Kang Rui Garrick Lim, Selina K. Kaiser, Connor J. Herring, Taek-Seung Kim, Marta Perxés Perich, Sadhya Garg, Christopher R. O’Connor, Michael Aizenberg, Jessi E. S. van der Hoeven, Christian Reece, Matthew M. Montemore, Joanna Aizenberg
Despite the broad catalytic relevance of metal–support interfaces, controlling their chemical nature, the interfacial contact perimeter (exposed to reactants), and consequently, their contributions to overall catalytic reactivity, remains challenging, as the nanoparticle and support characteristics are interdependent when catalysts are prepared by impregnation. Here, we decoupled both characteristics by using a raspberry-colloid-templating strategy that yields partially embedded PdAu nanoparticles within well-defined SiO 2 or TiO 2 supports, thereby increasing the metal–support interfacial contact compared to nonembedded catalysts that we prepared by attaching the same nanoparticles onto support surfaces. Between nonembedded PdAu/SiO 2 and PdAu/TiO 2 , we identified a support effect resulting in a 1.4-fold higher activity of PdAu/TiO 2 than PdAu/SiO 2 for benzaldehyde hydrogenation. Notably, partial nanoparticle embedding in the TiO 2 raspberry-colloid-templated support increased the metal–support interfacial perimeter and consequently, the number of Au/TiO 2 interfacial sites by 5.4-fold, which further enhanced the activity of PdAu/TiO 2 by an additional 4.1-fold. Theoretical calculations and in situ surface-sensitive desorption analyses reveal facile benzaldehyde binding at the Au/TiO 2 interface and at Pd ensembles on the nanoparticle surface, explaining the connection between the number of Au/TiO 2 interfacial sites (via the metal–support interfacial perimeter) and catalytic activity. Our results demonstrate partial nanoparticle embedding as a synthetic strategy to produce thermocatalytically stable catalysts and increase the number of catalytically active Au/TiO 2 interfacial sites to augment catalytic contributions arising from metal–support interfaces.
{"title":"Partial PdAu nanoparticle embedding into TiO 2 support accentuates catalytic contributions from the Au/TiO 2 interface","authors":"Kang Rui Garrick Lim, Selina K. Kaiser, Connor J. Herring, Taek-Seung Kim, Marta Perxés Perich, Sadhya Garg, Christopher R. O’Connor, Michael Aizenberg, Jessi E. S. van der Hoeven, Christian Reece, Matthew M. Montemore, Joanna Aizenberg","doi":"10.1073/pnas.2422628122","DOIUrl":"https://doi.org/10.1073/pnas.2422628122","url":null,"abstract":"Despite the broad catalytic relevance of metal–support interfaces, controlling their chemical nature, the interfacial contact perimeter (exposed to reactants), and consequently, their contributions to overall catalytic reactivity, remains challenging, as the nanoparticle and support characteristics are interdependent when catalysts are prepared by impregnation. Here, we decoupled both characteristics by using a raspberry-colloid-templating strategy that yields partially embedded PdAu nanoparticles within well-defined SiO <jats:sub>2</jats:sub> or TiO <jats:sub>2</jats:sub> supports, thereby increasing the metal–support interfacial contact compared to nonembedded catalysts that we prepared by attaching the same nanoparticles onto support surfaces. Between nonembedded PdAu/SiO <jats:sub>2</jats:sub> and PdAu/TiO <jats:sub>2</jats:sub> , we identified a support effect resulting in a 1.4-fold higher activity of PdAu/TiO <jats:sub>2</jats:sub> than PdAu/SiO <jats:sub>2</jats:sub> for benzaldehyde hydrogenation. Notably, partial nanoparticle embedding in the TiO <jats:sub>2</jats:sub> raspberry-colloid-templated support increased the metal–support interfacial perimeter and consequently, the number of Au/TiO <jats:sub>2</jats:sub> interfacial sites by 5.4-fold, which further enhanced the activity of PdAu/TiO <jats:sub>2</jats:sub> by an additional 4.1-fold. Theoretical calculations and in situ surface-sensitive desorption analyses reveal facile benzaldehyde binding at the Au/TiO <jats:sub>2</jats:sub> interface and at Pd ensembles on the nanoparticle surface, explaining the connection between the number of Au/TiO <jats:sub>2</jats:sub> interfacial sites (via the metal–support interfacial perimeter) and catalytic activity. Our results demonstrate partial nanoparticle embedding as a synthetic strategy to produce thermocatalytically stable catalysts and increase the number of catalytically active Au/TiO <jats:sub>2</jats:sub> interfacial sites to augment catalytic contributions arising from metal–support interfaces.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"75 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William P. J. Smith, Ewan Armstrong-Bond, Katharine Z. Coyte, Christopher G. Knight, Marek Basler, Michael A. Brockhurst
