The Jiangmen Underground Neutrino Observatory(JUNO)is a large liquid scintillator detector designed to explore many topics in fundamental physics.In this study,the potential of searching for proton decay in the p→νK...The Jiangmen Underground Neutrino Observatory(JUNO)is a large liquid scintillator detector designed to explore many topics in fundamental physics.In this study,the potential of searching for proton decay in the p→νK^(+)mode with JUNO is investigated.The kaon and its decay particles feature a clear three-fold coincidence signature that results in a high efficiency for identification.Moreover,the excellent energy resolution of JUNO permits suppression of the sizable background caused by other delayed signals.Based on these advantages,the detection efficiency for the proton decay via p→νK^(+)is 36.9%±4.9%with a background level of 0.2±0.05(syst)±0.2(stat)events after 10 years of data collection.The estimated sensitivity based on 200 kton-years of exposure is 9.6×1033 years,which is competitive with the current best limits on the proton lifetime in this channel and complements the use of different detection technologies.展开更多
Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells ...Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications.Here,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors.We next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK cells.The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)motif.Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells.Collectively,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.展开更多
JUNO is a multi-purpose neutrino observatory under construction in the south of China.This publication presents new sensitivity estimates for the measurement of the △m_(31)^(2),△m_(21)^(2),sin^(2)θ_(12),and sin^(2)...JUNO is a multi-purpose neutrino observatory under construction in the south of China.This publication presents new sensitivity estimates for the measurement of the △m_(31)^(2),△m_(21)^(2),sin^(2)θ_(12),and sin^(2)θ_(13) oscillation parameters using reactor antineutrinos,which is one of the primary physics goals of the experiment.The sensitivities are obtained using the best knowledge available to date on the location and overburden of the experimental site,the nuclear reactors in the surrounding area and beyond,the detector response uncertainties,and the reactor antineutrino spectral shape constraints expected from the TAO satellite detector.It is found that the △m_(21)^(2) and sin^(2)θ_(12) oscillation parameters will be determined to 0.5%precision or better in six years of data collection.In the same period,the △m_(31)^(2) parameter will be determined to about 0.2%precision for each mass ordering hypothesis.The new precision represents approximately an order of magnitude improvement over existing constraints for these three parameters.展开更多
Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbil...Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell(hUCMSC)sheet on myocardial infarction(MI).Methods:hUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells.We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet.Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system.Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet.Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function,angiogenesis and left ventricular remodelling.Results:When transplanted to the infarcted mouse hearts,hUCMSC sheet significantly improved the retention and survival compared with cell suspension.At the early stage of MI,hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages,preserving the cardiomyocytes from acute injury.Moreover,the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue,providing mechanical support and routes for revascularsation.These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.Conclusions:hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs,mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.Translational perspective:Due to its excellent availability as well as superior local cellular retention and survival,allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs,such as modulating inflammation and enhancing angiogenesis.Moreover,the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial,further improving its clinical applicability.展开更多
The particular physicochemical properties of nanomaterials are able to elicit unique biological responses. The property activity relationship is usually established for in-depth understanding of toxicity mechanisms an...The particular physicochemical properties of nanomaterials are able to elicit unique biological responses. The property activity relationship is usually established for in-depth understanding of toxicity mechanisms and designing safer nanomaterials. In this study, the toxic role of specific crystallographic facets of a series of polyhedral lead sulfide (PbS) nanocrystals, including truncated octahedrons, cuboctahedrons, truncated cubes, and cubes, was investigated in human bronchial epithelial cells (BEAS-2B) and murine alveolar macrophages (RAW 264.7) cells./100} facets were found capable of triggering facet-dependent cellular oxidative stress and heavy metal stress responses, such as glutathione depletion, lipid peroxidation, reactive oxygen species (ROS) production, heme oxygenase-1 (HO-1) and metallothionein (MT) expression, and mitochondrial dysfunction, while {111} facets remained inert under biological conditions. The {100}-facet-dependent toxicity was ascribed to {100}-facet-dependent lead dissolution, while the low lead dissolution of {111} facets was due to the strong protection afforded by poly(vinyl pyrrolidone) during synthesis. Based on this facet-toxicity relationship, a "safe-by-design" strategy was designed to prevent lead dissolution from {100} facets through the formation of atomically thin lead-chloride adlayers, resulting in safer polyhedral PbS nanocrystals.展开更多
