Laser powder bed fusion(LPBF)combined with reaction bonding(RB)of Al particles is an effective method for preparing high-performance 3D Al_(2)O_(3) ceramic foams.However,the indistinct microstructure evolution hinders...Laser powder bed fusion(LPBF)combined with reaction bonding(RB)of Al particles is an effective method for preparing high-performance 3D Al_(2)O_(3) ceramic foams.However,the indistinct microstructure evolution hinders the regulation of pore features and the improvement of synthetic properties.Herein,the microstructure evolution of the Al_(2)O_(3) ceramic foams during the LPBF/RB process is clarified by various characterization methods,and the corresponding mechanical property modulation is realized by optimizing LPBF parameters,organic binder(E12 epoxy resin)content,heating rate,sintering time,and coral-like Al_(2)O_(3) content.The expansion from Al_(2)O_(3) outward growth and Al granule precipitation counteracts the shrinkage from E12 decomposition and Al_(2)O_(3) sintering,resulting in an ultra-low shrinkage of 0.94%–3.01%.The pore structures of particle packing pores,hollow spheres,and microporous structures allow a tunable porosity of 52.6%–73.7%.The in-situ formation of multi-scale features including hollow spheres,flaky grains,whiskers,nanofibers,and bond bridges brings about a remarkably high bending strength of 6.5–38.3 MPa.Ourfindings reveal the relationship between microstructure evolution and property optimization of high-performance ceramic foams,with potential significance for microstructure design and practical application.展开更多
The combination of high efficiency and environmental stability is vital to promote the commercial appli-cations of microwave absorption(MA)materials,yet remains challenging in the absence of facile routes.Here,we put ...The combination of high efficiency and environmental stability is vital to promote the commercial appli-cations of microwave absorption(MA)materials,yet remains challenging in the absence of facile routes.Here,we put forward a graphene-reinforced construct approach for one-pot synthesis of 3D intercon-nected magnetic-dielectric frameworks via pre-functionalization and subsequent assembly.Multiple in-teractions among discrete precursors are capable of manipulating the confined growth and interfacial self-assembly.Significant enhancements in MA properties are triggered in a straightforward manner us-ing ultralow feeding fractions of graphene oxide nanosheet.The minimum reflection loss is up to-60.1 dB(99.9999%wave absorption)and the effective absorption bandwidth reaches 5.9 GHz(almost covering the Ku band).Remarkably,based on the optimization by ultralow concentrations of graphene,the as-prepared nanoarchitecture simultaneously integrates strong absorption,broad bandwidth,and low matching thick-ness.The embedded graphene nanosheets serve as high-speed electron transmission channels and hollow resonance cavities,facilitating multimode attenuations and impedance-matching characteristics.Mean-while,the graphene-reinforced framework suppresses the corrosion of magnetic components,whose cor-rosion rate reduces by an order of magnitude.This study provides a simple procedure to boost magnetic-dielectric absorbers for comprehensive MA performances and enhanced corrosion resistance.展开更多
Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic.Here,we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple rece...Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic.Here,we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain(RBD)scaffold protein(3R-NC)adjuvanted with a flagellin protein(KFD)(3R-NC+KFDi.n).In mice,the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year.This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG-and IgA-producing plasma cells,alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant.Based upon these preclinical findings,an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2(IAV)vaccine.With a favorable safety profile,the 3R-NC+KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions.To meet the challenge of frequently emerged variants,we further designed an updated triple-RBD scaffold protein with mutated RBD combinations,which can induce adaptable antibody responses to neutralize the newly emerging variants,including JN.1.Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.展开更多
The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Her...The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Here,we designed a chimeric tripleRBD immunogen,3Ro-NC,harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold.3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern.Notably,intranasal immunization with 3RoNC plus the mucosal adjuvant KFD(3Ro-NC+KFDi.n)elicits coordinated mucosal IgA and higher neutralizing antibody specificity(closer antigenic distance)against the Omicron variant.In Omicron-challenged human ACE2 transgenic mice,3Ro-NC+KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung(85.7-fold)and the nasal turbinate(13.6-fold).Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies.Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection,pathology and transmission potential.展开更多
B cell response plays a critical role against SARS-CoV-2 infection.However,little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection.Here,we ...B cell response plays a critical role against SARS-CoV-2 infection.However,little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection.Here,we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients,and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses.Via linking BCR to antigen specificity through sequencing(LIBRA-seq),we identified a distinct activated memory B cell subgroup(CD11c^(high) CD95^(high))had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells.Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection.The public antibody clonotypes were shared by distinct convalescent individuals.Moreover,several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain(RBD)or nucleoprotein(NP)via ELISA assay.Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro.Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.展开更多