The bacterial type 6 secretion system (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolve de novo resistance against T6SS attacks, but resistance is far from universal in natural communities, suggesting key features of T6SS weaponry may act to limit its evolution. Here, we combine ecoevolutionary modeling and experimental evolution to examine how toxin type and multiplicity in Acinetobacter baylyi attackers shape resistance evolution in susceptible Escherichia coli competitors. In both our models and experiments, we find that combinations of multiple distinct toxins limit resistance evolution by creating genetic bottlenecks, driving resistant lineages extinct before they can reach high frequency. We also show that, paradoxically, single-toxin attackers can drive the evolution of cross-resistance, protecting bacteria against unfamiliar toxin combinations, even though such evolutionary pathways were inaccessible against multitoxin attackers. Our findings indicate that, comparable to antimicrobial and anticancer combination therapies, multitoxin T6SS arsenals function to limit resistance evolution in competing microbes. This helps us to understand why T6SSs remain widespread and effective weapons in microbial communities, and why many T6SS-armed bacteria encode functionally diverse anticompetitor toxins.
{"title":"Multiplicity of type 6 secretion system toxins limits the evolution of resistance","authors":"William P. J. Smith, Ewan Armstrong-Bond, Katharine Z. Coyte, Christopher G. Knight, Marek Basler, Michael A. Brockhurst","doi":"10.1073/pnas.2416700122","DOIUrl":"https://doi.org/10.1073/pnas.2416700122","url":null,"abstract":"The bacterial type 6 secretion system (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolve de novo resistance against T6SS attacks, but resistance is far from universal in natural communities, suggesting key features of T6SS weaponry may act to limit its evolution. Here, we combine ecoevolutionary modeling and experimental evolution to examine how toxin type and multiplicity in <jats:italic>Acinetobacter baylyi</jats:italic> attackers shape resistance evolution in susceptible <jats:italic>Escherichia coli</jats:italic> competitors. In both our models and experiments, we find that combinations of multiple distinct toxins limit resistance evolution by creating genetic bottlenecks, driving resistant lineages extinct before they can reach high frequency. We also show that, paradoxically, single-toxin attackers can drive the evolution of cross-resistance, protecting bacteria against unfamiliar toxin combinations, even though such evolutionary pathways were inaccessible against multitoxin attackers. Our findings indicate that, comparable to antimicrobial and anticancer combination therapies, multitoxin T6SS arsenals function to limit resistance evolution in competing microbes. This helps us to understand why T6SSs remain widespread and effective weapons in microbial communities, and why many T6SS-armed bacteria encode functionally diverse anticompetitor toxins.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"75 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bang Ni, Lu Xiao, Da Lin, Tian-Lun Zhang, Qi Zhang, Yanjie Liu, Quan Chen, Dong Zhu, Haifeng Qian, Matthias C. Rillig, Yong-Guan Zhu
Pesticide application is essential for stabilizing agricultural production. However, the effects of increasing pesticide diversity on soil microbial functions remain unclear, particularly under varying nitrogen (N) fertilizer management practices. In this study, we investigated the stochasticity of soil microbes and multitrophic networks through amplicon sequencing, assessed soil community functions related to carbon (C), N, phosphorus (P), and sulfur (S) cycling, and characterized the dominant bacterial life history strategies via metagenomics along a gradient of increasing pesticide diversity under two N addition levels. Our findings show that higher pesticide diversity enriches the abundance of bacterial specialists and opportunists capable of degrading or resisting pesticides, reducing the proportion of bacterial generalists in the absence of N addition. These shifts can complicate multitrophic microbial networks. Under increased pesticide diversity, selective pressure may drive bacteria to streamline their average genome size to conserve energy while enhancing C, N, P, and S metabolic capacities, thus accelerating soil nutrient loss. In comparison, N addition was found to reduce bacterial niche differentiation at higher pesticide diversity, mitigating the impacts of network complexity and functional traits associated with pesticide diversity, ultimately alleviating soil nutrient loss. Our results reveal the contrasting impacts of pesticide diversity on microbial functions under different N input scenarios and emphasize that strategic N fertilizer management can mitigate the ecological effects of pesticide use in agricultural systems.
