The influence of hydrogen on magnetization is of substantial interest to spintronics. Understanding and controlling this phenomenon at the atomic scale, in particular in nanoscale systems, is crucial. In this study, we used scanning tunneling microscopy (STM) combined with a nickelocene molecule to sense the spin of a hydrogen-loaded nanoscale Co island grown on Cu(111). Magnetic exchange maps obtained from the molecular tip revealed the presence of a hydrogen superstructure and a 90° rotation of the magnetization compared to the pristine island. Ab initio calculations corroborate these observations, indicating that hydrogen hybridization with Co atoms on the island surface drives the spin reorientation of the island. This reorientation is further reinforced by hydrogen penetration into the island that locates at the Co/Cu interface. However, the subsurface sensitivity of the magnetic exchange maps indicates that this effect is limited. Our study provides valuable microscopic insights into the chemical control of magnetism at the nanoscale.
{"title":"Molecular spin-probe sensing of H-mediated changes in Co nanomagnets","authors":"Alex Fétida, Olivier Bengone, Christine Goyhenex, Fabrice Scheurer, Roberto Robles, Nicolás Lorente, Laurent Limot","doi":"10.1126/sciadv.ads1456","DOIUrl":"https://doi.org/10.1126/sciadv.ads1456","url":null,"abstract":"The influence of hydrogen on magnetization is of substantial interest to spintronics. Understanding and controlling this phenomenon at the atomic scale, in particular in nanoscale systems, is crucial. In this study, we used scanning tunneling microscopy (STM) combined with a nickelocene molecule to sense the spin of a hydrogen-loaded nanoscale Co island grown on Cu(111). Magnetic exchange maps obtained from the molecular tip revealed the presence of a hydrogen superstructure and a 90° rotation of the magnetization compared to the pristine island. Ab initio calculations corroborate these observations, indicating that hydrogen hybridization with Co atoms on the island surface drives the spin reorientation of the island. This reorientation is further reinforced by hydrogen penetration into the island that locates at the Co/Cu interface. However, the subsurface sensitivity of the magnetic exchange maps indicates that this effect is limited. Our study provides valuable microscopic insights into the chemical control of magnetism at the nanoscale.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"65 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393995","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}
Dominique Armstrong, Cheng-Yen Chang, Monica J. Hong, Linda Green, Yichao Shen, William Hudson, Kelsey E. Mauk, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Brianna Burns, Chad J. Creighton, Alexandre Carisey, Xiang H.-F. Zhang, Neil J. McKenna, Sung Wook Kang, Hyun-Sung Lee, William Decker, David B. Corry, Farrah Kheradmand
Adaptive immunity is critical in eliminating tumors, but cancer-intrinsic factors can subvert this function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in solid tumors and correlates with poor survival, but its role in tumorigenesis and antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN , a tumor suppressor, in human non–small cell lung cancers (NSCLC). Here, we show that constitutive expression of human MAGE-A4 with Pten loss in mouse airway epithelia results in metastatic adenocarcinoma. Tumors showed distinct enrichment in IgA + CD138 + CXCR4 + plasma cells (PCs) and increased expression of CXCL12 in endothelial cells. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138 + IgA + PCs surrounding tumors. Abrogation of PCs decreased tumor burden, increased activated T cell infiltration, and reduced CD163 + CD206 + macrophages in the MAGE-A4–induced lung tumors. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA + PCs in the lungs.
{"title":"MAGE-A4 induces non–small cell lung cancer and tumor-promoting plasma cell accumulation","authors":"Dominique Armstrong, Cheng-Yen Chang, Monica J. Hong, Linda Green, Yichao Shen, William Hudson, Kelsey E. Mauk, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Brianna Burns, Chad J. Creighton, Alexandre Carisey, Xiang H.-F. Zhang, Neil J. McKenna, Sung Wook Kang, Hyun-Sung Lee, William Decker, David B. Corry, Farrah Kheradmand","doi":"10.1126/sciadv.ads4227","DOIUrl":"https://doi.org/10.1126/sciadv.ads4227","url":null,"abstract":"Adaptive immunity is critical in eliminating tumors, but cancer-intrinsic factors can subvert this function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in solid tumors and correlates with poor survival, but its role in tumorigenesis and antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of <jats:italic>PTEN</jats:italic> , a tumor suppressor, in human non–small cell lung cancers (NSCLC). Here, we show that constitutive expression of human <jats:italic>MAGE-A4</jats:italic> with <jats:italic>Pten</jats:italic> loss in mouse airway epithelia results in metastatic adenocarcinoma. Tumors showed distinct enrichment in IgA <jats:sup>+</jats:sup> CD138 <jats:sup>+</jats:sup> CXCR4 <jats:sup>+</jats:sup> plasma cells (PCs) and increased expression of CXCL12 in endothelial cells. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138 <jats:sup>+</jats:sup> IgA <jats:sup>+</jats:sup> PCs surrounding tumors. Abrogation of PCs decreased tumor burden, increased activated T cell infiltration, and reduced CD163 <jats:sup>+</jats:sup> CD206 <jats:sup>+</jats:sup> macrophages in the MAGE-A4–induced lung tumors. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA <jats:sup>+</jats:sup> PCs in the lungs.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"13 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393743","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}
Peihang Jiang, Fangyang Huang, Liqiang Chen, Hao Zhou, Yudi Deng, Lian Li, Mao Chen, Yuan Huang
Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell “NETwork” of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.
