Zexiong Lin, Yuan Li, Yu Zhao, Dongteng Liu, Shuzi Deng, Jingkai Gu, Yanyan Li, Xudong Zhao, Peishan Wu, Yuan Xiao, Jiaping Su, Yiting Sun, Yihui Zhang, Yin Lau Lee, Yorino Sato, Haitao Zeng, Haonan Lu, Juanhui Zhang, Jennifer K.Y. Ko, Jing Zhao, Kazuhiro Kawamura, Ernest H.Y. Ng, Shanfang Jiang, Yu Li, Xi Xia, Karen K.L. Chan, William S.B. Yeung, Tianren R. Wang, Kui Liu
Currently, no effective treatment exists for infertility associated with premature ovarian insufficiency (POI) because affected patients lack hormone-responsive antral follicles. By screening a Food and Drug Administration (FDA)–approved drug library, we identified finerenone, a kidney disease medication, as a promising drug for restoring fertility in POI. Finerenone stimulated follicle development in aged mice and restored antral follicle development in patients with POI following oral administration, resulting in mature oocytes and embryos. Mechanistically, finerenone reduced fibrotic deposition in the ovarian stroma, alleviating collagen-mediated suppression of follicular development. Building on this insight, we identified additional FDA-approved oral antifibrotic drugs as potential treatments for POI-related infertility. Our findings highlight the ovarian stroma—rather than the follicles themselves—as the key therapeutic target and offer potential therapeutic leads for POI-related infertility.
{"title":"Antifibrotic drug finerenone restores fertility in premature ovarian insufficiency","authors":"Zexiong Lin, Yuan Li, Yu Zhao, Dongteng Liu, Shuzi Deng, Jingkai Gu, Yanyan Li, Xudong Zhao, Peishan Wu, Yuan Xiao, Jiaping Su, Yiting Sun, Yihui Zhang, Yin Lau Lee, Yorino Sato, Haitao Zeng, Haonan Lu, Juanhui Zhang, Jennifer K.Y. Ko, Jing Zhao, Kazuhiro Kawamura, Ernest H.Y. Ng, Shanfang Jiang, Yu Li, Xi Xia, Karen K.L. Chan, William S.B. Yeung, Tianren R. Wang, Kui Liu","doi":"10.1126/science.adz4075","DOIUrl":"10.1126/science.adz4075","url":null,"abstract":"<div >Currently, no effective treatment exists for infertility associated with premature ovarian insufficiency (POI) because affected patients lack hormone-responsive antral follicles. By screening a Food and Drug Administration (FDA)–approved drug library, we identified finerenone, a kidney disease medication, as a promising drug for restoring fertility in POI. Finerenone stimulated follicle development in aged mice and restored antral follicle development in patients with POI following oral administration, resulting in mature oocytes and embryos. Mechanistically, finerenone reduced fibrotic deposition in the ovarian stroma, alleviating collagen-mediated suppression of follicular development. Building on this insight, we identified additional FDA-approved oral antifibrotic drugs as potential treatments for POI-related infertility. Our findings highlight the ovarian stroma—rather than the follicles themselves—as the key therapeutic target and offer potential therapeutic leads for POI-related infertility.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterized by progressive paralysis and cognitive and behavioral decline, respectively. Traditionally classified as separate diseases, ALS and FTD are now understood to lie on a disease spectrum (ALS/FTD)—they share clinical, pathological, and genetic features. In 2011, two research groups independently discovered that a noncoding GGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS/FTD (1, 2), and they noted that the hexanucleotide repeat expansion can give rise to ALS, FTD, or a combined diagnosis, varying among affected individuals. However, how the C9orf72 hexanucleotide repeat expansion drives neurodegeneration has remained unresolved, with competing models implicating loss of C9orf72 function, toxic RNA accumulation, or toxic protein production. On page 573 of this issue, Jiang et al. (3) present data that clarify the relative contributions of these mechanisms, with implications for therapy development.
