ACS Central Science最新文献_第3页

Modulating Neutrophil Extracellular Trap Formation In Vivo with Locoregional Precision Using Differently Charged Self-Assembled Hydrogels 利用不同电荷的自组装水凝胶调节中性粒细胞胞外陷阱在体内的局部精确形成

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-12 DOI: 10.1021/acscentsci.4c0219810.1021/acscentsci.4c02198

Tania L. Lopez-Silva, Caleb F. Anderson and Joel P. Schneider*,

{"title":"Modulating Neutrophil Extracellular Trap Formation In Vivo with Locoregional Precision Using Differently Charged Self-Assembled Hydrogels","authors":"Tania L. Lopez-Silva, Caleb F. Anderson and Joel P. Schneider*, ","doi":"10.1021/acscentsci.4c0219810.1021/acscentsci.4c02198","DOIUrl":"https://doi.org/10.1021/acscentsci.4c02198https://doi.org/10.1021/acscentsci.4c02198","url":null,"abstract":"Neutrophil extracellular traps (NETs) are DNA networks released by neutrophils, first described as a defense response against pathogens but have since been associated with numerous inflammatory diseases. Diverse physical material properties have been shown to promote NET formation. Herein, we report the discovery that the charge of self-assembled peptide hydrogels predictably modulates the formation of NETs in vivo within the implanted material. Positively charged gels induce rapid NET release, whereas negatively charged gels do not. This differential immune response to our self-assembled peptide gels enabled the development of a material platform that allows rheostat-like modulation over the degree of NET formation with anatomical and locoregional control.Self-assembled peptide-based hydrogel strategy for controlling the formation of neutrophil extracellular traps (NETs) in vivo with anatomical and locoregional precision, and the ability to regulate the degree of the response.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"465–478 465–478"},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c02198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulating Neutrophil Extracellular Trap Formation In Vivo with Locoregional Precision Using Differently Charged Self-Assembled Hydrogels. 利用不同电荷的自组装水凝胶调节中性粒细胞胞外陷阱在体内的局部精确形成。

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-12 eCollection Date: 2025-03-26 DOI: 10.1021/acscentsci.4c02198

Tania L Lopez-Silva, Caleb F Anderson, Joel P Schneider

引用次数: 0

Challenging Reaction Prediction Models to Generalize to Novel Chemistry 具有挑战性的反应预测模型推广到新的化学

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-12 DOI: 10.1021/acscentsci.5c0005510.1021/acscentsci.5c00055

John Bradshaw, Anji Zhang, Babak Mahjour, David E. Graff, Marwin H. S. Segler and Connor W. Coley*,

{"title":"Challenging Reaction Prediction Models to Generalize to Novel Chemistry","authors":"John Bradshaw, Anji Zhang, Babak Mahjour, David E. Graff, Marwin H. S. Segler and Connor W. Coley*, ","doi":"10.1021/acscentsci.5c0005510.1021/acscentsci.5c00055","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00055https://doi.org/10.1021/acscentsci.5c00055","url":null,"abstract":"Deep learning models for anticipating the products of organic reactions have found many use cases, including validating retrosynthetic pathways and constraining synthesis-based molecular design tools. Despite compelling performance on popular benchmark tasks, strange and erroneous predictions sometimes ensue when using these models in practice. The core issue is that common benchmarks test models in an in-distribution setting, whereas many real-world uses for these models are in out-of-distribution settings and require a greater degree of extrapolation. To better understand how current reaction predictors work in out-of-distribution domains, we report a series of more challenging evaluations of a prototypical SMILES-based deep learning model. First, we illustrate how performance on randomly sampled data sets is overly optimistic compared to performance when generalizing to new patents or new authors. Second, we conduct time splits that evaluate how models perform when tested on reactions published years after those in their training set, mimicking real-world deployment. Finally, we consider extrapolation across reaction classes to reflect what would be required for the discovery of novel reaction types. This panel of tasks can reveal the capabilities and limitations of today’s reaction predictors, acting as a crucial first step in the development of tomorrow’s next-generation models capable of reaction discovery.Despite excellent benchmark performance, ML models for reaction prediction can struggle on real-world data─we evaluate these limitations by challenging a model on different out-of-distribution tasks.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"539–549 539–549"},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer 铱光敏剂通过线粒体调控巨噬细胞和肿瘤细胞的协同抗肿瘤免疫治疗

