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Unique electron transfer system of cytochrome P450 monooxygenase includes a mechanism of fatty acid β-oxidation. 细胞色素P450单加氧酶独特的电子传递系统包含脂肪酸β-氧化机制。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-25 DOI: 10.1038/s42003-025-08791-5
Saito Kojima, Kyosei Shinji, Hana Namiki, Kouta Suzuki, Motoyuki Shimizu, Chihiro Kadooka, Nozomi Katsuki, Shunsuke Masuo, Madoka Amahisa, Yuki Doi, Norio Takeshita, Naoki Takaya
{"title":"Unique electron transfer system of cytochrome P450 monooxygenase includes a mechanism of fatty acid β-oxidation.","authors":"Saito Kojima, Kyosei Shinji, Hana Namiki, Kouta Suzuki, Motoyuki Shimizu, Chihiro Kadooka, Nozomi Katsuki, Shunsuke Masuo, Madoka Amahisa, Yuki Doi, Norio Takeshita, Naoki Takaya","doi":"10.1038/s42003-025-08791-5","DOIUrl":"10.1038/s42003-025-08791-5","url":null,"abstract":"<p><p>Cytochrome P450 comprises a group of monooxygenases that hydroxylate xenobiotics and natural compounds with diverse electron transfer systems. Here we identify a natural fusion protein of cytochrome (Cyt) b<sub>5</sub> and Cyt b<sub>5</sub> reductase (CBBR) that transfers electrons from NADH to the cytochrome P450 CYP540A2. This cytochrome P450 system hydroxylates medium-chain fatty acids (MCFAs) to generate (R)-β-hydroxy-MCFAs with 7-12 carbon atoms. Kinetic studies of CYP540A2 mutants indicate that side chains of Ser431 and Gln542 residues bind the carboxyl moiety of MCFAs for hydroxylation at their β-carbons. Pre-steady state kinetics also indicate that a predicted linker region between the FAD- and Cyt b<sub>5</sub>-domains of CBBR modulates electron transfer from NADH to CYP540A2. The present study also identifies a dehydrogenase that oxidizes (R)-β-hydroxy-MCFAs to β-oxo-fatty acids that are substrates in the general β-oxidation mechanism of fatty acid degradation. The genes encoding CBBR, CYP540A2, and (R)-β-hydroxy-MCFA dehydrogenase are clustered in the genome of the fungus Aspergillus nidulans and related fungi. The A. nidulans genes are induced by MCFAs, and disrupting CBBR and CYP540A2 genes accumulated more intracellular decanoic acid. Our findings reveal an adaptive monooxygenase-dependent β-oxidation mechanism that alternates with conventional β-oxidation, thus allowing fungi to metabolize MCFAs.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1361"},"PeriodicalIF":5.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148088","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}
引用次数: 0
Visualization of RIM-BP2's crane-like function in neuronal vesicle transport using FRET. 利用FRET可视化RIM-BP2在神经元囊泡运输中的鹤样功能。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-25 DOI: 10.1038/s42003-025-08747-9
Tianyu Gao, Wang Li, Shuai Shao, Zhengyao Zhang, Na Li, Hangyu Zhang, Bo Liu
{"title":"Visualization of RIM-BP2's crane-like function in neuronal vesicle transport using FRET.","authors":"Tianyu Gao, Wang Li, Shuai Shao, Zhengyao Zhang, Na Li, Hangyu Zhang, Bo Liu","doi":"10.1038/s42003-025-08747-9","DOIUrl":"10.1038/s42003-025-08747-9","url":null,"abstract":"<p><p>\"The last mile\" of neuronal vesicles, from being tethered by the active zone filaments to docking at the presynaptic membrane, remains unclear, which limits the deep understanding of synaptic transmission and related physiological changes. Here, we develop two molecular biosensors (BKTS and RKTS) based on fluorescence resonance energy transfer technology according to the structure of RIM-BP2. By detecting the spatial distance between the two ends of the RIM-BP2 and the presynaptic membrane separately, the spatial posture changes in RIM-BP2 are reflected to explore how vesicles are transported to the presynaptic membrane for fusion. In the process of vesicle release, RIM-BP2 in primary cortical neurons and SH-SY5Y cells rotates like a \"crane\" with amino terminal deviating from the presynaptic membrane while the carboxyl terminal becomes closer. Furthermore, disturbing the microfilament or enhancing cell membrane fluidity inhibits the rotation of RIM-BP2. Through mutating RIM-BP2, we find that actin filaments provide mechanical stress through RIM-BP2 amino terminal, thereby regulating vesicle transport and release. Our work identifies a purely mechanical pathway of vesicle transport, in which microfilaments power the RIM-BP2 to drag vesicles to the presynaptic membrane as a \"crane\" for further release.