In this backstory, we feature four remarkable women in science who have collaborated with Prof. Arun Venkatnathan (referred to in this piece as Prof. Arun) from Indian Institute of Science Education and Research (IISER)-Pune at various stages of their careers and reflect on the importance of mentorship to foster interdisciplinary thinking. In his career, Prof. Arun has advocated for the importance of gender diversity and women empowerment and has incorporated this work into the development of his research program. This piece highlights the pivotal role of skilled mentorship as the cornerstone of a successful scientific career. The interview delves into how mentorship is essential in building scientists’ confidence and fostering an environment of mutual respect. This supportive atmosphere encourages collaboration and interdisciplinary thinking, helping researchers navigate the challenges of cross-disciplinary communication and acquire new skills. Ultimately, success in interdisciplinary research demands motivation, continuous learning, unwavering passion, and encouragement.
{"title":"Empowering through mentorship: The journey of women in interdisciplinary science","authors":"Uttama Mukherjee , Ramya Kormath Madam Raghupathy , Minal Sachin Pednekar , Sradha Jayan","doi":"10.1016/j.isci.2025.111865","DOIUrl":"10.1016/j.isci.2025.111865","url":null,"abstract":"<div><div>In this backstory, we feature four remarkable women in science who have collaborated with Prof. Arun Venkatnathan (referred to in this piece as Prof. Arun) from Indian Institute of Science Education and Research (IISER)-Pune at various stages of their careers and reflect on the importance of mentorship to foster interdisciplinary thinking. In his career, Prof. Arun has advocated for the importance of gender diversity and women empowerment and has incorporated this work into the development of his research program. This piece highlights the pivotal role of skilled mentorship as the cornerstone of a successful scientific career. The interview delves into how mentorship is essential in building scientists’ confidence and fostering an environment of mutual respect. This supportive atmosphere encourages collaboration and interdisciplinary thinking, helping researchers navigate the challenges of cross-disciplinary communication and acquire new skills. Ultimately, success in interdisciplinary research demands motivation, continuous learning, unwavering passion, and encouragement.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 3","pages":"Article 111865"},"PeriodicalIF":4.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
In this study, we explore the inherent trade-off between accuracy and robustness in neural networks, drawing an analogy to the uncertainty principle in quantum mechanics. We propose that neural networks are subject to an uncertainty relation, which manifests as a fundamental limitation in their ability to simultaneously achieve high accuracy and robustness against adversarial attacks. Through mathematical proofs and empirical evidence, we demonstrate that this trade-off is a natural consequence of the sharp boundaries formed between different class concepts during training. Our findings reveal that the complementarity principle, a cornerstone of quantum physics, applies to neural networks, imposing fundamental limits on their capabilities in simultaneous learning of conjugate features. Meanwhile, our work suggests that achieving human-level intelligence through a single-network architecture or massive datasets alone may be inherently limited. Our work provides new insights into the theoretical foundations of neural network vulnerability and opens up avenues for designing more robust neural network architectures.