{"title":"Intercellular NETwork-facilitated sarcoplasmic reticulum targeting for myocardial ischemia-reperfusion injury treatment","authors":"Peihang Jiang, Fangyang Huang, Liqiang Chen, Hao Zhou, Yudi Deng, Lian Li, Mao Chen, Yuan Huang","doi":"10.1126/sciadv.adr4333","DOIUrl":"https://doi.org/10.1126/sciadv.adr4333","url":null,"abstract":"Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> -ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell “NETwork” of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"41 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393748","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}
Kimia Kamelian, Benjamin Sievers, Michael Chen-Xu, Sam Turner, Mark Tsz Kin Cheng, Mazharul Altaf, Steven A. Kemp, Adam Abdullahi, Kata Csiba, Dami A. Collier, Petra Mlcochova, Bo Meng, Rachel B. Jones, The CITIID-NIHR BioResource COVID-19 Collaboration, Derek Smith, John Bradley, Kenneth G. C. Smith, Rainer Doffinger, Rona M. Smith, Ravindra K. Gupta
Immune suppression poses a challenge to vaccine immunogenicity. We show that serum antibody neutralization against SARS-CoV-2 Omicron descendants was largely absent post-doses 1 and 2 in individuals with vasculitis treated with rituximab. Detectable and increasing neutralizing titers were observed post-doses 3 and 4, except for XBB. Rituximab in vasculitis exacerbates neutralization deficits over standard immunosuppressive therapy, although impairment resolves over time since dosing. We observed discordance between detectable IgG binding and neutralizing activity specifically in the context of rituximab use, with high proportions of individuals showing reasonable IgG titer but no neutralization. ADCC response was more frequently detectable compared to neutralization in the context of rituximab, indicating that a notable proportion of binding antibodies are non-neutralizing. Therefore, use of rituximab is associated with severe impairment in neutralization against Omicron descendants despite repeated vaccinations, with better preservation of non-neutralizing antibody activity.
{"title":"Humoral responses to SARS-CoV-2 vaccine in vasculitis-related immune suppression","authors":"Kimia Kamelian, Benjamin Sievers, Michael Chen-Xu, Sam Turner, Mark Tsz Kin Cheng, Mazharul Altaf, Steven A. Kemp, Adam Abdullahi, Kata Csiba, Dami A. Collier, Petra Mlcochova, Bo Meng, Rachel B. Jones, The CITIID-NIHR BioResource COVID-19 Collaboration, Derek Smith, John Bradley, Kenneth G. C. Smith, Rainer Doffinger, Rona M. Smith, Ravindra K. Gupta","doi":"","DOIUrl":"","url":null,"abstract":"<div >Immune suppression poses a challenge to vaccine immunogenicity. We show that serum antibody neutralization against SARS-CoV-2 Omicron descendants was largely absent post-doses 1 and 2 in individuals with vasculitis treated with rituximab. Detectable and increasing neutralizing titers were observed post-doses 3 and 4, except for XBB. Rituximab in vasculitis exacerbates neutralization deficits over standard immunosuppressive therapy, although impairment resolves over time since dosing. We observed discordance between detectable IgG binding and neutralizing activity specifically in the context of rituximab use, with high proportions of individuals showing reasonable IgG titer but no neutralization. ADCC response was more frequently detectable compared to neutralization in the context of rituximab, indicating that a notable proportion of binding antibodies are non-neutralizing. Therefore, use of rituximab is associated with severe impairment in neutralization against Omicron descendants despite repeated vaccinations, with better preservation of non-neutralizing antibody activity.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 7","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq3342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mintu Chandra, Amy K. Kendall, Marijn G. J. Ford, Lauren P. Jackson
Endosomes are vital cellular hubs for sorting protein cargoes. Retromer (VPS26/VPS35/VPS29) binds multiple sorting nexin (SNX) proteins on endosomal membranes, but assembly mechanisms of metazoan SNX/Retromer complexes remain elusive. We combine biochemical and biophysical approaches with AlphaFold modeling to identify a previously unidentified direct interaction between SNX27 and VARP. A full biochemical reconstitution system using purified proteins systematically tests how and when coats are recruited to membranes to generate tubules. We demonstrate and measure how specific combinations of Retromer with SNX27, ESCPE-1 (SNX2/SNX6), or both complexes, remodel membranes containing physiological cargo and phospholipids. SNX27, alone and with Retromer, remodels membranes with PI(3)P and PDZbm cargo. ESCPE-1 deforms membranes with bis-phosphoinositides and CI-MPR cargo but surprisingly does not recruit Retromer. VARP co-immunoprecipitates all coat components in cells and is required to reconstitute a proposed endosomal “supercomplex” (SNX27, ESCPE-1, and Retromer) in vitro. These data suggest VARP regulates metazoan endosomal coat assembly to promote cargo sorting out of endosomes.