Radiotherapy remains the mainstay for treatment of various types of human cancer;however,the clinical efficacy is often limited by radioresistance,in which the underlying mechanism is largely unknown.Here,using esopha...Radiotherapy remains the mainstay for treatment of various types of human cancer;however,the clinical efficacy is often limited by radioresistance,in which the underlying mechanism is largely unknown.Here,using esophageal squamous cell carcinoma(ESCC)as a model,we demonstrate that guanine nucleotide exchange factor 2(VAV2),which is overexpressed in most human cancers,plays an important role in primary and secondary radioresistance.We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation.展开更多
The high porosity and interconnectivity of scaffolds are critical for nutrient transmission in bone tis-sue engineering but usually lead to poor mechanical properties.Herein,a novel method that combines acid etching(A...The high porosity and interconnectivity of scaffolds are critical for nutrient transmission in bone tis-sue engineering but usually lead to poor mechanical properties.Herein,a novel method that combines acid etching(AE)with selective laser sintering(SLS)and reaction bonding(RB)of Al particles is pro-posed to realize highly improved porosity,interconnectivity,mechanical strength,and in vitro bioactivity in 3D Al_(2)O_(3) scaffolds.By controlling the oxidation and etching behaviors of Al particles,a tunable hol-low spherical feature can be obtained,which brings about the distinction in compressive response and fracture path.The prevention of microcrack propagation on the in situ formed hollow spheres results in unique near elastic buckling rather than traditional brittle fracture,allowing an unparalleled compressive strength of 3.72±0.17 MPa at a high porosity of 87.7%±0.4%and pore interconnectivity of 94.7%±0.4%.Furthermore,scaffolds with an optimized pore structure and superhydrophilic surface show excellent cell proliferation and adhesion properties.Our findings offer a promising strategy for the coexistence of out-standing mechanical and biological properties,with great potential for tissue engineering applications.展开更多
Cell metabolism plays vital roles in organismal development,but it has been much less studied than transcriptional and epigenetic control of developmental programs.The difficulty might be largely attributed to the lac...Cell metabolism plays vital roles in organismal development,but it has been much less studied than transcriptional and epigenetic control of developmental programs.The difficulty might be largely attributed to the lack of in situ metabolite assays.Genetically encoded fluorescent sensors are powerful tools for noninvasive metabolic monitoring in living cells and in vivo by highly spatiotemporal visualization.Among all living organisms,the NAD(H)and NADP(H)pools are essential for maintaining redox homeostasis and for modulating cellular metabolism.Here,we introduce NAD(H)and NADP(H)biosensors,present example assays in developing organisms,and describe promising prospects for how sensors contribute to developmental biology research.展开更多
Non-small-cell lung cancer(NSCLC)is the primary histopathological subtype of lung cancer and accounts for around 82%of all pulmonary neoplasms[1].Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene th...Non-small-cell lung cancer(NSCLC)is the primary histopathological subtype of lung cancer and accounts for around 82%of all pulmonary neoplasms[1].Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene that regulates cellular responses to stress through DNA damage repair and is frequently mutated in breast and ovarian cancers[2].Furthermore,previous studies have increasingly shown that the expression of BRCA1 and the relevant poly(ADP-ribose)polymerase inhibitors is related to the prognosis and therapeutic response of other tumors,including lung cancer[3,4].However,previous findings on the prognostic value of BRCA1 for NSCLC have been inconsistent or conflicting,which may be attributed to the small number of patients from a single center or disparity in the ratio of patients with lung adenocarcinoma(LUAD)versus squamous cell carcinoma(LUSC)[5].The aim of this study was to determine the prognostic value of BRCA1 in NSCLC and its association with immune infiltration.展开更多
文摘Laser powder bed fusion(LPBF)combined with reaction bonding(RB)of Al particles is an effective method for preparing high-performance 3D Al_(2)O_(3) ceramic foams.However,the indistinct microstructure evolution hinders the regulation of pore features and the improvement of synthetic properties.Herein,the microstructure evolution of the Al_(2)O_(3) ceramic foams during the LPBF/RB process is clarified by various characterization methods,and the corresponding mechanical property modulation is realized by optimizing LPBF parameters,organic binder(E12 epoxy resin)content,heating rate,sintering time,and coral-like Al_(2)O_(3) content.The expansion from Al_(2)O_(3) outward growth and Al granule precipitation counteracts the shrinkage from E12 decomposition and Al_(2)O_(3) sintering,resulting in an ultra-low shrinkage of 0.94%–3.01%.The pore structures of particle packing pores,hollow spheres,and microporous structures allow a tunable porosity of 52.6%–73.7%.The in-situ formation of multi-scale features including hollow spheres,flaky grains,whiskers,nanofibers,and bond bridges brings about a remarkably high bending strength of 6.5–38.3 MPa.Ourfindings reveal the relationship between microstructure evolution and property optimization of high-performance ceramic foams,with potential significance for microstructure design and practical application.
