Neoadjuvant chemotherapy (NACT), a key strategy for various cancers, markedly improves patient prognosis and 5-year survival rates. However, numerous patients develop resistance to NACT and thus fail to benefit from it. Therefore, identifying reliable biomarkers to predict patient responsiveness to NACT remains a critical challenge. Here, we demonstrate that elevated expression of INCENP and CDCA8 contributes to poor NACT responsiveness across multiple cancers. Mechanistically, the 5′UTR (GGACT at position 113) of INCENP and the 3′UTR (GGACT at position 1041) of CDCA8 undergo m⁶A methylation and are recognized by YTHDF3, which facilitates their translation through interaction with eIF3A, ultimately driving poor response to NACT. Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.
{"title":"INCENP and CDCA8 predict neoadjuvant chemotherapy response and outcomes in esophageal squamous cell carcinoma","authors":"Xiangyu Wang, Ting Wang, Keke Wang, Chengjuan Zhang, Zhibo Li, Feifei Liu, Xueli Tian, Xiaodan Shi, Zihan Zhang, Rui Wang, Ludan Jia, Kyle Vaughn Laster, Qingxin Xia, Simin Zhao, Zigang Dong","doi":"10.1038/s41467-026-68371-x","DOIUrl":"https://doi.org/10.1038/s41467-026-68371-x","url":null,"abstract":"Neoadjuvant chemotherapy (NACT), a key strategy for various cancers, markedly improves patient prognosis and 5-year survival rates. However, numerous patients develop resistance to NACT and thus fail to benefit from it. Therefore, identifying reliable biomarkers to predict patient responsiveness to NACT remains a critical challenge. Here, we demonstrate that elevated expression of INCENP and CDCA8 contributes to poor NACT responsiveness across multiple cancers. Mechanistically, the 5′UTR (GGACT at position 113) of INCENP and the 3′UTR (GGACT at position 1041) of CDCA8 undergo m⁶A methylation and are recognized by YTHDF3, which facilitates their translation through interaction with eIF3A, ultimately driving poor response to NACT. Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"184 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006246","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 : 2026-01-21DOI: 10.1038/s41467-025-68129-x
Melisa Chuong,Deborah Thompson,Michael E Weale,Fernando Riveros-Mckay,Nilesh J Samani,Daniel Wells,Vincent Plagnol,Gil McVean,Euan A Ashley,Peter Donnelly,Seamus Harrison,Jack W O'Sullivan
Polygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remains stable throughout life, we explore the potential of PRS to optimize existing screening programs. Via an integrated modelling approach, we quantify the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs (abdominal aortic aneurysm, breast cancer, colorectal cancer, coronary artery disease, hypertension, prostate cancer, and type 2 diabetes). We identify individuals at high genetic risk (PRS OR>2) and very high genetic risk (PRS OR>3) and estimate the optimal screening ages for these genetically high-risk individuals, based on the equivalent risk to population-level risk at recommended screening ages. We then leverage published data on differential mortality and other outcomes, with and without screening-based interventions, to assess the potential benefits of tailoring screening age based on genetic risk. Very high risk individuals reach the risk level associated with usual starting screening age on average 10.8 years earlier, high risk individuals 8.9 years earlier and reduced risk individuals (OR<0.5) 16.8 years later. During this time, case enrichment (the ratio of the percentage of cases in the high PRS risk group and in the total population) in the high risk group is between 1.7 and 3.0, depending on the disease. Across all seven diseases, appropriate interventions following PRS-guided screening could reduce premature deaths in high-risk individuals by 23.3%. Knowledge of genetic risk, measured using PRS, has the potential to deliver substantial public health benefits when aggregated across conditions, and could reduce premature mortality by tailoring existing screening programs.
