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}
Wild dromedary camels in the Arabian Peninsula and Africa have harbored antibodies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) for decades, predating zoonotic spillover to humans. However, the potency, specificity, and structural characteristics of these antibodies remain poorly understood. Here, we characterize the antibody responses of naturally infected wild dromedary camels in Tunisia, a MERS-CoV-endemic region. Plasma antibodies from nine camels exhibited variable neutralizing activity, generally increasing with age, and were largely autologous, with minimal cross-reactivity to SARS-CoV-1 or SARS-CoV-2. From a VHH antibody library derived from the peripheral blood mononuclear cells (PBMCs) of a single camel (D17), we identified 34 unique sequences with previously unreported germline origins and unusually long complementarity-determining region 3 (CDR3) sequences. Eight representative VHHs, expressed as human Fc fusions, displayed high-affinity binding to the MERS-CoV receptor-binding domain (RBD) and broad neutralization to RBD mutants (IC 50 : 1.05 to 9.55 ng/mL). Crystal structural analysis revealed distinct neutralization mechanisms: VHH-227 fully blocked DPP4 binding, achieving complete neutralization, while VHH-T71, with partial neutralization (~80%), targeted the RBD core subdomain. This study provides comprehensive characterization of wild dromedary antibody responses, identifying novel nanobodies (Nbs) with broad and potent neutralization to naturally occurring RBD mutants. These findings offer insights into camel immunity and highlight promising candidates for MERS-CoV prophylactic and therapeutic development.
{"title":"Decoding antibody response to MERS-CoV in wild dromedary camels","authors":"Faten Idoudi, Ruoke Wang, Long Tian, Ziqing Yang, Kenn Ka-Heng Chik, Peng Chen, Rahma Benabderrazek, Lili Fu, Ruijie Tan, Sayda Dhaouadi, Zakaria Benlasfar, Mahmoud Somia, Qi Zhang, Xuanling Shi, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Xinquan Wang, Balkiss Bouhaouala-Zahar, Linqi Zhang","doi":"10.1073/pnas.2513716123","DOIUrl":"https://doi.org/10.1073/pnas.2513716123","url":null,"abstract":"Wild dromedary camels in the Arabian Peninsula and Africa have harbored antibodies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) for decades, predating zoonotic spillover to humans. However, the potency, specificity, and structural characteristics of these antibodies remain poorly understood. Here, we characterize the antibody responses of naturally infected wild dromedary camels in Tunisia, a MERS-CoV-endemic region. Plasma antibodies from nine camels exhibited variable neutralizing activity, generally increasing with age, and were largely autologous, with minimal cross-reactivity to SARS-CoV-1 or SARS-CoV-2. From a VHH antibody library derived from the peripheral blood mononuclear cells (PBMCs) of a single camel (D17), we identified 34 unique sequences with previously unreported germline origins and unusually long complementarity-determining region 3 (CDR3) sequences. Eight representative VHHs, expressed as human Fc fusions, displayed high-affinity binding to the MERS-CoV receptor-binding domain (RBD) and broad neutralization to RBD mutants (IC <jats:sub>50</jats:sub> : 1.05 to 9.55 ng/mL). Crystal structural analysis revealed distinct neutralization mechanisms: VHH-227 fully blocked DPP4 binding, achieving complete neutralization, while VHH-T71, with partial neutralization (~80%), targeted the RBD core subdomain. This study provides comprehensive characterization of wild dromedary antibody responses, identifying novel nanobodies (Nbs) with broad and potent neutralization to naturally occurring RBD mutants. These findings offer insights into camel immunity and highlight promising candidates for MERS-CoV prophylactic and therapeutic development.","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":"146146165","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}
Benjamin Cross, Léo Garcia, Elisabeth Charlaix, Patrick Kékicheff
Previous experimental reports of long-range interactions in ionic liquids (ILs) stand in contradiction with theoretical predictions and numerical simulations. To provide insights into the literature discrepancies regarding the experimental ranges of electrostatic screening, claimed with orders of magnitude larger, the interactions between pairs of mica and borosilicate surfaces confining ILs are investigated by two complementary advanced Surface Force Apparatuses. Regardless of differences in confinement geometries (crossed-cylinders, sphere-flat), radii of curvature (cm-mm), and measurement techniques (stepwise versus continuous approach), two ever present force regimes are evidenced. At small surface separations, oscillatory forces reflect IL structuration and layering, while outside this gap, the interaction is monotonic repulsive. In both regimes the spatial extent and force magnitude depend critically on motion conditions, as demonstrated by achieving velocities as low as 9 pm/s with equilibration times up to 90 s. At large separations, fast surface displacements generate long-range interactions (over tens of ion size) creating the illusion of anomalous underscreening, whereas increasingly slow ones shrink both magnitude and range of the repulsion with decay-lengths converging ultimately to a screening length consistent with Poisson–Boltzmann theory with finite ion sizes. The transition from apparent long-range to short-range screening unfolds over nearly two orders of magnitude in time, revealing slow relaxation dynamics reminiscent of aging phenomena. These findings definitely resolve a decade-old controversy on force measurements and reveal rich out-of-equilibrium dynamics. The hydrodynamic contribution to the net force is admittedly crucial to be reduced especially when relaxations span decades in time, but approaching thermodynamic equilibrium during measurements proves essential.
