{"title":"40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice.","authors":"Xiaoting Sun, Liliana Dias, Chenlei Peng, Ziyi Zhang, Haoting Ge, Zejun Wang, Jiayi Jin, Manli Jia, Tao Xu, Wei Guo, Wu Zheng, Yan He, Youru Wu, Xiaohong Cai, Paula Agostinho, Jia Qu, Rodrigo A Cunha, Xuzhao Zhou, Ruiliang Bai, Jiang-Fan Chen","doi":"10.1038/s41421-024-00701-z","DOIUrl":"10.1038/s41421-024-00701-z","url":null,"abstract":"<p><p>The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A<sub>2A</sub> receptor (A<sub>2A</sub>R) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A<sub>2A</sub>R, and by the physical and functional A<sub>2A</sub>R-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"81"},"PeriodicalIF":13.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892984","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}
{"title":"Structural basis of antagonist selectivity in endothelin receptors.","authors":"Junyi Hou, Shenhui Liu, Xiaodan Zhang, Guowei Tu, Lijie Wu, Yijie Zhang, Hao Yang, Xiangcheng Li, Junlin Liu, Longquan Jiang, Qiwen Tan, Fang Bai, Zhijie Liu, Changhong Miao, Tian Hua, Zhe Luo","doi":"10.1038/s41421-024-00705-9","DOIUrl":"10.1038/s41421-024-00705-9","url":null,"abstract":"<p><p>Endothelins and their receptors, ET<sub>A</sub> and ET<sub>B</sub>, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET<sub>A</sub> antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET<sub>A</sub> in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET<sub>A</sub> antagonist, respectively. Notably, a specialized anti-ET<sub>A</sub> antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET<sub>A</sub> and ET<sub>B</sub>, and the agonist BQ3020-bound ET<sub>B</sub>, in complex with G<sub>q</sub>, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET<sub>A</sub>. Furthermore, our results suggest that ECL2 in ET<sub>A</sub> can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"79"},"PeriodicalIF":13.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792050","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}
{"title":"Proteogenomic insights into the biology and treatment of pan-melanoma.","authors":"Hang Xiang, Rongkui Luo, Yunzhi Wang, Bing Yang, Sha Xu, Wen Huang, Shaoshuai Tang, Rundong Fang, Lingli Chen, Na Zhu, Zixiang Yu, Sujie Akesu, Chuanyuan Wei, Chen Xu, Yuhong Zhou, Jianying Gu, Jianyuan Zhao, Yingyong Hou, Chen Ding","doi":"10.1038/s41421-024-00688-7","DOIUrl":"10.1038/s41421-024-00688-7","url":null,"abstract":"<p><p>Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"78"},"PeriodicalIF":13.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747542","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}
Cell DiscoveryPub Date : 2024-07-16DOI: 10.1038/s41421-024-00696-7
Yundong Peng, Jingjing Du, Rui Li, Stefan Günther, Nina Wettschureck, Stefan Offermanns, Yan Wang, Andre Schneider, Thomas Braun
{"title":"RhoA-mediated G<sub>12</sub>-G<sub>13</sub> signaling maintains muscle stem cell quiescence and prevents stem cell loss.","authors":"Yundong Peng, Jingjing Du, Rui Li, Stefan Günther, Nina Wettschureck, Stefan Offermanns, Yan Wang, Andre Schneider, Thomas Braun","doi":"10.1038/s41421-024-00696-7","DOIUrl":"10.1038/s41421-024-00696-7","url":null,"abstract":"<p><p>Multiple processes control quiescence of muscle stem cells (MuSCs), which is instrumental to guarantee long-term replenishment of the stem cell pool. Here, we describe that the G-proteins G<sub>12</sub>-G<sub>13</sub> integrate signals from different G-protein-coupled receptors (GPCRs) to control MuSC quiescence via activation of RhoA. Comprehensive screening of GPCR ligands identified two MuSC-niche-derived factors, endothelin-3 (ET-3) and neurotensin (NT), which activate G<sub>12</sub>-G<sub>13</sub> signaling in MuSCs. Stimulation with ET-3 or NT prevented MuSC activation, whereas pharmacological inhibition of ET-3 or NT attenuated MuSC quiescence. Inactivation of Gna12-Gna13 or Rhoa but not of Gnaq-Gna11 completely abrogated MuSC quiescence, which depleted the MuSC pool and was associated with accelerated sarcopenia during aging. Expression of constitutively active RhoA prevented exit from quiescence in Gna12-Gna13 mutant MuSCs, inhibiting cell cycle entry and differentiation via Rock and formins without affecting Rac1-dependent MuSC projections, a hallmark of quiescent MuSCs. The study uncovers a critical role of G<sub>12</sub>-G<sub>13</sub> and RhoA signaling for active regulation of MuSC quiescence.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"76"},"PeriodicalIF":13.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619444","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}
{"title":"Synthetic macrolides overcoming MLS<sub>B</sub>K-resistant pathogens.","authors":"Cong-Xuan Ma, Ye Li, Wen-Tian Liu, Yun Li, Fei Zhao, Xiao-Tian Lian, Jing Ding, Si-Meng Liu, Xie-Peng Liu, Bing-Zhi Fan, Li-Yong Liu, Feng Xue, Jian Li, Jue-Ru Zhang, Zhao Xue, Xiao-Tong Pei, Jin-Zhong Lin, Jian-Hua Liang","doi":"10.1038/s41421-024-00702-y","DOIUrl":"10.1038/s41421-024-00702-y","url":null,"abstract":"<p><p>Conventional macrolide-lincosamide-streptogramin B-ketolide (MLS<sub>B</sub>K) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLS<sub>B</sub>K in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLS<sub>B</sub>K antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLS<sub>B</sub>K antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"75"},"PeriodicalIF":13.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589679","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}
{"title":"Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq.","authors":"Xiuzhen Bai, Zonggui Chen, Kexuan Chen, Zixin Wu, Rui Wang, Jun'e Liu, Liang Chang, Lu Wen, Fuchou Tang","doi":"10.1038/s41421-024-00694-9","DOIUrl":"10.1038/s41421-024-00694-9","url":null,"abstract":"<p><p>The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"74"},"PeriodicalIF":13.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558136","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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