Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adw5514
Tali Sharot
{"title":"Advancing the science of women's health.","authors":"Tali Sharot","doi":"10.1126/sciadv.adw5514","DOIUrl":"10.1126/sciadv.adw5514","url":null,"abstract":"","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadw5514"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adq0444
Jilin Zhang, Jinjin Duan, Wei Li, Xian Wang, Shimin Ren, Luyu Ye, Fang Liu, Xiaoting Tian, Yang Xie, Yiming Huang, Yidi Sun, Nan Song, Tianyu Li, Xiang Cai, Zhiqiang Liu, Hu Zhou, Chenggang Huang, Yang Li, Shujia Zhu, Fei Guo
{"title":"An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons.","authors":"Jilin Zhang, Jinjin Duan, Wei Li, Xian Wang, Shimin Ren, Luyu Ye, Fang Liu, Xiaoting Tian, Yang Xie, Yiming Huang, Yidi Sun, Nan Song, Tianyu Li, Xiang Cai, Zhiqiang Liu, Hu Zhou, Chenggang Huang, Yang Li, Shujia Zhu, Fei Guo","doi":"10.1126/sciadv.adq0444","DOIUrl":"10.1126/sciadv.adq0444","url":null,"abstract":"<p><p><i>N</i>-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-naïve and stress-exposed models, which are lost in mice with global or selective knockout of the <i>grin2d</i> gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadq0444"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Scalable acoustic virtual stirrer for enhanced interfacial enzymatic nucleic acid reactions.","authors":"Dayang Li, Kunjie Li, Jianquan Li, Dongfang Li, Heng Chen, Sen-Sen Li, Chaoyong Yang, Huimin Zhang, Lu-Jian Chen, Xuejia Hu","doi":"10.1126/sciadv.adt6955","DOIUrl":"10.1126/sciadv.adt6955","url":null,"abstract":"<p><p>Enzymatic nucleic acid reaction is a fundamental tool in molecular biology. However, high-complexity enzymatic DNA reactions and assays are still challenging due to the difficulties in integrating and scaling up microscale reaction units and mixing tools. Here, we present scalable acoustofluidic platform featuring acoustic virtual stirrer (AVS) arrays, serving as stirrers to increase the efficiency of interfacial enzymatic nucleic acid reactions. Analogous to magnetic stirrers, AVS arrays perturb the fluid through oscillating pressure nodes, controllable in terms of speeds and amplitudes via modulation. By optimizing the kinetics of surface-tethered DNA and enzymes via AVS, we achieve a 7.74% improvement in the stepwise yield of enzymatic DNA synthesis. In addition, the AVS enhanced DNA logic gate architecture can complete responses within 2 minutes, achieving average speed enhancement of 8.58 times compared to the non-AVS configuration. With its tunability, ease of integration, and efficiency, this technology holds promises for applications in biology and chemistry.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadt6955"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adt0576
Bronwyn M Graham, Cara Tannenbaum, Alice Witt, Keziah Bennett-Brook, Sue Haupt, Kate Womersley, Séverine Lamon, Robyn Norton
{"title":"The power-and complexity-of policy to drive advances in women's health.","authors":"Bronwyn M Graham, Cara Tannenbaum, Alice Witt, Keziah Bennett-Brook, Sue Haupt, Kate Womersley, Séverine Lamon, Robyn Norton","doi":"10.1126/sciadv.adt0576","DOIUrl":"10.1126/sciadv.adt0576","url":null,"abstract":"<p><p>As international investments in women's health increase, funders are adopting sex and gender policies and regulators are requiring disaggregated data, actions which impact research design.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadt0576"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adr1713
Mitchell Brüderlin, Maxim Kolesnikov, Florian Röthlin, Roderick Y H Lim, Marek Basler
