Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promisin...Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.展开更多
目的:探讨右美托咪定预先给药对高血压冠心病患者诱导插管时血流动力学及应激反应的影响。方法:将我院2012年7月-2013年3月择期行腹部手术且合并高血压冠心病患者50例随机均分为实验组(麻醉诱导前15 min静脉泵入剂量为1.0μg/kg的右美...目的:探讨右美托咪定预先给药对高血压冠心病患者诱导插管时血流动力学及应激反应的影响。方法:将我院2012年7月-2013年3月择期行腹部手术且合并高血压冠心病患者50例随机均分为实验组(麻醉诱导前15 min静脉泵入剂量为1.0μg/kg的右美托咪定稀释液15 m L)和对照组(麻醉诱导前15 min静脉泵入15 m L生理盐水),监测并记录两组患者在不同时刻的BP、HR、RPP,抽取静脉血测定血浆NE和E的浓度。结果:(1)与T0时刻相比,对照组患者的心率、血压、RPP在T1-T5各时刻是先有所下降后又上升的(P<0.05),其中对照组RPP在T3时明显上升(P<0.01),然而实验组内在各时刻变化不明显(P>0.05),两组间比较差异具有统计学意义(P<0.05);(2)与T0时刻进行比较,对照组患者血浆NE和E的含量水平在T3、T4时刻明显上升(P<0.05),而实验组则变化不明显,组间比较差异具有统计学意义(P<0.05)。结论:右美托咪定预先给药用于缓解高血压冠心病患者诱导插管时心血管反应效果显著,值得临床推广应用。展开更多
基金supported by the National Natural Science Foundation of China(82230041,91949205,31730035,81721005)the National Key R&D Program of China(2016YFC1305800)the Guangdong Provincial Key S&T Program(018B030336001)。
文摘Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.
文摘目的:探讨右美托咪定预先给药对高血压冠心病患者诱导插管时血流动力学及应激反应的影响。方法:将我院2012年7月-2013年3月择期行腹部手术且合并高血压冠心病患者50例随机均分为实验组(麻醉诱导前15 min静脉泵入剂量为1.0μg/kg的右美托咪定稀释液15 m L)和对照组(麻醉诱导前15 min静脉泵入15 m L生理盐水),监测并记录两组患者在不同时刻的BP、HR、RPP,抽取静脉血测定血浆NE和E的浓度。结果:(1)与T0时刻相比,对照组患者的心率、血压、RPP在T1-T5各时刻是先有所下降后又上升的(P<0.05),其中对照组RPP在T3时明显上升(P<0.01),然而实验组内在各时刻变化不明显(P>0.05),两组间比较差异具有统计学意义(P<0.05);(2)与T0时刻进行比较,对照组患者血浆NE和E的含量水平在T3、T4时刻明显上升(P<0.05),而实验组则变化不明显,组间比较差异具有统计学意义(P<0.05)。结论:右美托咪定预先给药用于缓解高血压冠心病患者诱导插管时心血管反应效果显著,值得临床推广应用。