{"title":"Preventing premature deaths through polygenic risk scores.","authors":"Melisa Chuong,Deborah Thompson,Michael E Weale,Fernando Riveros-Mckay,Nilesh J Samani,Daniel Wells,Vincent Plagnol,Gil McVean,Euan A Ashley,Peter Donnelly,Seamus Harrison,Jack W O'Sullivan","doi":"10.1038/s41467-025-68129-x","DOIUrl":"https://doi.org/10.1038/s41467-025-68129-x","url":null,"abstract":"Polygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remains stable throughout life, we explore the potential of PRS to optimize existing screening programs. Via an integrated modelling approach, we quantify the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs (abdominal aortic aneurysm, breast cancer, colorectal cancer, coronary artery disease, hypertension, prostate cancer, and type 2 diabetes). We identify individuals at high genetic risk (PRS OR>2) and very high genetic risk (PRS OR>3) and estimate the optimal screening ages for these genetically high-risk individuals, based on the equivalent risk to population-level risk at recommended screening ages. We then leverage published data on differential mortality and other outcomes, with and without screening-based interventions, to assess the potential benefits of tailoring screening age based on genetic risk. Very high risk individuals reach the risk level associated with usual starting screening age on average 10.8 years earlier, high risk individuals 8.9 years earlier and reduced risk individuals (OR<0.5) 16.8 years later. During this time, case enrichment (the ratio of the percentage of cases in the high PRS risk group and in the total population) in the high risk group is between 1.7 and 3.0, depending on the disease. Across all seven diseases, appropriate interventions following PRS-guided screening could reduce premature deaths in high-risk individuals by 23.3%. Knowledge of genetic risk, measured using PRS, has the potential to deliver substantial public health benefits when aggregated across conditions, and could reduce premature mortality by tailoring existing screening programs.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"65 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005176","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}
How biological machines harness ATP to drive mechanical work remains a crucial question. Structural studies of protein-translocating AAA+ machines proposed a coupled and sequential translocation process, whereby ATP hydrolysis events lead to short threading steps. Yet, direct real-time observation of these events remains elusive. Here, we employ single-molecule FRET spectroscopy to track substrate translocation through ClpB, a quality control AAA+ machine. We isolate ClpB and its substrate within lipid vesicles and find that translocation events, while dependent on ATP, take milliseconds, much faster than ATP hydrolysis times. Surprisingly, the translocation rate depends weakly on temperature and ATP concentration. Using three-color FRET experiments, we find that translocation events can occur bidirectionally but are not always complete. Replacing ATP with the slowly hydrolysable analog ATPγS abolishes both rapid translocation and directionality. These results indicate a fast, stochastic Brownian-motor-like mechanism, redefining how ATP is coupled with mechanical action in AAA+ machines.
{"title":"A stochastic mechanism drives fast substrate translocation in the AAA+ machine ClpB","authors":"Remi Casier, Dorit Levy, Inbal Riven, Yoav Barak, Gilad Haran","doi":"10.1038/s41467-026-68478-1","DOIUrl":"https://doi.org/10.1038/s41467-026-68478-1","url":null,"abstract":"How biological machines harness ATP to drive mechanical work remains a crucial question. Structural studies of protein-translocating AAA+ machines proposed a coupled and sequential translocation process, whereby ATP hydrolysis events lead to short threading steps. Yet, direct real-time observation of these events remains elusive. Here, we employ single-molecule FRET spectroscopy to track substrate translocation through ClpB, a quality control AAA+ machine. We isolate ClpB and its substrate within lipid vesicles and find that translocation events, while dependent on ATP, take milliseconds, much faster than ATP hydrolysis times. Surprisingly, the translocation rate depends weakly on temperature and ATP concentration. Using three-color FRET experiments, we find that translocation events can occur bidirectionally but are not always complete. Replacing ATP with the slowly hydrolysable analog ATPγS abolishes both rapid translocation and directionality. These results indicate a fast, stochastic Brownian-motor-like mechanism, redefining how ATP is coupled with mechanical action in AAA+ machines.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"276 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005975","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 : 2026-01-21DOI: 10.1038/s41467-025-67520-y
Liwei Jing, Mohammad Amini, Adolfo O. Fumega, Orlando J. Silveira, Jose L. Lado, Peter Liljeroth, Shawulienu Kezilebieke
Topological crystalline insulators host topological phases of matter protected by crystal symmetries. Despite the prediction of a two-dimensional topological crystalline insulator, materials challenges have, to the best of our knowledge, thus far prevented its experimental realization. Here we report the growth and characterization of bilayer SnTe on the 2H-NbSe2 substrate by molecular beam epitaxy and scanning tunneling microscopy. We experimentally observe bilayer SnTe experiences compressive strain and exhibits two anticorrelated, periodically modulated pairs of conducting edge states within a large band gap exceeding 0.2 eV. We identify these states as topological edge states through first-principles calculations. Finally, we experimentally probe the coupling of adjacent topological edge states and demonstrate the resulting energy shift driven by a combination of electrostatic interactions and tunneling coupling. Our work opens the door to investigations of tunable two-dimensional topological states, of potential impact for spintronics and nanoelectronics applications at room temperature.