{"title":"Increasing pesticide diversity impairs soil microbial functions","authors":"Bang Ni, Lu Xiao, Da Lin, Tian-Lun Zhang, Qi Zhang, Yanjie Liu, Quan Chen, Dong Zhu, Haifeng Qian, Matthias C. Rillig, Yong-Guan Zhu","doi":"10.1073/pnas.2419917122","DOIUrl":"https://doi.org/10.1073/pnas.2419917122","url":null,"abstract":"Pesticide application is essential for stabilizing agricultural production. However, the effects of increasing pesticide diversity on soil microbial functions remain unclear, particularly under varying nitrogen (N) fertilizer management practices. In this study, we investigated the stochasticity of soil microbes and multitrophic networks through amplicon sequencing, assessed soil community functions related to carbon (C), N, phosphorus (P), and sulfur (S) cycling, and characterized the dominant bacterial life history strategies via metagenomics along a gradient of increasing pesticide diversity under two N addition levels. Our findings show that higher pesticide diversity enriches the abundance of bacterial specialists and opportunists capable of degrading or resisting pesticides, reducing the proportion of bacterial generalists in the absence of N addition. These shifts can complicate multitrophic microbial networks. Under increased pesticide diversity, selective pressure may drive bacteria to streamline their average genome size to conserve energy while enhancing C, N, P, and S metabolic capacities, thus accelerating soil nutrient loss. In comparison, N addition was found to reduce bacterial niche differentiation at higher pesticide diversity, mitigating the impacts of network complexity and functional traits associated with pesticide diversity, ultimately alleviating soil nutrient loss. Our results reveal the contrasting impacts of pesticide diversity on microbial functions under different N input scenarios and emphasize that strategic N fertilizer management can mitigate the ecological effects of pesticide use in agricultural systems.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"28 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen Mok, Huey Liu, Didem Ağaç Çobanoğlu, Nana-Ama A. S. Anang, James J. Mancuso, E. John Wherry, James P. Allison
The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional Tcf7 - or Tox -knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.
{"title":"Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1","authors":"Stephen Mok, Huey Liu, Didem Ağaç Çobanoğlu, Nana-Ama A. S. Anang, James J. Mancuso, E. John Wherry, James P. Allison","doi":"10.1073/pnas.2418985122","DOIUrl":"https://doi.org/10.1073/pnas.2418985122","url":null,"abstract":"The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional <jats:italic>Tcf7</jats:italic> - or <jats:italic>Tox</jats:italic> -knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"24 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zheng Wu, Eric A. Cardona, Jesse A. Cohn, Jonathan T. Pierce
While traditionally studied for their proapoptotic functions in activating the caspase, research suggests BH3-only proteins also have other roles such as mitochondrial dynamics regulation. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans , promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the role of neuronal BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.
