Sarah Hamada, Jack Beadle, Alice Koenig, Basile Sugranes, John Ferdinand, Chien-Chia Chen, Virginie Mathias, Maeva Eloudzeri, Thomas Barba, Helena Paidassi, Carole Saison, Valérie Dubois, Emmanuel Morelon, Thierry Walzer, Antoine Marcais, Maud Rabeyrin, Marion Rabant, Patrick Bruneval, Maud Racapé, Jean Paul Duong Van Huyen, Menna R. Clatworthy, Candice Roufosse, Olivier Thaunat
The inability of graft endothelial cells to deliver HLA-I-dependent inhibitory signals to recipient natural killer (NK) cells (missing self, MS), drives donor-specific antibody-independent microvascular inflammation (MVI), leading to graft failure. This study aimed to elucidate the signaling pathways involved in MS-associated NK cell activation and explore therapeutic strategies. Analyses of kidney graft biopsies identified calcium signaling pathways and mTOR as a key regulator of MS-induced NK cell activation. Two experimental models were developed to mimic the pathological condition: in vitro cocultures of human NK cells with allogeneic microvascular endothelial cells and a murine heart transplantation model. These models showed that while calcineurin inhibitor (CNI) alone had a limited impact, combining CNI with mTOR inhibitors (mTORinh) synergistically reduced NK cell activation and endothelial damage. In a pilot clinical study involving 50 renal transplant recipients with MS-associated NK cell–mediated microvascular inflammation, patients who tolerated mTORinh introduced on top of CNI at diagnosis demonstrated reduced MVI lesions and improved graft survival compared to a historical cohort left on CNI and mycophenolate mofetil. This translational study identifies mTOR inhibition as a pivotal adjunct to CNI in mitigating MS-associated NK cell–mediated inflammation, potentially improving long-term graft outcomes.
{"title":"Dual inhibition of mTOR and calcineurin pathways mitigates missing self–induced NK cell–mediated microvascular rejection","authors":"Sarah Hamada, Jack Beadle, Alice Koenig, Basile Sugranes, John Ferdinand, Chien-Chia Chen, Virginie Mathias, Maeva Eloudzeri, Thomas Barba, Helena Paidassi, Carole Saison, Valérie Dubois, Emmanuel Morelon, Thierry Walzer, Antoine Marcais, Maud Rabeyrin, Marion Rabant, Patrick Bruneval, Maud Racapé, Jean Paul Duong Van Huyen, Menna R. Clatworthy, Candice Roufosse, Olivier Thaunat","doi":"10.1073/pnas.2516594123","DOIUrl":"https://doi.org/10.1073/pnas.2516594123","url":null,"abstract":"The inability of graft endothelial cells to deliver HLA-I-dependent inhibitory signals to recipient natural killer (NK) cells (missing self, MS), drives donor-specific antibody-independent microvascular inflammation (MVI), leading to graft failure. This study aimed to elucidate the signaling pathways involved in MS-associated NK cell activation and explore therapeutic strategies. Analyses of kidney graft biopsies identified calcium signaling pathways and mTOR as a key regulator of MS-induced NK cell activation. Two experimental models were developed to mimic the pathological condition: in vitro cocultures of human NK cells with allogeneic microvascular endothelial cells and a murine heart transplantation model. These models showed that while calcineurin inhibitor (CNI) alone had a limited impact, combining CNI with mTOR inhibitors (mTORinh) synergistically reduced NK cell activation and endothelial damage. In a pilot clinical study involving 50 renal transplant recipients with MS-associated NK cell–mediated microvascular inflammation, patients who tolerated mTORinh introduced on top of CNI at diagnosis demonstrated reduced MVI lesions and improved graft survival compared to a historical cohort left on CNI and mycophenolate mofetil. This translational study identifies mTOR inhibition as a pivotal adjunct to CNI in mitigating MS-associated NK cell–mediated inflammation, potentially improving long-term graft outcomes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"4 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160993","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}
Yulong Duan, Suraya Kazi, Dongqing Lin, Longzhu Liu, Magnus P. Jonsson
Plasmonic resonances in nanostructured conducting polymers provide a compelling route to actively tunable nanophotonics and metasurfaces, owing to their ability to be dynamically modulated through electrochemical doping. Although their lower mobility limits resonance quality compared to noble metal plasmonics, we experimentally demonstrate that the resonances of conducting polymer nanoantennas can effectively couple to epsilon-near-zero (ENZ) mode of an underlying thin indium tin oxide layer, in a manner analogous to noble metal plasmon–ENZ interactions. We show that the coupling strength can be modulated reversibly via electrical bias or chemical redox control, enabling dynamic tuning of electromagnetic field enhancement in the ENZ layer with a modulation depth exceeding 90%. These findings establish conducting polymer nanoantennas as a versatile platform for reconfigurable ENZ-based photonic systems, paving the way for nanophotonic devices with tunable linear and nonlinear optical functionalities.
