Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of therapeutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucia...Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of therapeutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of biological and chemical factors,leaving room for improvement.In this study,we present a structureconstrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS inhibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework’s effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets.展开更多
A series of barium-tungstate-based phosphors doped with different concentrations of Dy<sup>3+</sup> were synthesized by solid-state reaction method. Photoluminescence properties and decay lifetime of Dy<...A series of barium-tungstate-based phosphors doped with different concentrations of Dy<sup>3+</sup> were synthesized by solid-state reaction method. Photoluminescence properties and decay lifetime of Dy<sup>3+</sup>-doped BaWO<sub>4</sub> samples were studied. The results indicated that luminescent properties of BaWO<sub>4</sub>:Dy<sup>3+</sup> depended on the Dy<sup>3+</sup> concentration, and the inner energy could transfer from to Dy<sup>3+</sup>. The quality of the light was checked by estimating CIE parameters, and the results showed that BaWO<sub>4</sub>:Dy<sup>3+</sup> was a potential candidate as blue-green luminescent materials in white LED because of its excellent emission spectrum excited by UV light.展开更多
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
基金supported by National Key Research and Development Program of China(Grant Nos.:2022YFC3400504 and 2023YFC2305904)the Strategic Priority Research Program of the Chinese Academy of Sciences,China(Grant Nos.:XDB0830203 and XDB0830200)+2 种基金the National Natural Science Foundation of China(Grant Nos.:82204278,31960198,T2225002,and 82273855)SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program,China(Grant No.:E2G805H)Shanghai Municipal Science and Technology Major Project,China,and Key Technologies R&D Program of Guangdong Province,China(Grant No.:2023B1111030004).
文摘Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of therapeutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of biological and chemical factors,leaving room for improvement.In this study,we present a structureconstrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS inhibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework’s effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets.
文摘A series of barium-tungstate-based phosphors doped with different concentrations of Dy<sup>3+</sup> were synthesized by solid-state reaction method. Photoluminescence properties and decay lifetime of Dy<sup>3+</sup>-doped BaWO<sub>4</sub> samples were studied. The results indicated that luminescent properties of BaWO<sub>4</sub>:Dy<sup>3+</sup> depended on the Dy<sup>3+</sup> concentration, and the inner energy could transfer from to Dy<sup>3+</sup>. The quality of the light was checked by estimating CIE parameters, and the results showed that BaWO<sub>4</sub>:Dy<sup>3+</sup> was a potential candidate as blue-green luminescent materials in white LED because of its excellent emission spectrum excited by UV light.