基金support from the National Natural Science Foundation of China(No.52073039)Major Special Projects of Sichuan Province(Nos.2019ZDZX0027 and 2019ZDZX0016).
文摘The combination of high efficiency and environmental stability is vital to promote the commercial appli-cations of microwave absorption(MA)materials,yet remains challenging in the absence of facile routes.Here,we put forward a graphene-reinforced construct approach for one-pot synthesis of 3D intercon-nected magnetic-dielectric frameworks via pre-functionalization and subsequent assembly.Multiple in-teractions among discrete precursors are capable of manipulating the confined growth and interfacial self-assembly.Significant enhancements in MA properties are triggered in a straightforward manner us-ing ultralow feeding fractions of graphene oxide nanosheet.The minimum reflection loss is up to-60.1 dB(99.9999%wave absorption)and the effective absorption bandwidth reaches 5.9 GHz(almost covering the Ku band).Remarkably,based on the optimization by ultralow concentrations of graphene,the as-prepared nanoarchitecture simultaneously integrates strong absorption,broad bandwidth,and low matching thick-ness.The embedded graphene nanosheets serve as high-speed electron transmission channels and hollow resonance cavities,facilitating multimode attenuations and impedance-matching characteristics.Mean-while,the graphene-reinforced framework suppresses the corrosion of magnetic components,whose cor-rosion rate reduces by an order of magnitude.This study provides a simple procedure to boost magnetic-dielectric absorbers for comprehensive MA performances and enhanced corrosion resistance.
基金National Key R&D program of China(Grant number:2022YFC2304204 to Y.-Q.C.,2021YFC2302602 to J.Y.)National Natural Science Foundation of China(grant number:82341041 to H.Y.and 92169104 to Y.-Q.C.)+1 种基金Shanghai Science and Technology Innovation Action Plan(Grant number:22Y11901000 to Q.W.)Shenzhen Science and Technology Program(Grant number:RCJC20210706092009004,JCYJ2020010914243811,KQTD20200820145822023 to Y.-Q.C.)supported this work in whole or in part.
文摘Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic.Here,we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain(RBD)scaffold protein(3R-NC)adjuvanted with a flagellin protein(KFD)(3R-NC+KFDi.n).In mice,the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year.This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG-and IgA-producing plasma cells,alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant.Based upon these preclinical findings,an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2(IAV)vaccine.With a favorable safety profile,the 3R-NC+KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions.To meet the challenge of frequently emerged variants,we further designed an updated triple-RBD scaffold protein with mutated RBD combinations,which can induce adaptable antibody responses to neutralize the newly emerging variants,including JN.1.Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.
基金This work was supported in whole or in part by the National Key R&D Program of China(grant number:2021YFC2302602 to JY)the strategic priority research program(grant number XDB29010101)+1 种基金key project(2020YJFK-Z-0149)of the Chinese Academy of Sciences(to Z-LS)This study was also supported by the National Natural Science Foundation of China(31970878 to JY,92169104 and 31970881 to Y-QC),Shenzhen Science and Technology Program (Grant number: RCJC20210706092009004 and JCYJ20190807154603596 to Y-QC).
文摘The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Here,we designed a chimeric tripleRBD immunogen,3Ro-NC,harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold.3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern.Notably,intranasal immunization with 3RoNC plus the mucosal adjuvant KFD(3Ro-NC+KFDi.n)elicits coordinated mucosal IgA and higher neutralizing antibody specificity(closer antigenic distance)against the Omicron variant.In Omicron-challenged human ACE2 transgenic mice,3Ro-NC+KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung(85.7-fold)and the nasal turbinate(13.6-fold).Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies.Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection,pathology and transmission potential.
基金supported by National Natural Science Foundation of China(31970881)and(82041046)to Y.Q.C.Shenzhen Science and Technology Program under Grant(JCYJ20190807154603596 and JCYJ20200109142438111)+2 种基金the National Key Research and Development Project(2020YFC0841700)to M.W.the National Natural Science Foundation of China(32041002)to D.Y.G.the Special Fund for COVID-19 Epidemic Prevention&Control of Zhuhai City of China granted to S.D.C.
