In growing children,growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest.Interestingly,one type of fracture injuries within the growth plate achieve amazing ...In growing children,growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest.Interestingly,one type of fracture injuries within the growth plate achieve amazing self-healing,however,the mechanism is unclear.Using this type of fracture mouse model,we discovered the activation of Hedgehog(Hh)signaling in the injured growth plate,which could activate chondrocytes in growth plate and promote cartilage repair.展开更多
Deep learning(DL)is currently revolutionizing peptide drug development due to both computational advances and the substantial recent expansion of digitized biological data.However,progress in oligopeptide drug develop...Deep learning(DL)is currently revolutionizing peptide drug development due to both computational advances and the substantial recent expansion of digitized biological data.However,progress in oligopeptide drug development has been limited,likely due to the lack of suitable datasets and difficulty in identifying informative features to use as inputs for DL models.Here,we utilized an unsupervised deep learning model to learn a semantic pattern based on the intrinsically disordered regions of~171 known osteogenic proteins.Subsequently,oligopeptides were generated from this semantic pattern based on Monte Carlo simulation,followed by in vivo functional characterization.A five amino acid oligopeptide(AIB5P)had strong bone-formation-promoting effects,as determined in multiple mouse models(e.g.,osteoporosis,fracture,and osseointegration of implants).Mechanistically,we showed that AIB5P promotes osteogenesis by binding to the integrinα5 subunit and thereby activating FAK signaling.In summary,we successfully established an oligopeptide discovery strategy based on a DL model and demonstrated its utility from cytological screening to animal experimental verification.展开更多
The growth plate plays a crucial role in long bone development and elongation,housing stem cells that contribute to bone formation.This study investigates the role of primary cilia,specialized organelles that regulate...The growth plate plays a crucial role in long bone development and elongation,housing stem cells that contribute to bone formation.This study investigates the role of primary cilia,specialized organelles that regulate stem cell fate,in the development and repair of long bones.Here,we report the presence of primary cilia in all zones of the growth plate,particularly during embryonic development.Spatial transcriptomics and analysis of conditional knockout(CKO)mice identified that primary cilia mediate critical developmental signaling pathways within the growth plate.Disruption of primary cilia in growth plate chondroblasts or osteoblasts impaired long bone development by activating the Wnt signaling pathway and disrupting the cellular stemness.This resulted in elevated Mmp13 secretion,abnormal mineralization,and structural defects,ultimately hindering bone elongation.Time-lapse imaging showed an increased frequency of abnormal mitosis and a reduced rate of asymmetric division in skeletal stem cells(SSCs)from CKO mice.In conclusion,our findings indicated that primary cilia are critical for long bone development,regulating stem cell fate through key signaling pathways.Loss of primary cilia leads to excessive Wnt signaling and disruption of SSC stemness,impairing bone elongation.This study highlights the essential role of primary cilia in bone development and suggests potential therapeutic targets for skeletal disorders.展开更多
Artificial photosynthesis is an ideal method for solar-to-chemical energy conversion,wherein solar energy is stored in the form of chemical bonds of solar fuels.In particular,the photocatalytic reduction of CO_(2)has ...Artificial photosynthesis is an ideal method for solar-to-chemical energy conversion,wherein solar energy is stored in the form of chemical bonds of solar fuels.In particular,the photocatalytic reduction of CO_(2)has attracted considerable attention due to its dual benefits of fossil fuel production and CO_(2)pollution reduction.However,CO_(2)is a comparatively stable molecule and its photoreduction is thermodynamically and kinetically challenging.Thus,the photocatalytic efficiency of CO_(2)reduction is far below the level of industrial applications.Therefore,development of low-cost cocatalysts is crucial for significantly decreasing the activation energy of CO_(2)to achieving efficient photocatalytic CO_(2)reduction.Herein,we have reported the use of a Ni_(2)P material that can serve as a robust cocatalyst by cooperating with a photosensitizer for the photoconversion of CO_(2).An effective strategy for engineering Ni_(2)P in an ultrathin layered structure has been