{"title":"Short-range electrostatic screening in ionic liquids as inferred by direct force measurements","authors":"Benjamin Cross, Léo Garcia, Elisabeth Charlaix, Patrick Kékicheff","doi":"10.1073/pnas.2517939123","DOIUrl":"https://doi.org/10.1073/pnas.2517939123","url":null,"abstract":"Previous experimental reports of long-range interactions in ionic liquids (ILs) stand in contradiction with theoretical predictions and numerical simulations. To provide insights into the literature discrepancies regarding the experimental ranges of electrostatic screening, claimed with orders of magnitude larger, the interactions between pairs of mica and borosilicate surfaces confining ILs are investigated by two complementary advanced Surface Force Apparatuses. Regardless of differences in confinement geometries (crossed-cylinders, sphere-flat), radii of curvature (cm-mm), and measurement techniques (stepwise versus continuous approach), two ever present force regimes are evidenced. At small surface separations, oscillatory forces reflect IL structuration and layering, while outside this gap, the interaction is monotonic repulsive. In both regimes the spatial extent and force magnitude depend critically on motion conditions, as demonstrated by achieving velocities as low as 9 pm/s with equilibration times up to 90 s. At large separations, fast surface displacements generate long-range interactions (over tens of ion size) creating the illusion of anomalous underscreening, whereas increasingly slow ones shrink both magnitude and range of the repulsion with decay-lengths converging ultimately to a screening length consistent with Poisson–Boltzmann theory with finite ion sizes. The transition from apparent long-range to short-range screening unfolds over nearly two orders of magnitude in time, revealing slow relaxation dynamics reminiscent of aging phenomena. These findings definitely resolve a decade-old controversy on force measurements and reveal rich out-of-equilibrium dynamics. The hydrodynamic contribution to the net force is admittedly crucial to be reduced especially when relaxations span decades in time, but approaching thermodynamic equilibrium during measurements proves essential.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"35 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146163","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}
Grazing systems represent the most extensive production systems in the world and are highly sensitive to climate change. However, their global-scale sensitivity and vulnerability to climate impacts remain poorly understood. Here, we apply the safe climatic space framework to assess how changes in core climatic drivers of grazing suitability, including temperature, precipitation, humidity, and wind speed, will reshape global grassland-based grazing systems. Our analysis projects a net decline of 36 to 50% of areas in climate suitability for grazing by 2100, accompanied by inter- and intracontinental shift of grazing suitability. These changes are expected to negatively affect 110 to 140 million pastoralists and 1.4 to 1.6 billion livestock, with particularly severe impacts in Africa. We further show that 51 to 81% of these impacted populations reside in countries with low income, serious hunger, severe gender inequality, and high political fragility. Our study implies that future climate change will threaten grazing suitability across large portions of Earth, endangering the livelihoods of numerous communities and potentially triggering widespread socioeconomic consequences.