{"title":"Pinpointing protein as the problem","authors":"Frederick J. Arnold, Albert R. La Spada","doi":"10.1126/science.aee6924","DOIUrl":"10.1126/science.aee6924","url":null,"abstract":"<div >Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterized by progressive paralysis and cognitive and behavioral decline, respectively. Traditionally classified as separate diseases, ALS and FTD are now understood to lie on a disease spectrum (ALS/FTD)—they share clinical, pathological, and genetic features. In 2011, two research groups independently discovered that a noncoding GGGGCC (G<sub>4</sub>C<sub>2</sub>) hexanucleotide repeat expansion in the <i>C9orf72</i> gene is the most common genetic cause of ALS/FTD (<i>1</i>, <i>2</i>), and they noted that the hexanucleotide repeat expansion can give rise to ALS, FTD, or a combined diagnosis, varying among affected individuals. However, how the <i>C9orf72</i> hexanucleotide repeat expansion drives neurodegeneration has remained unresolved, with competing models implicating loss of C9orf72 function, toxic RNA accumulation, or toxic protein production. On page 573 of this issue, Jiang <i>et al</i>. (<i>3</i>) present data that clarify the relative contributions of these mechanisms, with implications for therapy development.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Love, connection, and happily ever after","authors":"Robert C. Brooks","doi":"10.1126/science.aed5189","DOIUrl":"10.1126/science.aed5189","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yao Tang, Tianren Zhang, Dai-Bei Yang, Jacob Schwartz, Christopher J. Kloxin, Jeffery G. Saven, Darrin J. Pochan
Programmable control of protein or colloidal nanoparticle self-assembly into targeted nanostructures, while maintaining stability across extreme pH conditions, remains a major challenge. We designed coiled-coil bundlemer peptide nanoparticles that form ordered, hierarchical materials across an unusually broad pH range (1, 7, and 14) dependent on patchy surface charge display. Nematic liquid crystal formation was observed at low concentration (~0.5 to 4 weight %) at pH 1 and pH 14, whereas higher concentration at pH 1 yielded hexagonal columnar phases. At neutral pH, the same patchy nanoparticles assembled into ordered lattices through electrostatic complexation. Molecular dynamics simulations revealed end-to-end particle stacking underlying all phases. Coiled coils with identical amino acid composition but lacking designed charge patches displayed no ordered assembly, demonstrating the importance of programmable electrostatic interactions with protein-like specificity of spatial display.
{"title":"Patchy peptide particles for pH-responsive assembly into liquid crystals or lattices","authors":"Yao Tang, Tianren Zhang, Dai-Bei Yang, Jacob Schwartz, Christopher J. Kloxin, Jeffery G. Saven, Darrin J. Pochan","doi":"10.1126/science.adz6812","DOIUrl":"10.1126/science.adz6812","url":null,"abstract":"<div >Programmable control of protein or colloidal nanoparticle self-assembly into targeted nanostructures, while maintaining stability across extreme pH conditions, remains a major challenge. We designed coiled-coil bundlemer peptide nanoparticles that form ordered, hierarchical materials across an unusually broad pH range (1, 7, and 14) dependent on patchy surface charge display. Nematic liquid crystal formation was observed at low concentration (~0.5 to 4 weight %) at pH 1 and pH 14, whereas higher concentration at pH 1 yielded hexagonal columnar phases. At neutral pH, the same patchy nanoparticles assembled into ordered lattices through electrostatic complexation. Molecular dynamics simulations revealed end-to-end particle stacking underlying all phases. Coiled coils with identical amino acid composition but lacking designed charge patches displayed no ordered assembly, demonstrating the importance of programmable electrostatic interactions with protein-like specificity of spatial display.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Internet platforms must be held accountable for their actions","authors":"Stephan Lewandowsky","doi":"10.1126/science.aee9835","DOIUrl":"10.1126/science.aee9835","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Turning the web against sex traffickers","authors":"Mayank Kejriwal","doi":"10.1126/science.aee1347","DOIUrl":"10.1126/science.aee1347","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brassica rapa (Br) encompasses many morphotypes and subspecies, so it is a good model with which to investigate plant diversification and subspeciation. Here, we resequenced the genomes of 1720 Br accessions and de novo assembled 11 representative telomere-to-telomere gapless genomes for seven elite subspecies that underwent intensive morphotypification and developed distinct agronomic traits valued to agriculture. We identified 6992 unknown genes, 110 complete (peri)centromeres, and five new satellites associated with Br morphotypes and subspecies and Brassica species evolution. The pangenome, built on 11 gapless and 20 published genomes, reveals structural variations and gene diversities among Br subspecies. Pangenome-wide association studies uncovered that the gene BrLH1 controls leaf-head formation. We show that structural changes have occurred in satellites, (peri)centromeres, and genes, contributing to fast subspeciation and morphotypification during the short history of Br cultivation, providing invaluable resources for Brassica breeding.