{"title":"On the uncertainty principle of neural networks","authors":"Jun-Jie Zhang , Dong-Xiao Zhang , Jian-Nan Chen , Long-Gang Pang , Deyu Meng","doi":"10.1016/j.isci.2025.112197","DOIUrl":"10.1016/j.isci.2025.112197","url":null,"abstract":"<div><div>In this study, we explore the inherent trade-off between accuracy and robustness in neural networks, drawing an analogy to the uncertainty principle in quantum mechanics. We propose that neural networks are subject to an uncertainty relation, which manifests as a fundamental limitation in their ability to simultaneously achieve high accuracy and robustness against adversarial attacks. Through mathematical proofs and empirical evidence, we demonstrate that this trade-off is a natural consequence of the sharp boundaries formed between different class concepts during training. Our findings reveal that the complementarity principle, a cornerstone of quantum physics, applies to neural networks, imposing fundamental limits on their capabilities in simultaneous learning of conjugate features. Meanwhile, our work suggests that achieving human-level intelligence through a single-network architecture or massive datasets alone may be inherently limited. Our work provides new insights into the theoretical foundations of neural network vulnerability and opens up avenues for designing more robust neural network architectures.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112197"},"PeriodicalIF":4.6,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-04DOI: 10.1016/j.isci.2025.112156
Amalia P.M. Bastos , Scott Claessens , Ximena J. Nelson , David Welch , Quentin D. Atkinson , Alex H. Taylor
Putatively rare behaviors like tool use are difficult to study because absence of evidence can arise from a species’ inability to produce the behavior or from insufficient research. We combine data from digital platforms and phylogenetic modeling to estimate rates of tool use in parrots. Videos on YouTube revealed novel instances of self-care tooling in 17 parrot species, more than doubling the number of tool-using parrots from 11 (3%) to 28 (7%). Phylogenetic modeling suggests 11–17% of extant parrot species may be capable of tool use and identifies likely candidates. These discoveries impact our understanding of the evolution of tool use in parrots, revealing associations with relative brain size and feeding generalism and indicating likely ancestral tool use in several genera. Our findings challenge the assumption that current sampling efforts fully capture the distribution of putatively rare animal behaviors and offer a fruitful approach for investigating other rare behaviors.
{"title":"Evidence of self-care tooling and phylogenetic modeling reveal parrot tool use is not rare","authors":"Amalia P.M. Bastos , Scott Claessens , Ximena J. Nelson , David Welch , Quentin D. Atkinson , Alex H. Taylor","doi":"10.1016/j.isci.2025.112156","DOIUrl":"10.1016/j.isci.2025.112156","url":null,"abstract":"<div><div>Putatively rare behaviors like tool use are difficult to study because absence of evidence can arise from a species’ inability to produce the behavior or from insufficient research. We combine data from digital platforms and phylogenetic modeling to estimate rates of tool use in parrots. Videos on YouTube revealed novel instances of self-care tooling in 17 parrot species, more than doubling the number of tool-using parrots from 11 (3%) to 28 (7%). Phylogenetic modeling suggests 11–17% of extant parrot species may be capable of tool use and identifies likely candidates. These discoveries impact our understanding of the evolution of tool use in parrots, revealing associations with relative brain size and feeding generalism and indicating likely ancestral tool use in several genera. Our findings challenge the assumption that current sampling efforts fully capture the distribution of putatively rare animal behaviors and offer a fruitful approach for investigating other rare behaviors.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112156"},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-04DOI: 10.1016/j.isci.2025.112162
Xunhui Cai , Jennifer Y. Cho , Lijun Chen , Yufeng Liu , Fenghu Ji , Katia Salgado , Siyi Ge , Dehua Yang , Hui Yu , Jianbo Shao , P. Andrew Futreal , Boris Sepesi , Don Gibbons , Yaobing Chen , Guoping Wang , Chao Cheng , Meng Wu , Jianjun Zhang , Ansel Hsiao , Tian Xia
Understanding the effect of gut microbiota function on immune checkpoint inhibitor (ICI) responses is urgently needed. Here, we integrated 821 fecal metagenomes from 12 datasets to identify differentially abundant genes and construct random forest models to predict ICI response. Gene markers demonstrated excellent predictive performance, with an average area under the curve (AUC) of 0.810. Pathway analyses revealed that quorum sensing (QS), ABC transporters, flagellar assembly, and amino acid biosynthesis pathways were enriched between responders (R) and non-responders (NRs) across 12 datasets. Furthermore, luxS, manA, fliC, and trpB exhibited consistent changes between R and NR across 12 datasets. Follow-up microbiota transplant experiments showed that inter-species signaling by different QS autoinducer-2 (AI-2) molecules (synthesized by luxS) can act on overall community function to promote the colonization of Akkermansia muciniphila, which is associated with superior ICI responses. Together, our data highlight the role of gut microbiota function in modulating the microbiome and antitumor immunity.