{"title":"Climate change drives a decline in global grazing systems","authors":"Chaohui Li, Maximilian Kotz, Prajal Pradhan, Xudong Wu, Yuanchao Hu, Zhi Li, Guoqian Chen","doi":"10.1073/pnas.2534015123","DOIUrl":"https://doi.org/10.1073/pnas.2534015123","url":null,"abstract":"Grazing systems represent the most extensive production systems in the world and are highly sensitive to climate change. However, their global-scale sensitivity and vulnerability to climate impacts remain poorly understood. Here, we apply the safe climatic space framework to assess how changes in core climatic drivers of grazing suitability, including temperature, precipitation, humidity, and wind speed, will reshape global grassland-based grazing systems. Our analysis projects a net decline of 36 to 50% of areas in climate suitability for grazing by 2100, accompanied by inter- and intracontinental shift of grazing suitability. These changes are expected to negatively affect 110 to 140 million pastoralists and 1.4 to 1.6 billion livestock, with particularly severe impacts in Africa. We further show that 51 to 81% of these impacted populations reside in countries with low income, serious hunger, severe gender inequality, and high political fragility. Our study implies that future climate change will threaten grazing suitability across large portions of Earth, endangering the livelihoods of numerous communities and potentially triggering widespread socioeconomic consequences.","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":"146146064","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}
Kate Tarvestad-Laise, Robert C. Monsen, Brandon L. M. Crotchett, Jamie S. Rush, Srinivasrao Ganipisetti, Rajachandrasekhar Valmon, Lynn DeLeeuw, Joseph Burlison, John O. Trent, Brian P. Ceresa
Growth factor receptor signaling is a critical component of tissue growth, homeostasis, and wound healing. However, receptor desensitization limits the use of exogenous growth factors as a restorative agent therapeutically. An example of this is the epidermal growth factor receptor (EGFR) in the corneal epithelium. Despite laboratory data indicating that EGFR activity accelerates corneal re-epithelialization in mice and rabbits, the clinical administration of EGF to damaged corneal epithelium has limited impact due to the attenuated signaling that occurs following sustained growth factor administration. We hypothesized that inhibition of receptor desensitization would prolong receptor activity and enhance tissue homeostasis. Having previously identified the E3 ubiquitin ligase, c-Cbl, as a key negative regulator of EGFR signaling in the corneal epithelium, we have developed a class of small molecule inhibitors of EGFR binding to CBL family proteins using virtual screening with experimental validation. Through multiple rounds of structural optimization, we have identified compound 3-120. This compound was designed to compete with phosphotyrosine 1045 of the EGFR for binding to c-Cbl. Compound 3-120 binds to c-Cbl with an ~10-fold higher affinity than phosphoEGFR, reduces EGFR ubiquitylation by 40%, and increases the magnitude of ligand-stimulated EGFR phosphorylation by 30 to 40%. Ultimately, this compound can enhance the restoration of corneal epithelial debridement wounds. Thus, compound 3-120 is an antagonist that specifically disrupts EGFR ubiquitylation to sustain receptor signaling.
{"title":"A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization","authors":"Kate Tarvestad-Laise, Robert C. Monsen, Brandon L. M. Crotchett, Jamie S. Rush, Srinivasrao Ganipisetti, Rajachandrasekhar Valmon, Lynn DeLeeuw, Joseph Burlison, John O. Trent, Brian P. Ceresa","doi":"10.1073/pnas.2518857123","DOIUrl":"https://doi.org/10.1073/pnas.2518857123","url":null,"abstract":"Growth factor receptor signaling is a critical component of tissue growth, homeostasis, and wound healing. However, receptor desensitization limits the use of exogenous growth factors as a restorative agent therapeutically. An example of this is the epidermal growth factor receptor (EGFR) in the corneal epithelium. Despite laboratory data indicating that EGFR activity accelerates corneal re-epithelialization in mice and rabbits, the clinical administration of EGF to damaged corneal epithelium has limited impact due to the attenuated signaling that occurs following sustained growth factor administration. We hypothesized that inhibition of receptor desensitization would prolong receptor activity and enhance tissue homeostasis. Having previously identified the E3 ubiquitin ligase, c-Cbl, as a key negative regulator of EGFR signaling in the