Cell reportsPub Date : 2025-06-13DOI: 10.1016/j.celrep.2025.115865
Xiaodan Huang, Shengnan Wang, Zhiqing Chen, Wenna Qu, Li Song, Zhengfang Hu, Yue Xi, Yan Yang, Weng-Hei Hong, Song Lin, Kwok-Fai So, Yulong Li, Lu Huang, Qian Tao, Chaoran Ren
{"title":"Bright-light treatment ameliorates motor and non-motor deficits through distinct visual circuits in a mouse model of Parkinson's disease.","authors":"Xiaodan Huang, Shengnan Wang, Zhiqing Chen, Wenna Qu, Li Song, Zhengfang Hu, Yue Xi, Yan Yang, Weng-Hei Hong, Song Lin, Kwok-Fai So, Yulong Li, Lu Huang, Qian Tao, Chaoran Ren","doi":"10.1016/j.celrep.2025.115865","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115865","url":null,"abstract":"<p><p>Light has a profound impact on non-visual functions, and clinical evidence suggests bright-light therapy's effectiveness in alleviating motor and non-motor symptoms of Parkinson's disease (PD). However, the neural mechanisms underlying these effects remain unclear. Here, we demonstrate that bright-light treatment alleviates PD symptoms in mice via distinct visual circuits. Specifically, bright-light signals transmitted by the ventral lateral geniculate nucleus alleviate non-motor symptoms, such as depressive-like behaviors and spatial memory deficits. Conversely, the improvement in motor symptoms with bright-light treatment depends on a separate, disynaptic visual pathway that connects the superficial layers of the superior colliculus to the substantia nigra pars compacta (SNc). Notably, in this pathway, bright-light signals enhance the bursting activity of SNc dopaminergic neurons by upregulating HCN2 expression, a mechanism essential for motor improvements. These findings provide valuable insights into the neural mechanisms by which bright-light therapy benefits PD.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115865"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293396","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 : 2025-06-13DOI: 10.1016/j.celrep.2025.115856
Iain F Davidson, Roman Barth, Kota Nagasaka, Wen Tang, Gordana Wutz, Sabrina Horn, Richard Janissen, Roman R Stocsits, Emilia Chlosta, Benedikt W Bauer, Cees Dekker, Jan-Michael Peters
{"title":"Cohesin supercoils DNA during loop extrusion.","authors":"Iain F Davidson, Roman Barth, Kota Nagasaka, Wen Tang, Gordana Wutz, Sabrina Horn, Richard Janissen, Roman R Stocsits, Emilia Chlosta, Benedikt W Bauer, Cees Dekker, Jan-Michael Peters","doi":"10.1016/j.celrep.2025.115856","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115856","url":null,"abstract":"<p><p>Cohesin extrudes genomic DNA into loops that promote chromatin assembly, gene regulation, and gene recombination. Loop extrusion depends on large-scale conformational changes in cohesin, but how these translocate DNA is poorly understood. Here, we provide evidence that cohesin negatively supercoils DNA during loop extrusion. Supercoiling requires the engagement of cohesin's ATPase heads, DNA clamping by these heads, and a DNA-binding site on cohesin's hinge, indicating that cohesin twists DNA when constraining it between the hinge and the clamp. A cohesin mutant defective in negative supercoiling forms shorter loops in cells, and a similar, although weaker, phenotype is observed after the depletion of topoisomerase I. These results suggest that supercoiling is an integral part of the loop-extrusion mechanism and that relaxation of supercoiled DNA is required for cohesin-mediated loop extrusion and genome architecture.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115856"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293397","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 : 2025-06-13DOI: 10.1016/j.celrep.2025.115851
Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen
{"title":"ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.","authors":"Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen","doi":"10.1016/j.celrep.2025.115851","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115851","url":null,"abstract":"<p><p>T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115851"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293399","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 : 2025-06-13DOI: 10.1016/j.celrep.2025.115848
Daniel J Morris, Jason Gorman, Tongqing Zhou, Jinery Lora, Andrew J Connell, Hui Li, Weimin Liu, Ryan S Roark, Mary S Campion, John W Carey, Rumi Habib, Yingying Li, Christian L Martella, Younghoon Park, Ajay Singh, Kirsten J Sowers, I-Ting Teng, Shuyi Wang, Neha Chohan, Wenge Ding, Craig Lauer, Emily Lewis, Rosemarie D Mason, Juliette M Rando, Lowrey Peyton, Chaim A Schramm, Kshitij Wagh, Bette Korber, Michael S Seaman, Daniel C Douek, Barton F Haynes, Daniel W Kulp, Mario Roederer, Beatrice H Hahn, Peter D Kwong, George M Shaw
