher agonistic activity as compared with LPA. Structural comparisons of LPA1 with other lipid GPCRs revealed that the negative charge in the characteristic binding pocket of LPA1 allows the selective recognition of CpY, which lacks a polar head. In addition, our structure show that the ethyl group of CpY directly pushes W2716.48 to fix the active conformation. Endogenous LPA lacks these chemical features, which thus represent the crucial elements of nonlipid agonists that potently activate LPA1. This study provides detailed mechanistic insights into the ligand recognition and activation of LPA1 by nonlipid agonists, expanding the scope for drug development targeting the LPA receptors.
{"title":"Structural mechanisms of potent lysophosphatidic acid receptor 1 activation by nonlipid basic agonists.","authors":"Hiroaki Akasaka, Fumiya K Sano, Wataru Shihoya, Osamu Nureki","doi":"10.1038/s42003-024-07152-y","DOIUrl":"10.1038/s42003-024-07152-y","url":null,"abstract":"<p><p>Lysophosphatidic acid receptor 1 (LPA<sub>1</sub>) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA<sub>1</sub> is associated with a variety of diseases, and LPA<sub>1</sub> agonists have potential therapeutic value for treating obesity and depression. Although potent nonlipid LPA<sub>1</sub> agonists have recently been identified, the mechanisms of nonlipid molecule-mediated LPA<sub>1</sub> activation remain unclear. Here, we report a cryo-electron microscopy structure of the human LPA<sub>1</sub>-G<sub>i</sub> complex bound to a nonlipid basic agonist, CpY, which has 30-fold higher agonistic activity as compared with LPA. Structural comparisons of LPA<sub>1</sub> with other lipid GPCRs revealed that the negative charge in the characteristic binding pocket of LPA<sub>1</sub> allows the selective recognition of CpY, which lacks a polar head. In addition, our structure show that the ethyl group of CpY directly pushes W271<sup>6.48</sup> to fix the active conformation. Endogenous LPA lacks these chemical features, which thus represent the crucial elements of nonlipid agonists that potently activate LPA<sub>1</sub>. This study provides detailed mechanistic insights into the ligand recognition and activation of LPA<sub>1</sub> by nonlipid agonists, expanding the scope for drug development targeting the LPA receptors.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1444"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590240","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 : 2024-11-06DOI: 10.1038/s42003-024-07120-6
James J Fink, Nathaniel Delaney-Busch, Ryan Dawes, Evanthia Nanou, Christopher Folts, Karthiayani Harikrishnan, Chris Hempel, Hansini Upadhyay, Trinh Nguyen, Himali Shroff, David Stoppel, Steven J Ryan, Jane Jacques, Jennifer Grooms, Elizabeth Berry-Kravis, Mark F Bear, Luis A Williams, David Gerber, Mark Bunnage, Brinley Furey, Graham T Dempsey
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by hypermethylation of expanded CGG repeats (>200) in the FMR1 gene leading to gene silencing and loss of Fragile X Messenger Ribonucleoprotein (FMRP) expression. FMRP plays important roles in neuronal function, and loss of FMRP in mouse and human FXS cell models leads to aberrant synaptic signaling and hyperexcitability. Multiple drug candidates have advanced into clinical trials for FXS, but no efficacious treatment has been identified to date, possibly as a consequence of poor translation from pre-clinical animal models to human. Here, we use a high resolution all-optical electrophysiology platform applied to multiple FXS patient-derived and CRISPR/Cas9-generated isogenic neuronal cell lines to develop a multi-parametric FXS disease phenotype. This neurophysiological phenotype was optimized and validated into a high throughput assay based on the amount of FMRP re-expression and the number of healthy neurons in a mosaic network necessary for functional rescue. The resulting highly sensitive and multiparameter functional assay can now be applied as a discovery platform to explore new therapeutic approaches for the treatment of FXS.