corneal epithelium, we have developed a class of small molecule inhibitors of EGFR binding to CBL family proteins using virtual screening with experimental validation. Through multiple rounds of structural optimization, we have identified compound 3-120. This compound was designed to compete with phosphotyrosine 1045 of the EGFR for binding to c-Cbl. Compound 3-120 binds to c-Cbl with an ~10-fold higher affinity than phosphoEGFR, reduces EGFR ubiquitylation by 40%, and increases the magnitude of ligand-stimulated EGFR phosphorylation by 30 to 40%. Ultimately, this compound can enhance the restoration of corneal epithelial debridement wounds. Thus, compound 3-120 is an antagonist that specifically disrupts EGFR ubiquitylation to sustain receptor signaling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"20 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146133","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}
Hongshuai Gao, Mujuan Guo, Xin Yang, Rongmin Hu, Kun Wu, Lan Pang, Xiqian Ye, Jianhua Huang, Xuexin Chen, Zhizhi Wang
Parasitic castration is a widespread strategy where parasites hijack host reproductive resources, yet the key molecular mechanisms driving this phenomenon remain poorly understood. Here, we reported that parasitization by the parasitic wasp Cotesia vestalis triggers apoptosis-mediated castration in the larval testes of its lepidopteran host, Plutella xylotella . Such a phenomenon was mediated by CvBV_22-9 , a testis-enriched protein tyrosine phosphatase (PTP) encoded by Cotesia vestalis bracovirus (CvBV), a domesticated virus endogenized in the wasp. Similarly, a homolog of CvBV_22-9, encoded by the Microplitis manilae bracovirus, is involved in testis castration by inducing apoptosis in parasitized fall armyworm, Spodoptera frugiperda . Mechanistically, CvBV_22-9 binds to a cell cycle checkpoint protein, Rad9A, but does not alter its tyrosine phosphorylation level. Crucially, CRISPR-Cas9 knockout of Rad9A causes embryonic lethality and severe testis defects. Validation in Drosophila melanogaster shows that testis-specific expression of CvBV_22-9 or Rad9A knockdown induces apoptosis, while combined targeting synergistically enhances this effect, suggesting a conserved function of both proteins in insects. Our study uncovers a regulatory mechanism where a parasitoid wasp deploys a domesticated viral PTP that functions as a pseudophosphatase to induce Rad9A-mediated apoptosis and disrupt host testis development and spermatogenesis. This mechanism highlights a sophisticated strategy of host exploitation by parasitoid wasps, providing insights for the biocontrol of lepidopteran pests.
{"title":"Parasitic castration by a viral protein tyrosine phosphatase targeting the host cell cycle checkpoint protein Rad9A","authors":"Hongshuai Gao, Mujuan Guo, Xin Yang, Rongmin Hu, Kun Wu, Lan Pang, Xiqian Ye, Jianhua Huang, Xuexin Chen, Zhizhi Wang","doi":"10.1073/pnas.2524949123","DOIUrl":"https://doi.org/10.1073/pnas.2524949123","url":null,"abstract":"Parasitic castration is a widespread strategy where parasites hijack host reproductive resources, yet the key molecular mechanisms driving this phenomenon remain poorly understood. Here, we reported that parasitization by the parasitic wasp <jats:italic toggle=\"yes\">Cotesia vestalis</jats:italic> triggers apoptosis-mediated castration in the larval testes of its lepidopteran host, <jats:italic toggle=\"yes\">Plutella xylotella</jats:italic> . Such a phenomenon was mediated by <jats:italic toggle=\"yes\">CvBV_22-9</jats:italic> , a testis-enriched <jats:italic toggle=\"yes\">protein tyrosine phosphatase</jats:italic> (PTP) encoded by Cotesia vestalis bracovirus (CvBV), a domesticated virus endogenized in the wasp. Similarly, a homolog of CvBV_22-9, encoded by the Microplitis manilae bracovirus, is involved in testis castration by inducing apoptosis in parasitized fall armyworm, <jats:italic toggle=\"yes\">Spodoptera frugiperda</jats:italic> . Mechanistically, CvBV_22-9 binds to a cell cycle checkpoint protein, Rad9A, but does not alter its tyrosine phosphorylation level. Crucially, CRISPR-Cas9 knockout of <jats:italic toggle=\"yes\">Rad9A</jats:italic> causes embryonic lethality and severe testis defects. Validation in <jats:italic toggle=\"yes\">Drosophila melanogaster</jats:italic> shows that testis-specific expression of <jats:italic toggle=\"yes\">CvBV_22-9</jats:italic> or <jats:italic toggle=\"yes\">Rad9A</jats:italic> knockdown induces apoptosis, while combined targeting synergistically enhances this effect, suggesting a conserved function of both proteins in insects. Our study uncovers a regulatory mechanism where a parasitoid wasp deploys a domesticated viral PTP that functions as a pseudophosphatase to induce Rad9A-mediated apoptosis and disrupt host testis development and spermatogenesis. This mechanism highlights a sophisticated strategy of host exploitation by parasitoid wasps, providing insights for the biocontrol of lepidopteran pests.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"77 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146136","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}