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1362"},"PeriodicalIF":5.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148068","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}
引用次数: 0
Elucidation of the structure and molecular mechanisms of the aspartate antiporter. 天冬氨酸反转运蛋白的结构和分子机制的阐明。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-25 DOI: 10.1038/s42003-025-08676-7
Kei Nanatani, Lan Guan, Ryo Kanno, Takeshi Kawabata, Satoshi Watanabe, Satoshi Katsube, Parameswaran Hariharan, Masafumi Hidaka, Takashi Yamanaka, Keita Toda, Takashi Fujiki, Kota Kunii, Akari Miyamoto, Fumika Chiba, Satoshi Ogasawara, Takeshi Murata, Kenji Inaba, Kaoru Mitsuoka, Keietsu Abe, Masayuki Yamamoto, Seizo Koshiba
{"title":"Elucidation of the structure and molecular mechanisms of the aspartate antiporter.","authors":"Kei Nanatani, Lan Guan, Ryo Kanno, Takeshi Kawabata, Satoshi Watanabe, Satoshi Katsube, Parameswaran Hariharan, Masafumi Hidaka, Takashi Yamanaka, Keita Toda, Takashi Fujiki, Kota Kunii, Akari Miyamoto, Fumika Chiba, Satoshi Ogasawara, Takeshi Murata, Kenji Inaba, Kaoru Mitsuoka, Keietsu Abe, Masayuki Yamamoto, Seizo Koshiba","doi":"10.1038/s42003-025-08676-7","DOIUrl":"10.1038/s42003-025-08676-7","url":null,"abstract":"<p><p>The transport of compounds across the cell membrane is essential for maintaining cellular homeostasis. Secondary exchange transporters mediate the movement of a wide range of substrates against their concentration gradients by harnessing the energy stored in electrochemical gradients. However, the molecular mechanism of substrate exchange by secondary transporters remains unclear. Here, we determined the structures of the aspartate exchanger AspT from Tetragenococcus halophilus using cryo-EM single-particle analysis and X-ray crystallography. We captured AspT in two distinct conformations: the apo outward-facing state and the substrate (L-Aspartate)-bound partially-open inward-facing intermediate state. AspT functions as a homodimer and comprises three domains: a dimerization domain, a substrate transport domain, and a soluble domain. Within each monomer, two hairpin loops in the transport domain form a single substrate-binding pocket. Upon L-aspartate binding, the transport domain carrying the substrate translocates toward the cytoplasmic side of the membrane, forming an outer barrier that blocks the periplasmic access to the binding pocket. These structural insights reveal that AspT mediates substrate translocation via an elevator-type alternating-access mechanism involving a stable partially-open inward-facing intermediate. By elucidating the mechanism of substrate exchange in secondary transporters, this study advances our understanding of membrane transport leading to translational applications in biotechnology.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1359"},"PeriodicalIF":5.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148110","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}
引用次数: 0
Evaluation of cell type annotation reliability using a large language model-based identifier. 基于大型语言模型标识符的单元格类型标注可靠性评估。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-25 DOI: 10.1038/s42003-025-08745-x
Wenjin Ye, Yuanchen Ma, Junkai Xiang, Hongjie Liang, Jintian Luo, Yuantao Li, Tao Wang, Qiuling Xiang, Wu Song, Weiqiang Li, Weijun Huang
