Cobalt-free,nickel-rich LiNi_(1-x)Al_(x)O_(2)(x≤0.1)is an attractive cathode material because of high energy density and low cost but suffers from severe structural degradation and poor rate performance.In this study...Cobalt-free,nickel-rich LiNi_(1-x)Al_(x)O_(2)(x≤0.1)is an attractive cathode material because of high energy density and low cost but suffers from severe structural degradation and poor rate performance.In this study,we propose a molten salt-assisted synthesis in combination with a Li-refeeding induced aluminum segregation strategy to prepare Li_(5)AlO_(4)-coated single-crystalline slightly Li-rich Li_(1.04)Ni_(0.92)Al_(0.04)O_(2).The symbiotic formation of Li_(5)AlO_(4)from reaction between molten lithium hydroxide and doped aluminum in the bulk ensures a high lattice matching between the Ni-rich oxide and the homogenous conductive Li_(5)AlO_(4)that permits high Li^(+)conductivity.Benefiting from mitigated undesirable side reactions and phase evolution,the Li_(5)AlO_(4)-coated single-crystalline Li_(1.04)Ni_(0.92)Al_(0.04)O_(2)delivers a high specific capacity of220.2 mA h g^(-1)at 0.1 C and considerable rate capability(182.5 mA h g^(-1)at 10 C).Besides,superior capacity retention of 90.8%is obtained at 1/3 C after 100 cycles in a 498.1 mA h pouch full cell.Furthermore,the particulate morphology of Li_(1.04)Ni_(0.92)Al_(0.04)O_(2)remains intact after cycling at a cutoff voltage of 4.3 V,whereas slightly Li-deficient Li_(0.98)Ni_(0.97)Al_(0.05)O_(2)features intragranular cracks and irreversible lattice distortion.The results highlight the value of molten salt-assisted synthesis and Li-refeeding induced elemental segregation strategy to upgrade Ni-based layered oxide cathode materials for advanced Li-ion batteries.展开更多
Nanosized tungsten carbide(WC)/carbon(C)catalyst was synthesized via a novel ultra-rapid confinement combustion synthesis method.The amount of activated carbon(AC)plays an important role in the morphology and structur...Nanosized tungsten carbide(WC)/carbon(C)catalyst was synthesized via a novel ultra-rapid confinement combustion synthesis method.The amount of activated carbon(AC)plays an important role in the morphology and structure,controlling both the precursor and final powder.The WC particles synthesized inside the pores of the AC had been 10-20 nm because of the confinement of the pore structure and the large specific surface area of AC.When used for oxygen reduction performance,the half-wave potential was−0.24 V,and the electron transfer number was 3.45,indicating the main reaction process was the transfer of four electrons.The detailed electrocatalytic performance and underlying mechanism were investigated in this work.Our study provides a novel approach for the design of catalysts with new compositions and new structures,which are significant for promoting the commercialization of fuel cells.展开更多
Delta and Omicron variants of 2019-nCoV are still spreading globally,and many imported infections have been identified in China as well.In order to control the spread chain from imported to local,China has implemented...Delta and Omicron variants of 2019-nCoV are still spreading globally,and many imported infections have been identified in China as well.In order to control the spread chain from imported to local,China has implemented the dynamic Covid-zero policy.In this article we summarized China’s governance models and practices of fighting potential imported infections in two directions.One targets at international travelers,which can be outlined as four lines of defense:customs epidemic prevention,quarantine upon arrival,relevant laws and regulations,and community tracking.The other is against other vectors potentially carrying 2019-nCoV,which can be outlined by three lines of defense:customs epidemic prevention,disinfection and personal protection,and information management.However,there are still some challenges that are yet to be addressed,such as illegal immigration,accidental occupational exposure to 2019-nCoV,etc.China’s experience indicates that no country can stay safe during the global pandemic as long as there are local outbreaks in other countries,and active prevention and control measures based on science and a complete set of laws and regulations are still necessary at current stage.What’s more,accountable government commitment and leadership,strengthened health and social governance systems,and whole society participation are required.It is suggested that the global community continue to closely cooperate together and take active rather than passive actions to block the potential imported 2019-nCoV from causing local spreading.展开更多
Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have ...Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have shown that SARS-CoV-2 infection during pregnancy may increase the incidence of adverse outcomes.展开更多