{"title":"VARP binds SNX27 to promote endosomal supercomplex formation on membranes","authors":"Mintu Chandra, Amy K. Kendall, Marijn G. J. Ford, Lauren P. Jackson","doi":"","DOIUrl":"","url":null,"abstract":"<div >Endosomes are vital cellular hubs for sorting protein cargoes. Retromer (VPS26/VPS35/VPS29) binds multiple sorting nexin (SNX) proteins on endosomal membranes, but assembly mechanisms of metazoan SNX/Retromer complexes remain elusive. We combine biochemical and biophysical approaches with AlphaFold modeling to identify a previously unidentified direct interaction between SNX27 and VARP. A full biochemical reconstitution system using purified proteins systematically tests how and when coats are recruited to membranes to generate tubules. We demonstrate and measure how specific combinations of Retromer with SNX27, ESCPE-1 (SNX2/SNX6), or both complexes, remodel membranes containing physiological cargo and phospholipids. SNX27, alone and with Retromer, remodels membranes with PI(3)P and PDZbm cargo. ESCPE-1 deforms membranes with bis-phosphoinositides and CI-MPR cargo but surprisingly does not recruit Retromer. VARP co-immunoprecipitates all coat components in cells and is required to reconstitute a proposed endosomal “supercomplex” (SNX27, ESCPE-1, and Retromer) in vitro. These data suggest VARP regulates metazoan endosomal coat assembly to promote cargo sorting out of endosomes.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 7","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr9340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The conjugate additions of nucleophiles to conjugate acceptors are among the most powerful hetero-carbon bond formation reactions. The conjugate addition normally occurs via a β-nucleophilic addition, resulting in the formation of a stabilized α-carbanion intermediate that can be subsequently quenched by electrophiles or protons. Nevertheless, the inverse conjugate addition involving an α-specific nucleophilic addition remains less explored because of the electronic mismatch. In this research, we disclosed an α-specific nucleophilic addition of the nucleophiles including Py·HF, TBACl, HOR, H 2 O, H 218 O, RCO 2 H, and pyrazole to conjugate acceptors concurrent with a trifluoromethylation. This umpolung and inversely regioselective conjugate addition, enabled by a visible light–induced redox photocatalysis, occurred via an unusual α-nucleophilic addition other than the normal β-nucleophilic addition to efficiently generate diverse α-functionalized CF 3 -containing amides/esters. The broad substrate scope, excellent functional-group tolerance, and versatile late-stage derivatizations as well as the biologically and functionally important CF 3 -containing products demonstrated the potential applications of this protocol in materials, agrochemicals, and pharmaceutical chemistry.