{"title":"Enriched pathways in gut microbiome predict response to immune checkpoint inhibitor treatment across demographic regions and various cancer types","authors":"Xunhui Cai , Jennifer Y. Cho , Lijun Chen , Yufeng Liu , Fenghu Ji , Katia Salgado , Siyi Ge , Dehua Yang , Hui Yu , Jianbo Shao , P. Andrew Futreal , Boris Sepesi , Don Gibbons , Yaobing Chen , Guoping Wang , Chao Cheng , Meng Wu , Jianjun Zhang , Ansel Hsiao , Tian Xia","doi":"10.1016/j.isci.2025.112162","DOIUrl":"10.1016/j.isci.2025.112162","url":null,"abstract":"<div><div>Understanding the effect of gut microbiota function on immune checkpoint inhibitor (ICI) responses is urgently needed. Here, we integrated 821 fecal metagenomes from 12 datasets to identify differentially abundant genes and construct random forest models to predict ICI response. Gene markers demonstrated excellent predictive performance, with an average area under the curve (AUC) of 0.810. Pathway analyses revealed that quorum sensing (QS), ABC transporters, flagellar assembly, and amino acid biosynthesis pathways were enriched between responders (R) and non-responders (NRs) across 12 datasets. Furthermore, <em>luxS</em>, <em>manA</em>, <em>fliC</em>, and <em>trpB</em> exhibited consistent changes between R and NR across 12 datasets. Follow-up microbiota transplant experiments showed that inter-species signaling by different QS autoinducer-2 (AI-2) molecules (synthesized by <em>luxS</em>) can act on overall community function to promote the colonization of <em>Akkermansia muciniphila</em>, which is associated with superior ICI responses. Together, our data highlight the role of gut microbiota function in modulating the microbiome and antitumor immunity.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112162"},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-04DOI: 10.1016/j.isci.2025.112146
Beatrice W. Awasthi , João A. Paulo , Deborah L. Burkhart , Ian R. Smith , Ryan L. Collins , J. Wade Harper , Steven P. Gygi , Kevin M. Haigis
Epidermal growth factor receptor (Egfr)-driven signaling regulates fundamental homeostatic processes. Dysregulated signaling via Egfr is implicated in numerous disease pathologies and distinct Egfr-associated disease etiologies are known to be tissue-specific. The molecular basis of this tissue-specificity remains poorly understood. Most studies of Egfr signaling to date have been performed in vitro or in tissue-specific mouse models of disease, which has limited insight into Egfr signaling patterns in healthy tissues. Here, we carried out integrated phosphoproteomic, proteomic, and transcriptomic analyses of signaling changes across various mouse tissues in response to short-term stimulation with the Egfr ligand Egf. We show how both baseline and Egf-stimulated signaling dynamics differ between tissues. Moreover, we propose how baseline phosphorylation and total protein levels may be associated with clinically relevant tissue-specific Egfr-associated phenotypes. Altogether, our analyses illustrate tissue-specific effects of Egf stimulation and highlight potential links between underlying tissue biology and Egfr signaling output.
{"title":"The network response to Egf is tissue-specific","authors":"Beatrice W. Awasthi , João A. Paulo , Deborah L. Burkhart , Ian R. Smith , Ryan L. Collins , J. Wade Harper , Steven P. Gygi , Kevin M. Haigis","doi":"10.1016/j.isci.2025.112146","DOIUrl":"10.1016/j.isci.2025.112146","url":null,"abstract":"<div><div>Epidermal growth factor receptor (Egfr)-driven signaling regulates fundamental homeostatic processes. Dysregulated signaling via Egfr is implicated in numerous disease pathologies and distinct Egfr-associated disease etiologies are known to be tissue-specific. The molecular basis of this tissue-specificity remains poorly understood. Most studies of Egfr signaling to date have been performed <em>in vitro</em> or in tissue-specific mouse models of disease, which has limited insight into Egfr signaling patterns in healthy tissues. Here, we carried out integrated phosphoproteomic, proteomic, and transcriptomic analyses of signaling changes across various mouse tissues in response to short-term stimulation with the Egfr ligand Egf. We show how both baseline and Egf-stimulated signaling dynamics differ between tissues. Moreover, we propose how baseline phosphorylation and total protein levels may be associated with clinically relevant tissue-specific Egfr-associated phenotypes. Altogether, our analyses illustrate tissue-specific effects of Egf stimulation and highlight potential links between underlying tissue biology and Egfr signaling output.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112146"},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-04DOI: 10.1016/j.isci.2025.112161