The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to i...The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles,as well as compensatory effects among TET family members,which has made the understanding of the enzymatic role of TET not accurate enough.To solve this problem,we successfully generated mice catalytically inactive for specific Tet members(Tetm/m).We observed that,compared with the reported KO mice,mutant mice exhibited distinct developmental defects,including growth retardation,sex imbalance,infertility,and perinatal lethality.Notably,Tetm/mmouse embryonic stem cells(mESCs)were successfully established but entered an impaired developmental program,demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation.Intriguingly,Tet3,traditionally considered less critical for m ESCs due to its lower expression level,had a significant impact on the global hydroxymethylation,gene expression,and differentiation potential of mESCs.Notably,there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation.In summary,our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.展开更多
Platelet-derived growth factor-BB(PDGF-BB)/platelet-derived growth factor receptor-β(PDGFR-β)pathway is conventionally considered as an important pathway to promote osteogenesis;however,recent study suggested its ro...Platelet-derived growth factor-BB(PDGF-BB)/platelet-derived growth factor receptor-β(PDGFR-β)pathway is conventionally considered as an important pathway to promote osteogenesis;however,recent study suggested its role during osteogenesis to be controversial.Regarding the differential functions of this pathway during 3 stages of bone healing,we hypothesized that temporal inhibition of PDGF-BB/PDGFR-βpathway could shift the proliferation/differentiation balance of skeletal stem and progenitor cells,toward osteogenic lineage,which leads to improved bone regeneration.We first validated that inhibition of PDGFR-βat late stage of osteogenic induction effectively enhanced differentiation toward osteoblasts.This effect was also replicated invivo by showing accelerated bone formation when block PDGFR-βpathway at late stage of critical bone defect healing mediated using biomaterials.Further,we found that such PDGFR-βinhibitor-initiated bone healing was also effective in the absence of scaffold implantation when administrated intraperitoneally.Mechanistically,timely inhibition of PDGFR-βblocked extracellular regulated protein kinase 1/2 pathway,which shift proliferation/differentiation balance of skeletal stem and progenitor cell to osteogenic lineage by upregulating osteogenesis-related products of Smad to induce osteogenesis.This study offered updated understanding of the use of PDGFR-βpathway and provides new insight routes of action and novel therapeutic methods in the field of bone repair.展开更多
Repair of large bone defects remains to be clinically challenging,yet current bone repair strategies focus on optimizing the osteogenic capacity of bone grafts,while the role of osteoclasts in bone regeneration has be...Repair of large bone defects remains to be clinically challenging,yet current bone repair strategies focus on optimizing the osteogenic capacity of bone grafts,while the role of osteoclasts in bone regeneration has been largely ignored.Herein,we designed a injectable self-curing bone grafting paste capable of regulating both an-abolic/catabolic activities during bone healing by immobilizing the RANKL inhibitor denosumab on dermal-derived extracellular matrix(ECM)microfibres,which were then incorporated into an injectable paste via a hydration reaction between𝛽-tricalcium phosphate(𝛽-TCP),monocalcium phosphate monohydrate(MCPM)and calcium sulfate hemihydrate(CSH).The incorporation of ECM microfibres not only serves as a sustained-release denosumab carrier to inhibit osteoclastogenesis but also improves the mechanical properties of the resulting com-posite by increasing the interaction between the organic and inorganic phases.In vitro,calcium supply from the composite along with ECM enhanced osteogenic differentiation of BMSC while release of denosumab effectively inhibits osteoclast fusion and alleviate osteoclastic activity.In vivo,it was observed that CSH/CP@ECM-Deno significantly reduced the number of osteoclasts,slowed down the process of bone resorption,and accelerated collagen deposition to promote new bone generation.These results suggest that modulation of osteoclastogenesis by interfering with bone homeostasis may be an effective bone repair strategy.展开更多
The coastal area of the East China Sea has experienced rapid urbanization and industrialization in China since 1980 s, resulting in severe pollution of its environments.Antibiotic resistance genes(ARGs) are regarded a...The coastal area of the East China Sea has experienced rapid urbanization and industrialization in China since 1980 s, resulting in severe pollution of its environments.Antibiotic resistance genes(ARGs) are regarded as a kind of emerging pollutant with potential high risk. The sediment samples were collected from Hangzhou Bay(HB),Xiangshan Bay(XB), and Taizhou Bay(TB) to investigate the spatial occurrence and distribution of 27 ARGs and class I integron–integrase gene(intI1) in the coastal area of the East China Sea. The PCR results showed the frequent presence of 11 ARGs and intI1 in the sediments of the three bays. The qPCR results further showed that sulfonamide resistance was the most prevalent ARG type and antibiotic target replacement and protection were the most important resistance mechanisms in the sediments. Regarding the subtype of ARGs, sulI, tetW, and dfrA13 were the most abundant ARGs, in which sulI was higher in TB(based on both the absolute and relative abundances) and dfrA13 was higher in HB(based on the relative abundances). The network analysis revealed that intI1 had significant correlations with tetC, sulI, sulII, and blaPSE-1. Oil was the key connected factor, which had positive connections with sulI, sulII, and blaPSE-1. In addition, the joint effect of heavy metals and nutrients & organic pollutants might be crucial for the fate of ARGs in the coastal sediments.展开更多