{"title":"Inverse conjugate additions of acrylic amides and esters with F/Cl/O/N-nucleophiles and CF 3 + reagents","authors":"Xiaoxiao Liu, Yuan Kou, Hao Wu, Tong-Xin Liu, Qingfeng Liu, Zhiguo Zhang, Xingjie Zhang, Guisheng Zhang","doi":"10.1126/sciadv.adt2715","DOIUrl":"https://doi.org/10.1126/sciadv.adt2715","url":null,"abstract":"The conjugate additions of nucleophiles to conjugate acceptors are among the most powerful hetero-carbon bond formation reactions. The conjugate addition normally occurs via a β-nucleophilic addition, resulting in the formation of a stabilized α-carbanion intermediate that can be subsequently quenched by electrophiles or protons. Nevertheless, the inverse conjugate addition involving an α-specific nucleophilic addition remains less explored because of the electronic mismatch. In this research, we disclosed an α-specific nucleophilic addition of the nucleophiles including Py·HF, TBACl, HOR, H <jats:sub>2</jats:sub> O, H <jats:sub>2</jats:sub> <jats:sup>18</jats:sup> O, RCO <jats:sub>2</jats:sub> H, and pyrazole to conjugate acceptors concurrent with a trifluoromethylation. This umpolung and inversely regioselective conjugate addition, enabled by a visible light–induced redox photocatalysis, occurred via an unusual α-nucleophilic addition other than the normal β-nucleophilic addition to efficiently generate diverse α-functionalized CF <jats:sub>3</jats:sub> -containing amides/esters. The broad substrate scope, excellent functional-group tolerance, and versatile late-stage derivatizations as well as the biologically and functionally important CF <jats:sub>3</jats:sub> -containing products demonstrated the potential applications of this protocol in materials, agrochemicals, and pharmaceutical chemistry.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393750","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}
Yiding Zhong, Wei Tang, He Gui, Qincheng Sheng, Huxiu Xu, Kecheng Qin, Xinyu Guo, Huayong Yang, Jun Zou
Developing a wearable, active, dynamic face-changing mask for human camouflage and expression is a substantial challenge. Many organisms achieve camouflage and expression through skin deformation and color change. Inspired by this, we report a reprogrammable chemical fluid skin, which achieves deformation through fluids like the skin of a pufferfish and achieves color change function like the skin of a chameleon. Based on the skin, we design a soft mask that allows switching between at least eight human faces at a time. The soft mask is lightweight, thin, and fits the wearer’s head. Its actuation is silent and safe, and can realize facial switching, including facial color and shape. By wearing the soft mask, robots can show facial changes and expression modulation, and humans can change their faces as needed. Our work enables the implementation of transforming a human into other humans in the real world to achieve camouflage and expression, which, to date, exists only in people’s imagination.
{"title":"Human camouflage and expression via soft mask from reprogrammable chemical fluid skin","authors":"Yiding Zhong, Wei Tang, He Gui, Qincheng Sheng, Huxiu Xu, Kecheng Qin, Xinyu Guo, Huayong Yang, Jun Zou","doi":"10.1126/sciadv.adq6141","DOIUrl":"https://doi.org/10.1126/sciadv.adq6141","url":null,"abstract":"Developing a wearable, active, dynamic face-changing mask for human camouflage and expression is a substantial challenge. Many organisms achieve camouflage and expression through skin deformation and color change. Inspired by this, we report a reprogrammable chemical fluid skin, which achieves deformation through fluids like the skin of a pufferfish and achieves color change function like the skin of a chameleon. Based on the skin, we design a soft mask that allows switching between at least eight human faces at a time. The soft mask is lightweight, thin, and fits the wearer’s head. Its actuation is silent and safe, and can realize facial switching, including facial color and shape. By wearing the soft mask, robots can show facial changes and expression modulation, and humans can change their faces as needed. Our work enables the implementation of transforming a human into other humans in the real world to achieve camouflage and expression, which, to date, exists only in people’s imagination.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"56 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393789","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}
Fei Qin, Runyu Cao, Wenjing Cui, Xuemei Bai, Jiahua Yuan, Yuling Zhang, Yaxing Liu, Nan Cao, Na Dong, Min Zhou, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Bingyu Liu, Chengjiang Gao
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal α-synuclein (α-syn) within dopaminergic neurons in the substantia nigra region of the brain. Despite excessive accumulation of α-syn being key to the pathogenesis of PD, the mechanisms governing its clearance remain elusive. In this study, we found that the endosomal sorting complex required for transport (ESCRT) system plays a crucial role in capturing and facilitating the degradation of ubiquitinated α-syn. The E3 ubiquitin ligase Listerin was found to promote K27-linked polyubiquitination of α-syn, directing it to the endosome for subsequent degradation. We showed that the deletion of the Listerin gene exacerbates the neurodegenerative progression in a mouse model of PD, whereas the overexpression of Listerin effectively mitigates disease progression in PD mice. Consequently, our study reveals a mechanism for α-syn degradation and identifies Listerin as a promising therapeutic target for the treatment of PD.