Richard J. Harris , Adam K. Hillberg , Lee D. Bastin , Blake S. Lausen , Saowaros Suwansa-Ard , Tianfang Wang , Abigail Elizur , Sakura Kikuchi , Keisuke Nakashima , Noriyuki Satoh , Cherie A. Motti , Scott F. Cummins
With growing interest in utilizing semiochemicals to control pest species, recent investigations have begun to consider semiochemicals to control outbreaks of crown-of-thorns starfish (CoTS; Acanthaster cf. solaris), a corallivore contributing to coral reef degradation. In this study, differential gene expression analysis of adult CoTS spines led to the identification of (1) numerous G-protein coupled receptor genes enriched at the reproductive stage, possibly reflecting enhanced sensitivity to semiochemicals and (2) genes encoding secreted proteins at the non-reproductive stage. We also demonstrated that these proteins belong to an uncharacterized family of secreted proteins that are unique to Acanthaster spp., being released into the surrounding water. A synthetic peptide mixture derived from this protein family demonstrated no toxicity yet did modify conspecific adult behavior, eliciting attraction. Based on this evidence, we suggest a pheromonal role beyond reproduction. The discovery of these provides a tool for future innovative semiochemical biocontrol in CoTS management strategies.
{"title":"A family of crown-of-thorns starfish spine-secreted proteins modify adult conspecific behavior","authors":"Richard J. Harris , Adam K. Hillberg , Lee D. Bastin , Blake S. Lausen , Saowaros Suwansa-Ard , Tianfang Wang , Abigail Elizur , Sakura Kikuchi , Keisuke Nakashima , Noriyuki Satoh , Cherie A. Motti , Scott F. Cummins","doi":"10.1016/j.isci.2025.112161","DOIUrl":"10.1016/j.isci.2025.112161","url":null,"abstract":"<div><div>With growing interest in utilizing semiochemicals to control pest species, recent investigations have begun to consider semiochemicals to control outbreaks of crown-of-thorns starfish (CoTS; <em>Acanthaster</em> cf. <em>solaris</em>), a corallivore contributing to coral reef degradation. In this study, differential gene expression analysis of adult CoTS spines led to the identification of (1) numerous G-protein coupled receptor genes enriched at the reproductive stage, possibly reflecting enhanced sensitivity to semiochemicals and (2) genes encoding secreted proteins at the non-reproductive stage. We also demonstrated that these proteins belong to an uncharacterized family of secreted proteins that are unique to <em>Acanthaster</em> spp., being released into the surrounding water. A synthetic peptide mixture derived from this protein family demonstrated no toxicity yet did modify conspecific adult behavior, eliciting attraction. Based on this evidence, we suggest a pheromonal role beyond reproduction. The discovery of these provides a tool for future innovative semiochemical biocontrol in CoTS management strategies.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112161"},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-03DOI: 10.1016/j.isci.2025.112153
Madeline W. Eibner-Gebhardt , Robert C. Fleischer , Michael G. Campana
Avipoxvirus is an avian pathogen that likely contributed to the declines and extinctions of endemic Hawaiian birds since its 19th century introduction. We surveyed 719 DNA libraries, including 639 representing 440 Hawaiian bird specimens, for evidence of Avipoxvirus infection. We reconstructed a 5.2× Avipoxvirus genome from an 1898 Hawaii ‘amakihi (Chlorodrepanis virens) specimen. Its sequence matched an extant Hawaiian Avipoxvirus strain, supporting the strain’s persistence in Hawaii over the last century. We identified the earliest molecularly verified case of Avipoxvirus in the Hawaiian Islands in an 1887 ʻalalā (Corvus hawaiiensis) specimen and reconstructed a partial Avipoxvirus genome from this specimen. Both specimens’ Avipoxvirus strains were most closely related to canarypox virus, suggesting that introduced passerines may be the source of Avipoxvirus in Hawaiian endemic land birds. These findings clarify the origins and evolution of Avipoxvirus in Hawaii and provide evidence for the broader role of pathogens in driving biodiversity loss.
