Aconitine,a common and main toxic component of Aconitum,is toxic to the central nervous system.However,the mechanism of aconitine neurotoxicity is not yet clear.In this work,we had the hypothesis that excitatory amino...Aconitine,a common and main toxic component of Aconitum,is toxic to the central nervous system.However,the mechanism of aconitine neurotoxicity is not yet clear.In this work,we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine.HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system.Meanwhile,to confirm the metabolic mechanism of aconitine toxicity on HT22 cells,the levels of lactate dehydrogenase,intracellular Ca^(2+),reactive oxygen species,glutathione and superoxide dismutase,and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology.Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid,which was followed by the accumulation of lactic acid and reduction of glucose.The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca^(2+)overload and oxidative stress,and eventually result in cell apoptosis.In general,we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.展开更多
Amine transaminases(ATAs)catalyze the asymmetric amination of prochiral ketones or aldehydes to their corresponding chiral amines.However,the trade-off between activity and stability in enzyme engineering represents a...Amine transaminases(ATAs)catalyze the asymmetric amination of prochiral ketones or aldehydes to their corresponding chiral amines.However,the trade-off between activity and stability in enzyme engineering represents a major obstacle to the practical application of ATAs.Overcoming this trade-off is important for developing robustly engineered enzymes and a universal approach for ATAs.Herein,we modified the binding pocket of co-ATA from Aspergillus terreus(AtATA)to identify the key amino acid residues controlling the activity and stability of AtATA toward 1-acetonaphthone.We discovered a structural switch comprising four key amino acid sites(R128,V149,L182,and L187),as well as the"best"mutant(AtATAD224K/V149A/L182 F/L187F;termed M4).Compared to the parent enzyme AtATAD224K(AtATAPa),M4 increased the catalytic efficiency(k_(cat)/K_(m)^(1-acetonaphthone),where kcatis the constant of catalytic activities and is 10.1 min^(-1),K_(m)^(1-acetonaphthoneis) Michaelis-Menten constant and is 1.7 mmol·L^(-1))and half-life(t1/2)by 59-fold to 5.9 L·min^(-1)·mmol-1and by 1.6-fold to 46.9 min,respectively.Moreover,using M4 as the biocatalyst,we converted a 20 mmol·L^(-1)aliquot of 1-acetonaphthone in a 50 mL scaled-up system to the desired product,(R)-(+)-1(1-naphthyl)ethylamine((R)-NEA),with 78%yield and high enantiomeric purity(R>99.5%)within 10 h.M4 also displayed significantly enhanced activity toward various 1-acetonaphthone analogs.The related structural properties derived by analyzing structure and sequence information of robust ATAs illustrated their enhanced activity and thermostability.Strengthening of intramolecular interactions and expansion of the angle between the substratebinding pocket and the pyridoxal 5’-phosphate(PLP)-binding pocket contributed to synchronous enhancement of ATA thermostability and activity.Moreover,this pocket engineering strategy successfully transferred enhanced activity and thermostability to three other ATAs,which exhibited 8%-22%sequence similarity with AtATA.This research has important implications for overcoming the trade-off between ATA activity and thermostability.展开更多
The remarkable ramping of record power conversion efficiencies in perovskite solar cells(PSCs) has stimulated the growth of this technology towards commercialization. However, there remain challenges and opportunities...The remarkable ramping of record power conversion efficiencies in perovskite solar cells(PSCs) has stimulated the growth of this technology towards commercialization. However, there remain challenges and opportunities for further improving their efficiency and stability. Featuring the variety of functional group in the constituting ions, ionic liquids(ILs) exhibit versatile properties and functions that can be leveraged to the development of improved PSCs. Herein with a systematic review on the recent progress in the application of ILs to PSCs, we show that based on the different roles of ILs in the film and device settings, IL can facilitate the thin-film synthesis of perovskites, improve the properties of chargetransport layers, and ameliorate the interfacial energetics at device interfaces. In particular, the ILsperovskite interactions of two different types(Lewis acid-base interaction and hydrogen bonding) are the essential chemistries underpinning observed efficiency and stability improvements in PSCs, which represent a vast research paradigm in the field of energy chemistry.展开更多
