Leonard F. Lebender, Alexander Seidinger, Michaela Matthey, Birte Dyck, Christian Schlamm, Abdullah Kaddoura, Maximilian Hausherr, Britta Eggers, Katrin Marcus, Evi Kostenis, Volkmar Gieselmann, Michael Adamzik, Anna Klinke, Björn Koos, Bernd K. Fleischmann, Daniela Wenzel
Pulmonary arterial hypertension (PAH) is a serious disorder, in which increased vascular tone is one of the critical hallmarks. Since beta arrestins (bArrs) have been shown to regulate smooth muscle tone in the airways, we investigated the function of bArr1 in the pulmonary vasculature. Here, we report that bArr1 is essential for maintaining normal pulmonary arterial tone. Specifically, pulmonary arteries from bArr1−/− mice exhibited reduced NO-dependent vasorelaxation due to impaired soluble guanylyl cyclase (sGC) activity, which was restored by the heme-independent sGC activator BAY58-2667. We identified bArr1 as a binding partner of sGC and the sGC heme reductase cytochrome b5 reductase (Cyb5r3), indicating that bArr1 is vital for sensitizing sGC to NO. Finally, mice with either ubiquitous or smooth muscle-specific bArr1 deficiency developed pulmonary hypertension (PH). These findings highlight the important role of bArr1 in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.
{"title":"Beta arrestin 1 is a key regulator of pulmonary vascular tone","authors":"Leonard F. Lebender, Alexander Seidinger, Michaela Matthey, Birte Dyck, Christian Schlamm, Abdullah Kaddoura, Maximilian Hausherr, Britta Eggers, Katrin Marcus, Evi Kostenis, Volkmar Gieselmann, Michael Adamzik, Anna Klinke, Björn Koos, Bernd K. Fleischmann, Daniela Wenzel","doi":"10.1073/pnas.2512602123","DOIUrl":"https://doi.org/10.1073/pnas.2512602123","url":null,"abstract":"Pulmonary arterial hypertension (PAH) is a serious disorder, in which increased vascular tone is one of the critical hallmarks. Since beta arrestins (bArrs) have been shown to regulate smooth muscle tone in the airways, we investigated the function of bArr1 in the pulmonary vasculature. Here, we report that bArr1 is essential for maintaining normal pulmonary arterial tone. Specifically, pulmonary arteries from bArr1−/− mice exhibited reduced NO-dependent vasorelaxation due to impaired soluble guanylyl cyclase (sGC) activity, which was restored by the heme-independent sGC activator BAY58-2667. We identified bArr1 as a binding partner of sGC and the sGC heme reductase cytochrome b5 reductase (Cyb5r3), indicating that bArr1 is vital for sensitizing sGC to NO. Finally, mice with either ubiquitous or smooth muscle-specific bArr1 deficiency developed pulmonary hypertension (PH). These findings highlight the important role of bArr1 in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"3 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146142","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}
Mosquito-disease vectors, such as Aedes aegypti , use their sense of taste before deciding whether to consume a blood meal, or fly away. However, the molecular mechanisms controlling gustatory decisions in mosquitoes are largely unknown. The transient receptor potential (TRP) channel, Painless1 (Pain1), is an intriguing candidate for participating in Ae. aegypti taste since pain1 transcripts are detected in gustatory receptor neurons (GRNs). The Drosophila homolog, painless ( pain ) is also expressed in GRNs, where it is required for sensing allyl-isothiocyanate. Here, to identify additional gustatory roles for pain homologs, we first focused on Drosophila pain , which is widely expressed in multiple GRN classes. We demonstrated that pain mutations eliminated gustatory attraction to low fatty acids levels, repulsion to high levels, and fatty acid-induced action potentials. The attraction and repulsion depended on pain expression in different GRN classes. In contrast to Drosophila , when Aedes contacts fatty acids, they induce gustatory rejection only. Aedes pain1 is expressed in taste organs, and is required for gustatory avoidance of fatty acids, and for fatty acid-induced action potentials. Given that Pain homologs are found in insects but not vertebrates, Pain1 represents an intriguing target for developing repellents to diminish biting, and transmission of infectious agents by mosquito disease vectors.