{"title":"Deep functional measurements of Fragile X syndrome human neurons reveal multiparametric electrophysiological disease phenotype.","authors":"James J Fink, Nathaniel Delaney-Busch, Ryan Dawes, Evanthia Nanou, Christopher Folts, Karthiayani Harikrishnan, Chris Hempel, Hansini Upadhyay, Trinh Nguyen, Himali Shroff, David Stoppel, Steven J Ryan, Jane Jacques, Jennifer Grooms, Elizabeth Berry-Kravis, Mark F Bear, Luis A Williams, David Gerber, Mark Bunnage, Brinley Furey, Graham T Dempsey","doi":"10.1038/s42003-024-07120-6","DOIUrl":"10.1038/s42003-024-07120-6","url":null,"abstract":"<p><p>Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by hypermethylation of expanded CGG repeats (>200) in the FMR1 gene leading to gene silencing and loss of Fragile X Messenger Ribonucleoprotein (FMRP) expression. FMRP plays important roles in neuronal function, and loss of FMRP in mouse and human FXS cell models leads to aberrant synaptic signaling and hyperexcitability. Multiple drug candidates have advanced into clinical trials for FXS, but no efficacious treatment has been identified to date, possibly as a consequence of poor translation from pre-clinical animal models to human. Here, we use a high resolution all-optical electrophysiology platform applied to multiple FXS patient-derived and CRISPR/Cas9-generated isogenic neuronal cell lines to develop a multi-parametric FXS disease phenotype. This neurophysiological phenotype was optimized and validated into a high throughput assay based on the amount of FMRP re-expression and the number of healthy neurons in a mosaic network necessary for functional rescue. The resulting highly sensitive and multiparameter functional assay can now be applied as a discovery platform to explore new therapeutic approaches for the treatment of FXS.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1447"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590203","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 : 2024-11-06DOI: 10.1038/s42003-024-07099-0
Andrew Wang, Anna-Marie Fairhurst, Kui Liu, Benjamin Wakeland, Spencer Barnes, Venkat S Malladi, Kasthuribai Viswanathan, Carlos Arana, Igor Dozmorov, Amrita Singhar, Yong Du, Marjaan Imam, Angela Moses, Christian Chen, Ashwini Sunkavalli, Jose Casco, Dinesh Rakheja, Quan-Zhen Li, Chandra Mohan, Carol Clayberger, Edward K Wakeland, Shaheen Khan
Although significant progress has been achieved in elucidating the genetic architecture of systemic lupus erythematosus (SLE), identifying genes underlying the pathogenesis has been challenging. The NZM2410-derived lupus susceptibility Sle3 locus is associated with T cell hyperactivity and activated myeloid cells. However, candidate genes associated with these phenotypes have not been identified. Here, we narrow the Sle3 locus to a smaller genomic segment (Sle3k) and show that mice carrying Sle3k and Sle1 loci developed lupus nephritis. We identify Klf13 as the primary candidate gene that is associated with genome-wide transcription changes resulting in higher levels of proinflammatory cytokines, enhanced T cell activation, and hyperresponsiveness of myeloid cells. Correspondingly, Klf13 -/- mice display repression of genes involved in mediating immune activation, including key proinflammatory cytokines/chemokines in T cells and dysregulation in cytokine signaling pathways in myeloid cells in response to toll receptor ligands. Klf13 upregulation is associated with increased production of RANTES, a key chemokine in lupus nephritis, in activated T cells and the kidneys of lupus-prone mice. In sum, our findings reveal Klf13 as a key gene in the Sle3 interval in mediating lupus pathogenesis that may have implications in the rational design of new therapies for SLE.