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-11 DOI: 10.1021/acscentsci.4c0215610.1021/acscentsci.4c02156

Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo* and Yuncong Chen*,

{"title":"Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer","authors":"Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo* and Yuncong Chen*, ","doi":"10.1021/acscentsci.4c0215610.1021/acscentsci.4c02156","DOIUrl":"https://doi.org/10.1021/acscentsci.4c02156https://doi.org/10.1021/acscentsci.4c02156","url":null,"abstract":"Mitochondrial targeting has emerged as an attractive method for antitumor treatment. However, most of the mitochondria targeted drugs focused on inhibiting tumor cells, while their potential for activation of immune responses in the tumor microenvironment has rarely been described. In this study, we report a photosensitive iridium complex MitoIrL2, which enabled the simultaneous mitochondrial modulation of macrophages and tumor cells to achieve synergistic antitumor immunity. The adjustment of the mitochondrial respiratory chain, HIF-1α, and the NF-κB pathway in macrophages drove the metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis, converting protumor M2 into the antitumor M1 phenotype. Downregulated expression of immunosuppressive checkpoint SIRPα has also been observed on macrophages. Meanwhile, the mitochondrial targeting MitoIrL2 enhanced the immunogenic cell death of tumor cells and reversed the immunosuppressive tumor microenvironment, which activated the systemic immune response and established long-term immune memory in vivo. This work illustrates a promising strategy to simultaneously regulate macrophages toward the antitumor phenotype and enhance immunogenic cell death in tumor cells for synergistic antitumor immunotherapy.A mitochondrial targeting iridium photosensitizer could achieve direct immune activation of both macrophages and tumor cells, synergistically enhancing antitumor immunity via mitochondrial modulation.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"441–451 441–451"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c02156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Researchers Face Challenges Devising a PFAS-Free Future 研究人员面临设计无pfas未来的挑战

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-11 DOI: 10.1021/acscentsci.5c0038910.1021/acscentsci.5c00389

XiaoZhi Lim,

引用次数: 0

Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer. 铱光敏剂通过线粒体调控巨噬细胞和肿瘤细胞的协同抗肿瘤免疫治疗。

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-11 eCollection Date: 2025-03-26 DOI: 10.1021/acscentsci.4c02156

Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo, Yuncong Chen

{"title":"Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer.","authors":"Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo, Yuncong Chen","doi":"10.1021/acscentsci.4c02156","DOIUrl":"10.1021/acscentsci.4c02156","url":null,"abstract":"Mitochondrial targeting has emerged as an attractive method for antitumor treatment. However, most of the mitochondria targeted drugs focused on inhibiting tumor cells, while their potential for activation of immune responses in the tumor microenvironment has rarely been described. In this study, we report a photosensitive iridium complex MitoIrL2, which enabled the simultaneous mitochondrial modulation of macrophages and tumor cells to achieve synergistic antitumor immunity. The adjustment of the mitochondrial respiratory chain, HIF-1α, and the NF-κB pathway in macrophages drove the metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis, converting protumor M2 into the antitumor M1 phenotype. Downregulated expression of immunosuppressive checkpoint SIRPα has also been observed on macrophages. Meanwhile, the mitochondrial targeting MitoIrL2 enhanced the immunogenic cell death of tumor cells and reversed the immunosuppressive tumor microenvironment, which activated the systemic immune response and established long-term immune memory in vivo. This work illustrates a promising strategy to simultaneously regulate macrophages toward the antitumor phenotype and enhance immunogenic cell death in tumor cells for synergistic antitumor immunotherapy.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"441-451"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Promiscuity in Nature Extends to Central Protein Biosynthetic Machinery. 自然界的乱交延伸到中心蛋白质生物合成机制。