{"title":"Gapless pangenome analyses reveal fast Brassica rapa subspeciation","authors":"Wei Ma, Yuanming Liu, Xiaochun Wei, Xiaomeng Zhang, Xiaonan Li, Zhaokun Liu, Lingyun Yuan, Guangguang Li, Shu Zhang, Qihang Yang, Xiaocong Chang, Zizhuo Han, Hao Liang, Zhaoshui Luan, Qianyun Wang, Yujie Gu, Xinlong Wang, Xianlei Zhao, Qing Liu, Xiaoxue Sun, Mengyang Liu, Daling Feng, Yin Lu, Shuangxia Luo, Lei Yang, Mengyuan Li, Robin Allaby, Kai Wang, Tianzhen Zhang, Shuxing Shen, Yves Van de Peer, Yiguo Hong, Yuxiang Yuan, Jianjun Zhao","doi":"10.1126/science.ady7590","DOIUrl":"10.1126/science.ady7590","url":null,"abstract":"<div ><i>Brassica rapa</i> (<i>Br</i>) encompasses many morphotypes and subspecies, so it is a good model with which to investigate plant diversification and subspeciation. Here, we resequenced the genomes of 1720 <i>Br</i> accessions and de novo assembled 11 representative telomere-to-telomere gapless genomes for seven elite subspecies that underwent intensive morphotypification and developed distinct agronomic traits valued to agriculture. We identified 6992 unknown genes, 110 complete (peri)centromeres, and five new satellites associated with <i>Br</i> morphotypes and subspecies and <i>Brassica</i> species evolution. The pangenome, built on 11 gapless and 20 published genomes, reveals structural variations and gene diversities among <i>Br</i> subspecies. Pangenome-wide association studies uncovered that the gene <i>BrLH1</i> controls leaf-head formation. We show that structural changes have occurred in satellites, (peri)centromeres, and genes, contributing to fast subspeciation and morphotypification during the short history of <i>Br</i> cultivation, providing invaluable resources for <i>Brassica</i> breeding.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
João Pedro Barreiros, Alfonso Aguilar-Perera, Antônio Batista Anderson, Luís M. D. Barcelos, Luciano B. Beheregaray, Edgardo Díaz-Ferguson
{"title":"Ineffective marine protected areas in Azores","authors":"João Pedro Barreiros, Alfonso Aguilar-Perera, Antônio Batista Anderson, Luís M. D. Barcelos, Luciano B. Beheregaray, Edgardo Díaz-Ferguson","doi":"10.1126/science.aed7607","DOIUrl":"10.1126/science.aed7607","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":"391 6785","pages":""},"PeriodicalIF":45.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eukaryotic gene expression is orchestrated by RNA polymerases (RNAPI, II, and III) and associated factors, yet their real-time dynamics remain obscure. Using single-molecule tracking in living yeast, we quantified the kinetics of 58 proteins encompassing three RNAP machineries. RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived chromatin interactions, contrasting with transient RNAPII PIC. We further report kinetics of RNAPII-associated factors for elongation, histone modification, C-terminal domain (CTD) modification, RNA processing, and termination. Many elongation factors show brief rather than persistent association, suggesting dynamic interactions with factor exchange, allowing a potential repertoire of regulatory events. CTD truncation reduces U1 snRNP residence time and intron retention in ribosomal protein genes, providing insights into co-transcriptional splicing. Our findings establish a framework of dynamic interactions of RNAP machineries.
{"title":"Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries","authors":"Yick Hin Ling, Chloe Liang, Sixiang Wang, Carl Wu","doi":"10.1126/science.ads0960","DOIUrl":"https://doi.org/10.1126/science.ads0960","url":null,"abstract":"Eukaryotic gene expression is orchestrated by RNA polymerases (RNAPI, II, and III) and associated factors, yet their real-time dynamics remain obscure. Using single-molecule tracking in living yeast, we quantified the kinetics of 58 proteins encompassing three RNAP machineries. RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived chromatin interactions, contrasting with transient RNAPII PIC. We further report kinetics of RNAPII-associated factors for elongation, histone modification, C-terminal domain (CTD) modification, RNA processing, and termination. Many elongation factors show brief rather than persistent association, suggesting dynamic interactions with factor exchange, allowing a potential repertoire of regulatory events. CTD truncation reduces U1 snRNP residence time and intron retention in ribosomal protein genes, providing insights into co-transcriptional splicing. Our findings establish a framework of dynamic interactions of RNAP machineries.","PeriodicalId":21678,"journal":{"name":"Science","volume":"23 1","pages":""},"PeriodicalIF":56.9,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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