{"title":"Strain-induced two-dimensional topological crystalline insulator in bilayer SnTe","authors":"Liwei Jing, Mohammad Amini, Adolfo O. Fumega, Orlando J. Silveira, Jose L. Lado, Peter Liljeroth, Shawulienu Kezilebieke","doi":"10.1038/s41467-025-67520-y","DOIUrl":"https://doi.org/10.1038/s41467-025-67520-y","url":null,"abstract":"Topological crystalline insulators host topological phases of matter protected by crystal symmetries. Despite the prediction of a two-dimensional topological crystalline insulator, materials challenges have, to the best of our knowledge, thus far prevented its experimental realization. Here we report the growth and characterization of bilayer SnTe on the 2H-NbSe2 substrate by molecular beam epitaxy and scanning tunneling microscopy. We experimentally observe bilayer SnTe experiences compressive strain and exhibits two anticorrelated, periodically modulated pairs of conducting edge states within a large band gap exceeding 0.2 eV. We identify these states as topological edge states through first-principles calculations. Finally, we experimentally probe the coupling of adjacent topological edge states and demonstrate the resulting energy shift driven by a combination of electrostatic interactions and tunneling coupling. Our work opens the door to investigations of tunable two-dimensional topological states, of potential impact for spintronics and nanoelectronics applications at room temperature.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"1 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006236","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 : 2026-01-20DOI: 10.1038/s41467-026-68729-1
Javier Martin-Broto,Antonio Casado,Gloria Marquina,Andres Redondo,Javier Martinez-Trufero,Claudia Valverde,Antonio Gutierrez,Daniel Bernabeu,Luis Ortega,Jose Merino,Rafael Ramos,Patricio Ledesma,Jose L Mondaza-Hernandez,David S Moura,Nadia Hindi
Exportin-1 (XPO-1) is related to drug resistance and poor prognosis in solid tumors. Selinexor, an XPO-1 inhibitor, has shown preclinical and clinical activity in sarcomas. This Phase I study explores the combination of gemcitabine and selinexor in a classic 3 + 3 design. Adult patients with selected advanced sarcomas receive gemcitabine and weekly selinexor in 21-day cycles. The main endpoint is to determine the recommended phase 2 dose (RP2D). Secondary end-points include safety, overall response rate (ORR), overall survival (OS), and quality of life. Seventeen patients are included in this study. One dose-limiting toxicity (grade 4 thrombocytopenia) is detected in dose-level +3, but the R2PD is established at dose-level +2 (gemcitabine at 1200 mg/m² at 10 mg/m²/min followed by 60 mg weekly selinexor) based on its better tolerability. The most frequent adverse events are neutropenia (82.4%) and thrombocytopenia (76.5%). The ORR is 31.25 %, and the median OS (mOS) is 39.5 months (95% CI, 12.4-67) with a 36-month OS rate of 50.2%. A phase II is currently exploring this combination in leiomyosarcoma and malignant peripheral nerve sheath tumors. Trial registration: NCT04595994.