{"title":"Listerin promotes α-synuclein degradation to alleviate Parkinson’s disease through the ESCRT pathway","authors":"Fei Qin, Runyu Cao, Wenjing Cui, Xuemei Bai, Jiahua Yuan, Yuling Zhang, Yaxing Liu, Nan Cao, Na Dong, Min Zhou, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Bingyu Liu, Chengjiang Gao","doi":"10.1126/sciadv.adp3672","DOIUrl":"https://doi.org/10.1126/sciadv.adp3672","url":null,"abstract":"Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal α-synuclein (α-syn) within dopaminergic neurons in the substantia nigra region of the brain. Despite excessive accumulation of α-syn being key to the pathogenesis of PD, the mechanisms governing its clearance remain elusive. In this study, we found that the endosomal sorting complex required for transport (ESCRT) system plays a crucial role in capturing and facilitating the degradation of ubiquitinated α-syn. The E3 ubiquitin ligase Listerin was found to promote K27-linked polyubiquitination of α-syn, directing it to the endosome for subsequent degradation. We showed that the deletion of the Listerin gene exacerbates the neurodegenerative progression in a mouse model of PD, whereas the overexpression of Listerin effectively mitigates disease progression in PD mice. Consequently, our study reveals a mechanism for α-syn degradation and identifies Listerin as a promising therapeutic target for the treatment of PD.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"151 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393799","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}
Moritz Ertelt, Rocco Moretti, Jens Meiler, Clara T. Schoeder
Machine learning (ML) is changing the world of computational protein design, with data-driven methods surpassing biophysical-based methods in experimental success. However, they are most often reported as case studies, lack integration and standardization, and are therefore hard to objectively compare. In this study, we established a streamlined and diverse toolbox for methods that predict amino acid probabilities inside the Rosetta software framework that allows for the side-by-side comparison of these models. Subsequently, existing protein fitness landscapes were used to benchmark novel ML methods in realistic protein design settings. We focused on the traditional problems of protein design: sampling and scoring. A major finding of our study is that ML approaches are better at purging the sampling space from deleterious mutations. Nevertheless, scoring resulting mutations without model fine-tuning showed no clear improvement over scoring with Rosetta. We conclude that ML now complements, rather than replaces, biophysical methods in protein design.
{"title":"Self-supervised machine learning methods for protein design improve sampling but not the identification of high-fitness variants","authors":"Moritz Ertelt, Rocco Moretti, Jens Meiler, Clara T. Schoeder","doi":"10.1126/sciadv.adr7338","DOIUrl":"https://doi.org/10.1126/sciadv.adr7338","url":null,"abstract":"Machine learning (ML) is changing the world of computational protein design, with data-driven methods surpassing biophysical-based methods in experimental success. However, they are most often reported as case studies, lack integration and standardization, and are therefore hard to objectively compare. In this study, we established a streamlined and diverse toolbox for methods that predict amino acid probabilities inside the Rosetta software framework that allows for the side-by-side comparison of these models. Subsequently, existing protein fitness landscapes were used to benchmark novel ML methods in realistic protein design settings. We focused on the traditional problems of protein design: sampling and scoring. A major finding of our study is that ML approaches are better at purging the sampling space from deleterious mutations. Nevertheless, scoring resulting mutations without model fine-tuning showed no clear improvement over scoring with Rosetta. We conclude that ML now complements, rather than replaces, biophysical methods in protein design.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"7 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393999","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}
Shangsong Li, Yuchen Wang, Zixiao Liu, Baohong Chen, Mingzhu Liu, Ximin He, Shu Yang
Pyroelectric materials that can generate electric charges when subjected to temperature changes are of interest for renewable energy. However, current flexible pyroelectric energy harvesters suffer from low output. Here, we present a nanocomposite of liquid crystalline elastomer (LCE) and pyroelectric lead zirconate titanate (PZT) nanoparticles and demonstrate a flexible heat harvesting device with high output. The overall pyroelectricity is enhanced by the secondary pyroelectricity generated from the thermal stress imposed on the LCE. Calculations and simulations corroborate with experiments, suggesting that the monodomain LCE/PZT with fixed boundaries offers the most enhancement. At a maximum heating rate of 0.20 kelvin per second, the fixed monodomain film (42.7 weight % PZT) shows an output current of 2.81 nanoamperes and a voltage of 6.23 volts, corresponding to a pyroelectric coefficient p of −4.01 nanocoulombs per square centimeter per kelvin, 49% higher than that of the widely used polyvinylidene fluoride. Our energy harvester can charge capacitors and power electronic devices such as light-emitting diodes.
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