IF 6.4 1区生物学

eLife Pub Date : 2025-09-25 DOI: 10.7554/eLife.100346

Lei Li, Guanghao Wu, Xiaolei Xu, Junling Yang, Lirong Yi, Ziqing Yang, Zheng Mo, Li Xing, Ying Shan, Zhuo Yu, Yinchuan Li

{"title":"The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus.","authors":"Lei Li, Guanghao Wu, Xiaolei Xu, Junling Yang, Lirong Yi, Ziqing Yang, Zheng Mo, Li Xing, Ying Shan, Zhuo Yu, Yinchuan Li","doi":"10.7554/eLife.100346","DOIUrl":"10.7554/eLife.100346","url":null,"abstract":"This study investigated 17α-estradiol's effects on aged hypothalamic physiological activity via long-term administration. Single-nucleus transcriptomic sequencing (snRNA-seq) was performed on pooled hypothalami from each group: aged male Norway brown rats treated with 17α-estradiol (O.T), aged controls (O), and young controls (Y). Supervised clustering of neurons (based on neuropeptides/receptors) evaluated subtype responses to aging and 17α-estradiol. Aging-induced elevation of neuronal cellular metabolism, stress, and reduced synapse formation-related pathways were significantly attenuated by 17α-estradiol. Neuron population analysis showed that subtypes regulating food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17α-estradiol. 17α-estradiol increased serum oxytocin (Oxt) and hypothalamic-pituitary-gonadal (HPG) axis activity (elevated plasma Gnrh, total testosterone; reduced estradiol). Gnrh1 upregulation mediated its effects on energy homeostasis, neural synapse, and stress response. Notably, Crh neurons in O.T showed prominent stress phenotypes, distinct from Agrp/Ghrl neurons. Thus, HPG axis and energy metabolism may be key 17α-estradiol targets in male hypothalamus. Additionally, our results demonstrate that supervised clustering (based on neuropeptides/receptors) effectively assesses the responses of hypothalamic neuron subtypes to aging and 17α-estradiol treatment.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136910","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

Ubiquitination-activated TAB-TAK1-IKK-NF-κB axis modulates gene expression for cell survival in the lysosomal damage response. 泛素化激活的TAB-TAK1-IKK-NF-κB轴调节溶酶体损伤反应中细胞存活的基因表达。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.106901

Akinori Endo, Chikage Takahashi, Naoko Ishibashi, Yasumasa Nishito, Koji Yamano, Keiji Tanaka, Yukiko Yoshida

引用次数: 0

Capturing enzymes in motion. 捕捉运动中的酶。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.108727

Álvaro de la Gándara, Agnieszka A Kendrick

引用次数: 0

Forecasting protein evolution by integrating birth-death population models with structurally constrained substitution models. 结合结构约束替代模型的出生-死亡种群模型预测蛋白质进化。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.106365

David Ferreiro, Luis Daniel González-Vázquez, Ana Prado-Comesaña, Miguel Arenas

{"title":"Forecasting protein evolution by integrating birth-death population models with structurally constrained substitution models.","authors":"David Ferreiro, Luis Daniel González-Vázquez, Ana Prado-Comesaña, Miguel Arenas","doi":"10.7554/eLife.106365","DOIUrl":"10.7554/eLife.106365","url":null,"abstract":"Evolutionary studies in population genetics and ecology were mainly focused on predicting and understanding past evolutionary events. Recently, however, a growing trend explores the prediction of evolutionary trajectories toward the future promoted by its wide variety of applications. In this context, we introduce a forecasting protein evolution method that integrates birth-death population models with substitution models that consider selection on protein folding stability. In contrast to traditional population genetics methods that usually make the unrealistic assumption of simulating molecular evolution separately from the evolutionary history, the present method combines both processes to simultaneously model forward-in-time birth-death evolutionary trajectories and protein evolution under structurally constrained substitution models that outperformed traditional empirical substitution models. We implemented the method into a freely available computer framework. We evaluated the accuracy of the predictions with several monitored viral proteins of broad interest. Overall, the method showed acceptable errors in predicting the folding stability of the forecasted protein variants, but, expectedly, the errors were larger in the prediction of the corresponding sequences. We conclude that forecasting protein evolution is feasible in certain evolutionary scenarios and provide suggestions to enhance its accuracy by improving the underlying models of evolution.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130374","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

Dimerization and dynamics of human angiotensin-I converting enzyme revealed by cryo-EM and MD simulations. 低温电镜和分子动力学模拟揭示人血管紧张素- 1转化酶的二聚化和动力学。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.106044

Jordan M Mancl, Xiaoyang Wu, Minglei Zhao, Wei-Jen Tang

{"title":"Dimerization and dynamics of human angiotensin-I converting enzyme revealed by cryo-EM and MD simulations.","authors":"Jordan M Mancl, Xiaoyang Wu, Minglei Zhao, Wei-Jen Tang","doi":"10.7554/eLife.106044","DOIUrl":"10.7554/eLife.106044","url":null,"abstract":"Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing four analogous catalytic sites, and exists in membrane-bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryo-EM structures. Here, we report the cryo-EM structure of the glycosylated full human sACE dimer. We resolved four structural states at 2.99 - 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130370","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