{"title":"Gemcitabine plus selinexor in selective advanced sarcomas: a phase I of the Spanish group for research on sarcoma study.","authors":"Javier Martin-Broto,Antonio Casado,Gloria Marquina,Andres Redondo,Javier Martinez-Trufero,Claudia Valverde,Antonio Gutierrez,Daniel Bernabeu,Luis Ortega,Jose Merino,Rafael Ramos,Patricio Ledesma,Jose L Mondaza-Hernandez,David S Moura,Nadia Hindi","doi":"10.1038/s41467-026-68729-1","DOIUrl":"https://doi.org/10.1038/s41467-026-68729-1","url":null,"abstract":"Exportin-1 (XPO-1) is related to drug resistance and poor prognosis in solid tumors. Selinexor, an XPO-1 inhibitor, has shown preclinical and clinical activity in sarcomas. This Phase I study explores the combination of gemcitabine and selinexor in a classic 3 + 3 design. Adult patients with selected advanced sarcomas receive gemcitabine and weekly selinexor in 21-day cycles. The main endpoint is to determine the recommended phase 2 dose (RP2D). Secondary end-points include safety, overall response rate (ORR), overall survival (OS), and quality of life. Seventeen patients are included in this study. One dose-limiting toxicity (grade 4 thrombocytopenia) is detected in dose-level +3, but the R2PD is established at dose-level +2 (gemcitabine at 1200 mg/m² at 10 mg/m²/min followed by 60 mg weekly selinexor) based on its better tolerability. The most frequent adverse events are neutropenia (82.4%) and thrombocytopenia (76.5%). The ORR is 31.25 %, and the median OS (mOS) is 39.5 months (95% CI, 12.4-67) with a 36-month OS rate of 50.2%. A phase II is currently exploring this combination in leiomyosarcoma and malignant peripheral nerve sheath tumors. Trial registration: NCT04595994.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"99 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005184","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}
Despite that enhancing site utilization (Usite) of single atoms (SAs) is crucial in electrocatalysis beyond increasing intrinsic activity and site density, numerous SAs are inaccessible during reaction due to the dense micropores and disordered stacking of carbon particles. Here, the enhancement for Usite of SAs is achieved through a surfactant-assis'ted freeze-casting (SAFC) strategy. The sodium dodecyl sulfate (SDS)-modified Fe-doped zeolitic imidazolate framework-8 (Fe/ZIF-8) particles assemble into single-layer two-dimensional (2D) superstructures along the ice-crystal. During pyrolysis, the dual-stress effect derived from SDS shell and tight alignment of particles induces Fe/ZIF-8 to transform into concave and mesopore-rich carbon. 2D FeNC with optimized structures at both macro- and micro-scales exhibits enhanced electron/mass transport capabilities, achieving near-100% Usite of SAs and a half-wave potential of 0.958 V for oxygen reduction in alkali. This SAFC strategy demonstrates its universality in improving the catalytic performance of various 2D MNCs across different electrocatalytic reactions.
{"title":"Near-100% site utilization of single atoms for efficient electrocatalysis.","authors":"Xiaoqian Wei,Meng An,Xiannong Tang,Jiamin Wei,Peng Yan,Yiwei Qiu,Dong Jiang,Yusuke Asakura,Xiaokai Song,Tour Asahi,Chengzhou Zhu,Yusuke Yamauchi","doi":"10.1038/s41467-025-67756-8","DOIUrl":"https://doi.org/10.1038/s41467-025-67756-8","url":null,"abstract":"Despite that enhancing site utilization (Usite) of single atoms (SAs) is crucial in electrocatalysis beyond increasing intrinsic activity and site density, numerous SAs are inaccessible during reaction due to the dense micropores and disordered stacking of carbon particles. Here, the enhancement for Usite of SAs is achieved through a surfactant-assis'ted freeze-casting (SAFC) strategy. The sodium dodecyl sulfate (SDS)-modified Fe-doped zeolitic imidazolate framework-8 (Fe/ZIF-8) particles assemble into single-layer two-dimensional (2D) superstructures along the ice-crystal. During pyrolysis, the dual-stress effect derived from SDS shell and tight alignment of particles induces Fe/ZIF-8 to transform into concave and mesopore-rich carbon. 2D FeNC with optimized structures at both macro- and micro-scales exhibits enhanced electron/mass transport capabilities, achieving near-100% Usite of SAs and a half-wave potential of 0.958 V for oxygen reduction in alkali. This SAFC strategy demonstrates its universality in improving the catalytic performance of various 2D MNCs across different electrocatalytic reactions.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"187 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005236","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 : 2026-01-20DOI: 10.1038/s41467-025-68121-5
Nicolas R Chevalier,Fanny Gayda,Nadège Bondurand,Ze Chi Chan,Thierry Savy,Monique Frain,Amira El Merhie,Lenuta Canta,Monica Dicu,Isabelle Le Parco,Léna Zig
Enteric neural crest cells (ENCCs) colonize the gut during embryogenesis and migration defects give rise to Hirschsprung disease (HD). Mutations in GDNF/RET and EDN3/EDNRB are known to be causal in HD. Here, we show that migrating ENCCs in mice exhibit endogenous EDN3/EDNRB-gated calcium activity, mediated by chloride channels, T-type Ca2+ channels and inositol trisphosphate-sensitive intracellular-store release. We find that inhibiting Ca2+ activity results in ENCC migration defects, while exciting it promotes migration by increasing ENCC contractility and traction force to the extracellular matrix. Our study demonstrates that embryonic endothelin-mediated neural crest migration and adult endothelin-mediated vasoconstriction is one and the same phenomenon, taking place in different cell types. Our results suggest a functional link between rare mutations of CACNA1H (the gene encoding CaV3.2) and HD, and pave the way for understanding neurocristopathies in terms of neural crest cell bioelectric activity deficits.