{"title":"Electrotunable coupling between an epsilon-near-zero thin film and conducting polymer nanoantennas","authors":"Yulong Duan, Suraya Kazi, Dongqing Lin, Longzhu Liu, Magnus P. Jonsson","doi":"10.1073/pnas.2517549123","DOIUrl":"https://doi.org/10.1073/pnas.2517549123","url":null,"abstract":"Plasmonic resonances in nanostructured conducting polymers provide a compelling route to actively tunable nanophotonics and metasurfaces, owing to their ability to be dynamically modulated through electrochemical doping. Although their lower mobility limits resonance quality compared to noble metal plasmonics, we experimentally demonstrate that the resonances of conducting polymer nanoantennas can effectively couple to epsilon-near-zero (ENZ) mode of an underlying thin indium tin oxide layer, in a manner analogous to noble metal plasmon–ENZ interactions. We show that the coupling strength can be modulated reversibly via electrical bias or chemical redox control, enabling dynamic tuning of electromagnetic field enhancement in the ENZ layer with a modulation depth exceeding 90%. These findings establish conducting polymer nanoantennas as a versatile platform for reconfigurable ENZ-based photonic systems, paving the way for nanophotonic devices with tunable linear and nonlinear optical functionalities.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"113 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161083","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}
Sung Chul Park, Livia D. S. Oster, Jacob Golan, Jillian Myers, Anne Pringle, Milton T. Drott, Nancy P. Keller
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are secondary metabolites produced by bacteria, plants, animals, and fungi. Canonical fungal RiPP precursors possess a leader sequence cleaved during maturation. The first RiPPs described in fungi were the MSDIN-derived peptides responsible for the toxicity of lethal Amanita mushrooms. In this study, we upend the conventional understanding of fungal RiPPs, discovering a subclass that has diversified and lacks a leader sequence, an empirical example of leaderless RiPPs in fungi. We use a combinatorial analysis of NMR and MS/MS with an updated bioinformatic pipeline to pair MSDIN genes to leaderless peptides in Amanita phalloides , a European species spreading in California. Leaderless MSDIN transcripts are expressed several orders of magnitude more than most canonical MSDINs, with significantly higher expression in invasive populations. Our results redefine the understanding of fungal RiPP architectures and suggest differential regulation of non-canonical RiPPs may contribute to the invasion biology of the world’s deadliest mushroom.