{"title":"Gustatory avoidance of fatty acids by Aedes aegypti depends on an arthropod-specific TRP channel","authors":"Subash Dhakal, Angela E. Bontempo, Ramandeep Singh, Pratik Dhavan, Craig Montell","doi":"10.1073/pnas.2522818123","DOIUrl":"https://doi.org/10.1073/pnas.2522818123","url":null,"abstract":"Mosquito-disease vectors, such as <jats:italic toggle=\"yes\">Aedes aegypti</jats:italic> , use their sense of taste before deciding whether to consume a blood meal, or fly away. However, the molecular mechanisms controlling gustatory decisions in mosquitoes are largely unknown. The transient receptor potential (TRP) channel, Painless1 (Pain1), is an intriguing candidate for participating in <jats:italic toggle=\"yes\">Ae. aegypti</jats:italic> taste since <jats:italic toggle=\"yes\">pain1</jats:italic> transcripts are detected in gustatory receptor neurons (GRNs). The <jats:italic toggle=\"yes\">Drosophila</jats:italic> homolog, <jats:italic toggle=\"yes\">painless</jats:italic> ( <jats:italic toggle=\"yes\">pain</jats:italic> ) is also expressed in GRNs, where it is required for sensing allyl-isothiocyanate. Here, to identify additional gustatory roles for <jats:italic toggle=\"yes\">pain</jats:italic> homologs, we first focused on <jats:italic toggle=\"yes\">Drosophila pain</jats:italic> , which is widely expressed in multiple GRN classes. We demonstrated that <jats:italic toggle=\"yes\">pain</jats:italic> mutations eliminated gustatory attraction to low fatty acids levels, repulsion to high levels, and fatty acid-induced action potentials. The attraction and repulsion depended on <jats:italic toggle=\"yes\">pain</jats:italic> expression in different GRN classes. In contrast to <jats:italic toggle=\"yes\">Drosophila</jats:italic> , when <jats:italic toggle=\"yes\">Aedes</jats:italic> contacts fatty acids, they induce gustatory rejection only. <jats:italic toggle=\"yes\">Aedes pain1</jats:italic> is expressed in taste organs, and is required for gustatory avoidance of fatty acids, and for fatty acid-induced action potentials. Given that Pain homologs are found in insects but not vertebrates, Pain1 represents an intriguing target for developing repellents to diminish biting, and transmission of infectious agents by mosquito disease vectors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"22 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146108","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}
Xiaolu Wang, Xu Jing, Ziheng Guo, Siwen Long, Xiaoting Sun, Sofia Appelberg, Gerald M. McInerney, Mikael Adner, Yihai Cao
COVID-19 has been associated with high prevalences of retinal diseases in humans. However, cellular and molecular mechanisms that underlie the COVID-19-associated retinopathy remains unknown. Here, we deployed a mouse COVID-19 model to investigate the causative link between SARS-CoV-2 infection and retinopathy development. Our data showed that COVID-19-induced pulmonary hypoxia triggered systemic hypoxia and markedly augmented VEGF expression levels in the retina and plasma. High VEGF levels altered vascular structures and functions in the retina, resulting in neovascularization, vascular disorganization, and increased leakiness. We deployed a terminology of coviretinopathy to accurately describe these COVID-19-induced pathological changes in the retina. Consequently, blocking VEGF by a specific neutralizing antibody (VEGF blockade) completely ablated the COVID-19-associated vascular changes in the retina. Together, these findings provide mechanistic insights into the COVID-19-associated retinopathy and propose a therapeutic paradigm for effective treatment of coviretinopathy.