The Jiangmen Underground Neutrino Observatory(JUNO)features a 20 kt multi-purpose underground liquid scintillator sphere as its main detector.Some of JUNO's features make it an excellent location for^8B solar neut...The Jiangmen Underground Neutrino Observatory(JUNO)features a 20 kt multi-purpose underground liquid scintillator sphere as its main detector.Some of JUNO's features make it an excellent location for^8B solar neutrino measurements,such as its low-energy threshold,high energy resolution compared with water Cherenkov detectors,and much larger target mass compared with previous liquid scintillator detectors.In this paper,we present a comprehensive assessment of JUNO's potential for detecting^8B solar neutrinos via the neutrino-electron elastic scattering process.A reduced 2 MeV threshold for the recoil electron energy is found to be achievable,assuming that the intrinsic radioactive background^(238)U and^(232)Th in the liquid scintillator can be controlled to 10^(-17)g/g.With ten years of data acquisition,approximately 60,000 signal and 30,000 background events are expected.This large sample will enable an examination of the distortion of the recoil electron spectrum that is dominated by the neutrino flavor transformation in the dense solar matter,which will shed new light on the inconsistency between the measured electron spectra and the predictions of the standard three-flavor neutrino oscillation framework.IfDelta m^(2)_(21)=4.8times10^(-5);(7.5times10^(-5))eV^(2),JUNO can provide evidence of neutrino oscillation in the Earth at approximately the 3sigma(2sigma)level by measuring the non-zero signal rate variation with respect to the solar zenith angle.Moreover,JUNO can simultaneously measureDelta m^2_(21)using^8B solar neutrinos to a precision of 20% or better,depending on the central value,and to sub-percent precision using reactor antineutrinos.A comparison of these two measurements from the same detector will help understand the current mild inconsistency between the value of Delta m^2_(21)reported by solar neutrino experiments and the KamLAND experiment.展开更多
CRISPR/Cas-mediated genome editing in human pluripotent stem cells(hPSCs)offers unprecedented opportunities for developing in vitro disease modeling,drug screening and cell-based therapies.To efficiently deliver the C...CRISPR/Cas-mediated genome editing in human pluripotent stem cells(hPSCs)offers unprecedented opportunities for developing in vitro disease modeling,drug screening and cell-based therapies.To efficiently deliver the CRISPR components,here we developed two all-in-one vectors containing Cas9/gRNA and inducible Cas13d/gRNA cassettes for robust genome editing and RNA interference respectively.These vectors utilized the PiggyBac transposon system,which allows stable expression of CRISPR components in hPSCs.The Cas9 vector PB-CRISPR exhibited high efficiency(up to 99%)of inducing gene knockout in both protein-coding genes and long non-coding RNAs.The other inducible Cas13d vector achieved extremely high efficiency in RNA knockdown(98%knockdown for CD90)with optimized gRNA designs.Taken together,our PiggyBac CRISPR vectors can serve as powerful toolkits for studying gene functions in hPSCs.展开更多
基金supported by the Chinese Academy of Sciencesthe National Key R&D Program of China+22 种基金the CAS Center for Excellence in Particle PhysicsWuyi Universitythe Tsung-Dao Lee Institute of Shanghai Jiao Tong University in Chinathe Institut National de Physique Nucléaire et de Physique de Particules (IN2P3) in Francethe Istituto Nazionale di Fisica Nucleare (INFN) in Italythe Italian-Chinese collaborative research program MAECI-NSFCthe Fond de la Recherche Scientifique (F.R.S-FNRS)FWO under the "Excellence of Science-EOS" in Belgiumthe Conselho Nacional de Desenvolvimento Científico e Tecnològico in Brazilthe Agencia Nacional de Investigacion y Desarrollo in Chilethe Charles University Research Centrethe Ministry of Education,Youth,and Sports in Czech Republicthe Deutsche Forschungsgemeinschaft (DFG)the Helmholtz Associationthe Cluster of Excellence PRISMA+ in Germanythe Joint Institute of Nuclear Research (JINR)Lomonosov Moscow State University in Russiathe joint Russian Science Foundation (RSF)National Natural Science Foundation of China (NSFC) research programthe MOST and MOE in Taiwan,Chinathe Chulalongkorn UniversitySuranaree University of Technology in Thailandthe University of California at Irvine in USA
文摘The Jiangmen Underground Neutrino Observatory(JUNO)is a large liquid scintillator detector designed to explore many topics in fundamental physics.In this study,the potential of searching for proton decay in the p→νK^(+)mode with JUNO is investigated.The kaon and its decay particles feature a clear three-fold coincidence signature that results in a high efficiency for identification.Moreover,the excellent energy resolution of JUNO permits suppression of the sizable background caused by other delayed signals.Based on these advantages,the detection efficiency for the proton decay via p→νK^(+)is 36.9%±4.9%with a background level of 0.2±0.05(syst)±0.2(stat)events after 10 years of data collection.The estimated sensitivity based on 200 kton-years of exposure is 9.6×1033 years,which is competitive with the current best limits on the proton lifetime in this channel and complements the use of different detection technologies.