{"title":"Evaluation of cell type annotation reliability using a large language model-based identifier.","authors":"Wenjin Ye, Yuanchen Ma, Junkai Xiang, Hongjie Liang, Jintian Luo, Yuantao Li, Tao Wang, Qiuling Xiang, Wu Song, Weiqiang Li, Weijun Huang","doi":"10.1038/s42003-025-08745-x","DOIUrl":"10.1038/s42003-025-08745-x","url":null,"abstract":"<p><p>Ensuring accurate cell type annotation in single-cell RNA sequencing data is a significant challenge, as both expert and automated methods can be biased or constrained by their training data, leading to errors and time-consuming revisions. To address this, we developed LICT (Large Language Model-based Identifier for Cell Types), a tool that leverages multi-model integration and a \"talk-to-machine\" approach. Validated across diverse datasets, LICT consistently aligns with expert annotations. With its objective framework for assessing annotation reliability, LICT can interpret cases where a single cell population exhibits multifaceted traits, allowing researchers to focus on the underlying biological insights. Comparisons with existing tools highlight LICT's superiority in efficiency, consistency, accuracy, and reliability, establishing it as a powerful tool for single-cell RNA sequencing analysis. Furthermore, its independence from reference data emphasizes LICT's generalizability, enhancing reproducibility and ensuring more reliable results in cellular research.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1360"},"PeriodicalIF":5.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148045","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}
引用次数: 0
Progress, challenges and future of linguistic neural decoding with deep learning. 深度学习语言神经解码的进展、挑战和未来。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08511-z
Yu Wang, Heyang Liu, Yuhao Wang, Chuan Xuan, Yixuan Hou, Sheng Feng, Hongcheng Liu, Yusheng Liao, Yanfeng Wang
{"title":"Progress, challenges and future of linguistic neural decoding with deep learning.","authors":"Yu Wang, Heyang Liu, Yuhao Wang, Chuan Xuan, Yixuan Hou, Sheng Feng, Hongcheng Liu, Yusheng Liao, Yanfeng Wang","doi":"10.1038/s42003-025-08511-z","DOIUrl":"10.1038/s42003-025-08511-z","url":null,"abstract":"<p><p>Language is the primary medium through which humans achieve information transfer and exchange. It enables the conveyance of ideas, concepts, and messages, thereby playing an indispensable role in social interaction and knowledge dissemination. Linguistic neural decoding aims to obtain outstanding language information from the evoked human brain during information interaction of both textual and spoken formats. In this work, we present a taxonomy of recent neural decoding progress, focusing on deep learning architectures and strategies, especially those implementing large language models (LLMs) for their powerful information understanding, processing, and generation capacity. We conclude with a concise observation of the challenges and potential future directions. This article aims to provide brain scientists and deep learning researchers with an overarching viewpoint of the significant correlations observed in the human brain during language perception and production from a methodological perspective, and thus facilitate their further investigation.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1350"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136712","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}
引用次数: 0
Lung NR3C1+ and CXCR6high T cells distinguish immunopathogenesis of human emphysema. 肺NR3C1+和cxcr6高T细胞区分人肺气肿的免疫发病机制。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08698-1
Yun Zhang, Maor Sauler, David B Corry, Scott A Ochsner, Sarah Perusich, Li-Zhen Song, Joshua Malo, Raul San Jose Estepar, Francesca Polverino, Farrah Kheradmand