{"title":"Coviretinopathy: COVID-19-induced VEGF-dependent retinopathy","authors":"Xiaolu Wang, Xu Jing, Ziheng Guo, Siwen Long, Xiaoting Sun, Sofia Appelberg, Gerald M. McInerney, Mikael Adner, Yihai Cao","doi":"10.1073/pnas.2516405123","DOIUrl":"https://doi.org/10.1073/pnas.2516405123","url":null,"abstract":"COVID-19 has been associated with high prevalences of retinal diseases in humans. However, cellular and molecular mechanisms that underlie the COVID-19-associated retinopathy remains unknown. Here, we deployed a mouse COVID-19 model to investigate the causative link between SARS-CoV-2 infection and retinopathy development. Our data showed that COVID-19-induced pulmonary hypoxia triggered systemic hypoxia and markedly augmented VEGF expression levels in the retina and plasma. High VEGF levels altered vascular structures and functions in the retina, resulting in neovascularization, vascular disorganization, and increased leakiness. We deployed a terminology of coviretinopathy to accurately describe these COVID-19-induced pathological changes in the retina. Consequently, blocking VEGF by a specific neutralizing antibody (VEGF blockade) completely ablated the COVID-19-associated vascular changes in the retina. Together, these findings provide mechanistic insights into the COVID-19-associated retinopathy and propose a therapeutic paradigm for effective treatment of coviretinopathy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146134","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}
Laura G. Elsler, Jessica A. Gephart, Jessica Zamborain-Mason, Tim Cashion, Max Troell, Rosamond L. Naylor, Rahul Agrawal Bejarano, Christopher D. Golden
Aquaculture, the single fastest growing food sector, is central to achieving key Sustainable Development Goals (e.g., SDG 2: Zero Hunger). Linking the nutrient composition of >2,800 aquatic species with >2 million fishmeal and farmed fish transactions in international aquatic food trade between 2015 and 2019, we examined aquaculture’s nutritional flows and distributional equity. We found that aquaculture provided adequate intakes for nearly a quarter of a million individuals, on average, across 14 key nutrients, and for up to 2.7 billion individuals for several nutrients, such as Vitamin B 12 . The vast majority of these nutrients (76.8%) were domestically retained, contributing to the nutritional security of producer countries. With most internationally traded nutrients originating from nutritionally vulnerable countries (57.7% for fishmeal and 66.3% for farmed aquatic foods), rethinking existing distribution policies with nutrition as the primary objective may help unlock the full potential of aquaculture to eliminate hunger and malnutrition.
{"title":"Global nutritional equity of fishmeal and aquaculture trade flows","authors":"Laura G. Elsler, Jessica A. Gephart, Jessica Zamborain-Mason, Tim Cashion, Max Troell, Rosamond L. Naylor, Rahul Agrawal Bejarano, Christopher D. Golden","doi":"10.1073/pnas.2506699123","DOIUrl":"https://doi.org/10.1073/pnas.2506699123","url":null,"abstract":"Aquaculture, the single fastest growing food sector, is central to achieving key Sustainable Development Goals (e.g., SDG 2: Zero Hunger). Linking the nutrient composition of >2,800 aquatic species with >2 million fishmeal and farmed fish transactions in international aquatic food trade between 2015 and 2019, we examined aquaculture’s nutritional flows and distributional equity. We found that aquaculture provided adequate intakes for nearly a quarter of a million individuals, on average, across 14 key nutrients, and for up to 2.7 billion individuals for several nutrients, such as Vitamin B <jats:sub>12</jats:sub> . The vast majority of these nutrients (76.8%) were domestically retained, contributing to the nutritional security of producer countries. With most internationally traded nutrients originating from nutritionally vulnerable countries (57.7% for fishmeal and 66.3% for farmed aquatic foods), rethinking existing distribution policies with nutrition as the primary objective may help unlock the full potential of aquaculture to eliminate hunger and malnutrition.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"72 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146140","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}
Allison A. Baczynski, Ophélie M. Mcintosh, Danielle N. Simkus, Hannah L. McLain, Jason P. Dworkin, Daniel P. Glavin, Jamie E. Elsila, Mila Matney, Christopher H. House, Katherine H. Freeman, Harold C. Connolly, Dante S. Lauretta
Samples collected from the carbonaceous near-Earth asteroid Bennu and delivered to Earth by NASA’s OSIRIS-REx mission contain organic molecules relevant to prebiotic chemistry. Stable isotopic measurements of extraterrestrial soluble organic matter provide critical insights into the formation pathways and alteration histories of such molecules, which hold significance for understanding the origins of life. We leverage state-of-the-art techniques for picomolar-scale isotopic analyses of amino acids in samples of Bennu and, for comparison, the carbonaceous meteorite Murchison. We report intramolecular δ 13 C values for glycine, which have not previously been measured in extraterrestrial materials; molecular-averaged δ 13 C values for amino acids, aldehydes, and ketones; and δ 15 N values for glycine, β-alanine, and D/L-glutamic acid. Intramolecular carbon isotope patterns of glycine in Bennu contrast with those in Murchison, suggesting distinct formation pathways. We explore several formation mechanisms and hypothesize that the observed glycine in Murchison formed dominantly by a Strecker-like synthesis under aqueous conditions, whereas the glycine currently found in Bennu may have formed mainly by modified radical–radical reactions in primordial ices at the cold, outer reaches of the early Solar System and retained its isotopic values throughout accretion and multiple episodes of aqueous alteration. This hypothesis is supported by the highly 15 N-enriched δ 15 N values in Bennu amino acids (+170 to 277‰). Differences in the δ 15 N values of D- and L-glutamic acid (Δ = 87‰) in Bennu affirm published reports of enantiomeric differences in meteoritic amino acids and challenge the assumption of isotopic uniformity between amino acid chiral pairs.