proposed to improve the CO_(2)adsorption capability and decrease the CO_(2)activation energy,resulting in efficient CO_(2)reduction.A series of physicochemical characterizations including X-ray diffraction(XRD),X-ray photoelectron spectroscopy(XPS),transmission electron microscopy(TEM),high-resolution transmission electron microscopy(HRTEM),and atomic force microscopy(AFM)were used to demonstrate the successful preparation of ultrathin Ni_(2)P nanosheets.The XRD and XPS results confirm the successful synthesis of Ni_(2)P from Ni(OH)2 by a low temperature phosphidation process.According to the TEM images,the prepared Ni_(2)P nanosheets exhibit a 2D and near-transparent sheet-like structure,suggesting their ultrathin thickness.The AFM images further demonstrated this result and also showed that the height of the Ni_(2)P nanosheets is ca 1.5 nm.The photoluminescence(PL)spectroscopy results revealed that the Ni_(2)P material could efficiently promote the separation of the photogenerated electrons and holes in[Ru(bpy)3]Cl2?6H2O.More importantly,the Ni_(2)P nanosheets could more efficiently promote the charge transfer and charge separation rate of[Ru(bpy)3]Cl2?6H2O compared with the Ni_(2)P particles.In addition,the electrochemical experiments revealed that the Ni_(2)P nanosheets,with their high active surface area and charge conductivity,can provide more active centers for CO_(2)conversion and accelerate the interfacial reaction dynamics.These results strongly suggest that the Ni_(2)P nanosheets are a promising material for photocatalytic CO_(2)reduction,and can achieve a CO generation rate of 64.8μmol·h^(-1),which is 4.4 times higher than that of the Ni_(2)P particles.In addition,the XRD and XPS measurements of the used Ni_(2)P nanosheets after the six cycles of the photocatalytic CO_(2)reduction reaction demonstrated their high stability.Overall,this study offers a new function for the 2D transition-metal phosphide catalysts in photocatalytic CO_(2)reduction.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFA1103200)National Natural Science Foundation Projects of China(81822012,82061130222,81771043,92049201,82001070)+1 种基金Shanghai Academic Leader of Science and Technology Innovation Action Plan(20XD1424000)the Shanghai Experimental Animal Research Project of Science and Technology Innovation Action Plan(8191101676,201409006400)。
文摘In growing children,growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest.Interestingly,one type of fracture injuries within the growth plate achieve amazing self-healing,however,the mechanism is unclear.Using this type of fracture mouse model,we discovered the activation of Hedgehog(Hh)signaling in the injured growth plate,which could activate chondrocytes in growth plate and promote cartilage repair.
基金This work was supported by grants from the National Science and Technology Major Project of China(2016YFC1102705)the National Natural Science Foundation Projects of China(8206113022,92049201,81770873,81822012,81771043,81802193,81970898)+1 种基金the Shanghai Academic Leader of Science and Technology Innovation Action Plan(20XD1424000)the Shanghai Experimental Animal Research Project of Science and Technology Innovation Action Plan(201409006400).
文摘Deep learning(DL)is currently revolutionizing peptide drug development due to both computational advances and the substantial recent expansion of digitized biological data.However,progress in oligopeptide drug development has been limited,likely due to the lack of suitable datasets and difficulty in identifying informative features to use as inputs for DL models.Here,we utilized an unsupervised deep learning model to learn a semantic pattern based on the intrinsically disordered regions of~171 known osteogenic proteins.Subsequently,oligopeptides were generated from this semantic pattern based on Monte Carlo simulation,followed by in vivo functional characterization.A five amino acid oligopeptide(AIB5P)had strong bone-formation-promoting effects,as determined in multiple mouse models(e.g.,osteoporosis,fracture,and osseointegration of implants).Mechanistically,we showed that AIB5P promotes osteogenesis by binding to the integrinα5 subunit and thereby activating FAK signaling.In summary,we successfully established an oligopeptide discovery strategy based on a DL model and demonstrated its utility from cytological screening to animal experimental verification.
基金supported by National Key R&D Program of China(2022YFA1103200)National,Natural Science Foundation Projects of China(U23A20444,82270963,82425014,82301048)+2 种基金Shanghai Municipal Education Commission Scientific Research Innovation Plan Project(2023ZKZD29)China Postdoctoral Science Foundation General Project(2022M722406)Shanghai Science and Technology Innovation Action Plan:Qimingxing Project(Sailing Special Program,23YF1450500).
