Cell reportsPub Date : 2025-10-17DOI: 10.1016/j.celrep.2025.116454
Kamini Sehrawat, Israel Nelken
{"title":"Sound preferences in mice are sex dependent.","authors":"Kamini Sehrawat, Israel Nelken","doi":"10.1016/j.celrep.2025.116454","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116454","url":null,"abstract":"<p><p>We investigated the impact of early exposure to sound and to silence on sound preferences later in life in mice. We exposed young mice during the critical periods to excerpts of music (first movement of Beethoven's symphony no. 9), non-music sounds, or to silence. We tested the sound preference behavior a few weeks later. Exposure affects mouse behavior in a sex-dependent manner: for example, male mice, but not female mice, exposed to silence show robust preference to silence relative to their naive controls. The neural activity in the auditory cortex is suppressed in mice exposed to either music or silence compared to naive controls. Remarkably, a robust negative correlation is found between neural response and sound preferences in female, but not in male, mice.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116454"},"PeriodicalIF":6.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318214","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":"Med20 regulates myelination in the peripheral nervous system by modulating ferroptosis of Schwann cells.","authors":"Wenyi Yang, Xiang Chen, Chunyan Yang, Yanqing Mao, Wei Zhuang, Yunshan Xiao, Xueqin Zhang, Zhimin Ou, Ying Chen","doi":"10.1016/j.celrep.2025.116448","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116448","url":null,"abstract":"<p><p>Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a \"DDB1-UHRF1-BACH1-Hmox1\" transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20-deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116448"},"PeriodicalIF":6.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318180","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}
Cell reportsPub Date : 2025-10-16DOI: 10.1016/j.celrep.2025.116451
Saira Cancela, Florencia Sena, Romina Pagotto, Martina Crispo, Maria E Francia, Mariela Bollati-Fogolín
{"title":"Enhancing pre-sexual and sexual differentiation of Toxoplasma gondii using retinal epithelial cells and intestinal organoids.","authors":"Saira Cancela, Florencia Sena, Romina Pagotto, Martina Crispo, Maria E Francia, Mariela Bollati-Fogolín","doi":"10.1016/j.celrep.2025.116451","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116451","url":null,"abstract":"<p><p>Toxoplasmosis, caused by Toxoplasma gondii, is a major global health concern due to its high prevalence, zoonotic transmission, and economic impact on livestock. The parasite's life cycle includes asexual, pre-sexual, and sexual stages, the latter responsible for oocyst shedding and genetic recombination. Understanding sexual differentiation is critical, but access has been limited because these stages occur only in the feline intestinal epithelium. Recent studies identify host metabolic cues and the microrchidia (MORC) protein complex as regulators of sexual commitment. We optimize in vitro approaches to enrich pre-sexual and sexual stages by combining a human retinal epithelial cell line and murine intestinal organoids with FELIX medium, which mimics feline intestinal biochemistry, and conditional MORC depletion. This system increases stage-specific gene expression and marker detection, demonstrating synergistic effects of host environment and genetic regulation. Our findings provide accessible models to study T. gondii sexual differentiation, with implications for controlling transmission and genetic diversity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116451"},"PeriodicalIF":6.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318212","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}
Cell reportsPub Date : 2025-10-16DOI: 10.1016/j.celrep.2025.116447
Sayanur Rahaman, Nicole Schiffelholz, Nitish Mittal, Klemens E Fröhlich, Mihaela Zavolan, Attila Becskei
{"title":"Heat shock induces silent ribosomes and reorganizes mRNA turnover.","authors":"Sayanur Rahaman, Nicole Schiffelholz, Nitish Mittal, Klemens E Fröhlich, Mihaela Zavolan, Attila Becskei","doi":"10.1016/j.celrep.2025.116447","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116447","url":null,"abstract":"<p><p>mRNAs associate with single or multiple ribosomes; these ribosomal assemblies-monosomes and polysomes-translate the mRNAs before degradation. The impact of heat stress on this mRNA turnover remains unclear. We show that in heat-shocked yeast cells, the proportion of monosomes increases without a corresponding rise in the number of associated mRNAs. Consequently, most monosomes are devoid of mRNAs and silent, lacking translational initiation factors and proteins facilitating posttranslational folding. Such silent monosomes also appear under other stress conditions, with proportions varying according to stress type, suggesting that they represent a general feature of cellular adaptation. In parallel with the induction of silent ribosomes, elevated temperatures reduce the overall rate of mRNA-ribosome association with few exceptions. Notably, heat shock promotes the ribosomal association of transcripts encoding heat shock proteins, without extension of the half-lives of these mRNAs. These mechanisms dynamically reorganize mRNA turnover to prioritize the translation of heat shock proteins over other proteins.