基金supported by startup funding from the Davidson School of Chemical Engineering and the College of Engineering at Purdue(X.B.)PICR Robbers New Investigators(X.B.),Showalter Research Trust(Young Investigator Award to X.B.)+2 种基金NSF CBET(grant no.2143064 to X.B.)NSF CBET(grant no.1943696 to X.L.L.)NIH NCI(grant no.R37CA265926 to X.B.).
文摘Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications.Here,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors.We next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK cells.The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)motif.Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells.Collectively,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.
基金Supported by the Chinese Academy of Sciencesthe National Key R&D Program of China+18 种基金the CAS Center for Excellence in Particle Physics,Wuyi Universitythe Tsung-Dao Lee Institute of Shanghai Jiao Tong University in Chinathe Institut National de Physique Nucléaire et de Physique de Particules(IN2P3)in Francethe Istituto Nazionale di Fisica Nucleare(INFN)in Italythe Italian-Chinese collaborative research program MAECI-NSFCthe Fond de la Recherche Scientifique(F.R.S-FNRS)FWO under the“Excellence of Science-EOS in Belgium”the Conselho Nacional de Desenvolvimento Científico e Tecnològico in Brazilthe Agencia Nacional de Investigacion y Desarrollo and ANID-Millennium Science Initiative Program-ICN2019_044 in Chilethe Charles University Research Centre and the Ministry of Education,Youth,and Sports in Czech Republicthe Deutsche Forschungsgemeinschaft(DFG)the Helmholtz Associationthe Cluster of Excellence PRISMA+in Germanythe Joint Institute of Nuclear Research(JINR)and Lomonosov Moscow State University in Russiathe joint Russian Science Foundation(RSF)National Natural Science Foundation of China(NSFC)research programthe MOST and MOE in Taiwanthe Chulalongkorn University and Suranaree University of Technology in Thailand,University of California at Irvinethe National Science Foundation in USA。
文摘JUNO is a multi-purpose neutrino observatory under construction in the south of China.This publication presents new sensitivity estimates for the measurement of the △m_(31)^(2),△m_(21)^(2),sin^(2)θ_(12),and sin^(2)θ_(13) oscillation parameters using reactor antineutrinos,which is one of the primary physics goals of the experiment.The sensitivities are obtained using the best knowledge available to date on the location and overburden of the experimental site,the nuclear reactors in the surrounding area and beyond,the detector response uncertainties,and the reactor antineutrino spectral shape constraints expected from the TAO satellite detector.It is found that the △m_(21)^(2) and sin^(2)θ_(12) oscillation parameters will be determined to 0.5%precision or better in six years of data collection.In the same period,the △m_(31)^(2) parameter will be determined to about 0.2%precision for each mass ordering hypothesis.The new precision represents approximately an order of magnitude improvement over existing constraints for these three parameters.
基金This work was supported by the Peking University Third Hospital Key Clinical Foundation[grant numbers BYSY2015007,BYSY2018039 and BYSYDL2019016 to Y.L.]the capital health research and development of special[grant number 2020-2-4096 to Y.L.]+1 种基金the Beijing Natural Science Foundation[grant number Z190013 to F.L.]the National Natural Science Foundation of China[grant number 81970205 to F.L.].
文摘Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell(hUCMSC)sheet on myocardial infarction(MI).Methods:hUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells.We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet.Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system.Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet.Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function,angiogenesis and left ventricular remodelling.Results:When transplanted to the infarcted mouse hearts,hUCMSC sheet significantly improved the retention and survival compared with cell suspension.At the early stage of MI,hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages,preserving the cardiomyocytes from acute injury.Moreover,the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue,providing mechanical support and routes for revascularsation.These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.Conclusions:hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs,mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.Translational perspective:Due to its excellent availability as well as superior local cellular retention and survival,allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs,such as modulating inflammation and enhancing angiogenesis.Moreover,the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial,further improving its clinical applicability.
基金This work was primarily supported by the National Natural Science Foundation of China (Nos. 21573216 and 21501170), Hundred Talent Program of CAS, Science and Technology Development Project Foundation of Jilin Province (Nos. 20160101304JC and 20160520134JH), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, the Start-up fund from Changchun Institute of Applied Chemistry, CAS, and Talent Development fund of Jilin, China.