Yi Liu, Daniel G. Oblinsky, Gianluca Dell’Orletta, Nico Di Fonte, Damien Sorigue, Claire G. Page, Isabella Daidone, Gregory D. Scholes, Todd K. Hyster
Cross-couplings are essential reactions in modern chemical synthesis, enabling the rapid construction of complex molecules from simple precursors. Transition metal catalysts are prized for these transformations because their reactivity and selectivity can be tuned via judicious selection of the metal and ligand. Although enzymes offer analogous opportunities for tuning via protein engineering, their application to cross-coupling remains limited, as nature relies on alternative paradigms for building molecular complexity. Here, we report the cross-coupling of alkyl halides and benzylic carboxylic acids using an engineered flavin-dependent lactate monooxygenase—a photoenzyme. The enzyme achieves this feat by exploiting the redox versatility of the flavin cofactor. Stoichiometric experiments, ultrafast spectroscopy, and computational studies support a mechanism in which photoexcited flavin quinone initiates the reaction via oxidative decarboxylation to generate a benzylic radical. The resulting flavin semiquinone can reduce the alkyl halide to form a second organic radical within the protein active site, which rapidly engages in C(sp 3 )–C(sp 3 ) bond formation. A variant was engineered to control the stereochemical outcome of this radical–radical coupling event, highlighting the ability of the protein to alter the energetic barrier for a mechanistic step that is traditionally understood to be near barrierless. This work demonstrates that the scope for nonnative reaction mechanisms in biocatalysis far exceeds previously established bounds and has potential to solve a variety of reactivity challenges in cross-coupling chemistry.
{"title":"Photoenzymatic Csp 3 –Csp 3 bond formation via enzyme-templated radical–radical coupling","authors":"Yi Liu, Daniel G. Oblinsky, Gianluca Dell’Orletta, Nico Di Fonte, Damien Sorigue, Claire G. Page, Isabella Daidone, Gregory D. Scholes, Todd K. Hyster","doi":"10.1073/pnas.2529018123","DOIUrl":"https://doi.org/10.1073/pnas.2529018123","url":null,"abstract":"Cross-couplings are essential reactions in modern chemical synthesis, enabling the rapid construction of complex molecules from simple precursors. Transition metal catalysts are prized for these transformations because their reactivity and selectivity can be tuned via judicious selection of the metal and ligand. Although enzymes offer analogous opportunities for tuning via protein engineering, their application to cross-coupling remains limited, as nature relies on alternative paradigms for building molecular complexity. Here, we report the cross-coupling of alkyl halides and benzylic carboxylic acids using an engineered flavin-dependent lactate monooxygenase—a photoenzyme. The enzyme achieves this feat by exploiting the redox versatility of the flavin cofactor. Stoichiometric experiments, ultrafast spectroscopy, and computational studies support a mechanism in which photoexcited flavin quinone initiates the reaction via oxidative decarboxylation to generate a benzylic radical. The resulting flavin semiquinone can reduce the alkyl halide to form a second organic radical within the protein active site, which rapidly engages in C(sp <jats:sup>3</jats:sup> )–C(sp <jats:sup>3</jats:sup> ) bond formation. A variant was engineered to control the stereochemical outcome of this radical–radical coupling event, highlighting the ability of the protein to alter the energetic barrier for a mechanistic step that is traditionally understood to be near barrierless. This work demonstrates that the scope for nonnative reaction mechanisms in biocatalysis far exceeds previously established bounds and has potential to solve a variety of reactivity challenges in cross-coupling chemistry.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"93 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146138","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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