N^(6)-methyladenosine(m^(6)A)on chromosome-associated regulatory RNAs(carRNAs),including repeat RNAs,plays important roles in tuning the chromatin state and transcription,but the intrinsic mechanism remains unclear.He...N^(6)-methyladenosine(m^(6)A)on chromosome-associated regulatory RNAs(carRNAs),including repeat RNAs,plays important roles in tuning the chromatin state and transcription,but the intrinsic mechanism remains unclear.Here,we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells(ESCs),which highly depends on the m^(6)A-binding ability.Ythdcl is required for sufficient rRNA synthesis and repression of the 2-cell(2C)transcriptional program in ESCs,which recapitulates the transcriptome regulation by the LINE1 scaffold.Detailed analyses revealed that YTHDC1 recognizes m^(6)A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1.Moreover,the establishment of H3K9me3 on 2C-related retrotrans-posons is interrupted in Ythdcl-depleted ESCs and inner cell mass(ICM)cells,which consequently increases the transcriptional activities.Our study reveals a role of m^(6)A in regulating the RNA scaffold,providing a new model for the RNA-chromatin cross-talk.展开更多
Recently,metal-organic framework(MOF)-based multienzyme systems integrating different functional natural enzymes and/or nanomaterial-basedartificial enzymes are attracting increasing attention due to their high cataly...Recently,metal-organic framework(MOF)-based multienzyme systems integrating different functional natural enzymes and/or nanomaterial-basedartificial enzymes are attracting increasing attention due to their high catalytic efficiency and promising application in sensing.Simpleand controllable integration of enzymes or nanozymes within MOFs is crucial for achieving efficient cascade catalysis and high stability.Here,we report a facile electrochemical assisted biomimetic mineralization strategy to prepare an artificial multienzyme system for efficient electrochemicaldetection of biomolecules.By using the G0x@Cu-MOF/copper foam(G0x@Cu-MOF/CF)architecture as a proof of concept,efficientenzyme immobilization and cascade catalysis were achieved by in situ encapsulation of glucose oxidase(GOx)within MOFs layer grown onthree-dimensional(3D)porous conducting CF via a facile one-step electrochemical assisted biomimetic mineralization strategy.Due to thebio-electrocatalytic cascade reaction mechanism,this well-designed GOx@Cu-MOF modified electrode exhibited superior catalytic activityand thermal stability for glucose sensing.Notably,the activity of GOx@Cu-MOF/CF still remained at ca.80%after being incubated at 80℃.In sharp contrast,the activity of the unprotected electrode was reduced to the original 10%after the same treatment.The design strategypresented here may be useful in fabricating highly stable enzyme@MOF composites applied for efficient photothermal therapy and otherplatform under high temperature.展开更多
Spatial transcriptomics enables the study of localization-indexed gene expression activity in tissues,providing the transcriptional landscape that in turn indicates the potential regulatory networks of gene expression...Spatial transcriptomics enables the study of localization-indexed gene expression activity in tissues,providing the transcriptional landscape that in turn indicates the potential regulatory networks of gene expression.In situ sequencing(ISS)is a targeted spatial transcriptomic technique,based on padlock probe and rolling circle amplification combined with next-generation sequencing chemistry,for highly multiplexed in situ gene expression profiling.Here,we present improved in situ sequencing(IISS)that exploits a new probing and barcoding approach,combined with advanced image analysis pipelines for high-resolution targeted spatial gene expression profiling.We develop an improved combinatorial probe anchor ligation chemistry using a 2-base encoding strategy for barcode interrogation.The new encoding strategy results in higher signal intensity as well as improved specificity for in situ sequencing,while maintaining a streamlined analysis pipeline for targeted spatial transcriptomics.We show that IISS can be applied to both fresh frozen tissue and formalin-fixed paraffin-embedded tissue sections for single-cell level spatial gene expression analysis,based on which the developmental trajectory and cell-cell communication networks can also be constructed.展开更多
Chemically defined medium is widely used for culturing mouse embryonic stem cells(mESCs),in which N2B27 works as a substitution for serum,and GSK3βand MEK inhibitors(2i)help to promote ground-state pluripo-tency.Howe...Chemically defined medium is widely used for culturing mouse embryonic stem cells(mESCs),in which N2B27 works as a substitution for serum,and GSK3βand MEK inhibitors(2i)help to promote ground-state pluripo-tency.However,recent studies suggested that MEKi might cause irreversible defects that compromise the developmental potential of mESCs.Here,we demon-strated the deficient bone morphogenetic protein(BMP)signal in the chemically defined condition is one of the main causes for the impaired pluripotency.Mechanisti-cally,activating the BMP signal pathway by BMP4 could safeguard the chromosomal integrity and proliferation capacity of mESCs through regulating downstream tar-gets Ube2s and Chmp4b.More importantly,BMP4 pro-motes a distinct in vivo developmental potential and a long-term pluripotency preservation.Besides,the pluripotent improvements driven by BMP4 are superior to those by attenuating MEK suppression.Taken together,our study shows appropriate activation of BMP signal is essential for regulating functional pluripotency and reveals that BMP4 should be applied in the serum-free culture system.展开更多
Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essenti...Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.展开更多
Self-organized blastoids from extended pluripotent stem(EPs)cells possess enormous potential for investigating postimplantation embryo development and related diseases.However,the limited ability of postimplantation d...Self-organized blastoids from extended pluripotent stem(EPs)cells possess enormous potential for investigating postimplantation embryo development and related diseases.However,the limited ability of postimplantation development of Eps-blastoids hinders its further application.In this study,single-cell transcriptomic analysis indicated that the“trophectoderm(TE)-like structure”of EPSblastoids was primarily composed of primitive endoderm(PrE)-related cells instead of TE-related cells.We further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like structure.Inhibition of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid formation.Furthermore,we demonstrated that blastocyst-like structures reconstituted by combining the EPs-derived bilineage embryo-like structure(BLEs)with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live fetuses.In summary,our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.展开更多
The maximum seismic response of curved bridge is significantly related to the input angle of designated earthquake. Owing to structure irregularities, bridge reactions result from the interaction between the moment an...The maximum seismic response of curved bridge is significantly related to the input angle of designated earthquake. Owing to structure irregularities, bridge reactions result from the interaction between the moment and torsion forces. Based on the solving of the seismic response of structure excited by a one-way earthquake input, a uniform expression of the unfavorable angle of the earthquake input was derived, and the corresponding maximum response of structure was determined. Considering the orthotropic and skewed dual- directional earthquake input manners, the most unfavorable angles for the two cases were also derived, respectively. Furthermore, a series finite element models were built to analyze the multi-component seismic responses by examining an example of curved girder bridge considering the variation of curvature radius and the bearings arrangement. The seismic responses of the case bridges, were excited by earthquakes at different input angles, and were calculated and analyzed using a response spectrum method. The input angles of earthquake excitation were progressively increased. From the analysis and comparison based on the calculation results mentioned above, the most unfavorable angle of earthquake excitation corresponding to the maximum seismic response of the curved bridge could be determined. It was shown that the most unfavorable angles of earthquake input resulted from the different response combination methods were essentially coherent.展开更多
基金supported by the China National Funds for Distinguished Young Scientists(21925503)the National Natural Science Foundation of China(21835004)the Jilin Scientific and Technological Development Program(20220301018GX)。
文摘Cobalt-free,nickel-rich LiNi_(1-x)Al_(x)O_(2)(x≤0.1)is an attractive cathode material because of high energy density and low cost but suffers from severe structural degradation and poor rate performance.In this study,we propose a molten salt-assisted synthesis in combination with a Li-refeeding induced aluminum segregation strategy to prepare Li_(5)AlO_(4)-coated single-crystalline slightly Li-rich Li_(1.04)Ni_(0.92)Al_(0.04)O_(2).The symbiotic formation of Li_(5)AlO_(4)from reaction between molten lithium hydroxide and doped aluminum in the bulk ensures a high lattice matching between the Ni-rich oxide and the homogenous conductive Li_(5)AlO_(4)that permits high Li^(+)conductivity.Benefiting from mitigated undesirable side reactions and phase evolution,the Li_(5)AlO_(4)-coated single-crystalline Li_(1.04)Ni_(0.92)Al_(0.04)O_(2)delivers a high specific capacity of220.2 mA h g^(-1)at 0.1 C and considerable rate capability(182.5 mA h g^(-1)at 10 C).Besides,superior capacity retention of 90.8%is obtained at 1/3 C after 100 cycles in a 498.1 mA h pouch full cell.Furthermore,the particulate morphology of Li_(1.04)Ni_(0.92)Al_(0.04)O_(2)remains intact after cycling at a cutoff voltage of 4.3 V,whereas slightly Li-deficient Li_(0.98)Ni_(0.97)Al_(0.05)O_(2)features intragranular cracks and irreversible lattice distortion.The results highlight the value of molten salt-assisted synthesis and Li-refeeding induced elemental segregation strategy to upgrade Ni-based layered oxide cathode materials for advanced Li-ion batteries.