{"title":"Transient glycan shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques.","authors":"Daniel J Morris, Jason Gorman, Tongqing Zhou, Jinery Lora, Andrew J Connell, Hui Li, Weimin Liu, Ryan S Roark, Mary S Campion, John W Carey, Rumi Habib, Yingying Li, Christian L Martella, Younghoon Park, Ajay Singh, Kirsten J Sowers, I-Ting Teng, Shuyi Wang, Neha Chohan, Wenge Ding, Craig Lauer, Emily Lewis, Rosemarie D Mason, Juliette M Rando, Lowrey Peyton, Chaim A Schramm, Kshitij Wagh, Bette Korber, Michael S Seaman, Daniel C Douek, Barton F Haynes, Daniel W Kulp, Mario Roederer, Beatrice H Hahn, Peter D Kwong, George M Shaw","doi":"10.1016/j.celrep.2025.115848","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115848","url":null,"abstract":"<p><p>Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryoelectron microscopy (cryo-EM) structure of RHA10 with the HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting that glycan deletions in infecting SHIVs could induce CD4bs bNAbs. To test this hypothesis, we constructed SHIV.CH505 variants with CD4bs-proximal glycan deletions. Infection of 11 macaques resulted in accelerated CD4bs bNAb responses in 9 compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and serve as a model for HIV vaccine design.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115848"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293401","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 : 2025-06-13DOI: 10.1016/j.celrep.2025.115772
Janina Werner, Weiliang Zuo, Tom Winkler, Gunther Doehlemann
{"title":"A recombinant hybrid provides insights into gene regulation, pathogenesis, and tumorigenesis of phytopathogenic smut fungi.","authors":"Janina Werner, Weiliang Zuo, Tom Winkler, Gunther Doehlemann","doi":"10.1016/j.celrep.2025.115772","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115772","url":null,"abstract":"<p><p>The closely related maize smut fungi Ustilago maydis and Sporisorium reilianum share genome structures but differ in their pathogenic behavior. U. maydis causes local tumors, while S. reilianum spreads systemically and affects inflorescences. To investigate the genetic basis of these differences, we generate an interspecific recombinant hybrid (recombinant U. maydis x S. reilianum hybrid [rUSH]) carrying the S. reilianum mating type. rUSH exhibits in planta proliferation and an S. reilianum-like phenotype, except for teliospore formation. Transcriptome profiling reveals that pathogenicity-related effector orthologs are induced in rUSH but not in a wild-type hybrid control. Comparative transcriptomics identifies 253 differentially expressed one-to-one effector orthologs with cis-, trans-, and a rUSH-specific phenomenon of cis/trans. CRISPR-Cas9 uncovers three novel virulence factors among the rUSH-specific expressed effectors. Ultimately, we pinpoint the transcription factor UmHdp2 as a key regulator of U. maydis-induced tumorigenesis. Our findings highlight the utility of a recombinant, interspecific hybrid in unraveling the molecular mechanisms underlying pathogenic differences in closely related fungal pathogens.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115772"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293395","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 : 2025-06-13DOI: 10.1016/j.celrep.2025.115806
Qianqian Zhang, Mingliang Xu
{"title":"Decoding fungal pathogenicity: Recombinant hybrids unveil secrets in smut fungi.","authors":"Qianqian Zhang, Mingliang Xu","doi":"10.1016/j.celrep.2025.115806","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115806","url":null,"abstract":"<p><p>A groundbreaking study by Werner et al. illuminates the genetic and regulatory factors driving distinct disease outcomes by engineering an interspecific hybrid of two maize smut fungi. This innovative approach opens new avenues for understanding fungal evolution and plant-pathogen interactions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115806"},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293398","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 : 2025-06-12DOI: 10.1016/j.celrep.2025.115858
Dong Won Kim, Leighton H Duncan, Zheng Xu, Minzi Chang, Sara Sejer, Chantelle E Terrillion, Patrick O Kanold, Elsie Place, Seth Blackshaw
