Sina B Kirchhofer, Claudia Kurz, Lorenz Geier, Anna-Lena Krett, Cornelius Krasel, Moritz Bünemann
{"title":"Dynamics of agonist-evoked opioid receptor activation revealed by FRET- and BRET-based opioid receptor conformation sensors.","authors":"Sina B Kirchhofer, Claudia Kurz, Lorenz Geier, Anna-Lena Krett, Cornelius Krasel, Moritz Bünemann","doi":"10.1038/s42003-025-07630-x","DOIUrl":"10.1038/s42003-025-07630-x","url":null,"abstract":"<p><p>The opioid receptor family, particularly the µ opioid receptor, are the main drug targets in the management of severe pain. However, their pain-relieving effects are often accompanied by severe adverse effects, underlining the necessity for extensive research on this receptor family. Opioids, the agonists targeting these receptors, differ in their chemical structure and also in their mode of action in different aspects of signaling. Here we introduce novel tools that facilitate the analysis of this receptor family, by the development of FRET- and BRET-based receptor conformation sensors. With these sensors we were able to characterize especially the µ opioid receptor in more detail and reveal a strongly agonist-dependent activation kinetics for this receptor. Moreover, our sensors offer an assay independent from other signaling pathways, thereby minimizing the potential for interfering influences or biases within the system.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"198"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Priestia megaterium cells are primed for surviving lethal doses of antibiotics and chemical stress.","authors":"Manisha Guha, Abhyudai Singh, Nicholas C Butzin","doi":"10.1038/s42003-025-07639-2","DOIUrl":"https://doi.org/10.1038/s42003-025-07639-2","url":null,"abstract":"<p><p>Antibiotic resistant infections kill millions worldwide yearly. However, a key factor in recurrent infections is antibiotic persisters. Persisters are not inherently antibiotic-resistant but can withstand antibiotic exposure by entering a non-dividing state. This tolerance often results in prolonged antibiotic usage, increasing the likelihood of developing resistant strains. Here, we show the existence of \"primed cells\" in the Gram-positive bacterium Priestia megaterium, formerly known as Bacillus megaterium. These cells are pre-adapted to become persisters prior to lethal antibiotic stress. Remarkably, this prepared state is passed down through multiple generations via epigenetic memory, enhancing survival against antibiotics and other chemical stress. Previously, two distinct types of persisters were proposed: Type I and Type II, formed during stationary and log phases, respectively. However, our findings reveal that primed cells contribute to an increase in persisters during transition and stationary phases, with no evidence supporting distinct phenotypes between Type I and Type II persisters.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"206"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guirong Liang, Chenjing Zhao, Qin Wei, Suying Feng, Yetao Wang
{"title":"Single cell transcriptome profiling reveals pathogenesis of bullous pemphigoid.","authors":"Guirong Liang, Chenjing Zhao, Qin Wei, Suying Feng, Yetao Wang","doi":"10.1038/s42003-025-07629-4","DOIUrl":"https://doi.org/10.1038/s42003-025-07629-4","url":null,"abstract":"<p><p>Bullous pemphigoid (BP) triggers profound functional changes in both immune and non-immune cells in the skin and circulation, though the underlying mechanisms remain unclear. In this study, we conduct single-cell transcriptome analysis of lesional and non-lesional skin, as well as blood samples from BP patients. In lesional skin, non-immune cells upregulate pathways related to metabolism, wound healing, immune activation, and cell migration. LAMP3<sup>+</sup>DCs from cDC2 show stronger pro-inflammatory signatures than those from cDC1, and VEGFA<sup>+</sup> mast cells, crucial for BP progression, are predominantly in lesional skin. As BP patients transition from active to remission stages, blood B cell function shifts from differentiation and memory formation to increased type 1 interferon signaling and reduced IL-4 response. Blood CX3CR1<sup>+</sup> ZNF683<sup>+</sup> and LAG3<sup>+</sup> exhausted T cells exhibit the highest TCR expansion among clones shared with skin CD8<sup>+</sup>T cells, suggesting their role in fueling skin CD8<sup>+</sup>T cell clonal expansion. Clinical BP severity correlates positively with blood NK cell IFN-γ production and negatively with amphiregulin (AREG) production. NK cell-derived AREG mitigates IFN-γ-induced keratinocyte apoptosis, suggesting a crucial balance between AREG and IFN-γ in BP progression. These findings highlight functional shifts in BP pathology and suggest potential therapeutic targets.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"203"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antoine Davière, Aline Voxeur, Sylvie Jolivet, Luka Lelas, Samantha Vernhettes, Marie-Christine Soulié, Mathilde Fagard