{"title":"Multiple formation pathways for amino acids in the early Solar System based on carbon and nitrogen isotopes in asteroid Bennu samples","authors":"Allison A. Baczynski, Ophélie M. Mcintosh, Danielle N. Simkus, Hannah L. McLain, Jason P. Dworkin, Daniel P. Glavin, Jamie E. Elsila, Mila Matney, Christopher H. House, Katherine H. Freeman, Harold C. Connolly, Dante S. Lauretta","doi":"10.1073/pnas.2517723123","DOIUrl":"https://doi.org/10.1073/pnas.2517723123","url":null,"abstract":"Samples collected from the carbonaceous near-Earth asteroid Bennu and delivered to Earth by NASA’s OSIRIS-REx mission contain organic molecules relevant to prebiotic chemistry. Stable isotopic measurements of extraterrestrial soluble organic matter provide critical insights into the formation pathways and alteration histories of such molecules, which hold significance for understanding the origins of life. We leverage state-of-the-art techniques for picomolar-scale isotopic analyses of amino acids in samples of Bennu and, for comparison, the carbonaceous meteorite Murchison. We report intramolecular δ <jats:sup>13</jats:sup> C values for glycine, which have not previously been measured in extraterrestrial materials; molecular-averaged δ <jats:sup>13</jats:sup> C values for amino acids, aldehydes, and ketones; and δ <jats:sup>15</jats:sup> N values for glycine, β-alanine, and D/L-glutamic acid. Intramolecular carbon isotope patterns of glycine in Bennu contrast with those in Murchison, suggesting distinct formation pathways. We explore several formation mechanisms and hypothesize that the observed glycine in Murchison formed dominantly by a Strecker-like synthesis under aqueous conditions, whereas the glycine currently found in Bennu may have formed mainly by modified radical–radical reactions in primordial ices at the cold, outer reaches of the early Solar System and retained its isotopic values throughout accretion and multiple episodes of aqueous alteration. This hypothesis is supported by the highly <jats:sup>15</jats:sup> N-enriched δ <jats:sup>15</jats:sup> N values in Bennu amino acids (+170 to 277‰). Differences in the δ <jats:sup>15</jats:sup> N values of D- and L-glutamic acid (Δ = 87‰) in Bennu affirm published reports of enantiomeric differences in meteoritic amino acids and challenge the assumption of isotopic uniformity between amino acid chiral pairs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"88 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146135","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}
Stratospheric CH 4 oxidation represents both an important sink in the global CH 4 budget and a major source of stratospheric water vapor and hydrogen radicals, exerting strong influences on global climate and ozone chemistry. Yet, the magnitude of stratospheric CH 4 chemical loss remains highly uncertain, with previous estimates largely relying on chemistry-climate models (CCMs). Here, we present an observationally based estimate of stratospheric CH 4 loss ( L STR ), derived from the CH 4 diabatic flux across the isentropic surface fitted to the tropical tropopause, using satellite measurements of CH 4 concentration, temperature, and radiative heating rates for 2007–2010. We obtain an L STR of 49.8 ± 7.8 Tg/y, compared with 38.1 Tg/y estimated from reanalysis, and 25.7 Tg/y (range: 19.6 to 35.9 Tg/y) derived from CCMs, indicating that both reanalysis and CCMs systematically underestimate stratospheric CH 4 loss. We show that discrepancies in global CH 4 diabatic fluxes from the reanalysis and CCMs, when compared with observations, are mainly driven by biases in CH 4 concentrations and further enhanced by errors in temperature and radiative heating. Substituting our observational estimate for the model-based stratospheric loss in the bottom-up global CH 4 budget reduces the reported imbalance for the 2000s from 23 to 3 Tg/y, bringing it into close agreement with the 5 Tg/y (range: −4 to 13 Tg/y) imbalance inferred from top-down estimates. These findings highlight the critical role of observational constraints on L STR in reconciling the global CH 4 budget. They also carry important implications for understanding stratospheric water vapor and ozone chemistry.
