死亡相关蛋白(Thanatos-associated proteins,THAP)家族的许多成员已被证实与细胞增殖、凋亡和癌症密切相关,而THAP8的功能尚不清楚。为了探究THAP8在癌症中的表达,对TCGA和Oncomine数据库进行了分析,发现THAP8 m RNA在肺癌组织的表达...死亡相关蛋白(Thanatos-associated proteins,THAP)家族的许多成员已被证实与细胞增殖、凋亡和癌症密切相关,而THAP8的功能尚不清楚。为了探究THAP8在癌症中的表达,对TCGA和Oncomine数据库进行了分析,发现THAP8 m RNA在肺癌组织的表达显著高于癌旁正常组织;接着采用荧光定量PCR技术分析了22对肺癌和癌旁正常组织中THAP8的表达差异,结果与数据库分析一致。为了探讨THAP8在肺癌组织中高表达的原因,用JASPAR软件预测THAP8启动子上的转录因子结合位点,发现THAP8基因启动子区含有4个缺氧诱导元件。荧光素酶活性分析实验证明,缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)可以结合到THAP8启动子上的缺氧诱导元件并促进THAP8基因的转录。在CoCl_(2)诱导的缺氧模型中,随着CoCl_(2)浓度的增加,HIF-1α和THAP8蛋白的表达水平升高。此外,在Beas-2B细胞中,过表达HIF-1α可以促进THAP8的表达。为了进一步研究THAP8在肺癌细胞中的功能,用慢病毒介导的shRNA敲低THAP8基因,分析THAP8基因沉默对肺癌细胞生物学行为的影响。结果表明:在H460和H1437肺癌细胞中,敲低THAP8基因可显著降低细胞的活力、克隆形成和侵袭能力。这些结果说明:THAP8可以受缺氧诱导,并促进肺癌细胞的活力、克隆形成和侵袭,是一个新的癌基因。展开更多
Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protei...Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.展开更多
The Lower Mekong Delta in Vietnam experiences widespread flooding annually. About 17 million people live in the Delta with agriculture as the major economic activity. The suspended sediment load in the Mekong River pl...The Lower Mekong Delta in Vietnam experiences widespread flooding annually. About 17 million people live in the Delta with agriculture as the major economic activity. The suspended sediment load in the Mekong River plays an important role in carrying contaminants and nutrients to the delta and changing the geomorphology of the delta river system. In recent decades, it is generally perceived that the flow and sediment transport in the Mekong River have changed due to climate change and development activities, but observed sediment data are lacking. Moreover, after natural floodplains, the sediment deposition has replaced by dense river systems as resulting in floodplain compartments protected by embankments. This study is aimed to investigate impacts of changing water flow on erosion/deposition in the Lower Mekong Delta. We used Mike 11 hydrodynamic model and sediment transport model for simulating the flow and sediment transport. Various scenarios were simulated based on anticipated upstream discharges. Our findings provide the positive and negative impacts to the changes in sediment transport on agriculture cultivation in the Lower Mekong Delta.展开更多
文摘死亡相关蛋白(Thanatos-associated proteins,THAP)家族的许多成员已被证实与细胞增殖、凋亡和癌症密切相关,而THAP8的功能尚不清楚。为了探究THAP8在癌症中的表达,对TCGA和Oncomine数据库进行了分析,发现THAP8 m RNA在肺癌组织的表达显著高于癌旁正常组织;接着采用荧光定量PCR技术分析了22对肺癌和癌旁正常组织中THAP8的表达差异,结果与数据库分析一致。为了探讨THAP8在肺癌组织中高表达的原因,用JASPAR软件预测THAP8启动子上的转录因子结合位点,发现THAP8基因启动子区含有4个缺氧诱导元件。荧光素酶活性分析实验证明,缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)可以结合到THAP8启动子上的缺氧诱导元件并促进THAP8基因的转录。在CoCl_(2)诱导的缺氧模型中,随着CoCl_(2)浓度的增加,HIF-1α和THAP8蛋白的表达水平升高。此外,在Beas-2B细胞中,过表达HIF-1α可以促进THAP8的表达。为了进一步研究THAP8在肺癌细胞中的功能,用慢病毒介导的shRNA敲低THAP8基因,分析THAP8基因沉默对肺癌细胞生物学行为的影响。结果表明:在H460和H1437肺癌细胞中,敲低THAP8基因可显著降低细胞的活力、克隆形成和侵袭能力。这些结果说明:THAP8可以受缺氧诱导,并促进肺癌细胞的活力、克隆形成和侵袭,是一个新的癌基因。
基金financially supported by the National Natural Science Foundation of China(82402177,82171846,82422025,82471430)Clinical Medicine Plus X-Young Scholars Project of Peking University(PKU2025PKULCXQ026)+1 种基金National High Level Hospital Clinical Research Funding(Interdepartmental Research Project of Peking University First Hospital,2023IR51,High Quality Clinical Research Project of Peking University First Hospital,2022CR69)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317).
文摘Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.
文摘The Lower Mekong Delta in Vietnam experiences widespread flooding annually. About 17 million people live in the Delta with agriculture as the major economic activity. The suspended sediment load in the Mekong River plays an important role in carrying contaminants and nutrients to the delta and changing the geomorphology of the delta river system. In recent decades, it is generally perceived that the flow and sediment transport in the Mekong River have changed due to climate change and development activities, but observed sediment data are lacking. Moreover, after natural floodplains, the sediment deposition has replaced by dense river systems as resulting in floodplain compartments protected by embankments. This study is aimed to investigate impacts of changing water flow on erosion/deposition in the Lower Mekong Delta. We used Mike 11 hydrodynamic model and sediment transport model for simulating the flow and sediment transport. Various scenarios were simulated based on anticipated upstream discharges. Our findings provide the positive and negative impacts to the changes in sediment transport on agriculture cultivation in the Lower Mekong Delta.