{"title":"Lung NR3C1<sup>+</sup> and CXCR6<sup>high</sup> T cells distinguish immunopathogenesis of human emphysema.","authors":"Yun Zhang, Maor Sauler, David B Corry, Scott A Ochsner, Sarah Perusich, Li-Zhen Song, Joshua Malo, Raul San Jose Estepar, Francesca Polverino, Farrah Kheradmand","doi":"10.1038/s42003-025-08698-1","DOIUrl":"10.1038/s42003-025-08698-1","url":null,"abstract":"<p><p>There is a significant knowledge gap in how T cells promote emphysema in smokers with chronic obstructive pulmonary disease (COPD). Single-cell RNA sequencing (scRNA seq) analysis of human samples and relevant clinical data can provide new mechanistic insights into disease pathogenesis. We generated a human lung scRNA seq dataset with extensive disease characteristic annotation and analyzed a second independent scRNA seq dataset to examine the pathophysiological role of T cells in emphysema. Comparisons of pulmonary immune landscapes in emphysematous (E)-COPD, non-emphysematous (NE)-COPD, and control showed positive enrichment of T cells in E-COPD. Pathway analyses identified upregulated inflammatory states in CD4 T cells as a distinguishing feature of E-COPD.  Compared to controls, glucocorticoid receptor NR3C1 CD4 T cells were enriched in NE-COPD but were reduced in E-COPD. Interactions between macrophages and NR3C1<sup>+</sup> CD4 T cell subsets via CXCL signaling were strongly predicted in E-COPD but were absent in NE-COPD and control. The relative abundance of CD4 CXCR6<sup>high</sup> effector memory T cells positively correlated with preserved lung function in E-COPD but not in NE-COPD. These findings suggest that NR3C1<sup>+</sup> and CXCR6<sup>high</sup> effector memory subsets of CD4 T cells distinguish the immune-pathophysiological features of emphysema in human lungs. Targeting relevant T cell subsets in emphysema might provide new therapeutic opportunities.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1353"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136765","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}
引用次数: 0
Analysis of the microbiota of raw commercial feline diets to prioritize food safety investigations. 分析商业生猫饲料中的微生物群,以确定食品安全调查的重点。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08756-8
Guillaume Reboul, Aaron C Malkowski, Y Tina Yu, Yunman M Gu, Kelly L Sams, J Marie Umbarger, Rebecca J Franklin-Guild, Yuhan Jin, Zhiwei Chen, Bryce J Stanhope, Breanna R Wendel, Laura B Goodman
{"title":"Analysis of the microbiota of raw commercial feline diets to prioritize food safety investigations.","authors":"Guillaume Reboul, Aaron C Malkowski, Y Tina Yu, Yunman M Gu, Kelly L Sams, J Marie Umbarger, Rebecca J Franklin-Guild, Yuhan Jin, Zhiwei Chen, Bryce J Stanhope, Breanna R Wendel, Laura B Goodman","doi":"10.1038/s42003-025-08756-8","DOIUrl":"10.1038/s42003-025-08756-8","url":null,"abstract":"<p><p>Microbiota sharing between people and their companion animals is a concern for development of antimicrobial resistance. To assess the risks associated with feeding raw products to cats, with an emphasis on previously understudied freeze-dried products, a collection of 112 conventional and raw products was purchased and investigated using a combination of cultivation and high-throughput sequencing techniques. Here we show that bacterial cultures were exclusively isolated from raw foods. A total of 19 genera were cultured including Salmonella, Clostridium, Escherichia, Klebsiella, Enterobacter, and Cronobacter. Carbapenem-resistant Pseudomonas aeruginosa and Pseudomonas fulva, and Stenotrophomonas lactitubi were isolated from frozen raw products, and 6 Bacillus strains harbored carbapenemase gene bla<sub>2</sub>. Multidrug efflux pumps were highly abundant in frozen raw isolates. Clostridium sensu stricto I genus detection predicted a raw, freeze-dried product with 95% sensitivity and 78% specificity. Genera Pseudomonas, Paraclostridium and Peptostreptococcus were associated with frozen raw food products while the Bacillus genus was associated with conventional processing. Parasite genes were exclusively detected in raw foods. The presence of pathogenic species and high load of resistance genes in raw commercial food products, particularly those sold on shelves at room temperature, suggests a considerable health risk to cats and the families who care for them.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1349"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136767","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}