{"title":"Global stratospheric methane loss from satellite observations","authors":"Qiang Fu, Cong Dong","doi":"10.1073/pnas.2529774123","DOIUrl":"https://doi.org/10.1073/pnas.2529774123","url":null,"abstract":"Stratospheric CH <jats:sub>4</jats:sub> oxidation represents both an important sink in the global CH <jats:sub>4</jats:sub> budget and a major source of stratospheric water vapor and hydrogen radicals, exerting strong influences on global climate and ozone chemistry. Yet, the magnitude of stratospheric CH <jats:sub>4</jats:sub> chemical loss remains highly uncertain, with previous estimates largely relying on chemistry-climate models (CCMs). Here, we present an observationally based estimate of stratospheric CH <jats:sub>4</jats:sub> loss ( <jats:italic toggle=\"yes\"> L <jats:sub>STR</jats:sub> </jats:italic> ), derived from the CH <jats:sub>4</jats:sub> diabatic flux across the isentropic surface fitted to the tropical tropopause, using satellite measurements of CH <jats:sub>4</jats:sub> concentration, temperature, and radiative heating rates for 2007–2010. We obtain an <jats:italic toggle=\"yes\"> L <jats:sub>STR</jats:sub> </jats:italic> of 49.8 ± 7.8 Tg/y, compared with 38.1 Tg/y estimated from reanalysis, and 25.7 Tg/y (range: 19.6 to 35.9 Tg/y) derived from CCMs, indicating that both reanalysis and CCMs systematically underestimate stratospheric CH <jats:sub>4</jats:sub> loss. We show that discrepancies in global CH <jats:sub>4</jats:sub> diabatic fluxes from the reanalysis and CCMs, when compared with observations, are mainly driven by biases in CH <jats:sub>4</jats:sub> concentrations and further enhanced by errors in temperature and radiative heating. Substituting our observational estimate for the model-based stratospheric loss in the bottom-up global CH <jats:sub>4</jats:sub> budget reduces the reported imbalance for the 2000s from 23 to 3 Tg/y, bringing it into close agreement with the 5 Tg/y (range: −4 to 13 Tg/y) imbalance inferred from top-down estimates. These findings highlight the critical role of observational constraints on <jats:italic toggle=\"yes\"> L <jats:sub>STR</jats:sub> </jats:italic> in reconciling the global CH <jats:sub>4</jats:sub> budget. They also carry important implications for understanding stratospheric water vapor and ozone chemistry.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"314 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146137","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}
Aryan Yazdanpanah, Heejung Jung, Alireza Soltani, Tor D. Wager
Expectations can shape perception and potentially lead to self-fulfilling prophecies such as placebo effects that persist or grow over time. Nonetheless, whether and how unreinforced and unconditioned social cues (i.e., suggestions about future experiences that have not been reinforced with reward or punishment) can create and sustain such effects is unknown. We conducted a set of experiments in which participants (N = 111) experienced stimuli eliciting somatic pain (heat), vicarious pain (videos of others in pain), and cognitive effort (a mental-rotation task), at three intensity levels each. Before each stimulus, participants viewed a social cue that ostensibly indicated ratings from 10 other participants but was in fact randomized to a high or low mean aversiveness level independent of actual stimulus intensity. Across all tasks, participants’ expectations and experience ratings shifted in line with the cues, with high-aversive cues leading to higher perceived aversiveness. Computational modeling and behavioral analysis revealed lower learning rates for prediction errors inconsistent with the trial’s cue value (e.g., better than expected for high-aversive cues) and higher learning rates for prediction errors consistent with the cue value (e.g., worse than expected for high-aversive cues). These findings reveal a confirmation bias in learning: people update more when outcomes align with expectations. Combined with expectation effects on perception, this bias helps sustain social cue effects. Together, these mechanisms show how social information can shape perception and learning, giving rise to self-fulfilling prophecies.