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116447"},"PeriodicalIF":6.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318154","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}
Cell reportsPub Date : 2025-10-16DOI: 10.1016/j.celrep.2025.116443
Feng Xuan, Guochuan Li, Yulong Li, Daniel A Dombeck
{"title":"Modulation of speed-dependent acetylcholine release in the hippocampus by spatial task engagement.","authors":"Feng Xuan, Guochuan Li, Yulong Li, Daniel A Dombeck","doi":"10.1016/j.celrep.2025.116443","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116443","url":null,"abstract":"<p><p>Acetylcholine (ACh) plays important roles in memory encoding and attention in the hippocampus. However, changes in ACh signaling patterns during different neural and behavioral states remain poorly understood. Here, we used a genetically encoded ACh sensor and multi-plane, dual-color two-photon microscopy to establish the ACh signaling patterns in hippocampal CA1 of mice performing spatial behaviors. We observed spatially homogeneous signaling across volumes spanning hundreds of microns, which was positively correlated with locomotion speed. In novel environments, there was an increase in release persisting for dozens of laps while maintaining a positive speed correlation. When mice voluntarily disengaged, the magnitude of the speed-correlated release decreased, and this was accompanied by reduced place cell numbers and less precise place maps. Administration of scopolamine mimicked the effects of voluntary disengagement in terms of behavior and place cell metrics. These findings establish behaviorally correlated ACh signaling patterns in the hippocampus.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116443"},"PeriodicalIF":6.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312508","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}
Cell reportsPub Date : 2025-10-16DOI: 10.1016/j.celrep.2025.116446
Dia A Ghose, Carl B W Soderstrom, Emily M Mahoney, Michael T Laub
{"title":"Multi-environment deep mutational scanning reveals the distribution of temperature-sensitive variants in a bacterial kinase.","authors":"Dia A Ghose, Carl B W Soderstrom, Emily M Mahoney, Michael T Laub","doi":"10.1016/j.celrep.2025.116446","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116446","url":null,"abstract":"<p><p>Deep mutational scanning is a powerful technique for determining sequence-function landscapes of biological macromolecules, but it is often performed under a single condition. Thus, how changing environmental conditions affect these landscapes remains opaque. Here, we address this by performing multi-environment deep mutational scanning to characterize the functional landscape of a bacterial kinase at multiple temperatures. By doing so, we systematically identify temperature-sensitive (ts) and temperature-resistant variants, providing a global view of their prevalence and identities. Substitutions leading to temperature-associated changes in activity are rare, reflecting high mutational tolerance across conditions, but ts and temperature-resistant substitutions are identified. In contrast to existing paradigms, we find that substitutions causing temperature sensitivity are prevalent in both the protein core and the surface. Temperature-resistant variants also arise but exhibit increased enzymatic activity, not improved thermal stability. Our results could not be recapitulated by the state-of-the-art computational stability prediction, demonstrating the importance of systematic experimental approaches to identifying condition-dependent mutation effects.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116446"},"PeriodicalIF":6.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312528","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}
Cell reportsPub Date : 2025-10-15DOI: 10.1016/j.celrep.2025.116429
Hao Wang, Tong Xiao, Hao Zhuang, Yi Liu, Kexing Jin, Jing Li, Jun Li, Yan Gao, Dan Yue, Wei Cui, Qingxia Xu, Jingxuan Pan, Kangdong Liu, Yong Wang, Ruibing Chen, Hongle Li