尽管在阐明系统性红斑狼疮(SLE)的遗传结构方面取得了重大进展,但确定其发病机制的基因一直是个挑战。源自 NZM2410 的狼疮易感性 Sle3 基因座与 T 细胞过度活跃和活化的髓样细胞有关。然而,与这些表型相关的候选基因尚未发现。在这里,我们将 Sle3 基因座缩小到一个较小的基因组片段(Sle3k),并证明携带 Sle3k 和 Sle1 基因座的小鼠会患上狼疮肾炎。我们发现 Klf13 是与全基因组转录变化相关的主要候选基因,这种转录变化导致促炎细胞因子水平升高、T 细胞活化增强以及髓系细胞反应性增高。相应地,Klf13 -/-小鼠显示出参与介导免疫激活的基因受到抑制,包括 T 细胞中的关键促炎细胞因子/凝血因子,以及髓系细胞中细胞因子信号通路对收费受体配体反应的失调。Klf13 的上调与活化 T 细胞和狼疮易感小鼠肾脏中狼疮肾炎的关键趋化因子 RANTES 的产生增加有关。总之,我们的发现揭示了 Klf13 是 Sle3 区间介导狼疮发病机制的一个关键基因,这可能对合理设计系统性红斑狼疮的新疗法具有重要意义。
{"title":"KLF13 promotes SLE pathogenesis by modifying chromatin accessibility of key proinflammatory cytokine genes.","authors":"Andrew Wang, Anna-Marie Fairhurst, Kui Liu, Benjamin Wakeland, Spencer Barnes, Venkat S Malladi, Kasthuribai Viswanathan, Carlos Arana, Igor Dozmorov, Amrita Singhar, Yong Du, Marjaan Imam, Angela Moses, Christian Chen, Ashwini Sunkavalli, Jose Casco, Dinesh Rakheja, Quan-Zhen Li, Chandra Mohan, Carol Clayberger, Edward K Wakeland, Shaheen Khan","doi":"10.1038/s42003-024-07099-0","DOIUrl":"10.1038/s42003-024-07099-0","url":null,"abstract":"<p><p>Although significant progress has been achieved in elucidating the genetic architecture of systemic lupus erythematosus (SLE), identifying genes underlying the pathogenesis has been challenging. The NZM2410-derived lupus susceptibility Sle3 locus is associated with T cell hyperactivity and activated myeloid cells. However, candidate genes associated with these phenotypes have not been identified. Here, we narrow the Sle3 locus to a smaller genomic segment (Sle3k) and show that mice carrying Sle3k and Sle1 loci developed lupus nephritis. We identify Klf13 as the primary candidate gene that is associated with genome-wide transcription changes resulting in higher levels of proinflammatory cytokines, enhanced T cell activation, and hyperresponsiveness of myeloid cells. Correspondingly, Klf13 <sup>-/-</sup> mice display repression of genes involved in mediating immune activation, including key proinflammatory cytokines/chemokines in T cells and dysregulation in cytokine signaling pathways in myeloid cells in response to toll receptor ligands. Klf13 upregulation is associated with increased production of RANTES, a key chemokine in lupus nephritis, in activated T cells and the kidneys of lupus-prone mice. In sum, our findings reveal Klf13 as a key gene in the Sle3 interval in mediating lupus pathogenesis that may have implications in the rational design of new therapies for SLE.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1446"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590130","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 : 2024-11-06DOI: 10.1038/s42003-024-07137-x
Julia Debik, Katarzyna Mrowiec, Agata Kurczyk, Piotr Widłak, Karol Jelonek, Tone F Bathen, Guro F Giskeødegård
The aim of this study was to explore the intricate relationship between serum metabolomics and lifestyle factors, shedding light on their impact on health in the context of breast cancer risk. Detailed metabolic profiles of 2283 female participants in the Trøndelag Health Study (HUNT study) were obtained through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).We show that lifestyle-related variables can explain up to 30% of the variance in individual metabolites. Age and obesity were the primary factors affecting the serum metabolic profile, both associated with increased levels of triglyceride-rich very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), amino acids and glycolysis-related metabolites, and decreased levels of high-density lipoproteins (HDL). Moreover, factors like hormonal changes associated with menstruation and contraceptive use or education level influence the metabolite levels.Participants were clustered into three distinct clusters based on lifestyle-related factors, revealing metabolic similarities between obese and older individuals, despite diverse lifestyle factors, suggesting accelerated metabolic aging with obesity. Our results show that metabolic associations to cancer risk may partly be explained by modifiable lifestyle factors.