基金This work was financially supported by the China Postdoctoral Science Foundation(No.2019M652169)the University Synergy Innovation Program of Anhui Province(No.GXXT-2019-016)+1 种基金the Natural Science Foundation of Anhui(No.JZ2018AKZR0063)the Fundamental Research Funds for the Central University,China(No.PA2019GDPK0044).
文摘Nanosized tungsten carbide(WC)/carbon(C)catalyst was synthesized via a novel ultra-rapid confinement combustion synthesis method.The amount of activated carbon(AC)plays an important role in the morphology and structure,controlling both the precursor and final powder.The WC particles synthesized inside the pores of the AC had been 10-20 nm because of the confinement of the pore structure and the large specific surface area of AC.When used for oxygen reduction performance,the half-wave potential was−0.24 V,and the electron transfer number was 3.45,indicating the main reaction process was the transfer of four electrons.The detailed electrocatalytic performance and underlying mechanism were investigated in this work.Our study provides a novel approach for the design of catalysts with new compositions and new structures,which are significant for promoting the commercialization of fuel cells.
基金supported by the Research on International Legal Issues on Public Health Emergency of International Concern funded by the National Social Science Fund of China(Grant Number 20&ZD201).
文摘Delta and Omicron variants of 2019-nCoV are still spreading globally,and many imported infections have been identified in China as well.In order to control the spread chain from imported to local,China has implemented the dynamic Covid-zero policy.In this article we summarized China’s governance models and practices of fighting potential imported infections in two directions.One targets at international travelers,which can be outlined as four lines of defense:customs epidemic prevention,quarantine upon arrival,relevant laws and regulations,and community tracking.The other is against other vectors potentially carrying 2019-nCoV,which can be outlined by three lines of defense:customs epidemic prevention,disinfection and personal protection,and information management.However,there are still some challenges that are yet to be addressed,such as illegal immigration,accidental occupational exposure to 2019-nCoV,etc.China’s experience indicates that no country can stay safe during the global pandemic as long as there are local outbreaks in other countries,and active prevention and control measures based on science and a complete set of laws and regulations are still necessary at current stage.What’s more,accountable government commitment and leadership,strengthened health and social governance systems,and whole society participation are required.It is suggested that the global community continue to closely cooperate together and take active rather than passive actions to block the potential imported 2019-nCoV from causing local spreading.
基金supported by the Chinese National Program on the Key Basic Research Project(2021YFA1100300,2020YFA0112500)the National Natural Science Foundation of China(31721003,31820103009,32270856,32070857,32270858)。
文摘Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have shown that SARS-CoV-2 infection during pregnancy may increase the incidence of adverse outcomes.
基金supported by the National Key Research and Development Program of China(2020YFA0112500,2021YFA1100300,2021YFC2700300 and 2022YFC2702200)supported by the Fundamental Research Funds for the Central Universities+2 种基金National Natural Science Foundation of China(32070857 and 32270856,and 32270858)the Science and Technology Commission of Shanghai Municipality(23JC1403700)Peak Disciplines(TypeⅣ)of Institutions of Higher Learning in Shanghai。
文摘The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles,as well as compensatory effects among TET family members,which has made the understanding of the enzymatic role of TET not accurate enough.To solve this problem,we successfully generated mice catalytically inactive for specific Tet members(Tetm/m).We observed that,compared with the reported KO mice,mutant mice exhibited distinct developmental defects,including growth retardation,sex imbalance,infertility,and perinatal lethality.Notably,Tetm/mmouse embryonic stem cells(mESCs)were successfully established but entered an impaired developmental program,demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation.Intriguingly,Tet3,traditionally considered less critical for m ESCs due to its lower expression level,had a significant impact on the global hydroxymethylation,gene expression,and differentiation potential of mESCs.Notably,there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation.In summary,our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.