文摘The growth plate plays a crucial role in long bone development and elongation,housing stem cells that contribute to bone formation.This study investigates the role of primary cilia,specialized organelles that regulate stem cell fate,in the development and repair of long bones.Here,we report the presence of primary cilia in all zones of the growth plate,particularly during embryonic development.Spatial transcriptomics and analysis of conditional knockout(CKO)mice identified that primary cilia mediate critical developmental signaling pathways within the growth plate.Disruption of primary cilia in growth plate chondroblasts or osteoblasts impaired long bone development by activating the Wnt signaling pathway and disrupting the cellular stemness.This resulted in elevated Mmp13 secretion,abnormal mineralization,and structural defects,ultimately hindering bone elongation.Time-lapse imaging showed an increased frequency of abnormal mitosis and a reduced rate of asymmetric division in skeletal stem cells(SSCs)from CKO mice.In conclusion,our findings indicated that primary cilia are critical for long bone development,regulating stem cell fate through key signaling pathways.Loss of primary cilia leads to excessive Wnt signaling and disruption of SSC stemness,impairing bone elongation.This study highlights the essential role of primary cilia in bone development and suggests potential therapeutic targets for skeletal disorders.
文摘Artificial photosynthesis is an ideal method for solar-to-chemical energy conversion,wherein solar energy is stored in the form of chemical bonds of solar fuels.In particular,the photocatalytic reduction of CO_(2)has attracted considerable attention due to its dual benefits of fossil fuel production and CO_(2)pollution reduction.However,CO_(2)is a comparatively stable molecule and its photoreduction is thermodynamically and kinetically challenging.Thus,the photocatalytic efficiency of CO_(2)reduction is far below the level of industrial applications.Therefore,development of low-cost cocatalysts is crucial for significantly decreasing the activation energy of CO_(2)to achieving efficient photocatalytic CO_(2)reduction.Herein,we have reported the use of a Ni_(2)P material that can serve as a robust cocatalyst by cooperating with a photosensitizer for the photoconversion of CO_(2).An effective strategy for engineering Ni_(2)P in an ultrathin layered structure has been proposed to improve the CO_(2)adsorption capability and decrease the CO_(2)activation energy,resulting in efficient CO_(2)reduction.A series of physicochemical characterizations including X-ray diffraction(XRD),X-ray photoelectron spectroscopy(XPS),transmission electron microscopy(TEM),high-resolution transmission electron microscopy(HRTEM),and atomic force microscopy(AFM)were used to demonstrate the successful preparation of ultrathin Ni_(2)P nanosheets.The XRD and XPS results confirm the successful synthesis of Ni_(2)P from Ni(OH)2 by a low temperature phosphidation process.According to the TEM images,the prepared Ni_(2)P nanosheets exhibit a 2D and near-transparent sheet-like structure,suggesting their ultrathin thickness.The AFM images further demonstrated this result and also showed that the height of the Ni_(2)P nanosheets is ca 1.5 nm.The photoluminescence(PL)spectroscopy results revealed that the Ni_(2)P material could efficiently promote the separation of the photogenerated electrons and holes in[Ru(bpy)3]Cl2?6H2O.More importantly,the Ni_(2)P nanosheets could more efficiently promote the charge transfer and charge separation rate of[Ru(bpy)3]Cl2?6H2O compared with the Ni_(2)P particles.In addition,the electrochemical experiments revealed that the Ni_(2)P nanosheets,with their high active surface area and charge conductivity,can provide more active centers for CO_(2)conversion and accelerate the interfacial reaction dynamics.These results strongly suggest that the Ni_(2)P nanosheets are a promising material for photocatalytic CO_(2)reduction,and can achieve a CO generation rate of 64.8μmol·h^(-1),which is 4.4 times higher than that of the Ni_(2)P particles.In addition,the XRD and XPS measurements of the used Ni_(2)P nanosheets after the six cycles of the photocatalytic CO_(2)reduction reaction demonstrated their high stability.Overall,this study offers a new function for the 2D transition-metal phosphide catalysts in photocatalytic CO_(2)reduction.