{"title":"Nonapoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans","authors":"Zheng Wu, Eric A. Cardona, Jesse A. Cohn, Jonathan T. Pierce","doi":"10.1073/pnas.2407909122","DOIUrl":"https://doi.org/10.1073/pnas.2407909122","url":null,"abstract":"While traditionally studied for their proapoptotic functions in activating the caspase, research suggests BH3-only proteins also have other roles such as mitochondrial dynamics regulation. Here, we find that EGL-1, the BH3-only protein in <jats:italic>Caenorhabditis elegans</jats:italic> , promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the role of neuronal BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"16 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Understanding the role of metabolic processes during inner ear development is essential for identifying targets for hair cell (HC) regeneration, as metabolic choices play a crucial role in cell proliferation and differentiation. Among the metabolic processes, growing evidence shows that glucose metabolism is closely related to organ development. However, the role of glucose metabolism in mammalian inner ear development and HC regeneration remains unclear. In this study, we found that glycolytic metabolism is highly active during mouse and human cochlear prosensory epithelium expansion. Using mouse cochlear organoids, we revealed that glycolytic activity in cochlear nonsensory epithelial cells was predominantly dominated by pyruvate kinase M2 (PKM2). Deletion of PKM2 induced a metabolic switch from glycolysis to oxidative phosphorylation, impairing cochlear organoid formation. Furthermore, conditional loss of PKM2 in cochlear progenitors hindered sensory epithelium morphogenesis, as demonstrated in PKM2 knockout mice. Mechanistically, pyruvate is generated by PKM2 catalysis and then converted into lactate, which then lactylates histone H3, regulating the transcription of key genes for cochlear development. Specifically, accumulated lactate causes histone H3 lactylation at lysine 9 (H3K9la), upregulating the expression of Sox family transcription factors through epigenetic modification. Moreover, overexpression of PKM2 in supporting cells (SCs) triggered metabolism reprogramming and enhanced HC generation in cultured mouse and human cochlear explants. Our findings uncover a molecular mechanism of sensory epithelium formation driven by glycolysis-lactate flow and suggest unique approaches for mammalian HC regeneration.
{"title":"PKM2 controls cochlear development through lactate-dependent transcriptional regulation","authors":"Mingxuan Wu, Gaogan Jia, Yaoqian Liu, Yiyun Lou, Yunjie Li, Mingyu Xia, Huawei Li, Wenyan Li","doi":"10.1073/pnas.2410829122","DOIUrl":"https://doi.org/10.1073/pnas.2410829122","url":null,"abstract":"Understanding the role of metabolic processes during inner ear development is essential for identifying targets for hair cell (HC) regeneration, as metabolic choices play a crucial role in cell proliferation and differentiation. Among the metabolic processes, growing evidence shows that glucose metabolism is closely related to organ development. However, the role of glucose metabolism in mammalian inner ear development and HC regeneration remains unclear. In this study, we found that glycolytic metabolism is highly active during mouse and human cochlear prosensory epithelium expansion. Using mouse cochlear organoids, we revealed that glycolytic activity in cochlear nonsensory epithelial cells was predominantly dominated by pyruvate kinase M2 (PKM2). Deletion of PKM2 induced a metabolic switch from glycolysis to oxidative phosphorylation, impairing cochlear organoid formation. Furthermore, conditional loss of PKM2 in cochlear progenitors hindered sensory epithelium morphogenesis, as demonstrated in PKM2 knockout mice. Mechanistically, pyruvate is generated by PKM2 catalysis and then converted into lactate, which then lactylates histone H3, regulating the transcription of key genes for cochlear development. Specifically, accumulated lactate causes histone H3 lactylation at lysine 9 (H3K9la), upregulating the expression of <jats:italic>Sox</jats:italic> family transcription factors through epigenetic modification. Moreover, overexpression of PKM2 in supporting cells (SCs) triggered metabolism reprogramming and enhanced HC generation in cultured mouse and human cochlear explants. Our findings uncover a molecular mechanism of sensory epithelium formation driven by glycolysis-lactate flow and suggest unique approaches for mammalian HC regeneration.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"19 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carlos Ancatén-González, Rodrigo C. Meza, Naileth Gonzalez-Sanabria, Ignacio Segura, Alejandro Alcaino, Antonio Peña-Pichicoi, Ramón Latorre, Chiayu Q. Chiu, Andrés E. Chávez
BK channels can control neuronal function, but their functional relevance in activity-dependent changes of synaptic function remains elusive. Here, we report that repetitive low-frequency stimulation activates BK channels through 12(S)HPETE, an arachidonic acid metabolite, produced downstream of postsynaptic metabotropic glutamate receptors (mGluRs) to trigger long-term depression (LTD) at CA3–CA1 synapses in hippocampal slices from P7–P10 mice. Activation of BK channels is subunit specific, as paxilline but not iberiotoxin blocked mGluR-LTD. Also, 12(S)HPETE does not change the electrophysiological properties of the BK channel when the BKα subunit is expressed alone but increases the channel open probability when the BKα is coexpressed with the β4-subunit. Our findings reveal an interaction between 12(S)HPETE and BK channels to regulate synaptic strength at central synapses and increase our understanding of the mechanisms underlying mGluR-LTD in the neonatal hippocampus that likely contribute to circuit maturation necessary for learning.