{"title":"Leaderless RiPPs expand the repertoire of fungal secondary metabolites","authors":"Sung Chul Park, Livia D. S. Oster, Jacob Golan, Jillian Myers, Anne Pringle, Milton T. Drott, Nancy P. Keller","doi":"10.1073/pnas.2529748123","DOIUrl":"https://doi.org/10.1073/pnas.2529748123","url":null,"abstract":"Ribosomally synthesized and post-translationally modified peptides (RiPPs) are secondary metabolites produced by bacteria, plants, animals, and fungi. Canonical fungal RiPP precursors possess a leader sequence cleaved during maturation. The first RiPPs described in fungi were the MSDIN-derived peptides responsible for the toxicity of lethal <jats:italic toggle=\"yes\">Amanita</jats:italic> mushrooms. In this study, we upend the conventional understanding of fungal RiPPs, discovering a subclass that has diversified and lacks a leader sequence, an empirical example of leaderless RiPPs in fungi. We use a combinatorial analysis of NMR and MS/MS with an updated bioinformatic pipeline to pair MSDIN genes to leaderless peptides in <jats:italic toggle=\"yes\">Amanita phalloides</jats:italic> , a European species spreading in California. Leaderless MSDIN transcripts are expressed several orders of magnitude more than most canonical MSDINs, with significantly higher expression in invasive populations. Our results redefine the understanding of fungal RiPP architectures and suggest differential regulation of non-canonical RiPPs may contribute to the invasion biology of the world’s deadliest mushroom.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"33 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160982","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}
Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a fertile ground for uncovering new enzymatic chemistry and structural complexity. Here, we describe minviopeptin, an unusual ADP-ribosylated triceptide accessed through heterologous expression of a cryptic biosynthetic gene cluster. Structural and functional analyses reveal a combination of crosslinking, ADP-ribosylation, and oxidative peptide cleavage, underscoring the capacity of RiPP pathways to generate densely functionalized molecular scaffolds. By revealing ADP-ribosylation as a previously unrecognized RiPP modification and exposing reactivity within radical SAM and nonheme iron enzymes, this work broadens the landscape of RiPP biosynthetic chemistries and offers opportunities for natural product diversification and peptide engineering.
{"title":"A ribosomally synthesized and posttranslationally modified peptide with ADP-ribosylation","authors":"Sijia Guo, Suze Ma, Lulu Song, Jun Wang, Tonghai Liu, Wupeng Yan, Wei Zhang, Zixin Deng, Wei Ding, Qi Zhang","doi":"10.1073/pnas.2527653123","DOIUrl":"https://doi.org/10.1073/pnas.2527653123","url":null,"abstract":"Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a fertile ground for uncovering new enzymatic chemistry and structural complexity. Here, we describe minviopeptin, an unusual ADP-ribosylated triceptide accessed through heterologous expression of a cryptic biosynthetic gene cluster. Structural and functional analyses reveal a combination of crosslinking, ADP-ribosylation, and oxidative peptide cleavage, underscoring the capacity of RiPP pathways to generate densely functionalized molecular scaffolds. By revealing ADP-ribosylation as a previously unrecognized RiPP modification and exposing reactivity within radical SAM and nonheme iron enzymes, this work broadens the landscape of RiPP biosynthetic chemistries and offers opportunities for natural product diversification and peptide engineering.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"242 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160980","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}
Changyuan Wang, Denis F. Faerberg, Yuka Sekine, Takeaki Ozawa, John J. Tyson, Robert A. Marmion, Stanislav Y. Shvartsman
System identification approaches are commonly used in engineering to infer simple yet predictive models of complex systems from their responses to time-dependent perturbations. Here, we apply this strategy at the whole organism scale, establishing a predictive model of commitment to metamorphosis in Drosophila . At this critical point in animal development, the larva stops feeding and proceeds to take on the adult form. The neuroendocrine circuits governing commitment to metamorphosis assess the growth and patterning programs, eventually triggering the production of systemic hormones that terminate growth and initiate metamorphosis. Previous studies of these circuits relied on relatively static genetic perturbations and starvation experiments. Here, we take advantage of optogenetic approaches in Drosophila to flexibly perturb a key signaling node within the endocrine gland in otherwise undisturbed larvae. We used this approach to infer parameters in a compact mathematical model and demonstrate that it makes accurate predictions of larval commitment to metamorphosis. Our work paves the way for quantitative studies of other juvenile-to-adult transitions, including mammalian puberty, which relies on strikingly similar mechanisms.