文摘B cell response plays a critical role against SARS-CoV-2 infection.However,little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection.Here,we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients,and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses.Via linking BCR to antigen specificity through sequencing(LIBRA-seq),we identified a distinct activated memory B cell subgroup(CD11c^(high) CD95^(high))had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells.Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection.The public antibody clonotypes were shared by distinct convalescent individuals.Moreover,several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain(RBD)or nucleoprotein(NP)via ELISA assay.Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro.Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.
基金This project was supported by National Science Fund for Distinguished Young Scholars(81725015 to C.W.)Medical and Health Technology Innovation Project of Chinese Academy of Medical Sciences(2016-I2M-3-019 to D.L.,2016-I2M-4-002 to C.W.,2019-I2M-2-001 to D.L.and C.W.,2016-I2M-1-001 and 2019-12M-1-003 to W.T.)+1 种基金Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023027 to C.W.)National Natural Science Foundation of China(81988101 to D.L and C.W.).
文摘Radiotherapy remains the mainstay for treatment of various types of human cancer;however,the clinical efficacy is often limited by radioresistance,in which the underlying mechanism is largely unknown.Here,using esophageal squamous cell carcinoma(ESCC)as a model,we demonstrate that guanine nucleotide exchange factor 2(VAV2),which is overexpressed in most human cancers,plays an important role in primary and secondary radioresistance.We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation.
文摘The high porosity and interconnectivity of scaffolds are critical for nutrient transmission in bone tis-sue engineering but usually lead to poor mechanical properties.Herein,a novel method that combines acid etching(AE)with selective laser sintering(SLS)and reaction bonding(RB)of Al particles is pro-posed to realize highly improved porosity,interconnectivity,mechanical strength,and in vitro bioactivity in 3D Al_(2)O_(3) scaffolds.By controlling the oxidation and etching behaviors of Al particles,a tunable hol-low spherical feature can be obtained,which brings about the distinction in compressive response and fracture path.The prevention of microcrack propagation on the in situ formed hollow spheres results in unique near elastic buckling rather than traditional brittle fracture,allowing an unparalleled compressive strength of 3.72±0.17 MPa at a high porosity of 87.7%±0.4%and pore interconnectivity of 94.7%±0.4%.Furthermore,scaffolds with an optimized pore structure and superhydrophilic surface show excellent cell proliferation and adhesion properties.Our findings offer a promising strategy for the coexistence of out-standing mechanical and biological properties,with great potential for tissue engineering applications.
基金This research is supported by National Key Research and Development Program of China(2019YFA0904800 to Y.Zhao)NSFC(32030065,92049304,32121005 to Y.Zhao,31901033 to T.L.)+4 种基金Research Unit of New Techniques for Live-cell Metabolic Imaging(Chinese Academy of Medical Sciences,2019RU01,2019-I2M-5-013 to Y.Zhao)Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Y.Zhao)Innovative research team of high-level local universities in Shanghai,the Shanghai Science and Technology Commission(19YF1411300 to T.L.)China Postdoctoral Science Foundation(2019 M651413 to T.L.)the State Key Laboratory of Bioreactor Engineering,the Fundamental Research Funds for the Central Universities.
文摘Cell metabolism plays vital roles in organismal development,but it has been much less studied than transcriptional and epigenetic control of developmental programs.The difficulty might be largely attributed to the lack of in situ metabolite assays.Genetically encoded fluorescent sensors are powerful tools for noninvasive metabolic monitoring in living cells and in vivo by highly spatiotemporal visualization.Among all living organisms,the NAD(H)and NADP(H)pools are essential for maintaining redox homeostasis and for modulating cellular metabolism.Here,we introduce NAD(H)and NADP(H)biosensors,present example assays in developing organisms,and describe promising prospects for how sensors contribute to developmental biology research.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-014。
文摘Non-small-cell lung cancer(NSCLC)is the primary histopathological subtype of lung cancer and accounts for around 82%of all pulmonary neoplasms[1].Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene that regulates cellular responses to stress through DNA damage repair and is frequently mutated in breast and ovarian cancers[2].Furthermore,previous studies have increasingly shown that the expression of BRCA1 and the relevant poly(ADP-ribose)polymerase inhibitors is related to the prognosis and therapeutic response of other tumors,including lung cancer[3,4].However,previous findings on the prognostic value of BRCA1 for NSCLC have been inconsistent or conflicting,which may be attributed to the small number of patients from a single center or disparity in the ratio of patients with lung adenocarcinoma(LUAD)versus squamous cell carcinoma(LUSC)[5].The aim of this study was to determine the prognostic value of BRCA1 in NSCLC and its association with immune infiltration.