{"title":"Unravelling the interplay of nitrogen nutrition and the Botrytis cinerea pectin lyase BcPNL1 in modulating Arabidopsis thaliana susceptibility.","authors":"Antoine Davière, Aline Voxeur, Sylvie Jolivet, Luka Lelas, Samantha Vernhettes, Marie-Christine Soulié, Mathilde Fagard","doi":"10.1038/s42003-025-07642-7","DOIUrl":"https://doi.org/10.1038/s42003-025-07642-7","url":null,"abstract":"<p><p>In this study, we investigated the interplay between nitrogen nutrition and the pectin degradation dynamics during Arabidopsis and Botrytis interaction. Our findings revealed that infected detached leaves from nitrogen-sufficient plants released more pectin lyase (PNL)-derived oligogalacturonides compared to nitrogen-deficient ones. We then focused on BcPNL1, the most highly expressed Botrytis PNL upon infection. Using mutant strains lacking BcPNL1, we observed reduced pathogenicity, a delay in germination and a lag in triggering the plant defense response. Additionally, in nitrogen-sufficient detached leaves, the elevated expression of jasmonic acid repressor genes observed upon infection with the wild-type strain was abolished with the mutants. These results linked the increased production of BcPNL-derived products to the increased expression of jasmonic acid repressor genes, contributing partially to the higher susceptibility of nitrogen-sufficient detached leaves. These findings could lay the foundation for new strategies aimed at reconciling both crop resistance to pathogens and the improvement of nitrogen nutrition.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"204"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Isoacteoside alleviates hepatocellular carcinoma progression by inhibiting PDHB-mediated reprogramming of glucose metabolism.","authors":"Lijun Zhao, Haonan Qi, Weiting Liu, Huiying Lv, Peixian Li, Wenyue Liu, Ruili Sun, Qiongzi Wang, Xiangpeng Wang","doi":"10.1038/s42003-025-07622-x","DOIUrl":"https://doi.org/10.1038/s42003-025-07622-x","url":null,"abstract":"<p><p>Pyruvate dehydrogenase B (PDHB) is an important component of the pyruvate dehydrogenase complex and is implicated in altering tumor metabolism and promoting malignancy. However, the specific impact of PDHB on hepatocellular carcinoma (HCC) metabolic reprogramming and its role in tumor progression remain to be elucidated. In our investigation, we have discerned a pronounced elevation in PDHB expression within HCC, intricately linked to delayed tumor staging, heightened tumor grading, and diminished prognostic outcomes. PDHB overexpression drives tumor growth and metastasis in vitro and in vivo. Mechanistically, PDHB mediates metabolic reprogramming by binding to the promoter regions of SLC2A1, GPI, and PKM2, promoting glycolysis-related gene transcription, contributes to HCC sorafenib resistance. In addition, Isoacteoside is a targeted inhibitor of PDHB and exert antitumor effects on HCC. In the mouse xenograft model, the combination of isoacteoside and sorafenib shows significantly better effects than sorafenib alone. In summary, our study validates PDHB as an oncogenic drug resistance-related gene capable of predicting HCC tumor progression. PDHB and Isoacteoside could be potential avenues for targeted and combination therapies in liver cancer.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"205"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA.","authors":"Shigeru Matsuda, Masunari Nakayama, Yura Do, Takashi Ishiuchi, Mikako Yagi, Sjoerd Wanrooij, Kazuto Nakada, Fan-Yan Wei, Kenji Ichiyanagi, Hiroyuki Sasaki, Dongchon Kang, Takehiro Yasukawa","doi":"10.1038/s42003-025-07645-4","DOIUrl":"https://doi.org/10.1038/s42003-025-07645-4","url":null,"abstract":"<p><p>Transcription of human mitochondrial DNA (mtDNA) begins from specific transcription promoters. In strand-asynchronous mtDNA replication, transcripts from the light-strand promoter serve as primers for leading-strand synthesis at the origin of the H-strand replication (O<sub>H</sub>). A 7S DNA strand, a presumed aborted replication product, is also synthesized from O<sub>H</sub>. Transition from RNA synthesis to DNA synthesis at O<sub>H</sub> is crucial for balancing replication with transcription, yet the mechanism remains unclear. Herein, we examine the role of mitochondrial transcription elongation factor (TEFM) in this process. TEFM knockout results in decreased 7S DNA, strand-asynchronous replication intermediates, and mtDNA copy number, all of which are concordant with downregulation of RNA-to-DNA transition at O<sub>H</sub>. Conversely, levels of tRNAs encoded near transcription promoters increase, indicating enhanced transcription initiation frequency. Taken together, we propose that, in addition to conferring processivity to the mitochondrial RNA polymerase, TEFM plays a crucial role in maintaining the balance between mitochondrial transcription and replication.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"202"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Misako Katsuura, Jun Homma, Yuhei Higashi, Hidekazu Sekine, Tatsuya Shimizu
