Intervertebral disc degeneration(IVDD),a disease associated with ageing,is characterised by a notable increase in senescent nucleus pulposus cells(NPCs)as IVDD progresses.However,the specific mechanisms that regulate ...Intervertebral disc degeneration(IVDD),a disease associated with ageing,is characterised by a notable increase in senescent nucleus pulposus cells(NPCs)as IVDD progresses.However,the specific mechanisms that regulate the senescence of NPCs remain unknown.In this study,we observed impaired autophagy in IVDD-NPCs,which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype(SASP).The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation.Conversely,the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4(GATA4).Moreover,we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation(H3K4me3)modification and N6-methyladenosine(m6A)-methylated modification regulates autophagy in IVDD-NPCs.Mechanistically,lysine methyltransferase 2A(KMT2A)promoted the expression of methyltransferase-like 3(METTL3)through H3K4me3 modification,whereas METTL3-mediated m6A modification reduced the expression of autophagy-associated 4a(ATG4a)by attenuating its RNA stability,leading to autophagy damage in NPCs.Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs.Therefore,targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.展开更多
Optimization calculations of 209 polychlorinated biphenyls （PCBs） were carried out at the B3LYP/6-31G^＊ level. It was found that there is significant correlation between the Cl substitution position and some struct...Optimization calculations of 209 polychlorinated biphenyls （PCBs） were carried out at the B3LYP/6-31G^＊ level. It was found that there is significant correlation between the Cl substitution position and some structural parameters. Consequently, Cl substitution positions were taken as theoretical descriptors to establish a novel QSPR model for predicting –lgSw of all PCB congeners. The model achieved in this work contains four variables, of which r^2 = 0.9527, q^2 = 0.9490 and SD = 0.25 with large t values. In addition, the variation inflation factors （VIFs） of variables in this model are all less than 5.0, suggesting high accuracy of the –lgSw predicting model. And the results of cross-validation test and method validation also show that the model exhibits optimum stability and better predictive capability than that from the AM1 method.展开更多
中点钳位(neutral point clamped,NPC)型三电平逆变器并网工作环境恶劣,IGBT面临单管与双管同时故障的挑战,这使得故障特征之间的差异变得非常微弱,进而导致双管故障的识别精度难以有效提升。为此,提出了一种新的故障诊断方法,该方法结...中点钳位(neutral point clamped,NPC)型三电平逆变器并网工作环境恶劣,IGBT面临单管与双管同时故障的挑战,这使得故障特征之间的差异变得非常微弱,进而导致双管故障的识别精度难以有效提升。为此,提出了一种新的故障诊断方法,该方法结合了多通道的二维递归融合图和轻量化多尺度残差(lightweightmultiscale convolutional residuals,LMCR)网络。首先,通过仿真获取三相电流信号作为故障信号;再利用递归图(recurrence plot,RP)将三相电流信号分别转化为二维图并进行多通道融合,以捕捉时间序列中的周期性、突变点和趋势等特征;最后,将递归融合图作为输入,输入到LMCR模型中进行故障识别,LMCR模型整合多级Inception结构和残差网络,用于提取不同尺度的特征并融合这些特征,从而保证网络的梯度消失和爆炸。实验结果显示,该方法在IGBT故障识别中表现出色,无噪声环境下平均识别准确率达100%,噪声环境中也达到了92.53%,充分证明了该方法具有较强的特征提取能力和优异的抗噪性能。展开更多
Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source fo...Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
During the National People's Congress(NPC)and the Chinese People's Political Consultative Conference(CPPCC)in 2025,ESG-related issues have received widespread attention.Several NPC deputies and CPPCC members h...During the National People's Congress(NPC)and the Chinese People's Political Consultative Conference(CPPCC)in 2025,ESG-related issues have received widespread attention.Several NPC deputies and CPPCC members have put forward suggestions on ESG policies,green finance,corporate ESG practices and other topics,aiming to promote China's ESG development to a new stage.展开更多
基金supported by the National Natural Science Foundation of China (82272555,82272522,82422044,82101647)Zhejiang Provincial Natural Science Foundation of China (LGF21H060010,LR22H060001,LY23H060011)+1 种基金Wenzhou Major Scientific and Technological Innovation Project (ZY2022010)Zhejiang Provincial Medical Technology Foundation of China (2022PY071)。
文摘Intervertebral disc degeneration(IVDD),a disease associated with ageing,is characterised by a notable increase in senescent nucleus pulposus cells(NPCs)as IVDD progresses.However,the specific mechanisms that regulate the senescence of NPCs remain unknown.In this study,we observed impaired autophagy in IVDD-NPCs,which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype(SASP).The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation.Conversely,the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4(GATA4).Moreover,we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation(H3K4me3)modification and N6-methyladenosine(m6A)-methylated modification regulates autophagy in IVDD-NPCs.Mechanistically,lysine methyltransferase 2A(KMT2A)promoted the expression of methyltransferase-like 3(METTL3)through H3K4me3 modification,whereas METTL3-mediated m6A modification reduced the expression of autophagy-associated 4a(ATG4a)by attenuating its RNA stability,leading to autophagy damage in NPCs.Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs.Therefore,targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.
基金This work was supported by the 973 National Basic Research Program of China (2003CB415002)the China Postdoctoral Science Foundation (No. 2003033486)
文摘Optimization calculations of 209 polychlorinated biphenyls （PCBs） were carried out at the B3LYP/6-31G^＊ level. It was found that there is significant correlation between the Cl substitution position and some structural parameters. Consequently, Cl substitution positions were taken as theoretical descriptors to establish a novel QSPR model for predicting –lgSw of all PCB congeners. The model achieved in this work contains four variables, of which r^2 = 0.9527, q^2 = 0.9490 and SD = 0.25 with large t values. In addition, the variation inflation factors （VIFs） of variables in this model are all less than 5.0, suggesting high accuracy of the –lgSw predicting model. And the results of cross-validation test and method validation also show that the model exhibits optimum stability and better predictive capability than that from the AM1 method.
基金supported by the National Nature Science Foundation of China(No.82002345 to J.D and 81902179 to L.S)the Gusu Talent Program(No.Qngg2022008 and GSWS2021027 to J.D)the Preliminary Research Project of the Second Affiliated Hospital of Soochow University(No.SDFEYBS1905 to J.D).
文摘Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
文摘During the National People's Congress(NPC)and the Chinese People's Political Consultative Conference(CPPCC)in 2025,ESG-related issues have received widespread attention.Several NPC deputies and CPPCC members have put forward suggestions on ESG policies,green finance,corporate ESG practices and other topics,aiming to promote China's ESG development to a new stage.