{"title":"Decoding gene networks controlling hypothalamic and prethalamic neuron development.","authors":"Dong Won Kim, Leighton H Duncan, Zheng Xu, Minzi Chang, Sara Sejer, Chantelle E Terrillion, Patrick O Kanold, Elsie Place, Seth Blackshaw","doi":"10.1016/j.celrep.2025.115858","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115858","url":null,"abstract":"<p><p>The hypothalamus and prethalamus regulate diverse physiological and behavioral processes, yet the gene regulatory networks guiding their development remain poorly defined. Using single-cell RNA and ATAC sequencing, we profile over 660,000 cells in the developing mouse hypothalamus and prethalamus between embryonic day 11 and postnatal day 8. This resource maps key transcriptional and chromatin dynamics underlying regionalization, neurogenesis, and neuronal subtype differentiation. We identify distinct neurogenic progenitor populations and uncover gene regulatory networks controlling their spatial and temporal identity. Integration with genome-wide association study data reveals that transcription factors active in supramammillary and prethalamic lineages are associated with metabolic and neuropsychiatric traits. Cross-repressive interactions among regional transcription factors reinforce hypothalamic boundaries. Functional analysis of Dlx1/2 shows that their loss disrupts GABAergic neuron specification, leading to impaired thalamic inhibition and hyperactivity. This study provides a foundational atlas of hypothalamic and prethalamic development and highlights the importance of early gene regulatory programs in health and disease.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115858"},"PeriodicalIF":7.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289385","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":"Maternal vitamin D regulates the metabolic rearrangement of offspring CD4<sup>+</sup> T cells in response to intestinal inflammation.","authors":"Binjun Zhu, Jingwei Yang, Ruiling Fan, Haiyang Song, Lanlan Zhong, Tianli Zeng, Runmin Long, Xing Wan, Qingxi Li, Lei Liu, Jiang Xie","doi":"10.1016/j.celrep.2025.115857","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115857","url":null,"abstract":"<p><p>Children with autism spectrum disorders often have increased susceptibility to intestinal inflammation. However, the mechanisms and prevention of gastrointestinal immune dysfunction remain unclear. We demonstrate that maternal high vitamin D (VitD) level can rescue abnormal intestinal immune phenotypes in offspring that exhibit autism-like phenotypes due to exposure to maternal inflammation. Offspring exposed to dual insult of maternal inflammation and VitD deprivation show increased susceptibility to intestinal inflammation. Maternal high VitD level altered the metabolic patterns and chromatin accessibility of offspring CD4<sup>+</sup> T cells and rescued the abnormal immune state of offspring induced by maternal immune activation (MIA). Additionally, MIA has long-term impacts on the immune phenotype of offspring in the second litter. Our findings suggest why exposure in utero to high inflammation and low maternal VitD levels increase the risk of inflammatory diseases in offspring.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115857"},"PeriodicalIF":7.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289388","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 : 2025-06-12DOI: 10.1016/j.celrep.2025.115840
Zachary R Lanzar, Daniel L Aldridge, Bhargavi Jayaraman, Breanne Haskins, Christian A Howard, Kathya Arana, Molly E Bunkofske, Kathleen Mulka, Ryan D Pardy, Jessica Byerly, Boris Striepen, Patrick Lupardus, Christopher A Hunter
{"title":"De-coupling immune parameters and toxicity associated with IL-12 agonism.","authors":"Zachary R Lanzar, Daniel L Aldridge, Bhargavi Jayaraman, Breanne Haskins, Christian A Howard, Kathya Arana, Molly E Bunkofske, Kathleen Mulka, Ryan D Pardy, Jessica Byerly, Boris Striepen, Patrick Lupardus, Christopher A Hunter","doi":"10.1016/j.celrep.2025.115840","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115840","url":null,"abstract":"<p><p>Interleukin-12 (IL-12) stimulates natural killer (NK) and T cell production of interferon gamma (IFN-γ), but adverse events from NK cell activation have limited its clinical use. This study shows the impact of half-life-extended, full (IL-12Fc) and partial (IL-12 3x AlaFc) IL-12 agonists on the immune system. In naive mice, serial treatment with IL-12Fc induces systemic IFN-γ, multi-organ pathology, and alterations in myelopoiesis. IL-12 Fc stimulates NK cell production of IFN-γ but also activates CD4<sup>+</sup>, CD8<sup>+</sup> T, and NKT cells. IL-12 Fc's ability to enhance the production of IFN-γ facilitates myelopoiesis, but IFN-γ is not required for the development of systemic toxicity. In contrast, IL-12 3x Ala Fc avoids overt disease, activates CD4<sup>+</sup> and CD8<sup>+</sup> T cells, and induces myelopoiesis. These differential activities were harnessed to enhance resistance to infection, indicating that a threshold of IL-12 signaling is tolerated under steady-state conditions and that fine-tuning IL-12 agonism can bolster resistance without triggering pathology.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115840"},"PeriodicalIF":7.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289386","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}