Conformational changes, excess area, and elasticity of the Piezo protein-membrane nanodome from coarse-grained and atomistic simulations. 从粗粒度和原子模拟的压电蛋白膜纳米圆顶的构象变化，多余面积和弹性。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.105138

Sneha Dixit, Frank Noé, Thomas R Weikl

{"title":"Conformational changes, excess area, and elasticity of the Piezo protein-membrane nanodome from coarse-grained and atomistic simulations.","authors":"Sneha Dixit, Frank Noé, Thomas R Weikl","doi":"10.7554/eLife.105138","DOIUrl":"10.7554/eLife.105138","url":null,"abstract":"The mechanosensitive ion channels Piezo 1 and 2 induce a curved protein-membrane nanodome that flattens with increasing membrane tension γ. The tension-induced flattening of the nanodome is associated with Piezo activation and driven by the energy γΔA where ΔA is the excess area of the curved nanodome relative to its planar projected area. Based on extensive coarse-grained and atomistic simulations of membrane-embedded Piezo 1 and 2 proteins, we report here an excess area ΔA for the Piezo protein-membrane nanodome of about 40 nm2 in tensionless membranes, and a half-maximal reduction of ΔA at tension values of about 3-4 mN/m, which is within the range of experimentally determined values for the half-maximal activation of Piezo 1. In line with recent experimental investigations of Piezo proteins in cell membranes and membrane vesicles, the membrane-embedded Piezo proteins adopt conformations in our simulations that are significantly less curved than the protein conformation in the detergent micelles of cryo-EM structures. An elasticity analysis of the nanodome shapes and protein conformations obtained from our simulations leads to an elastic model for Piezo activation that distinguishes the different energy components of the protein and the membrane in the tension-induced flattening of the nanodome. According to this model, the Piezo proteins resist flattening with a force constant of about 60 pN/nm.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130391","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

Online reinforcement learning of state representation in recurrent network supported by the power of random feedback and biological constraints. 基于随机反馈和生物约束的循环网络状态表示在线强化学习。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-24 DOI: 10.7554/eLife.104101

Takayuki Tsurumi, Ayaka Kato, Arvind Kumar, Kenji Morita

{"title":"Online reinforcement learning of state representation in recurrent network supported by the power of random feedback and biological constraints.","authors":"Takayuki Tsurumi, Ayaka Kato, Arvind Kumar, Kenji Morita","doi":"10.7554/eLife.104101","DOIUrl":"10.7554/eLife.104101","url":null,"abstract":"Representation of external and internal states in the brain plays a critical role in enabling suitable behavior. Recent studies suggest that state representation and state value can be simultaneously learned through Temporal-Difference-Reinforcement-Learning (TDRL) and Backpropagation-Through-Time (BPTT) in recurrent neural networks (RNNs) and their readout. However, neural implementation of such learning remains unclear as BPTT requires offline update using transported downstream weights, which is suggested to be biologically implausible. We demonstrate that simple online training of RNNs using TD reward prediction error and random feedback, without additional memory or eligibility trace, can still learn the structure of tasks with cue-reward delay and timing variability. This is because TD learning itself is a solution for temporal credit assignment, and feedback alignment, a mechanism originally proposed for supervised learning, enables gradient approximation without weight transport. Furthermore, we show that biologically constraining downstream weights and random feedback to be non-negative not only preserves learning but may even enhance it because the non-negative constraint ensures loose alignment-allowing the downstream and feedback weights to roughly align from the beginning. These results provide insights into the neural mechanisms underlying the learning of state representation and value, highlighting the potential of random feedback and biological constraints.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130462","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

The increase in cell volume and nuclear number of the koji-fungus Aspergillus oryzae contributes to its high enzyme productivity. 曲菌米曲霉细胞体积和核数的增加是其高产酶的重要原因。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-23 DOI: 10.7554/eLife.107043

Ayaka Itani, Haruto Motomura, Ken Oda, Hideyuki Yamashita, Kanae Sakai, Ken-Ichi Kusumoto, Shinsuke Shigeto, Takehiko Ichikawa, Hosain Mohammad Mubarak, Takeshi Fukuma, Takuya Katayama, Jun-Ichi Maruyama, Shunsuke Masuo, Naoki Takaya, Norio Takeshita