{"title":"BK channels mediate a presynaptic form of mGluR-LTD in the neonatal hippocampus","authors":"Carlos Ancatén-González, Rodrigo C. Meza, Naileth Gonzalez-Sanabria, Ignacio Segura, Alejandro Alcaino, Antonio Peña-Pichicoi, Ramón Latorre, Chiayu Q. Chiu, Andrés E. Chávez","doi":"10.1073/pnas.2411506122","DOIUrl":"https://doi.org/10.1073/pnas.2411506122","url":null,"abstract":"BK channels can control neuronal function, but their functional relevance in activity-dependent changes of synaptic function remains elusive. Here, we report that repetitive low-frequency stimulation activates BK channels through 12(S)HPETE, an arachidonic acid metabolite, produced downstream of postsynaptic metabotropic glutamate receptors (mGluRs) to trigger long-term depression (LTD) at CA3–CA1 synapses in hippocampal slices from P7–P10 mice. Activation of BK channels is subunit specific, as paxilline but not iberiotoxin blocked mGluR-LTD. Also, 12(S)HPETE does not change the electrophysiological properties of the BK channel when the BKα subunit is expressed alone but increases the channel open probability when the BKα is coexpressed with the β4-subunit. Our findings reveal an interaction between 12(S)HPETE and BK channels to regulate synaptic strength at central synapses and increase our understanding of the mechanisms underlying mGluR-LTD in the neonatal hippocampus that likely contribute to circuit maturation necessary for learning.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"44 9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peijian Shi, Yi Li, Zhi Li, Xin Jiang, Jie Yan, Rui Zhou, Yi Qin, Yifan Lin, Jingran Huang, Bodong Tan, Yinan Wang, Tongqi Wen, Beilin Ye, Chunyan Ling, Junhua Luan, Zhe Shen, Biao Ding, Qiang Li, Tianxiang Zheng, Weili Ren, Tianlong Zhang, Yang Ren, Yunbo Zhong, C. T. Liu, Huajian Gao, Yuntian Zhu
The strength−ductility trade-off exists ubiquitously, especially in brittle intermetallic-containing multiple principal element alloys (MPEAs), where the intermetallic phases often induce premature failure leading to severe ductility reduction. Hierarchical heterogeneities represent a promising microstructural solution to achieve simultaneous strength−ductility enhancement. However, it remains fundamentally challenging to tailor hierarchical heterostructures using conventional methods, which often rely on costly and time-consuming processing. Here, we report a multiscale microstructural inheritance and refinement strategy to process “structural hierarchy precursors” in as-cast heterogeneous Al 0.7 CoCrFeNi MPEAs, which lead directly to a hierarchical hetero-lamellar structure (HLS) after simple rolling and annealing. Interestingly, it takes only 10 min of annealing time, two orders of magnitude less than that required to render the state-of-the-art properties during conventional processing of Al 0.7 CoCrFeNi, for us to achieve record-high strength−ductility combinations via the hierarchical HLS design that sequentially stimulates multiple unusual deformation and reinforcement mechanisms. In particular, the HLS-enabled high hetero-deformation-induced (HDI) internal stress triggers profuse <111>-type dislocations on over five independent slip systems in the supposedly brittle intermetallic phase and activates extensive stacking faults (SFs) and nanotwinning in the adjoining soft phase with a rather high SF energy. These unexpected, dynamically reinforcing hetero-deformation mechanisms across multiple length scales facilitate high sustained HDI strain hardening, along with a salient microcrack-mediated extrinsic ductilization effect, suggesting that the proposed microstructural inheritance and refinement strategy provides an efficient, fast, and low-cost approach to overcome the strength−ductility trade-off in a broad range of structural materials.