引用次数: 0
A case study on the γ-octalactone induced expression of Obp83g-2 in Bactrocera dorsalis (Hendel) revealed the transcriptional regulation of insect odorant binding protein. 以γ-辛内酯诱导背小实蝇(Bactrocera dorsalis)表达Obp83g-2为例,揭示了昆虫气味结合蛋白的转录调控。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08724-2
Xiaofeng Chen, Quan Lei, Changhao Liang, JinJun Wang, Hongbo Jiang
{"title":"A case study on the γ-octalactone induced expression of Obp83g-2 in Bactrocera dorsalis (Hendel) revealed the transcriptional regulation of insect odorant binding protein.","authors":"Xiaofeng Chen, Quan Lei, Changhao Liang, JinJun Wang, Hongbo Jiang","doi":"10.1038/s42003-025-08724-2","DOIUrl":"10.1038/s42003-025-08724-2","url":null,"abstract":"<p><p>As crucial components of the insect olfactory system, odorant binding proteins (OBPs) are involved in detecting environmental chemical cues. Expression alterations of OBPs induced by odorants are conserved in many species. It presents an intriguing initial screening tool when searching for novel OBP-odorant interaction. However, the transcriptional regulation mechanism that causes this expression alteration of OBPs still remains unclear. Here, we reported a case study on the transcriptional regulation of OBP in an invasive species, Bactrocera dorsalis, upon γ-octalactone (a host volatile that strongly attracts its females to lay eggs) induction. We identified OBP83g-2 as a key OBP was involved in γ-octalactone perception through in vitro and in vivo functional assay. In addition, we found transcription factor ADF-1-like positively regulated the expression of Obp83g-2 upon γ-octalactone induction through expression pattern analysis, dual-luciferase reporter system, electrophoretic mobility shift assay (EMSA) and RNAi. Based on this, we proposed a model for the transcriptional regulatory mechanism of OBP gene in B. dorsalis. Our data not only highlights the significant role of OBP83g-2 in γ-octalactone mediated oviposition behavior, but also provides a theoretical foundation for a deeper understanding of the transcriptional regulation of OBPs triggered by external odorants in insects.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1355"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136718","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}
引用次数: 0
Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program. 来自精准医学反式组学(TOPMed)项目的不同祖先队列中,与胰岛素抵抗相关的遗传评分与神经预后的关联
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08674-9
Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M P Shade, Daniel DiCorpo, Xueqiu Jian, Donna K Arnett, Thomas R Austin, Alexa Beiser, Joshua C Bis, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Charles S DeCarli, Harsha Doddapaneni, Josée Dupuis, David W Fardo, Jose C Florez, Stacey Gabriel, Richard A Gibbs, David C Glahn, Namrata Gupta, Hector M González, Kevin A González, Konstantinos Hatzikotoulas, Kathleen M Hayden, Susan R Heckbert, Bertha Hidalgo, Alicia Huerta-Chagoya, Timothy M Hughes, Sharon L R Kardia, Charles L Kooperberg, Lenore J Launer, W T Longstreth, Ravi Mandla, Rasika A Mathias, Andrew P Morris, Thomas H Mosley, Ilya M Nasrallah, Paul Nyquist, Bruce M Psaty, Qibin Qi, Laura M Raffield, Nigel W Rayner, Alexander P Reiner, Claudia L Satizabal, Elizabeth Selvin, Magdalena D R Sevilla-Gonzalez, Albert V Smith, Jennifer A Smith, Kirk Smith, Beverly M Snively, Lorraine Southam, Tamar Sofer, Ken Suzuki, Henry J Taylor, Miriam S Udler, Karine A Viaud-Martinez, Sylvia Wassertheil-Smoller, Alexis C Wood, Lisa R Yanek, Xianyong Yin, Alisa K Manning, Jerome I Rotter, Stephen S Rich, James B Meigs, Myriam Fornage, Sudha Seshadri, Alanna C Morrison
