In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible impli...In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration.We wondered how SARS-CoV-2 could be related to the amyloid-βcascade and how it could lead to the pathological hallmarks of the disease.We also predict a paradigm change in clinical medicine,which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer’s disease.展开更多
Soil liquefaction is one of the complex research topics in geotechnical engineering and engineering geology. Especially after the 1964 Niigata earthquake (Japan) induced many soil liquefaction incidents, a variety of ...Soil liquefaction is one of the complex research topics in geotechnical engineering and engineering geology. Especially after the 1964 Niigata earthquake (Japan) induced many soil liquefaction incidents, a variety of soil liquefaction studies were conducted and reported, including the liquefaction potential assessment methods utilizing the shear wave velocity (V<sub>s</sub>) or SPT-N profiles (SPT: standard penetration test). This study used the V<sub>s</sub> and SPT methods recommended by the National Center for Earthquake Engineering Research (NCEER) to examine which is more conservative according to the assessment results on 41 liquefiable soil layers at sites in two major cities in Taiwan. Statistical hypothesis testing was used to make the analysis more quantitative and objective. Based on three sets of hypothesis tests, it shows that the hypothesis—the SPT method is more conservative than the V<sub>s</sub> method—was not rejected on a 5% level of significance.展开更多
DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecu...DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecule DNMT1 modulators are attractive for biochemical epigenetic studies and have the potential to become drugs. So far, more than five hundred small molecules have been reported as DNMT1 inhibitors. However, only a limited number of DNMT1 activators have been disclosed because, at least in part, DNMT1 activators are typically regarded as negative data in virtual screening campaigns or optimization projects. This manuscript aims to report the chemical structures and biological activity of small molecules that increase the enzymatic activity of DNMT1. Results of the biochemical experimental assays are discussed. It was found that small molecule activators have a large variety of chemical scaffolds but share pharmacophore features. Visual analysis of the chemical space and multiverse based on molecular fingertips supported that activators are structurally diverse. This is the first report of eight small molecules that increase the enzymatic activity of DNMT1 by more than 400% in an enzymatic-based assay. The outcome warrants further investigation of the epigenetic activity of the compounds in a counter-screen assay, e.g., cell-based and in vivo context.展开更多
目的:研究抗肿瘤靶点人MutT同源体1蛋白(Human MutT Homolog-1,MTH1)抑制剂的构效关系,构建药效团筛选模型筛选潜在的MTH1抑制剂。方法:采用计算机辅助药物设计方法,通过Discovery Studio 3.0软件包中分子共同特征药效团HipHop算法,使...目的:研究抗肿瘤靶点人MutT同源体1蛋白(Human MutT Homolog-1,MTH1)抑制剂的构效关系,构建药效团筛选模型筛选潜在的MTH1抑制剂。方法:采用计算机辅助药物设计方法,通过Discovery Studio 3.0软件包中分子共同特征药效团HipHop算法,使用14个已知MTH1抑制剂分子作为训练集构建药效团模型,并通过Decoy Set验证准确性。结果:获得富集率为13.1的HipHop药效团模型,通过分子对接验证虚拟筛选出的75个候选化合物,得到先导化合物GK01945和HTS07767,能与受体形成良好的相互作用。结论:构建的药效团模型可以作为筛选模型,筛选出的MTH1潜在抑制剂,为抗肿瘤药物MTH1抑制剂开发提供了新思路。展开更多
基金国家自然科学基金面上项目“基于高压人群身心健康的工作环境绿色空间体系研究”(编号51978364)国家自然科学基金青年科学基金项目“北京地区城市森林疗养空间特征识别及健康效益定量评价”(编号51908310)Tsinghua-Toyota Joint Research Institute Cross discipline Program共同资助。
基金supported by grants to DD from Agencia Nacional de Promoción de la Investigación,el desarrollo tecnológico y la innovación(ANPCyT,PICT N°03893).
文摘In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration.We wondered how SARS-CoV-2 could be related to the amyloid-βcascade and how it could lead to the pathological hallmarks of the disease.We also predict a paradigm change in clinical medicine,which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer’s disease.
文摘Soil liquefaction is one of the complex research topics in geotechnical engineering and engineering geology. Especially after the 1964 Niigata earthquake (Japan) induced many soil liquefaction incidents, a variety of soil liquefaction studies were conducted and reported, including the liquefaction potential assessment methods utilizing the shear wave velocity (V<sub>s</sub>) or SPT-N profiles (SPT: standard penetration test). This study used the V<sub>s</sub> and SPT methods recommended by the National Center for Earthquake Engineering Research (NCEER) to examine which is more conservative according to the assessment results on 41 liquefiable soil layers at sites in two major cities in Taiwan. Statistical hypothesis testing was used to make the analysis more quantitative and objective. Based on three sets of hypothesis tests, it shows that the hypothesis—the SPT method is more conservative than the V<sub>s</sub> method—was not rejected on a 5% level of significance.
文摘DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecule DNMT1 modulators are attractive for biochemical epigenetic studies and have the potential to become drugs. So far, more than five hundred small molecules have been reported as DNMT1 inhibitors. However, only a limited number of DNMT1 activators have been disclosed because, at least in part, DNMT1 activators are typically regarded as negative data in virtual screening campaigns or optimization projects. This manuscript aims to report the chemical structures and biological activity of small molecules that increase the enzymatic activity of DNMT1. Results of the biochemical experimental assays are discussed. It was found that small molecule activators have a large variety of chemical scaffolds but share pharmacophore features. Visual analysis of the chemical space and multiverse based on molecular fingertips supported that activators are structurally diverse. This is the first report of eight small molecules that increase the enzymatic activity of DNMT1 by more than 400% in an enzymatic-based assay. The outcome warrants further investigation of the epigenetic activity of the compounds in a counter-screen assay, e.g., cell-based and in vivo context.