{"title":"Endothelin-3 and T-type Ca2+ channels drive enteric neural crest cell calcium activity, contractility and migration.","authors":"Nicolas R Chevalier,Fanny Gayda,Nadège Bondurand,Ze Chi Chan,Thierry Savy,Monique Frain,Amira El Merhie,Lenuta Canta,Monica Dicu,Isabelle Le Parco,Léna Zig","doi":"10.1038/s41467-025-68121-5","DOIUrl":"https://doi.org/10.1038/s41467-025-68121-5","url":null,"abstract":"Enteric neural crest cells (ENCCs) colonize the gut during embryogenesis and migration defects give rise to Hirschsprung disease (HD). Mutations in GDNF/RET and EDN3/EDNRB are known to be causal in HD. Here, we show that migrating ENCCs in mice exhibit endogenous EDN3/EDNRB-gated calcium activity, mediated by chloride channels, T-type Ca2+ channels and inositol trisphosphate-sensitive intracellular-store release. We find that inhibiting Ca2+ activity results in ENCC migration defects, while exciting it promotes migration by increasing ENCC contractility and traction force to the extracellular matrix. Our study demonstrates that embryonic endothelin-mediated neural crest migration and adult endothelin-mediated vasoconstriction is one and the same phenomenon, taking place in different cell types. Our results suggest a functional link between rare mutations of CACNA1H (the gene encoding CaV3.2) and HD, and pave the way for understanding neurocristopathies in terms of neural crest cell bioelectric activity deficits.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"22 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005284","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}
The healing of infected tendons is hindered by mechanical dysfunction, tissue adhesion, bacterial colonization, and immune imbalance. Inspired by the biphasic "adhesion-lubrication" structure of tendon sheaths, we developed a Janus hydrogel, named HAPP@H-EXO, for spatiotemporal repair. The material exhibits antifatigue properties and redistributes mechanical stress through a dynamic network formed by norbornylated PVA and boronic acid-modified hyaluronic acid-PVA. Its high-adhesion side integrates tissue via borate and hydrogen bonds, whereas the lotus leaf-induced low-adhesion side prevents postsurgical adhesion. The incorporation of oligo-polyethyleneimine and phenylboronic acid groups traps and kills bacteria, overcoming resistance. The pH-responsive release of hypoxic tendon stem cell exosomes reprogrammes macrophages via inhibition of the NF-κB pathway, reducing inflammation and promoting regeneration. In an infected Achilles tendon model, HAPP@H-EXO eliminated MRSA, suppressed early inflammation, and enhanced regeneration. Within 8 weeks, it significantly improved biomechanical strength, prevented adhesion, and restored motor function, establishing a mechanoimmunotherapeutic strategy for infected tissue regeneration.
{"title":"Bionic Janus hydrogel drives infected Achilles tendon regeneration via mechano-immune spatiotemporal steering.","authors":"Jie Li,Zishuo Wang,Wenjing Yang,Yuchen Zhang,Yanjun Wang,Xuhui Wang,Hongrui Wang,Yang Xie,Shuogui Xu,Yan Shang,Chunyu Xue,Yuntong Zhang,Shuo Fang","doi":"10.1038/s41467-026-68514-0","DOIUrl":"https://doi.org/10.1038/s41467-026-68514-0","url":null,"abstract":"The healing of infected tendons is hindered by mechanical dysfunction, tissue adhesion, bacterial colonization, and immune imbalance. Inspired by the biphasic \"adhesion-lubrication\" structure of tendon sheaths, we developed a Janus hydrogel, named HAPP@H-EXO, for spatiotemporal repair. The material exhibits antifatigue properties and redistributes mechanical stress through a dynamic network formed by norbornylated PVA and boronic acid-modified hyaluronic acid-PVA. Its high-adhesion side integrates tissue via borate and hydrogen bonds, whereas the lotus leaf-induced low-adhesion side prevents postsurgical adhesion. The incorporation of oligo-polyethyleneimine and phenylboronic acid groups traps and kills bacteria, overcoming resistance. The pH-responsive release of hypoxic tendon stem cell exosomes reprogrammes macrophages via inhibition of the NF-κB pathway, reducing inflammation and promoting regeneration. In an infected Achilles tendon model, HAPP@H-EXO eliminated MRSA, suppressed early inflammation, and enhanced regeneration. Within 8 weeks, it significantly improved biomechanical strength, prevented adhesion, and restored motor function, establishing a mechanoimmunotherapeutic strategy for infected tissue regeneration.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"123 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005515","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}