{"title":"Sources of variation in the serum metabolome of female participants of the HUNT2 study.","authors":"Julia Debik, Katarzyna Mrowiec, Agata Kurczyk, Piotr Widłak, Karol Jelonek, Tone F Bathen, Guro F Giskeødegård","doi":"10.1038/s42003-024-07137-x","DOIUrl":"10.1038/s42003-024-07137-x","url":null,"abstract":"<p><p>The aim of this study was to explore the intricate relationship between serum metabolomics and lifestyle factors, shedding light on their impact on health in the context of breast cancer risk. Detailed metabolic profiles of 2283 female participants in the Trøndelag Health Study (HUNT study) were obtained through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).We show that lifestyle-related variables can explain up to 30% of the variance in individual metabolites. Age and obesity were the primary factors affecting the serum metabolic profile, both associated with increased levels of triglyceride-rich very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), amino acids and glycolysis-related metabolites, and decreased levels of high-density lipoproteins (HDL). Moreover, factors like hormonal changes associated with menstruation and contraceptive use or education level influence the metabolite levels.Participants were clustered into three distinct clusters based on lifestyle-related factors, revealing metabolic similarities between obese and older individuals, despite diverse lifestyle factors, suggesting accelerated metabolic aging with obesity. Our results show that metabolic associations to cancer risk may partly be explained by modifiable lifestyle factors.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1450"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590148","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 : 2024-11-06DOI: 10.1038/s42003-024-07158-6
Gábor Gulyás, Balázs Kakuk, Ákos Dörmő, Tamás Járay, István Prazsák, Zsolt Csabai, Miksa Máté Henkrich, Zsolt Boldogkői, Dóra Tombácz
The rapid advancements in sequencing technologies and bioinformatics have enabled metagenomic research of complex microbial systems, but reliable results depend on consistent laboratory and bioinformatics approaches. Current efforts to identify best practices often focus on optimizing specific steps, making it challenging to understand the influence of each stage on microbial population analysis and compare data across studies. This study evaluated DNA extraction, library construction methodologies, sequencing platforms, and computational approaches using a dog stool sample, two synthetic microbial community mixtures, and various sequencing data sources. Our work, the most comprehensive evaluation of metagenomic methods to date. We developed a software tool, termed minitax, which provides consistent results across the range of platforms and methodologies. Our findings showed that the Zymo Research Quick-DNA HMW MagBead Kit, Illumina DNA Prep library preparation method, and the minitax bioinformatics tool were the most effective for high-quality microbial diversity analysis. However, the effectiveness of pipelines or method combinations is sample-specific, making it difficult to identify a universally optimal approach. Therefore, employing multiple approaches is crucial for obtaining reliable outcomes in microbial systems.
测序技术和生物信息学的快速发展使复杂微生物系统的元基因组研究成为可能,但可靠的结果取决于一致的实验室和生物信息学方法。目前,确定最佳实践的工作往往侧重于优化特定步骤,这使得了解每个阶段对微生物种群分析的影响以及比较不同研究的数据具有挑战性。本研究利用狗粪便样本、两种合成微生物群落混合物和各种测序数据源,对 DNA 提取、文库构建方法、测序平台和计算方法进行了评估。我们的工作是迄今为止对元基因组学方法最全面的评估。我们开发了一种称为 minitax 的软件工具,它能在各种平台和方法中提供一致的结果。我们的研究结果表明,Zymo Research Quick-DNA HMW MagBead Kit、Illumina DNA Prep 文库制备方法和 minitax 生物信息学工具对高质量微生物多样性分析最为有效。然而,管道或方法组合的有效性取决于具体样本,因此很难确定一种普遍适用的最佳方法。因此,要在微生物系统中获得可靠的结果,采用多种方法至关重要。
{"title":"Cross-comparison of gut metagenomic profiling strategies.","authors":"Gábor Gulyás, Balázs Kakuk, Ákos Dörmő, Tamás Járay, István Prazsák, Zsolt Csabai, Miksa Máté Henkrich, Zsolt Boldogkői, Dóra Tombácz","doi":"10.1038/s42003-024-07158-6","DOIUrl":"10.1038/s42003-024-07158-6","url":null,"abstract":"<p><p>The rapid advancements in sequencing technologies and bioinformatics have enabled metagenomic research of complex microbial systems, but reliable results depend on consistent laboratory and bioinformatics approaches. Current efforts to identify best practices often focus on optimizing specific steps, making it challenging to understand the influence of each stage on microbial population analysis and compare data across studies. This study evaluated DNA extraction, library construction methodologies, sequencing platforms, and computational approaches using a dog stool sample, two synthetic microbial community mixtures, and various sequencing data sources. Our work, the most comprehensive evaluation of metagenomic methods to date. We developed a software tool, termed minitax, which provides consistent results across the range of platforms and methodologies. Our findings showed that the Zymo Research Quick-DNA HMW MagBead Kit, Illumina DNA Prep library preparation method, and the minitax bioinformatics tool were the most effective for high-quality microbial diversity analysis. However, the effectiveness of pipelines or method combinations is sample-specific, making it difficult to identify a universally optimal approach. Therefore, employing multiple approaches is crucial for obtaining reliable outcomes in microbial systems.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"7 1","pages":"1445"},"PeriodicalIF":5.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590199","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 : 2024-11-06DOI: 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":"7 1","pages":"1451"},"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":" ","pages":"1-17"},"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}