{"title":"Social information creates self-fulfilling prophecies in judgments of pain, vicarious pain, and cognitive effort","authors":"Aryan Yazdanpanah, Heejung Jung, Alireza Soltani, Tor D. Wager","doi":"10.1073/pnas.2513856123","DOIUrl":"https://doi.org/10.1073/pnas.2513856123","url":null,"abstract":"Expectations can shape perception and potentially lead to self-fulfilling prophecies such as placebo effects that persist or grow over time. Nonetheless, whether and how unreinforced and unconditioned social cues (i.e., suggestions about future experiences that have not been reinforced with reward or punishment) can create and sustain such effects is unknown. We conducted a set of experiments in which participants (N = 111) experienced stimuli eliciting somatic pain (heat), vicarious pain (videos of others in pain), and cognitive effort (a mental-rotation task), at three intensity levels each. Before each stimulus, participants viewed a social cue that ostensibly indicated ratings from 10 other participants but was in fact randomized to a high or low mean aversiveness level independent of actual stimulus intensity. Across all tasks, participants’ expectations and experience ratings shifted in line with the cues, with high-aversive cues leading to higher perceived aversiveness. Computational modeling and behavioral analysis revealed lower learning rates for prediction errors inconsistent with the trial’s cue value (e.g., better than expected for high-aversive cues) and higher learning rates for prediction errors consistent with the cue value (e.g., worse than expected for high-aversive cues). These findings reveal a confirmation bias in learning: people update more when outcomes align with expectations. Combined with expectation effects on perception, this bias helps sustain social cue effects. Together, these mechanisms show how social information can shape perception and learning, giving rise to self-fulfilling prophecies.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"25 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146139","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}
Niti Kumari, Xu Chen, Amber M. Baldwin, Kristin I. Clemons, Mohammad El-Harakeh, Lilian E. Calisto, Balawant Kumar, Qiaoqiao Zhang, Jiang Min, Bin Xiao, Amar B. Singh, Bin Wang, Brian J. North
The kinase MAPKAPK2 regulates cell survival, proliferation, and death, and is upregulated in colorectal carcinoma (CRC) where it is associated with tumor growth and progression. However, how it regulates tumor progression in conjunction with other signaling pathways, such as MEK/ERK, remains elusive. Solid tumors are often subjected to metabolic stress, notably glucose deprivation. Here, we demonstrate that MAPKAPK2 protein levels in CRC regulate cell fate decision during stress conditions, such as glucose deprivation and therapeutic treatment. While MAPKAPK2 expression is a limiting factor for CRC growth in vitro, depleting MAPKAPK2 or inhibiting its activity pharmacologically provides a survival advantage to CRC cells under glucose limiting conditions. Subjecting CRC cells to low glucose resulted in an ERK1/2-mediated decline in MAPKAPK2 to promote survival. Additionally, cells with reduced MAPKAPK2 activity were less sensitive to trametinib under glucose limiting conditions. Utilizing transcriptomic profiling, we found that glucose deprivation and MAPKAPK2 depletion activate pathways associated with survival during metabolic stress. This relationship was also observed in CRC patients (TCGA), where tumors with low MAPKAPK2 expression had higher ERK1/2 activation and upregulated stress-induced pathways, leading to poor survival. Finally, MAPKAPK2 modulated growth of CRC organoids, subcutaneous tumors, and patient-derived xenografts (PDX), and reduced MAPKAPK2 levels decreased efficacy of trametinib, in vitro and in vivo. Overall, this study identifies an interrelationship between MEK/ERK and p38/MAPKAPK2 signaling pathways during glucose deprivation to support cell survival and features MAPKAPK2 loss as a possible mechanism leading to reduced efficacy of trametinib-based anticancer therapy and poor patient outcomes in CRC.