{"title":"Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program.","authors":"Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M P Shade, Daniel DiCorpo, Xueqiu Jian, Donna K Arnett, Thomas R Austin, Alexa Beiser, Joshua C Bis, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Charles S DeCarli, Harsha Doddapaneni, Josée Dupuis, David W Fardo, Jose C Florez, Stacey Gabriel, Richard A Gibbs, David C Glahn, Namrata Gupta, Hector M González, Kevin A González, Konstantinos Hatzikotoulas, Kathleen M Hayden, Susan R Heckbert, Bertha Hidalgo, Alicia Huerta-Chagoya, Timothy M Hughes, Sharon L R Kardia, Charles L Kooperberg, Lenore J Launer, W T Longstreth, Ravi Mandla, Rasika A Mathias, Andrew P Morris, Thomas H Mosley, Ilya M Nasrallah, Paul Nyquist, Bruce M Psaty, Qibin Qi, Laura M Raffield, Nigel W Rayner, Alexander P Reiner, Claudia L Satizabal, Elizabeth Selvin, Magdalena D R Sevilla-Gonzalez, Albert V Smith, Jennifer A Smith, Kirk Smith, Beverly M Snively, Lorraine Southam, Tamar Sofer, Ken Suzuki, Henry J Taylor, Miriam S Udler, Karine A Viaud-Martinez, Sylvia Wassertheil-Smoller, Alexis C Wood, Lisa R Yanek, Xianyong Yin, Alisa K Manning, Jerome I Rotter, Stephen S Rich, James B Meigs, Myriam Fornage, Sudha Seshadri, Alanna C Morrison","doi":"10.1038/s42003-025-08674-9","DOIUrl":"10.1038/s42003-025-08674-9","url":null,"abstract":"<p><p>To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10<sup>-5</sup>) and European (P<sub>EA</sub> = 3.0 × 10<sup>-8</sup>) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (B<sub>EA</sub> = -0.13, P<sub>EA</sub> = 0.0002) and lateral ventricular volume (B<sub>EA</sub> = 0.09, P<sub>EA</sub> = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1352"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136743","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}
引用次数: 0
Periaxin gene variants are linked to age-related cataracts in Cx46 deficient lenses. 环轴蛋白基因变异与Cx46晶状体缺乏患者的老年性白内障有关。
IF 5.1 1区 生物学
Communications Biology Pub Date : 2025-09-24 DOI: 10.1038/s42003-025-08722-4
Chun-Hong Xia, Eddie Wang, Lin Li, Dong Wang, Bo Chang, Mei Li, Xiaohua Gong
{"title":"Periaxin gene variants are linked to age-related cataracts in Cx46 deficient lenses.","authors":"Chun-Hong Xia, Eddie Wang, Lin Li, Dong Wang, Bo Chang, Mei Li, Xiaohua Gong","doi":"10.1038/s42003-025-08722-4","DOIUrl":"10.1038/s42003-025-08722-4","url":null,"abstract":"<p><p>Genetic predisposition affects cataract severity and progression, but no specific genetic modifier has been identified to date. This study reveals Periaxin (Prx) gene variants that cause four amino acid substitutions in the cytoskeletal scaffold protein Periaxin (PRX) between C57BL/6J (B6) and 129S4 (129) mouse strains, modulating the severity of age-related cataracts in connexin 46 knockout (Cx46KO) mice. Expression of 129-PRX is significantly higher than B6-PRX in the lens. Additionally, 129-PRX is broadly distributed across lens fibers, accumulates at fiber cell tricellular vertices, and co-localizes with actin filaments at surface protrusions in inner fibers and cultured cells. Aberrant membrane/F-actin aggregates and irregular fibers appear only in the 129-Cx46KO lens core with severe nuclear cataracts. These findings suggest that Cx46 deficiency and the gain-of-function 129-Prx variant synergistically disrupt fiber cell homeostasis and promote membrane/F-actin aggregation, leading to severe age-related cataracts.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"1356"},"PeriodicalIF":5.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136737","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}
引用次数: 0
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