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-10 eCollection Date: 2025-03-26 DOI: 10.1021/acscentsci.5c00387

April L Lukowski

引用次数: 0

Promiscuity in Nature Extends to Central Protein Biosynthetic Machinery 自然界的乱交延伸到中心蛋白质生物合成机制

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-10 DOI: 10.1021/acscentsci.5c0038710.1021/acscentsci.5c00387

April L. Lukowski,

引用次数: 0

Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System. 文库物质的多样性尺度：mRNA文库多样性尺度对快速系统发现靶向蛋白质的大环肽的影响

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-10 eCollection Date: 2025-03-26 DOI: 10.1021/acscentsci.4c01021

Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa, Hiroaki Suga

{"title":"Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System.","authors":"Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa, Hiroaki Suga","doi":"10.1021/acscentsci.4c01021","DOIUrl":"10.1021/acscentsci.4c01021","url":null,"abstract":"Macrocyclic peptides make up a unique class of modalities known for their high affinity, specificity, and ability to modulate protein-protein interactions, including receptor activation. Messenger RNA display, including the Random Nonstandard Peptides Integrated Discovery (RaPID) system, stands out in identifying target-specific macrocyclic peptides, producing potent binders with low to subnanomolar dissociation constants against diverse targets. It has often been discussed that this success is partly attributed to the vast library of over a trillion different peptide sequences expressed from the corresponding mRNA sequences. However, the impact of library scales on the identification of various binders has not been experimentally validated. Here, we report the RaPID selections against an ectodomain of a receptor tyrosine kinase MET using peptide libraries ranging from 106 to 1014 unique members of mRNAs. We thoroughly analyzed the outcomes, including the binding kinetic properties, of the enriched peptide families. This study provides valuable guidelines for designing libraries with various numbers of sequences and selection conditions to enrich macrocyclic peptides with the desired characteristics.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"431-440"},"PeriodicalIF":12.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System 文库物质的多样性尺度：mRNA文库多样性尺度对快速系统发现靶向蛋白质的大环肽的影响

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-03-09 DOI: 10.1021/acscentsci.4c0102110.1021/acscentsci.4c01021

Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa and Hiroaki Suga*,

{"title":"Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System","authors":"Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa and Hiroaki Suga*, ","doi":"10.1021/acscentsci.4c0102110.1021/acscentsci.4c01021","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01021https://doi.org/10.1021/acscentsci.4c01021","url":null,"abstract":"Macrocyclic peptides make up a unique class of modalities known for their high affinity, specificity, and ability to modulate protein–protein interactions, including receptor activation. Messenger RNA display, including the Random Nonstandard Peptides Integrated Discovery (RaPID) system, stands out in identifying target-specific macrocyclic peptides, producing potent binders with low to subnanomolar dissociation constants against diverse targets. It has often been discussed that this success is partly attributed to the vast library of over a trillion different peptide sequences expressed from the corresponding mRNA sequences. However, the impact of library scales on the identification of various binders has not been experimentally validated. Here, we report the RaPID selections against an ectodomain of a receptor tyrosine kinase MET using peptide libraries ranging from 106 to 1014 unique members of mRNAs. We thoroughly analyzed the outcomes, including the binding kinetic properties, of the enriched peptide families. This study provides valuable guidelines for designing libraries with various numbers of sequences and selection conditions to enrich macrocyclic peptides with the desired characteristics.The initial sampling of the sequence space determines the evolution of the families by the RaPID selection pressure for slow dissociation rates.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"431–440 431–440"},"PeriodicalIF":12.7,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0