{"title":"Strong, ductile, and hierarchical hetero-lamellar-structured alloys through microstructural inheritance and refinement","authors":"Peijian Shi, Yi Li, Zhi Li, Xin Jiang, Jie Yan, Rui Zhou, Yi Qin, Yifan Lin, Jingran Huang, Bodong Tan, Yinan Wang, Tongqi Wen, Beilin Ye, Chunyan Ling, Junhua Luan, Zhe Shen, Biao Ding, Qiang Li, Tianxiang Zheng, Weili Ren, Tianlong Zhang, Yang Ren, Yunbo Zhong, C. T. Liu, Huajian Gao, Yuntian Zhu","doi":"10.1073/pnas.2409317121","DOIUrl":"https://doi.org/10.1073/pnas.2409317121","url":null,"abstract":"The strength−ductility trade-off exists ubiquitously, especially in brittle intermetallic-containing multiple principal element alloys (MPEAs), where the intermetallic phases often induce premature failure leading to severe ductility reduction. Hierarchical heterogeneities represent a promising microstructural solution to achieve simultaneous strength−ductility enhancement. However, it remains fundamentally challenging to tailor hierarchical heterostructures using conventional methods, which often rely on costly and time-consuming processing. Here, we report a multiscale microstructural inheritance and refinement strategy to process “structural hierarchy precursors” in as-cast heterogeneous Al <jats:sub>0.7</jats:sub> CoCrFeNi MPEAs, which lead directly to a hierarchical hetero-lamellar structure (HLS) after simple rolling and annealing. Interestingly, it takes only 10 min of annealing time, two orders of magnitude less than that required to render the state-of-the-art properties during conventional processing of Al <jats:sub>0.7</jats:sub> CoCrFeNi, for us to achieve record-high strength−ductility combinations via the hierarchical HLS design that sequentially stimulates multiple unusual deformation and reinforcement mechanisms. In particular, the HLS-enabled high hetero-deformation-induced (HDI) internal stress triggers profuse <111>-type dislocations on over five independent slip systems in the supposedly brittle intermetallic phase and activates extensive stacking faults (SFs) and nanotwinning in the adjoining soft phase with a rather high SF energy. These unexpected, dynamically reinforcing hetero-deformation mechanisms across multiple length scales facilitate high sustained HDI strain hardening, along with a salient microcrack-mediated extrinsic ductilization effect, suggesting that the proposed microstructural inheritance and refinement strategy provides an efficient, fast, and low-cost approach to overcome the strength−ductility trade-off in a broad range of structural materials.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steven Schulz, Timothy J. C. Tan, Nicholas C. Wu, Shenshen Wang
The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence–function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype. It is unclear to what extent local topography of a real epistatic landscape represents its global shape. Here, we demonstrate that epistatic landscapes can be heterogeneously rugged and this heterogeneity may render biomolecules more evolvable. By characterizing a multipeaked fitness landscape of a SARS-CoV-2 antibody mutant library, we show that heterogeneous ruggedness arises from sparse epistatic hotspots, whose mutation impacts the fitness effect of numerous sequence sites. Surprisingly, mutating an epistatic hotspot may enhance, rather than reduce, the accessibility of the fittest genotype, while increasing the overall ruggedness. Further, migratory constraints in real space alleviate mutational constraints in sequence space, which not only diversify direct paths taken but may also turn a road-blocking fitness peak into a stepping stone leading toward the global optimum. Our results suggest that a hierarchy of epistatic hotspots may organize the fitness landscape in such a way that path-orienting ruggedness confers global smoothness.