{"title":"Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma","authors":"Niti Kumari, Xu Chen, Amber M. Baldwin, Kristin I. Clemons, Mohammad El-Harakeh, Lilian E. Calisto, Balawant Kumar, Qiaoqiao Zhang, Jiang Min, Bin Xiao, Amar B. Singh, Bin Wang, Brian J. North","doi":"10.1073/pnas.2505331123","DOIUrl":"https://doi.org/10.1073/pnas.2505331123","url":null,"abstract":"The kinase MAPKAPK2 regulates cell survival, proliferation, and death, and is upregulated in colorectal carcinoma (CRC) where it is associated with tumor growth and progression. However, how it regulates tumor progression in conjunction with other signaling pathways, such as MEK/ERK, remains elusive. Solid tumors are often subjected to metabolic stress, notably glucose deprivation. Here, we demonstrate that MAPKAPK2 protein levels in CRC regulate cell fate decision during stress conditions, such as glucose deprivation and therapeutic treatment. While MAPKAPK2 expression is a limiting factor for CRC growth in vitro, depleting MAPKAPK2 or inhibiting its activity pharmacologically provides a survival advantage to CRC cells under glucose limiting conditions. Subjecting CRC cells to low glucose resulted in an ERK1/2-mediated decline in MAPKAPK2 to promote survival. Additionally, cells with reduced MAPKAPK2 activity were less sensitive to trametinib under glucose limiting conditions. Utilizing transcriptomic profiling, we found that glucose deprivation and MAPKAPK2 depletion activate pathways associated with survival during metabolic stress. This relationship was also observed in CRC patients (TCGA), where tumors with low MAPKAPK2 expression had higher ERK1/2 activation and upregulated stress-induced pathways, leading to poor survival. Finally, MAPKAPK2 modulated growth of CRC organoids, subcutaneous tumors, and patient-derived xenografts (PDX), and reduced MAPKAPK2 levels decreased efficacy of trametinib, in vitro and in vivo. Overall, this study identifies an interrelationship between MEK/ERK and p38/MAPKAPK2 signaling pathways during glucose deprivation to support cell survival and features MAPKAPK2 loss as a possible mechanism leading to reduced efficacy of trametinib-based anticancer therapy and poor patient outcomes in CRC.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146143","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}
Keigo Shobu, Mayu Takai, Hiroki Tanino, Yohta Fukuda, Tsuyoshi Inoue
Glycogen phosphorylase (GP) plays a central role in glycogen metabolism. While the structure and regulation of mammalian GPs have been extensively studied, the corresponding mechanisms in gut bacterial GPs remain poorly understood. Here, we investigate GPs from Escherichia coli ( Ec GP), Segatella copri ( Sc GP), and Dorea longicatena ( Dl GP), which represent three phylogenetic clades of GPs, using enzymatic assays, cryo–electron microscopy (cryo-EM), and X-ray crystallography. We find that Sc GP forms a unique pentamer that undergoes adenosine monophosphate (AMP)-dependent assembly into a dimer-of-pentamer, which inhibits activity by restricting substrate access to the catalytic site. Ec GP exists in equilibrium among monomers, dimers, and tetramers, with AMP promoting tetramer dissociation and enhancing catalytic efficiency. In contrast, Dl GP remains predominantly monomeric and is unresponsive to AMP. These findings uncover structural and regulatory diversity among gut bacterial GPs. Notably, the oligomeric states of GPs modulate substrate accessibility and enzyme activation, suggesting a distinct mode of allosteric regulation beyond the canonical T-to-R transition model. Because bacterial GPs contribute to the generation of glucose, their regulation may influence the composition of gut-derived metabolites that affect host glucose homeostasis and insulin sensitivity. Our study provides mechanistic insight into the structural and functional diversity of gut bacterial GPs and lays a foundation for future exploration of microbiome-mediated metabolic interactions.