{"title":"A historical Hawaiian Avipoxvirus genome reconstructed from an 1898 museum specimen","authors":"Madeline W. Eibner-Gebhardt , Robert C. Fleischer , Michael G. Campana","doi":"10.1016/j.isci.2025.112153","DOIUrl":"10.1016/j.isci.2025.112153","url":null,"abstract":"<div><div><em>Avipoxvirus</em> is an avian pathogen that likely contributed to the declines and extinctions of endemic Hawaiian birds since its 19th century introduction. We surveyed 719 DNA libraries, including 639 representing 440 Hawaiian bird specimens, for evidence of <em>Avipoxvirus</em> infection. We reconstructed a 5.2× <em>Avipoxvirus</em> genome from an 1898 Hawaii ‘amakihi (<em>Chlorodrepanis virens</em>) specimen. Its sequence matched an extant Hawaiian <em>Avipoxvirus</em> strain, supporting the strain’s persistence in Hawaii over the last century. We identified the earliest molecularly verified case of <em>Avipoxvirus</em> in the Hawaiian Islands in an 1887 ʻalalā (<em>Corvus hawaiiensis</em>) specimen and reconstructed a partial <em>Avipoxvirus</em> genome from this specimen. Both specimens’ <em>Avipoxvirus</em> strains were most closely related to canarypox virus, suggesting that introduced passerines may be the source of <em>Avipoxvirus</em> in Hawaiian endemic land birds. These findings clarify the origins and evolution of <em>Avipoxvirus</em> in Hawaii and provide evidence for the broader role of pathogens in driving biodiversity loss.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112153"},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Motor performance improvement through self-modulation of brain activity has been demonstrated through neurofeedback. However, the sensorimotor plasticity induced through the training remains unclear. Here, we combined individually tailored closed-loop neurofeedback, neurophysiology, and behavioral assessment to characterize how the training can modulate the somatosensory system and improve performance. The real-time neurofeedback of human electroencephalogram (EEG) signals enhanced participants’ self-modulation ability of intrinsic neural oscillations in the primary somatosensory cortex (S1) within 30 min. Further, the short-term reorganization in S1 was corroborated by the post-training changes in somatosensory evoked potential (SEP) amplitude of the early component from S1. Meanwhile those derived from peripheral and spinal sensory fibers were maintained (N9 and N13 components), suggesting that the training manipulated S1 activities. Behavioral evaluation demonstrated improved performance during keyboard touch-typing indexed by resolved speed-accuracy trade-off. Collectively, our results provide evidence that neurofeedback training induces functional reorganization of S1 and sensorimotor function.
{"title":"Enhanced human sensorimotor integration via self-modulation of the somatosensory activity","authors":"Seitaro Iwama , Takamasa Ueno , Tatsuro Fujimaki , Junichi Ushiba","doi":"10.1016/j.isci.2025.112145","DOIUrl":"10.1016/j.isci.2025.112145","url":null,"abstract":"<div><div>Motor performance improvement through self-modulation of brain activity has been demonstrated through neurofeedback. However, the sensorimotor plasticity induced through the training remains unclear. Here, we combined individually tailored closed-loop neurofeedback, neurophysiology, and behavioral assessment to characterize how the training can modulate the somatosensory system and improve performance. The real-time neurofeedback of human electroencephalogram (EEG) signals enhanced participants’ self-modulation ability of intrinsic neural oscillations in the primary somatosensory cortex (S1) within 30 min. Further, the short-term reorganization in S1 was corroborated by the post-training changes in somatosensory evoked potential (SEP) amplitude of the early component from S1. Meanwhile those derived from peripheral and spinal sensory fibers were maintained (N9 and N13 components), suggesting that the training manipulated S1 activities. Behavioral evaluation demonstrated improved performance during keyboard touch-typing indexed by resolved speed-accuracy trade-off. Collectively, our results provide evidence that neurofeedback training induces functional reorganization of S1 and sensorimotor function.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112145"},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.