{"title":"Epistatic hotspots organize antibody fitness landscape and boost evolvability","authors":"Steven Schulz, Timothy J. C. Tan, Nicholas C. Wu, Shenshen Wang","doi":"10.1073/pnas.2413884122","DOIUrl":"https://doi.org/10.1073/pnas.2413884122","url":null,"abstract":"The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence–function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype. It is unclear to what extent local topography of a real epistatic landscape represents its global shape. Here, we demonstrate that epistatic landscapes can be heterogeneously rugged and this heterogeneity may render biomolecules more evolvable. By characterizing a multipeaked fitness landscape of a SARS-CoV-2 antibody mutant library, we show that heterogeneous ruggedness arises from sparse epistatic hotspots, whose mutation impacts the fitness effect of numerous sequence sites. Surprisingly, mutating an epistatic hotspot may enhance, rather than reduce, the accessibility of the fittest genotype, while increasing the overall ruggedness. Further, migratory constraints in real space alleviate mutational constraints in sequence space, which not only diversify direct paths taken but may also turn a road-blocking fitness peak into a stepping stone leading toward the global optimum. Our results suggest that a hierarchy of epistatic hotspots may organize the fitness landscape in such a way that path-orienting ruggedness confers global smoothness.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Swaksha Rachuri, Binod Nepal, Anurag Shukla, Aarti Ramanathan, Joanne M. Morrisey, Thomas Daly, Michael W. Mather, Lawrence W. Bergman, Sandhya Kortagere, Akhil B. Vaidya
Among new antimalarials discovered over the past decade are multiple chemical scaffolds that target Plasmodium falciparum P-type ATPase ( Pf ATP4). This essential protein is a Na + pump responsible for the maintenance of Na + homeostasis. Pf ATP4 belongs to the type two-dimensional (2D) subfamily of P-type ATPases, for which no structures have been determined. To gain better insight into the structure/function relationship of this validated drug target, we generated a homology model of Pf ATP4 based on sarco/endoplasmic reticulum Ca 2+ ATPase, a P2A-type ATPase, and refined the model using molecular dynamics in its explicit membrane environment. This model predicted several residues in Pf ATP4 critical for its function, as well as those that impart resistance to various Pf ATP4 inhibitors. To validate our model, we developed a genetic system involving merodiploid states of Pf ATP4 in which the endogenous gene was conditionally expressed, and the second allele was mutated to assess its effect on the parasite. Our model predicted residues involved in Na + coordination as well as the phosphorylation cycle of Pf ATP4. Phenotypic characterization of these mutants involved assessment of parasite growth, localization of mutated Pf ATP4, response to treatment with known Pf ATP4 inhibitors, and evaluation of the downstream consequences of Na + influx. Our results were consistent with modeled predictions of the essentiality of the critical residues. Additionally, our approach confirmed the phenotypic consequences of resistance-associated mutations as well as a potential structural basis for the fitness cost associated with some mutations. Taken together, our approach provides a means to explore the structure/function relationship of essential genes in haploid organisms.
{"title":"Mutational analysis of an antimalarial drug target, Pf ATP4","authors":"Swaksha Rachuri, Binod Nepal, Anurag Shukla, Aarti Ramanathan, Joanne M. Morrisey, Thomas Daly, Michael W. Mather, Lawrence W. Bergman, Sandhya Kortagere, Akhil B. Vaidya","doi":"10.1073/pnas.2403689122","DOIUrl":"https://doi.org/10.1073/pnas.2403689122","url":null,"abstract":"Among new antimalarials discovered over the past decade are multiple chemical scaffolds that target <jats:italic>Plasmodium falciparum</jats:italic> P-type ATPase ( <jats:italic>Pf</jats:italic> ATP4). This essential protein is a Na <jats:sup>+</jats:sup> pump responsible for the maintenance of Na <jats:sup>+</jats:sup> homeostasis. <jats:italic>Pf</jats:italic> ATP4 belongs to the type two-dimensional (2D) subfamily of P-type ATPases, for which no structures have been determined. To gain better insight into the structure/function relationship of this validated drug target, we generated a homology model of <jats:italic>Pf</jats:italic> ATP4 based on sarco/endoplasmic reticulum Ca <jats:sup>2+</jats:sup> ATPase, a P2A-type ATPase, and refined the model using molecular dynamics in its explicit membrane environment. This model predicted several residues in <jats:italic>Pf</jats:italic> ATP4 critical for its function, as well as those that impart resistance to various <jats:italic>Pf</jats:italic> ATP4 inhibitors. To validate our model, we developed a genetic system involving merodiploid states of <jats:italic>Pf</jats:italic> ATP4 in which the endogenous gene was conditionally expressed, and the second allele was mutated to assess its effect on the parasite. Our model predicted residues involved in Na <jats:sup>+</jats:sup> coordination as well as the phosphorylation cycle of <jats:italic>Pf</jats:italic> ATP4. Phenotypic characterization of these mutants involved assessment of parasite growth, localization of mutated <jats:italic>Pf</jats:italic> ATP4, response to treatment with known <jats:italic>Pf</jats:italic> ATP4 inhibitors, and evaluation of the downstream consequences of Na <jats:sup>+</jats:sup> influx. Our results were consistent with modeled predictions of the essentiality of the critical residues. Additionally, our approach confirmed the phenotypic consequences of resistance-associated mutations as well as a potential structural basis for the fitness cost associated with some mutations. Taken together, our approach provides a means to explore the structure/function relationship of essential genes in haploid organisms.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"49 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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