基金supported by the National Key Research and Development Projects(2018YFC1105400)the National Natural Science Foundation of China(81872173,82072959,and 31870959)+1 种基金the Zhejiang Provincial Natural Science Foundation(GF22H068757)the Zhejiang Undergraduate Talent Project(2021R401214).
文摘Platelet-derived growth factor-BB(PDGF-BB)/platelet-derived growth factor receptor-β(PDGFR-β)pathway is conventionally considered as an important pathway to promote osteogenesis;however,recent study suggested its role during osteogenesis to be controversial.Regarding the differential functions of this pathway during 3 stages of bone healing,we hypothesized that temporal inhibition of PDGF-BB/PDGFR-βpathway could shift the proliferation/differentiation balance of skeletal stem and progenitor cells,toward osteogenic lineage,which leads to improved bone regeneration.We first validated that inhibition of PDGFR-βat late stage of osteogenic induction effectively enhanced differentiation toward osteoblasts.This effect was also replicated invivo by showing accelerated bone formation when block PDGFR-βpathway at late stage of critical bone defect healing mediated using biomaterials.Further,we found that such PDGFR-βinhibitor-initiated bone healing was also effective in the absence of scaffold implantation when administrated intraperitoneally.Mechanistically,timely inhibition of PDGFR-βblocked extracellular regulated protein kinase 1/2 pathway,which shift proliferation/differentiation balance of skeletal stem and progenitor cell to osteogenic lineage by upregulating osteogenesis-related products of Smad to induce osteogenesis.This study offered updated understanding of the use of PDGFR-βpathway and provides new insight routes of action and novel therapeutic methods in the field of bone repair.
基金supported by the National Natural Science Foundation of China(Grant No.82372381,52071277)the National Natural Science Foundation of Zhejiang Province(Grant No.LY23H060013).
文摘Repair of large bone defects remains to be clinically challenging,yet current bone repair strategies focus on optimizing the osteogenic capacity of bone grafts,while the role of osteoclasts in bone regeneration has been largely ignored.Herein,we designed a injectable self-curing bone grafting paste capable of regulating both an-abolic/catabolic activities during bone healing by immobilizing the RANKL inhibitor denosumab on dermal-derived extracellular matrix(ECM)microfibres,which were then incorporated into an injectable paste via a hydration reaction between𝛽-tricalcium phosphate(𝛽-TCP),monocalcium phosphate monohydrate(MCPM)and calcium sulfate hemihydrate(CSH).The incorporation of ECM microfibres not only serves as a sustained-release denosumab carrier to inhibit osteoclastogenesis but also improves the mechanical properties of the resulting com-posite by increasing the interaction between the organic and inorganic phases.In vitro,calcium supply from the composite along with ECM enhanced osteogenic differentiation of BMSC while release of denosumab effectively inhibits osteoclast fusion and alleviate osteoclastic activity.In vivo,it was observed that CSH/CP@ECM-Deno significantly reduced the number of osteoclasts,slowed down the process of bone resorption,and accelerated collagen deposition to promote new bone generation.These results suggest that modulation of osteoclastogenesis by interfering with bone homeostasis may be an effective bone repair strategy.
基金supported by the National Natural Science Foundation of China(No.51678003)
文摘The coastal area of the East China Sea has experienced rapid urbanization and industrialization in China since 1980 s, resulting in severe pollution of its environments.Antibiotic resistance genes(ARGs) are regarded as a kind of emerging pollutant with potential high risk. The sediment samples were collected from Hangzhou Bay(HB),Xiangshan Bay(XB), and Taizhou Bay(TB) to investigate the spatial occurrence and distribution of 27 ARGs and class I integron–integrase gene(intI1) in the coastal area of the East China Sea. The PCR results showed the frequent presence of 11 ARGs and intI1 in the sediments of the three bays. The qPCR results further showed that sulfonamide resistance was the most prevalent ARG type and antibiotic target replacement and protection were the most important resistance mechanisms in the sediments. Regarding the subtype of ARGs, sulI, tetW, and dfrA13 were the most abundant ARGs, in which sulI was higher in TB(based on both the absolute and relative abundances) and dfrA13 was higher in HB(based on the relative abundances). The network analysis revealed that intI1 had significant correlations with tetC, sulI, sulII, and blaPSE-1. Oil was the key connected factor, which had positive connections with sulI, sulII, and blaPSE-1. In addition, the joint effect of heavy metals and nutrients & organic pollutants might be crucial for the fate of ARGs in the coastal sediments.