Background:We evaluated whether the serum procalcitonin(PCT)level could predict death in severe and critical coronavirus disease 2019(COVID-19)patients.Methods:This study included 129 COVID-19 patients.PCT levels on a...Background:We evaluated whether the serum procalcitonin(PCT)level could predict death in severe and critical coronavirus disease 2019(COVID-19)patients.Methods:This study included 129 COVID-19 patients.PCT levels on admission,treatment,and death were collected.The outcomes were compared.Results:The optimum cutoff value of the PCT level determined by receiver operator characteristic curve analysis to predict all-cause death was 0.085 ng/mL,with sensitivity of 95.7%and specifi city of 72.6%.Overall,78 patients had a PCT level below 0.085 ng/mL and 51 patients had a PCT level of 0.085 ng/mL or greater.High-PCT-level patients had lower levels of lymphocytes(P=0.001)and albumin(P=0.002)and higher levels of creatinine(P=0.024),D-dimer(P=0.002),and white blood cells,neutrocytes(P<0.001),high-sensitivity C-reactive protein(P<0.001),interleukin-6(P<0.001),interleukin-8(P=0.001),interleukin-10(P=0.001),tumor necrosis factor(P<0.001),erythrocyte sedimentation rate(P=0.001),and ferritin(P=0.001).During the 30-day observation period,23 patients died.Mortality was significantly higher in high-PCT-level patients than in patients with low PCT levels(43.1%vs.1.3%;P<0.001).The risks of death(P<0.0001)and ventilator use(P<0.0001)were increased in patients with PCT levels of 0.085 ng/mL or greater.Conclusions:A PCT level of 0.085 ng/mL or greater on admission could effectively predict death and ventilator use in severe and critical COVID-19 patients.展开更多
Rechargeable aqueous zinc-ion batteries(AZIBs)offer high energy density,low cost,and are environmentally friendly,rendering them potential energy storage devices.However,dendrite growth on the zinc anode and numerous ...Rechargeable aqueous zinc-ion batteries(AZIBs)offer high energy density,low cost,and are environmentally friendly,rendering them potential energy storage devices.However,dendrite growth on the zinc anode and numerous side reac-tions during operation challenge their commercialization.Recent advancements have introduced various materials for the functionalization of zinc anodes.These developments effectively mitigate the performance degradation of zinc anode,enhancing both its cycle stability and the overall performance of AZIBs.Herein,the construction of functionalized zinc anodes is discussed,current materials(including organic,inorganic and their composites)for modified zinc anodes are categorized,and the protective mechanism behind functionalized zinc anodes is analyzed.The study concludes by outlining the characteristics of materials suitable for dendritic-free zinc anode construction and the prospects for future development directions of functionalized zinc anodes in AZIBs.展开更多
Over the last 30 years,the number of people with cardiovascular disease(CVD)has continued to increase globally,with hypertension being the leading risk factor for CVD.The burden of hypertension is especially large in ...Over the last 30 years,the number of people with cardiovascular disease(CVD)has continued to increase globally,with hypertension being the leading risk factor for CVD.The burden of hypertension is especially large in countries and regions undergoing economic development and lifestyle transition.The latest survey data from China show that from 2012 to 2015,the prevalence of hypertension among residents aged18 years was as high as 27.9%;that is,one in four adults suffer from hypertension[1].It follows that the current prevention and control of hypertension is poor.Therefore,how best to improve hypertension management to reduce the CVD burden is a major global consideration.Here we depict the challenges that cardiologists and neurologist face in the present era of CVD.展开更多
基金supported the National Natural Science Foundation of China(Grant Nos.:81973569,82130113,and 22034005)the National Key R&D Program of China(Grant No.:2021YFF0600700)the“Xinglin Scholars”Research Promotion Program of Chengdu University of Traditional Chinese Medicine(Grant No.:BSH2021009).
文摘Aconitine,a common and main toxic component of Aconitum,is toxic to the central nervous system.However,the mechanism of aconitine neurotoxicity is not yet clear.In this work,we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine.HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system.Meanwhile,to confirm the metabolic mechanism of aconitine toxicity on HT22 cells,the levels of lactate dehydrogenase,intracellular Ca^(2+),reactive oxygen species,glutathione and superoxide dismutase,and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology.Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid,which was followed by the accumulation of lactic acid and reduction of glucose.The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca^(2+)overload and oxidative stress,and eventually result in cell apoptosis.In general,we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.