{"title":"The increase in cell volume and nuclear number of the koji-fungus Aspergillus oryzae contributes to its high enzyme productivity.","authors":"Ayaka Itani, Haruto Motomura, Ken Oda, Hideyuki Yamashita, Kanae Sakai, Ken-Ichi Kusumoto, Shinsuke Shigeto, Takehiko Ichikawa, Hosain Mohammad Mubarak, Takeshi Fukuma, Takuya Katayama, Jun-Ichi Maruyama, Shunsuke Masuo, Naoki Takaya, Norio Takeshita","doi":"10.7554/eLife.107043","DOIUrl":"10.7554/eLife.107043","url":null,"abstract":"While the ratio of nuclei to cell volume is well regulated, it remains largely unexplored in multinucleate organisms. The koji-fungus Aspergillus oryzae, traditionally used in Japanese brewing and fermentation for over a thousand years, is now widely utilized in modern biotechnology as a host for enzyme production. We discovered that, over time in culture, hyphae become thicker, resulting in a tenfold increase in cell volume, and the number of nuclei in hyphal cells also increases tenfold, exceeding 200. The increase in cell volume and nuclear number is unique among the investigated Aspergillus species and correlates with its high enzyme production capabilities. Since nuclear number and cell volume are correlated, both must increase simultaneously for either to expand. Our analyses identified genetic factors and nutritional environmental signals involved in each of these increases. Increases in nuclear number and cell volume were also observed in other fungi bred for industrial use. This study not only deepens our understanding of the evolutionary processes that promote high enzyme productivity through fungal breeding, but also provides insights into the molecular mechanisms regulating cell volume and nuclear number in multinucleate organisms.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124402","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

Oxytocin restores context-specific hyperaltruistic preference. 催产素恢复情境特定的超利他主义偏好。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-23 DOI: 10.7554/eLife.102756

Hong Zhang, Yinmei Ni, Jian Li

{"title":"Oxytocin restores context-specific hyperaltruistic preference.","authors":"Hong Zhang, Yinmei Ni, Jian Li","doi":"10.7554/eLife.102756","DOIUrl":"10.7554/eLife.102756","url":null,"abstract":"Recent advances in moral decision-making research show people are hyperaltruistic by being more willing to sacrifice monetary gains to spare others from suffering than to spare themselves. Yet other studies indicate an opposite egoistic bias: subjects are less willing to harm themselves for others' benefits than for their own. These results underscore the complexities of moral decisions and demand a mechanistic explanation for hyperaltruistic preferences. We investigated hyperaltruism using trade-off choices combining monetary gains and painful electric shocks and choices combining monetary losses and shocks. Study 1 revealed that switching the decision context from gains to losses effectively eliminated the hyperaltruistic preference, accompanied by the altered relationship between subjects' instrumental harm (IH) trait attitudes and relative pain sensitivities. In the pre-registered study 2, we found that oxytocin, a neuropeptide linked to parochial altruism, restored the context-dependent hyperaltruistic preference. Furthermore, oxytocin increased the degree to which subjects framed the task as harming others, which mediated the correlation between IH and relative pain sensitivities. Thus, the loss decision context and oxytocin diminished and restored the mediation effect of subjective harm framing, respectively. Our results help elucidate the psychological processes underpinning the contextual specificity of hyperaltruism and carry implications in promoting prosocial interactions.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124411","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

Strip cropping shows promising increases in ground beetle community diversity compared to monocultures. 与单一栽培相比，带状种植有希望增加地面甲虫群落多样性。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-23 DOI: 10.7554/eLife.104762

Luuk Croijmans, Fogelina Cuperus, Dirk F van Apeldoorn, Felix J J A Bianchi, Walter A H Rossing, Erik H Poelman

{"title":"Strip cropping shows promising increases in ground beetle community diversity compared to monocultures.","authors":"Luuk Croijmans, Fogelina Cuperus, Dirk F van Apeldoorn, Felix J J A Bianchi, Walter A H Rossing, Erik H Poelman","doi":"10.7554/eLife.104762","DOIUrl":"10.7554/eLife.104762","url":null,"abstract":"Global biodiversity is declining at an unprecedented rate, with agriculture as one of the major drivers. There is mounting evidence that intercropping can increase insect biodiversity while maintaining or increasing yield. Yet, intercropping is often considered impractical for mechanized farming systems. Strip cropping is a type of intercropping that is compatible with standard farm machinery and has been pioneered by Dutch farmers since 2014. Here, we present ground beetle data from four organically managed experimental farms across four years. Ground beetles are sensitive to changes in habitats and disturbances, and hold keystone positions in agroecosystem food webs. We show that strip cropping systems can enhance ground beetle biodiversity, while other studies showed that these increases have been achieved without incurring major yield loss. Strip-cropped fields had on average 15% more ground beetle species and 30% more individuals than monocultural fields. The higher ground beetle richness in strip crops was explained by the merger of crop-related ground beetle communities, rather than by ground beetle species unique to strip cropping systems. The increase in field-level beetle species richness in organic agriculture through strip cropping approached increases found for other readily deployed biodiversity conservation methods, like shifting from conventional to organic agriculture (+19% -+23%). This indicates that strip cropping is a potentially useful tool supporting ground beetle biodiversity in agricultural fields without compromising food production.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130413","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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