Fucosyltransferase 8(Fut8)and core fucosylation play critical roles in regulating various biological processes,including immune response,signal transduction,proteasomal degradation,and energy metabolism.However,the fu...Fucosyltransferase 8(Fut8)and core fucosylation play critical roles in regulating various biological processes,including immune response,signal transduction,proteasomal degradation,and energy metabolism.However,the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown.We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells(aNSPCs)and postnatal brain development.Fut8 depletion reduces the proliferation of a NSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo,respectively.Additionally,Fut8 deficiency impairs learning and memory in mice.Mechanistically,Fut8 directly interacts with integrinα6(Itga6),an upstream regulator of the PI3kAkt signaling pathway,and catalyzes core fucosylation of Itga6.Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6.Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway.Moreover,the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency.In summary,our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.展开更多
In the manufacturing of thin wall components for aerospace industry,apart from the side wall contour error,the Remaining Bottom Thickness Error(RBTE)for the thin-wall pocket component(e.g.rocket shell)is of the same i...In the manufacturing of thin wall components for aerospace industry,apart from the side wall contour error,the Remaining Bottom Thickness Error(RBTE)for the thin-wall pocket component(e.g.rocket shell)is of the same importance but overlooked in current research.If the RBTE reduces by 30%,the weight reduction of the entire component will reach up to tens of kilograms while improving the dynamic balance performance of the large component.Current RBTE control requires the off-process measurement of limited discrete points on the component bottom to provide the reference value for compensation.This leads to incompleteness in the remaining bottom thickness control and redundant measurement in manufacturing.In this paper,the framework of data-driven physics based model is proposed and developed for the real-time prediction of critical quality for large components,which enables accurate prediction and compensation of RBTE value for the thin wall components.The physics based model considers the primary root cause,in terms of tool deflection and clamping stiffness induced Axial Material Removal Thickness(AMRT)variation,for the RBTE formation.And to incorporate the dynamic and inherent coupling of the complicated manufacturing system,the multi-feature fusion and machine learning algorithm,i.e.kernel Principal Component Analysis(kPCA)and kernel Support Vector Regression(kSVR),are incorporated with the physics based model.Therefore,the proposed data-driven physics based model combines both process mechanism and the system disturbance to achieve better prediction accuracy.The final verification experiment is implemented to validate the effectiveness of the proposed method for dimensional accuracy prediction in pocket milling,and the prediction accuracy of AMRT achieves 0.014 mm and 0.019 mm for straight and corner milling,respectively.展开更多
N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles a...N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here,we examined the function of Mettl3,the key component of the complex,in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neu-ronal development and skewed the differentiation of aNSCs more toward glial lineage,but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecip-itation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically,m6A was present on the transcripts of histone methyltransferase Ezh2,and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively,our results uncover a crosstalk between RNA and histone modifica-tions and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.展开更多
基金supported in part by the National Natural Science Foundation of China(92049108,82371182)Central Guiding Fund for Local Science and Technology Development Projects(2023ZY1058)the National Key Research and Development Program of China(2017YFE0196600)。
文摘Fucosyltransferase 8(Fut8)and core fucosylation play critical roles in regulating various biological processes,including immune response,signal transduction,proteasomal degradation,and energy metabolism.However,the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown.We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells(aNSPCs)and postnatal brain development.Fut8 depletion reduces the proliferation of a NSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo,respectively.Additionally,Fut8 deficiency impairs learning and memory in mice.Mechanistically,Fut8 directly interacts with integrinα6(Itga6),an upstream regulator of the PI3kAkt signaling pathway,and catalyzes core fucosylation of Itga6.Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6.Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway.Moreover,the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency.In summary,our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.
基金the Science and Technology Major Project of China(No.2019ZX04020001-004,2017ZX04007001)。
文摘In the manufacturing of thin wall components for aerospace industry,apart from the side wall contour error,the Remaining Bottom Thickness Error(RBTE)for the thin-wall pocket component(e.g.rocket shell)is of the same importance but overlooked in current research.If the RBTE reduces by 30%,the weight reduction of the entire component will reach up to tens of kilograms while improving the dynamic balance performance of the large component.Current RBTE control requires the off-process measurement of limited discrete points on the component bottom to provide the reference value for compensation.This leads to incompleteness in the remaining bottom thickness control and redundant measurement in manufacturing.In this paper,the framework of data-driven physics based model is proposed and developed for the real-time prediction of critical quality for large components,which enables accurate prediction and compensation of RBTE value for the thin wall components.The physics based model considers the primary root cause,in terms of tool deflection and clamping stiffness induced Axial Material Removal Thickness(AMRT)variation,for the RBTE formation.And to incorporate the dynamic and inherent coupling of the complicated manufacturing system,the multi-feature fusion and machine learning algorithm,i.e.kernel Principal Component Analysis(kPCA)and kernel Support Vector Regression(kSVR),are incorporated with the physics based model.Therefore,the proposed data-driven physics based model combines both process mechanism and the system disturbance to achieve better prediction accuracy.The final verification experiment is implemented to validate the effectiveness of the proposed method for dimensional accuracy prediction in pocket milling,and the prediction accuracy of AMRT achieves 0.014 mm and 0.019 mm for straight and corner milling,respectively.
基金supported in part by the International Collaboration Program of the Ministry of Science and Technology of China (Grant No. YS2017YFGH001214)the National Natural Science Foundation of China (Grant Nos. 31771395 and 31571518)+6 种基金the National Key R&D Program of China (Grant No. 2016YFC0900400)supported by the National Natural Science Foundation of China (Grant No. 31770872)the Youth Innovation Promotion Association (Grant No. CAS2018133)the National Key R&D Program of China, Stem Cell and Translational Research (Grant No. 2018YFA0109700)supported in part by the National Key R&D Program of China (Grant No. 2017YFC1001703)the Key R&D Program of Zhejiang Province (Grant No. 2017C03009)Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (2016-6), China
文摘N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here,we examined the function of Mettl3,the key component of the complex,in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neu-ronal development and skewed the differentiation of aNSCs more toward glial lineage,but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecip-itation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically,m6A was present on the transcripts of histone methyltransferase Ezh2,and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively,our results uncover a crosstalk between RNA and histone modifica-tions and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.