文摘The particular physicochemical properties of nanomaterials are able to elicit unique biological responses. The property activity relationship is usually established for in-depth understanding of toxicity mechanisms and designing safer nanomaterials. In this study, the toxic role of specific crystallographic facets of a series of polyhedral lead sulfide (PbS) nanocrystals, including truncated octahedrons, cuboctahedrons, truncated cubes, and cubes, was investigated in human bronchial epithelial cells (BEAS-2B) and murine alveolar macrophages (RAW 264.7) cells./100} facets were found capable of triggering facet-dependent cellular oxidative stress and heavy metal stress responses, such as glutathione depletion, lipid peroxidation, reactive oxygen species (ROS) production, heme oxygenase-1 (HO-1) and metallothionein (MT) expression, and mitochondrial dysfunction, while {111} facets remained inert under biological conditions. The {100}-facet-dependent toxicity was ascribed to {100}-facet-dependent lead dissolution, while the low lead dissolution of {111} facets was due to the strong protection afforded by poly(vinyl pyrrolidone) during synthesis. Based on this facet-toxicity relationship, a "safe-by-design" strategy was designed to prevent lead dissolution from {100} facets through the formation of atomically thin lead-chloride adlayers, resulting in safer polyhedral PbS nanocrystals.
基金This work was supported by the Chinese Academy of Sciences,the National Key R&D Program of China,the CAS Center for Excellence in Particle Physics,the Joint Large Scale Scientific Facility Funds of the NSFC and CAS,Wuyi University,and the Tsung-Dao Lee Instiute of Shanghai Jiao Tong University in China,the In stiut National de Physique Nucleaire et de Physique de Particules(IN2P3)in France,the Istituto Nazionale di Fisica Nucleare(INFN)in Italy,the Fond de la Recherche Scintifique(F.R.S-FNRS)and FWO under the"Excellence of Science-EOS"in Belgium,the Conselho Nacional de Desenvolvimento Cientificoce Tecnologico in Brazil,the Agencia Nacional de Investigacion y Desrrollo in Chile,the Charles University Research Centre and the Ministry of Education,Youth,and Sports in Czech Republic,the Deutsche Forschungsgemeinschaft(DFG),the Helmholtz Association,and the Cluster of Exellence PRISMA+in Germany,the Joint Institute of Nuclear Research(JINR),Lomonosov Moscow State University,and Russian Foundation for Basic Research(RFBR)in Russia,the MOST and MOE in Taiwan,the Chu-lalongkorm University and Suranaree University of Technology in Thailand,and the University of aliformia at Irvine in USA.
文摘The Jiangmen Underground Neutrino Observatory(JUNO)features a 20 kt multi-purpose underground liquid scintillator sphere as its main detector.Some of JUNO's features make it an excellent location for^8B solar neutrino measurements,such as its low-energy threshold,high energy resolution compared with water Cherenkov detectors,and much larger target mass compared with previous liquid scintillator detectors.In this paper,we present a comprehensive assessment of JUNO's potential for detecting^8B solar neutrinos via the neutrino-electron elastic scattering process.A reduced 2 MeV threshold for the recoil electron energy is found to be achievable,assuming that the intrinsic radioactive background^(238)U and^(232)Th in the liquid scintillator can be controlled to 10^(-17)g/g.With ten years of data acquisition,approximately 60,000 signal and 30,000 background events are expected.This large sample will enable an examination of the distortion of the recoil electron spectrum that is dominated by the neutrino flavor transformation in the dense solar matter,which will shed new light on the inconsistency between the measured electron spectra and the predictions of the standard three-flavor neutrino oscillation framework.IfDelta m^(2)_(21)=4.8times10^(-5);(7.5times10^(-5))eV^(2),JUNO can provide evidence of neutrino oscillation in the Earth at approximately the 3sigma(2sigma)level by measuring the non-zero signal rate variation with respect to the solar zenith angle.Moreover,JUNO can simultaneously measureDelta m^2_(21)using^8B solar neutrinos to a precision of 20% or better,depending on the central value,and to sub-percent precision using reactor antineutrinos.A comparison of these two measurements from the same detector will help understand the current mild inconsistency between the value of Delta m^2_(21)reported by solar neutrino experiments and the KamLAND experiment.
基金supported by NIH R21EB026035(X.L.L.)NIH R21AI149312(C.E.C.,and X.L.L.)+1 种基金NSF CBET-1943696(X.L.L.)Penn State startup funding to X.L.L.
文摘CRISPR/Cas-mediated genome editing in human pluripotent stem cells(hPSCs)offers unprecedented opportunities for developing in vitro disease modeling,drug screening and cell-based therapies.To efficiently deliver the CRISPR components,here we developed two all-in-one vectors containing Cas9/gRNA and inducible Cas13d/gRNA cassettes for robust genome editing and RNA interference respectively.These vectors utilized the PiggyBac transposon system,which allows stable expression of CRISPR components in hPSCs.The Cas9 vector PB-CRISPR exhibited high efficiency(up to 99%)of inducing gene knockout in both protein-coding genes and long non-coding RNAs.The other inducible Cas13d vector achieved extremely high efficiency in RNA knockdown(98%knockdown for CD90)with optimized gRNA designs.Taken together,our PiggyBac CRISPR vectors can serve as powerful toolkits for studying gene functions in hPSCs.