{"title":"Structural and mechanistic diversity of glycogen phosphorylases from gut bacteria","authors":"Keigo Shobu, Mayu Takai, Hiroki Tanino, Yohta Fukuda, Tsuyoshi Inoue","doi":"10.1073/pnas.2518513123","DOIUrl":"https://doi.org/10.1073/pnas.2518513123","url":null,"abstract":"Glycogen phosphorylase (GP) plays a central role in glycogen metabolism. While the structure and regulation of mammalian GPs have been extensively studied, the corresponding mechanisms in gut bacterial GPs remain poorly understood. Here, we investigate GPs from <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Escherichia coli</jats:italic> </jats:italic> ( <jats:italic toggle=\"yes\">Ec</jats:italic> GP), <jats:italic toggle=\"yes\">Segatella copri</jats:italic> ( <jats:italic toggle=\"yes\">Sc</jats:italic> GP), and <jats:italic toggle=\"yes\">Dorea longicatena</jats:italic> ( <jats:italic toggle=\"yes\">Dl</jats:italic> GP), which represent three phylogenetic clades of GPs, using enzymatic assays, cryo–electron microscopy (cryo-EM), and X-ray crystallography. We find that <jats:italic toggle=\"yes\">Sc</jats:italic> GP forms a unique pentamer that undergoes adenosine monophosphate (AMP)-dependent assembly into a dimer-of-pentamer, which inhibits activity by restricting substrate access to the catalytic site. <jats:italic toggle=\"yes\">Ec</jats:italic> GP exists in equilibrium among monomers, dimers, and tetramers, with AMP promoting tetramer dissociation and enhancing catalytic efficiency. In contrast, <jats:italic toggle=\"yes\">Dl</jats:italic> GP remains predominantly monomeric and is unresponsive to AMP. These findings uncover structural and regulatory diversity among gut bacterial GPs. Notably, the oligomeric states of GPs modulate substrate accessibility and enzyme activation, suggesting a distinct mode of allosteric regulation beyond the canonical T-to-R transition model. Because bacterial GPs contribute to the generation of glucose, their regulation may influence the composition of gut-derived metabolites that affect host glucose homeostasis and insulin sensitivity. Our study provides mechanistic insight into the structural and functional diversity of gut bacterial GPs and lays a foundation for future exploration of microbiome-mediated metabolic interactions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146006","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}
Alphaviruses establish persistent infections in mosquito vectors despite robust antiviral RNA interference (RNAi) pathways, suggesting that they employ mechanisms to counteract host immunity. We demonstrate that the nsP2 protein of Sindbis virus (SINV), the prototype alphavirus, functions as a viral suppressor of RNA silencing in Aedes aegypti mosquitoes. Using a SINV mutant (2V) that prevents cleavage at the nsP2–nsP3 junction, we show that proper proteolytic processing to release mature nsP2 is essential for efficient viral replication in mosquitoes with intact RNAi pathways. Replication defects in the 2V mutant were rescued in Dicer-2 ( Dcr-2 ) null mutant mosquitoes or by expressing the mature nsP2 protein. Biochemical assays revealed that recombinant nsP2 directly binds double-stranded RNA and inhibits Dicer-mediated processing into small interfering RNAs (siRNAs). Furthermore, mosquitoes infected with the 2V mutant exhibited higher ratios of virus-derived siRNAs per viral RNA compared to wild-type infections, confirming that mature nsP2 suppresses the RNAi response. Our findings provide compelling evidence that nsP2 antagonizes RNA silencing in mosquito vectors, representing a critical adaptation that facilitates alphavirus replication.
{"title":"Antagonism of RNA silencing in the yellow fever mosquito, Aedes aegypti , by the nsP2 protein of the prototype alphavirus","authors":"Adarsh K. Gupta, Michael R. Wiley, Kevin M. Myles","doi":"10.1073/pnas.2521417123","DOIUrl":"https://doi.org/10.1073/pnas.2521417123","url":null,"abstract":"Alphaviruses establish persistent infections in mosquito vectors despite robust antiviral RNA interference (RNAi) pathways, suggesting that they employ mechanisms to counteract host immunity. We demonstrate that the nsP2 protein of Sindbis virus (SINV), the prototype alphavirus, functions as a viral suppressor of RNA silencing in <jats:italic toggle=\"yes\">Aedes aegypti</jats:italic> mosquitoes. Using a SINV mutant (2V) that prevents cleavage at the nsP2–nsP3 junction, we show that proper proteolytic processing to release mature nsP2 is essential for efficient viral replication in mosquitoes with intact RNAi pathways. Replication defects in the 2V mutant were rescued in <jats:italic toggle=\"yes\">Dicer-2</jats:italic> ( <jats:italic toggle=\"yes\">Dcr-2</jats:italic> ) null mutant mosquitoes or by expressing the mature nsP2 protein. Biochemical assays revealed that recombinant nsP2 directly binds double-stranded RNA and inhibits Dicer-mediated processing into small interfering RNAs (siRNAs). Furthermore, mosquitoes infected with the 2V mutant exhibited higher ratios of virus-derived siRNAs per viral RNA compared to wild-type infections, confirming that mature nsP2 suppresses the RNAi response. Our findings provide compelling evidence that nsP2 antagonizes RNA silencing in mosquito vectors, representing a critical adaptation that facilitates alphavirus replication.","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":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146132","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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