{"title":"Densely vascularized thick 3D tissue shows enhanced protein secretion constructed with intermittent positive pressure.","authors":"Misako Katsuura, Jun Homma, Yuhei Higashi, Hidekazu Sekine, Tatsuya Shimizu","doi":"10.1038/s42003-025-07627-6","DOIUrl":"https://doi.org/10.1038/s42003-025-07627-6","url":null,"abstract":"<p><p>Constructing a dense vascular endothelial network within engineered tissue is crucial for successful engraftment. The present study investigated the effects of air-compressing intermittent positive pressure (IPP) on co-cultured mesenchymal stem cells and vascular endothelial cells and evaluated the potential of IPP-cultured cell sheets for transplantation therapy. The results demonstrated that the IPP (+) group exhibited a denser vascular endothelial network and significantly increased cell sheet thickness compared to the IPP (-) group. Furthermore, in vivo experiments showed that IPP-cultured cell sheets enhanced the secretion of Gaussian luciferase by genetically modified mesenchymal stem cells. These findings highlight the IPP method as a technique that simultaneously enables the thickening of planar tissues and the construction of vascular networks. This approach demonstrates promise for fabricating functional, transplantable, and thick tissues with dense vascularization and a high capacity for protein secretion, paving the way for novel applications in regenerative medicine.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"201"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lewis E Fry, Lauren Major, Ahmed Salman, Lucy A McDermott, Jun Yang, Andrew J King, Michelle E McClements, Robert E MacLaren
{"title":"Comparison of CRISPR-Cas13b RNA base editing approaches for USH2A-associated inherited retinal degeneration.","authors":"Lewis E Fry, Lauren Major, Ahmed Salman, Lucy A McDermott, Jun Yang, Andrew J King, Michelle E McClements, Robert E MacLaren","doi":"10.1038/s42003-025-07557-3","DOIUrl":"https://doi.org/10.1038/s42003-025-07557-3","url":null,"abstract":"<p><p>CRISPR-Cas13 systems have therapeutic promise for the precise correction of point mutations in RNA. Using adenosine deaminase acting on RNA (ADAR) effectors, A-I base conversions can be targeted using guide RNAs (gRNAs). We compare the Cas13 effectors PspCas13b and Cas13bt3 for the repair of the gene USH2A, a common cause of inherited retinal disease and Usher syndrome. In cultured cells, we demonstrate up to 80% efficiency for the repair of the common c.11864 G > A and its murine equivalent c.11840 G > A, across different gRNAs and promoters. We develop and characterize a mouse model of Usher syndrome carrying the c.11840 G > A mutation designed for the evaluation of base editors for inherited retinal disease. Finally, we compare Cas13 effectors delivered via AAV for the repair of Ush2a in photoreceptors. Mean RNA editing rates in photoreceptors across different constructs ranged from 0.32% to 2.04%, with greater efficiency in those injected with PspCas13b compared to Cas13bt3 constructs. In mice injected with PspCas13b constructs, usherin protein was successfully restored and correctly localized to the connecting cilium following RNA editing. These results support the development of transcriptome targeting gene editing therapies for retinal disease.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"200"},"PeriodicalIF":5.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Multiomics identify the gene expression signature of the spinal cord during aging process.","authors":"Lintao Xu, Jingyu Wang, Jinjie Zhong, Weiwei Lin, Gerong Shen, Ning He, Xingjia Mao, Chunyan Fu, Zhaobo Huang, Fengdong Zhao, Xin Ye, Yongjian Zhu, Mingzhi Zheng, Hui Li, Lin-Lin Wang, Kai Zhong, Lijun Zhu, Ying-Ying Chen","doi":"10.1038/s42003-025-07475-4","DOIUrl":"https://doi.org/10.1038/s42003-025-07475-4","url":null,"abstract":"<p><p>Age-related long-term disability is attracting increasing attention due to the growing ageing population worldwide. However, the current understanding of the senescent spinal cord remains insufficient. Bulk RNA sequencing reveals that 526 genes are upregulated and 300 genes are downregulated in senescent spinal cords. Pathway enrichment analysis of differentially expressed genes shows that senescence in spinal cords is related to phagosome function, neuroinflammation, ferroptosis, and necroptosis. Prediction of upstream transcription factors and interactome analysis identify Spi1 as a transcription factor that potentially plays a core role in senescent spinal cords. Spatial transcriptomics illustrates the spatial distribution of the transcriptomic landscape in both young and senescent spinal cords and identifies distinct neuronal and glial subtypes. The ferroptosis-associated gene Fth1 is upregulated in aged spinal cords. Flow cytometry reveals increased accumulation of free Fe<sup>2+</sup> and ROS in senescent mixed glial cells; however, CCK-8 assays reveal that these cells are resistant to ferroptosis. SiRNA and lentivirus experiments indicate that the overexpression of Fth1 in normal mixed glial cells reduces their sensitivity to ferroptosis, whereas Fth1 knockdown increases their sensitivity to ferroptosis. In summary, spatial and bulk transcriptomics elucidate the transcriptional characteristics of young versus senescent spinal cords, thus highlighting the role of Fth1 in mediating ferroptosis resistance in senescent mixed glial cells.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"193"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}