{"title":"<i>Pseudomonas aeruginosa</i> assembles H1-T6SS in response to physical and chemical damage of the outer membrane.","authors":"Mitchell Brüderlin, Maxim Kolesnikov, Florian Röthlin, Roderick Y H Lim, Marek Basler","doi":"10.1126/sciadv.adr1713","DOIUrl":"10.1126/sciadv.adr1713","url":null,"abstract":"<p><p>Bacteria respond to environmental stimuli and attacks from competing organisms. <i>Pseudomonas aeruginosa</i> assembles the type VI secretion system (H1-T6SS) to precisely retaliate against aggressive competing bacteria. However, we lack an understanding of how the H1-T6SS assembly dynamically responds to nanomechanical forces. To address this, we analyzed live cells using correlative atomic force microscopy (AFM) and fluorescence microscopy. We show that indentation forces above 7 nanonewtons trigger local, repeated and targeted H1-T6SS assemblies within seconds of impact by the AFM tip. Analysis of the corresponding AFM force curves shows that a breach of a single layer of the cell envelope is necessary and sufficient for triggering H1-T6SS assembly. Accordingly, polymyxin B nonapeptide, which damages the outer membrane, also triggers H1-T6SS assembly. This suggests that <i>P. aeruginosa</i> has evolved a danger-sensing mechanism that enables rapid and precise deployment of its antibacterial H1-T6SS in response to breaches in the outer membrane.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadr1713"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of antimicrobial peptides with notable antibacterial potency by an LLM-based foundation model.","authors":"Jike Wang, Jianwen Feng, Yu Kang, Peichen Pan, Jingxuan Ge, Yan Wang, Mingyang Wang, Zhenxing Wu, Xingcai Zhang, Jiameng Yu, Xujun Zhang, Tianyue Wang, Lirong Wen, Guangning Yan, Yafeng Deng, Hui Shi, Chang-Yu Hsieh, Zhihui Jiang, Tingjun Hou","doi":"10.1126/sciadv.ads8932","DOIUrl":"https://doi.org/10.1126/sciadv.ads8932","url":null,"abstract":"<p><p>Large language models (LLMs) have shown remarkable advancements in chemistry and biomedical research, acting as versatile foundation models for various tasks. We introduce AMP-Designer, an LLM-based approach, for swiftly designing antimicrobial peptides (AMPs) with desired properties. Within 11 days, AMP-Designer achieved the de novo design of 18 AMPs with broad-spectrum activity against Gram-negative bacteria. In vitro validation revealed a 94.4% success rate, with two candidates demonstrating exceptional antibacterial efficacy, minimal hemotoxicity, stability in human plasma, and low potential to induce resistance, as evidenced by significant bacterial load reduction in murine lung infection experiments. The entire process, from design to validation, concluded in 48 days. AMP-Designer excels in creating AMPs targeting specific strains despite limited data availability, with a top candidate displaying a minimum inhibitory concentration of 2.0 micrograms per milliliter against <i>Propionibacterium acnes</i>. Integrating advanced machine learning techniques, AMP-Designer demonstrates remarkable efficiency, paving the way for innovative solutions to antibiotic resistance.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eads8932"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568011","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}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adr8146
Kaiming Li, Yu Q Yap, Donia M Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas E Lew, Melanie De Silva, Meng-Xiao Luo, Jia-Nan Gong, Zheng Yuan, Richard W Birkinshaw, Peter E Czabotar, Kym Lowes, David C S Huang, Benjamin T Kile, Andrew H Wei, Grant Dewson, Mark F van Delft, Guillaume Lessene
{"title":"Differential regulation of BAX and BAK apoptotic activity revealed by small molecules.","authors":"Kaiming Li, Yu Q Yap, Donia M Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas E Lew, Melanie De Silva, Meng-Xiao Luo, Jia-Nan Gong, Zheng Yuan, Richard W Birkinshaw, Peter E Czabotar, Kym Lowes, David C S Huang, Benjamin T Kile, Andrew H Wei, Grant Dewson, Mark F van Delft, Guillaume Lessene","doi":"10.1126/sciadv.adr8146","DOIUrl":"10.1126/sciadv.adr8146","url":null,"abstract":"<p><p>Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2-associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadr8146"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adq8538