{"title":"Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity","authors":"Mamoru Oyabu , Yuto Ohira , Mariko Fujita , Kiyoshi Yoshioka , Runa Kawaguchi , Atsushi Kubo , Yukino Hatazawa , Hinako Yukitoshi , Huascar Pedro Ortuste Quiroga , Naoki Horii , Fumihito Miura , Hiromitsu Araki , Masaki Okano , Izuho Hatada , Hitoshi Gotoh , Tatsuya Yoshizawa , So-ichiro Fukada , Yoshihiro Ogawa , Takashi Ito , Kengo Ishihara , Yasutomi Kamei","doi":"10.1016/j.isci.2025.112144","DOIUrl":"10.1016/j.isci.2025.112144","url":null,"abstract":"<div><div>Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112144"},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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}
Pub Date : 2025-03-03DOI: 10.1016/j.isci.2025.112135
Nicola Gericke , Dardan Beqaj , Thales Kronenberger , Andreas Kulik , Athina Gavriilidou , Mirita Franz-Wachtel , Ulrich Schoppmeier , Theresa Harbig , Johanna Rapp , Iwan Grin , Nadine Ziemert , Hannes Link , Kay Nieselt , Boris Macek , Wolfgang Wohlleben , Evi Stegmann , Samuel Wagner
Glycopeptide antibiotics (GPA) such as vancomycin are essential last-resort antibiotics produced by actinomycetes. Their biosynthesis is encoded within biosynthetic gene clusters, also harboring genes for regulation, and transport. Diverse types of GPAs have been characterized that differ in peptide backbone composition and modification patterns. However, little is known about the ATP-binding cassette (ABC) transporters facilitating GPA export. Employing a multifaceted approach, we investigated the substrate specificity of GPA ABC-transporters toward the type-I GPA balhimycin. Phylogenetic analysis suggested and trans-complementation experiments confirmed that balhimycin is exported only by the related type I GPA transporters Tba and Tva (transporter of vancomycin). Molecular dynamics simulations and mutagenesis experiments showed that Tba exhibits specificity toward the peptide backbone rather than the modifications. Unexpectedly, deletion or functional inactivation of Tba halted balhimycin biosynthesis. Combined with proximity biotinylation experiments, this suggested that the interaction of the active transporter with the biosynthetic machinery is required for biosynthesis.
{"title":"Unveiling the substrate specificity of the ABC transporter Tba and its role in glycopeptide biosynthesis","authors":"Nicola Gericke , Dardan Beqaj , Thales Kronenberger , Andreas Kulik , Athina Gavriilidou , Mirita Franz-Wachtel , Ulrich Schoppmeier , Theresa Harbig , Johanna Rapp , Iwan Grin , Nadine Ziemert , Hannes Link , Kay Nieselt , Boris Macek , Wolfgang Wohlleben , Evi Stegmann , Samuel Wagner","doi":"10.1016/j.isci.2025.112135","DOIUrl":"10.1016/j.isci.2025.112135","url":null,"abstract":"<div><div>Glycopeptide antibiotics (GPA) such as vancomycin are essential last-resort antibiotics produced by actinomycetes. Their biosynthesis is encoded within biosynthetic gene clusters, also harboring genes for regulation, and transport. Diverse types of GPAs have been characterized that differ in peptide backbone composition and modification patterns. However, little is known about the ATP-binding cassette (ABC) transporters facilitating GPA export. Employing a multifaceted approach, we investigated the substrate specificity of GPA ABC-transporters toward the type-I GPA balhimycin. Phylogenetic analysis suggested and <em>trans</em>-complementation experiments confirmed that balhimycin is exported only by the related type I GPA transporters Tba and Tva (transporter of vancomycin). Molecular dynamics simulations and mutagenesis experiments showed that Tba exhibits specificity toward the peptide backbone rather than the modifications. Unexpectedly, deletion or functional inactivation of Tba halted balhimycin biosynthesis. Combined with proximity biotinylation experiments, this suggested that the interaction of the active transporter with the biosynthetic machinery is required for biosynthesis.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 4","pages":"Article 112135"},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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