{"title":"STBD1 mediates the crosstalk between glycogen and lipid droplets in clear cell renal cell carcinoma.","authors":"Hao Wang, Tong Xiao, Hao Zhuang, Yi Liu, Kexing Jin, Jing Li, Jun Li, Yan Gao, Dan Yue, Wei Cui, Qingxia Xu, Jingxuan Pan, Kangdong Liu, Yong Wang, Ruibing Chen, Hongle Li","doi":"10.1016/j.celrep.2025.116429","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116429","url":null,"abstract":"<p><p>The accumulation of lipid droplets (LDs) and glycogen is a major hallmark of clear cell renal cell carcinoma (ccRCC), yet their interplay remains unclear. By proteomic profiling of 50 ccRCC tumors, we observe activation of glycogen- and LD-related pathways. Using proximity labeling of the LD proteome, we identify starch-binding domain-containing protein 1 (STBD1), a glycogen-binding protein involved in glycophagy, as a novel LD component. Further mechanistic investigation shows that STBD1 targets LDs via N-terminal myristoylation and mediates glycogen-LD colocalization. Its depletion decreases LD abundance and impairs both glycophagy and lipophagy, suggesting a critical role of STBD1 in both the biogenesis and autophagic degradation of LDs. Furthermore, STBD1 knockdown alters lipid composition, enhances ferroptosis sensitivity, and suppresses tumor growth both in vitro and in vivo. Collectively, our findings establish STBD1 as a critical mediator of glycogen-LD crosstalk and highlight its potential as a therapeutic target in ccRCC.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116429"},"PeriodicalIF":6.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312587","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":"Adipose m<sup>6</sup>A reader YTHDF2 promotes obesity, insulin resistance, and liver steatosis by suppressing β-adrenergic signaling and lipolysis.","authors":"Ruoyu Zhou, Liping Ju, Qianqian Kang, Qiantao Zheng, Decheng Ren, Liangyou Rui","doi":"10.1016/j.celrep.2025.116445","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116445","url":null,"abstract":"<p><p>RNA N6-methyladenosine (m<sup>6</sup>A) modification induces catecholamine resistance and lipolysis inhibition in white adipose tissue (WAT), contributing to obesity pathogenesis; however, the responsible m<sup>6</sup>A readers remain elusive. Here, we identify YTHDF2 as a key m<sup>6</sup>A reader governing both β-adrenergic signaling and lipolytic machinery. YTHDF2 binds to m<sup>6</sup>A-marked mRNAs encoding β3-adrenergic receptor (Adrb3), adipose triacylglycerol lipase (Atgl), and comparative gene identification-58 (Cgi-58), promoting their degradation and thereby suppressing β-adrenergic signaling and lipolysis. Deletion of adipose Ythdf2 enhances lipolysis in vivo, in WAT explants ex vivo, and in cultured adipocytes. Conversely, YTHDF2 overexpression suppresses adipocyte lipolysis. High-fat diet feeding upregulates adipose YTHDF2 and increases its binding to Adrb3, Atgl, and Cgi-58 mRNAs. Adipocyte-specific deletion of Ythdf2 protects against diet-induced obesity, insulin resistance, and liver steatosis. Moreover, deletion of adipose Mettl14-but not Ythdf2-disrupts brown adipose tissue development. These results unveil an adipose-intrinsic METTL3/METTL14/m<sup>6</sup>A/YTHDF2 pathway that drives catecholamine resistance and lipolysis suppression in obesity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116445"},"PeriodicalIF":6.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306898","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":"The m<sup>6</sup>A reader IGF2BP2 promotes homologous recombination-mediated DNA repair by eliminating DNA-RNA hybrids.","authors":"Yating Sun, Haojie Zhang, Shiwei Li, Jinzhi Zhang, Bin Lyu, Liping Kang, Xinkun Teng, Mingwei Yin, Weidong Peng, Jingjing Wang, Zhimin Chu, Chengying Cui, Dejie Kong, Mingqing Wu, Yongqiang Wang, Jiadong Wang, Yang Li","doi":"10.1016/j.celrep.2025.116438","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116438","url":null,"abstract":"<p><p>Double-strand breaks (DSBs) are among the most deleterious forms of DNA damage and are precisely repaired through homologous recombination (HR). DNA-RNA hybrids formed at DSB sites play a critical role in HR-mediated repair and must be tightly regulated. Here, we identify the m<sup>6</sup>A reader IGF2BP2, together with the RNA helicase DHX9, as key factors recruited to DSBs that remove DNA-RNA hybrids in an m<sup>6</sup>A-dependent manner. This axis prevents hybrid accumulation, enables RAD51 loading, and promotes HR-mediated repair. Loss of IGF2BP2 sensitizes cancer cells and xenograft tumors to DNA damage-inducing therapies, revealing therapeutic implications.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 10","pages":"116438"},"PeriodicalIF":6.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306963","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}