基金This work was supported by the National Key R&D Program of China(2016YFA0100400,2020YFA0113200,2018YFA0108900 and 2016YFC1000600)the National Natural Science Foundation of China(31922022,31771646,82022027,31721003,31970796,31871448 and 31871446)+3 种基金the Shanghai Rising-Star Program(19QA1409600)the Shanghai Municipal Medical and Health Discipline Construction Projects(2017ZZ02015)the Fundamental Research Funds for the Central Universities(1515219049 and 22120200410)the Major Program of the Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone(ZJ2018-ZD-004).
文摘N^(6)-methyladenosine(m^(6)A)on chromosome-associated regulatory RNAs(carRNAs),including repeat RNAs,plays important roles in tuning the chromatin state and transcription,but the intrinsic mechanism remains unclear.Here,we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells(ESCs),which highly depends on the m^(6)A-binding ability.Ythdcl is required for sufficient rRNA synthesis and repression of the 2-cell(2C)transcriptional program in ESCs,which recapitulates the transcriptome regulation by the LINE1 scaffold.Detailed analyses revealed that YTHDC1 recognizes m^(6)A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1.Moreover,the establishment of H3K9me3 on 2C-related retrotrans-posons is interrupted in Ythdcl-depleted ESCs and inner cell mass(ICM)cells,which consequently increases the transcriptional activities.Our study reveals a role of m^(6)A in regulating the RNA scaffold,providing a new model for the RNA-chromatin cross-talk.
基金This work was supported by the National Key Research and Development Program of China(Nos.2017YFA0206500 and 2017YFA0206801)the National Basic Research Program of China(No.2015CB932301)the National Natural Science Foundation of China(Nos.21671163,21721001,and J1310024).
文摘Recently,metal-organic framework(MOF)-based multienzyme systems integrating different functional natural enzymes and/or nanomaterial-basedartificial enzymes are attracting increasing attention due to their high catalytic efficiency and promising application in sensing.Simpleand controllable integration of enzymes or nanozymes within MOFs is crucial for achieving efficient cascade catalysis and high stability.Here,we report a facile electrochemical assisted biomimetic mineralization strategy to prepare an artificial multienzyme system for efficient electrochemicaldetection of biomolecules.By using the G0x@Cu-MOF/copper foam(G0x@Cu-MOF/CF)architecture as a proof of concept,efficientenzyme immobilization and cascade catalysis were achieved by in situ encapsulation of glucose oxidase(GOx)within MOFs layer grown onthree-dimensional(3D)porous conducting CF via a facile one-step electrochemical assisted biomimetic mineralization strategy.Due to thebio-electrocatalytic cascade reaction mechanism,this well-designed GOx@Cu-MOF modified electrode exhibited superior catalytic activityand thermal stability for glucose sensing.Notably,the activity of GOx@Cu-MOF/CF still remained at ca.80%after being incubated at 80℃.In sharp contrast,the activity of the unprotected electrode was reduced to the original 10%after the same treatment.The design strategypresented here may be useful in fabricating highly stable enzyme@MOF composites applied for efficient photothermal therapy and otherplatform under high temperature.
基金supported by the Natural Science Foundation of Fujian Province(2022J06022)the Quanzhou Science and Technology Plan Project(2021C040R)the Scientific Research Funds of Huaqiao University.
文摘Spatial transcriptomics enables the study of localization-indexed gene expression activity in tissues,providing the transcriptional landscape that in turn indicates the potential regulatory networks of gene expression.In situ sequencing(ISS)is a targeted spatial transcriptomic technique,based on padlock probe and rolling circle amplification combined with next-generation sequencing chemistry,for highly multiplexed in situ gene expression profiling.Here,we present improved in situ sequencing(IISS)that exploits a new probing and barcoding approach,combined with advanced image analysis pipelines for high-resolution targeted spatial gene expression profiling.We develop an improved combinatorial probe anchor ligation chemistry using a 2-base encoding strategy for barcode interrogation.The new encoding strategy results in higher signal intensity as well as improved specificity for in situ sequencing,while maintaining a streamlined analysis pipeline for targeted spatial transcriptomics.We show that IISS can be applied to both fresh frozen tissue and formalin-fixed paraffin-embedded tissue sections for single-cell level spatial gene expression analysis,based on which the developmental trajectory and cell-cell communication networks can also be constructed.