G proteins and arrestins are key transducers for G protein-coupled receptor (GPCR) signaling, mediating distinct downstream pathways. Recent evidence suggests that G proteins and β-arrestins (βarrs) can directly or functionally interact. However, the molecular details and functional consequences of Gα-βarr interactions remain poorly understood. Here, we quantify the binding affinities between βarr1 and Gαs or Gαi1 in various activation states using microscale thermophoresis (MST). βarr1 in the active conformational ensemble state favors binding, whereas Gα activation status is less determinant. Hydrogen/deuterium exchange mass spectrometry reveals distinct conformational changes between Gαs versus Gαi1 upon βarr1 binding, suggesting differential binding mechanism between Gαs-βarr1 and Gαi1-βarr1 complexes. Both the Ras-like domain and the α-helical domain of Gα contribute to complex formation. Functionally, a BODIPY-FL-GTPγS assay shows that βarr1 does not alter GDP/GTP turnover of Gαs or Gαi1, whereas β-strand XX (βXX) release assays demonstrate that Gαs enhances βarr1 C-tail release. Together, these results propose molecular mechanism of the interaction and asymmetric functional coupling within Gα-βarr complexes and uncover a previously underappreciated layer of GPCR signal transduction.
{"title":"Functional and structural insights into interactions between β-Arrestin 1 and Gαs or Gαi1.","authors":"Longhan Duan,Hyunbin Kim,Yeongjun Suh,Donghoon Ahn,Seungmi Kim,Jaekyung Hyun,Yonghoon Kwon,Jihye Seong,Ka Young Chung","doi":"10.1038/s41467-026-68690-z","DOIUrl":"https://doi.org/10.1038/s41467-026-68690-z","url":null,"abstract":"G proteins and arrestins are key transducers for G protein-coupled receptor (GPCR) signaling, mediating distinct downstream pathways. Recent evidence suggests that G proteins and β-arrestins (βarrs) can directly or functionally interact. However, the molecular details and functional consequences of Gα-βarr interactions remain poorly understood. Here, we quantify the binding affinities between βarr1 and Gαs or Gαi1 in various activation states using microscale thermophoresis (MST). βarr1 in the active conformational ensemble state favors binding, whereas Gα activation status is less determinant. Hydrogen/deuterium exchange mass spectrometry reveals distinct conformational changes between Gαs versus Gαi1 upon βarr1 binding, suggesting differential binding mechanism between Gαs-βarr1 and Gαi1-βarr1 complexes. Both the Ras-like domain and the α-helical domain of Gα contribute to complex formation. Functionally, a BODIPY-FL-GTPγS assay shows that βarr1 does not alter GDP/GTP turnover of Gαs or Gαi1, whereas β-strand XX (βXX) release assays demonstrate that Gαs enhances βarr1 C-tail release. Together, these results propose molecular mechanism of the interaction and asymmetric functional coupling within Gα-βarr complexes and uncover a previously underappreciated layer of GPCR signal transduction.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"30 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005574","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 : 2026-01-20DOI: 10.1038/s41467-026-68572-4
Tao Liu,Zhicheng Jing
The composition of Earth's Fe-rich liquid outer core has long been debated. Available models incorporating light elements, such as Si, O, C, S, and H, cannot explain the seismically low velocity layer in the uppermost outer core (E' layer). Here we employ first-principles molecular dynamics simulations to determine the density and sound velocity (VP) of Fe-Mg liquids under outer core conditions, which were unknown previously. Results show that the presence of Mg slightly decreases the VP of liquid Fe, in contrast to the enhancing effects of other light elements. Our modeling suggests that 0.5-1.79 wt% Mg is required to match seismically observed core densities and velocities. Such amount of Mg could have entered the outermost outer core following the Moon-forming giant impact, thereby providing a viable explanation for the formation of the E' layer and contributing to the slight Mg depletion in the bulk silicate Earth relative to chondritic meteorites.
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