{"title":"Optogenetic control of transition to metamorphosis","authors":"Changyuan Wang, Denis F. Faerberg, Yuka Sekine, Takeaki Ozawa, John J. Tyson, Robert A. Marmion, Stanislav Y. Shvartsman","doi":"10.1073/pnas.2524141123","DOIUrl":"https://doi.org/10.1073/pnas.2524141123","url":null,"abstract":"System identification approaches are commonly used in engineering to infer simple yet predictive models of complex systems from their responses to time-dependent perturbations. Here, we apply this strategy at the whole organism scale, establishing a predictive model of commitment to metamorphosis in <jats:italic toggle=\"yes\">Drosophila</jats:italic> . At this critical point in animal development, the larva stops feeding and proceeds to take on the adult form. The neuroendocrine circuits governing commitment to metamorphosis assess the growth and patterning programs, eventually triggering the production of systemic hormones that terminate growth and initiate metamorphosis. Previous studies of these circuits relied on relatively static genetic perturbations and starvation experiments. Here, we take advantage of optogenetic approaches in <jats:italic toggle=\"yes\">Drosophila</jats:italic> to flexibly perturb a key signaling node within the endocrine gland in otherwise undisturbed larvae. We used this approach to infer parameters in a compact mathematical model and demonstrate that it makes accurate predictions of larval commitment to metamorphosis. Our work paves the way for quantitative studies of other juvenile-to-adult transitions, including mammalian puberty, which relies on strikingly similar mechanisms.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"91 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160978","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}
Pub Date : 2026-02-10Epub Date: 2025-02-10DOI: 10.1073/iti0626123
{"title":"In This Issue.","authors":"","doi":"10.1073/iti0626123","DOIUrl":"https://doi.org/10.1073/iti0626123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 6","pages":"eiti0626123"},"PeriodicalIF":9.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150527","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}
Pub Date : 2026-02-10Epub Date: 2026-02-04DOI: 10.1073/pnas.2537439123
Amir AghaKouchak, Annika Hjelmstad, Kasra Khodkar, Debora de Oliveira, Esra Aleisa, Augustina C Alexander, David Lewis Feldman, Temur Khujanazarov, Kaveh Madani, Ali Mirchi, Daniel Placht, Dalal Najib
{"title":"Transboundary water conflicts, cooperation, and pathways forward.","authors":"Amir AghaKouchak, Annika Hjelmstad, Kasra Khodkar, Debora de Oliveira, Esra Aleisa, Augustina C Alexander, David Lewis Feldman, Temur Khujanazarov, Kaveh Madani, Ali Mirchi, Daniel Placht, Dalal Najib","doi":"10.1073/pnas.2537439123","DOIUrl":"https://doi.org/10.1073/pnas.2537439123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 6","pages":"e2537439123"},"PeriodicalIF":9.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119909","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}
Pub Date : 2026-02-10Epub Date: 2026-02-06DOI: 10.1073/pnas.2602205123
{"title":"Correction for Singer, Confronting the inevitable: Harnessing technology to contain systemic scientific fraud.","authors":"","doi":"10.1073/pnas.2602205123","DOIUrl":"https://doi.org/10.1073/pnas.2602205123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 6","pages":"e2602205123"},"PeriodicalIF":9.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132993","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}
Pub Date : 2026-02-10Epub Date: 2026-02-02DOI: 10.1073/pnas.2600481123
{"title":"Correction for Ajourlou et al., Upper mantle temperatures illuminate the Iceland hotspot track and understanding of ice-Earth interactions in Greenland.","authors":"","doi":"10.1073/pnas.2600481123","DOIUrl":"https://doi.org/10.1073/pnas.2600481123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 6","pages":"e2600481123"},"PeriodicalIF":9.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106947","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}
Pub Date : 2026-02-10Epub Date: 2026-02-02DOI: 10.1073/pnas.2532925123
Zachary T Compton, Amy M Boddy, Lisa M Abegglen, Daniel Chávez, Joshua D Schiffman, Marc Tollis, Carlo C Maley
{"title":"Divergent understandings in comparative oncology.","authors":"Zachary T Compton, Amy M Boddy, Lisa M Abegglen, Daniel Chávez, Joshua D Schiffman, Marc Tollis, Carlo C Maley","doi":"10.1073/pnas.2532925123","DOIUrl":"https://doi.org/10.1073/pnas.2532925123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 6","pages":"e2532925123"},"PeriodicalIF":9.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146107072","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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