基金This work was supported by the National Key R&D Program of China(2020YFA0112500 and 2021YFA1100300)the National Natural Science Foundation of China(31721003,31820103009,92168205,32070857 and 31871446)+3 种基金the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001)the key project of the Science and Technology of Shanghai Municipality(19JC1415300)the Shanghai Rising-Star Program(19QA1409600)the Shanghai municipal medical and health discipline construction projects(no.2017ZZ02015).
文摘Chemically defined medium is widely used for culturing mouse embryonic stem cells(mESCs),in which N2B27 works as a substitution for serum,and GSK3βand MEK inhibitors(2i)help to promote ground-state pluripo-tency.However,recent studies suggested that MEKi might cause irreversible defects that compromise the developmental potential of mESCs.Here,we demon-strated the deficient bone morphogenetic protein(BMP)signal in the chemically defined condition is one of the main causes for the impaired pluripotency.Mechanisti-cally,activating the BMP signal pathway by BMP4 could safeguard the chromosomal integrity and proliferation capacity of mESCs through regulating downstream tar-gets Ube2s and Chmp4b.More importantly,BMP4 pro-motes a distinct in vivo developmental potential and a long-term pluripotency preservation.Besides,the pluripotent improvements driven by BMP4 are superior to those by attenuating MEK suppression.Taken together,our study shows appropriate activation of BMP signal is essential for regulating functional pluripotency and reveals that BMP4 should be applied in the serum-free culture system.
基金the National Key R&D Program of China (2016YFA0100400)the National Natural Science Foundation of China (31721003)+6 种基金the Ministry of Science and Technology of China (2015CB964800, 2015CB964503, and 2018YFA0108900)the National Natural Science Foundation of China (81630035, 31871446, and 31771646)the Shanghai Rising-Star Program (17QA1404200)the Shanghai Chenguang Program (16CG17)the Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015)National Postdoctoral Program for Innovative Talents (BX201700307)China Postdoctoral Science Foundation (2017M621527).
文摘Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.
基金supported by the Natural Key R&D Project of China(2020YFA0113200,2018YFC1003102,and 2021YFC2700300)the National Natural Science Foundation of China(31721003,31970814,31871438,31820103009,and 82071565)+1 种基金the 2115 Talent Development Program of China Agricultural Universitythe Youth Innovation Promotion Association of Chinese Academy of Sciences(2020104)。
基金supported by the National Key R&D Program of China(Nos.2020YFA0112500 and 2021YFA1102900)the National Natural Science Foundation of China(Nos.31721003,81630035,82022027,31871448,32000418 and 31820103009)+2 种基金supported by the key project of the Science and Technology of Shanghai Municipality(Nos.19JC1415300 and 21JC1405500)the Shanghai municipal medical and health discipline construction projects(No.2017ZZ02015)the China Postdoctoral Science Foundation 2021M692437 and the Fundamental Research Funds for the Central Universities.
文摘Self-organized blastoids from extended pluripotent stem(EPs)cells possess enormous potential for investigating postimplantation embryo development and related diseases.However,the limited ability of postimplantation development of Eps-blastoids hinders its further application.In this study,single-cell transcriptomic analysis indicated that the“trophectoderm(TE)-like structure”of EPSblastoids was primarily composed of primitive endoderm(PrE)-related cells instead of TE-related cells.We further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like structure.Inhibition of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid formation.Furthermore,we demonstrated that blastocyst-like structures reconstituted by combining the EPs-derived bilineage embryo-like structure(BLEs)with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live fetuses.In summary,our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.
基金supported by the National Natural Science Foundation of China(No.51378050)China Scholarship Council(No.201307095008)
文摘The maximum seismic response of curved bridge is significantly related to the input angle of designated earthquake. Owing to structure irregularities, bridge reactions result from the interaction between the moment and torsion forces. Based on the solving of the seismic response of structure excited by a one-way earthquake input, a uniform expression of the unfavorable angle of the earthquake input was derived, and the corresponding maximum response of structure was determined. Considering the orthotropic and skewed dual- directional earthquake input manners, the most unfavorable angles for the two cases were also derived, respectively. Furthermore, a series finite element models were built to analyze the multi-component seismic responses by examining an example of curved girder bridge considering the variation of curvature radius and the bearings arrangement. The seismic responses of the case bridges, were excited by earthquakes at different input angles, and were calculated and analyzed using a response spectrum method. The input angles of earthquake excitation were progressively increased. From the analysis and comparison based on the calculation results mentioned above, the most unfavorable angle of earthquake excitation corresponding to the maximum seismic response of the curved bridge could be determined. It was shown that the most unfavorable angles of earthquake input resulted from the different response combination methods were essentially coherent.