Pei Zhu, Eric M Pfrender, Adam W T Steffeck, Colleen R Reczek, Yalu Zhou, Abhishek Vijay Thakkar, Neha R Gupta, Ariana Kupai, Amber Willbanks, Richard L Lieber, Ishan Roy, Navdeep S Chandel, Clara B Peek
{"title":"Immunomodulatory role of the stem cell circadian clock in muscle repair.","authors":"Pei Zhu, Eric M Pfrender, Adam W T Steffeck, Colleen R Reczek, Yalu Zhou, Abhishek Vijay Thakkar, Neha R Gupta, Ariana Kupai, Amber Willbanks, Richard L Lieber, Ishan Roy, Navdeep S Chandel, Clara B Peek","doi":"10.1126/sciadv.adq8538","DOIUrl":"10.1126/sciadv.adq8538","url":null,"abstract":"<p><p>Circadian rhythms orchestrate physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day (TOD). This study identifies an interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We reveal that the SC clock triggers TOD-dependent inflammatory gene transcription after injury, particularly genes related to neutrophil activity and chemotaxis. These responses are driven by cytosolic regeneration of the signaling metabolite nicotinamide adenine dinucleotide (oxidized form) (NAD<sup>+</sup>), as enhancing cytosolic NAD<sup>+</sup> regeneration in SCs is sufficient to induce inflammatory responses that influence muscle regeneration. Mononuclear single-cell sequencing of the regenerating muscle niche further implicates the cytokine CCL2 in mediating SC-neutrophil cross-talk in a TOD-dependent manner. Our findings highlight the intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadq8538"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adr5086
Monika Haoui, Citlalli Vergara, Lina Kenzler, Jerome Schröer, Geraldine Zimmer-Bensch, David Fleck, Christopher Wiesbrock, Marc Spehr, Polina V Lishko
{"title":"Kir7.1 is the physiological target for hormones and steroids that regulate uteroplacental function.","authors":"Monika Haoui, Citlalli Vergara, Lina Kenzler, Jerome Schröer, Geraldine Zimmer-Bensch, David Fleck, Christopher Wiesbrock, Marc Spehr, Polina V Lishko","doi":"10.1126/sciadv.adr5086","DOIUrl":"10.1126/sciadv.adr5086","url":null,"abstract":"<p><p>Preterm birth is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, but another direct mode of action has long been suspected. Here, we reveal the nongenomic molecular mechanism of progesterone as the activation of human and murine inwardly rectifying potassium channel Kir7.1, which is expressed in myometrium and placental pericytes during late gestation. Kir7.1 is also activated by selective steroids, including those used to prevent premature labor, such as 17-α-hydroxyprogesterone caproate and dydrogesterone, revealing their unexpected mode of action. Our results reveal that Kir7.1 is the molecular target of both endogenous and synthetic steroids that control uterine excitability and placental function. Kir7.1, therefore, is a promising therapeutic target to support healthy pregnancy during mid and late gestation.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadr5086"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science AdvancesPub Date : 2025-03-07Epub Date: 2025-03-05DOI: 10.1126/sciadv.adt1763
Jessica L Minder, Sarah B Winokur, Janaye Stephens, Jie Tong, Naomi L Cassel, Luisa Schuster, Habon A Issa, Michael Cammer, Latika Khatri, Gaia Moisan, Maria Alvarado-Torres, Orlando Aristizábal, Youssef Z Wadghiri, Sang Yong Kim, Silvana Valtcheva, Catherine Pei-Ju Lu, Moses V Chao, Robert C Froemke
{"title":"Oxytocin induces embryonic diapause.","authors":"Jessica L Minder, Sarah B Winokur, Janaye Stephens, Jie Tong, Naomi L Cassel, Luisa Schuster, Habon A Issa, Michael Cammer, Latika Khatri, Gaia Moisan, Maria Alvarado-Torres, Orlando Aristizábal, Youssef Z Wadghiri, Sang Yong Kim, Silvana Valtcheva, Catherine Pei-Ju Lu, Moses V Chao, Robert C Froemke","doi":"10.1126/sciadv.adt1763","DOIUrl":"10.1126/sciadv.adt1763","url":null,"abstract":"<p><p>Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 10","pages":"eadt1763"},"PeriodicalIF":11.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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