基金National Natural Science Foundation of China(32071268 and 31971372)the Ningbo"Scientific and Technological Innovation 2025"Key Project(2020Z080)for financial support。
文摘Amine transaminases(ATAs)catalyze the asymmetric amination of prochiral ketones or aldehydes to their corresponding chiral amines.However,the trade-off between activity and stability in enzyme engineering represents a major obstacle to the practical application of ATAs.Overcoming this trade-off is important for developing robustly engineered enzymes and a universal approach for ATAs.Herein,we modified the binding pocket of co-ATA from Aspergillus terreus(AtATA)to identify the key amino acid residues controlling the activity and stability of AtATA toward 1-acetonaphthone.We discovered a structural switch comprising four key amino acid sites(R128,V149,L182,and L187),as well as the"best"mutant(AtATAD224K/V149A/L182 F/L187F;termed M4).Compared to the parent enzyme AtATAD224K(AtATAPa),M4 increased the catalytic efficiency(k_(cat)/K_(m)^(1-acetonaphthone),where kcatis the constant of catalytic activities and is 10.1 min^(-1),K_(m)^(1-acetonaphthoneis) Michaelis-Menten constant and is 1.7 mmol·L^(-1))and half-life(t1/2)by 59-fold to 5.9 L·min^(-1)·mmol-1and by 1.6-fold to 46.9 min,respectively.Moreover,using M4 as the biocatalyst,we converted a 20 mmol·L^(-1)aliquot of 1-acetonaphthone in a 50 mL scaled-up system to the desired product,(R)-(+)-1(1-naphthyl)ethylamine((R)-NEA),with 78%yield and high enantiomeric purity(R>99.5%)within 10 h.M4 also displayed significantly enhanced activity toward various 1-acetonaphthone analogs.The related structural properties derived by analyzing structure and sequence information of robust ATAs illustrated their enhanced activity and thermostability.Strengthening of intramolecular interactions and expansion of the angle between the substratebinding pocket and the pyridoxal 5’-phosphate(PLP)-binding pocket contributed to synchronous enhancement of ATA thermostability and activity.Moreover,this pocket engineering strategy successfully transferred enhanced activity and thermostability to three other ATAs,which exhibited 8%-22%sequence similarity with AtATA.This research has important implications for overcoming the trade-off between ATA activity and thermostability.
基金financial support from the Taishan Scholars Project of Shandong Province (201909121)the start-up grants, Initiation Grant - Faculty Niche Research Areas (IG-FNRA) 2020/21 and Interdisciplinary Matching Scheme 2020/21 of the Hong Kong Baptist University (HKBU) and the Early Career Scheme (22300221) from the Hong Kong Research Grant Councilthe support of the Hong Kong Ph D Fellowship Scheme。
文摘The remarkable ramping of record power conversion efficiencies in perovskite solar cells(PSCs) has stimulated the growth of this technology towards commercialization. However, there remain challenges and opportunities for further improving their efficiency and stability. Featuring the variety of functional group in the constituting ions, ionic liquids(ILs) exhibit versatile properties and functions that can be leveraged to the development of improved PSCs. Herein with a systematic review on the recent progress in the application of ILs to PSCs, we show that based on the different roles of ILs in the film and device settings, IL can facilitate the thin-film synthesis of perovskites, improve the properties of chargetransport layers, and ameliorate the interfacial energetics at device interfaces. In particular, the ILsperovskite interactions of two different types(Lewis acid-base interaction and hydrogen bonding) are the essential chemistries underpinning observed efficiency and stability improvements in PSCs, which represent a vast research paradigm in the field of energy chemistry.
文摘Background:We evaluated whether the serum procalcitonin(PCT)level could predict death in severe and critical coronavirus disease 2019(COVID-19)patients.Methods:This study included 129 COVID-19 patients.PCT levels on admission,treatment,and death were collected.The outcomes were compared.Results:The optimum cutoff value of the PCT level determined by receiver operator characteristic curve analysis to predict all-cause death was 0.085 ng/mL,with sensitivity of 95.7%and specifi city of 72.6%.Overall,78 patients had a PCT level below 0.085 ng/mL and 51 patients had a PCT level of 0.085 ng/mL or greater.High-PCT-level patients had lower levels of lymphocytes(P=0.001)and albumin(P=0.002)and higher levels of creatinine(P=0.024),D-dimer(P=0.002),and white blood cells,neutrocytes(P<0.001),high-sensitivity C-reactive protein(P<0.001),interleukin-6(P<0.001),interleukin-8(P=0.001),interleukin-10(P=0.001),tumor necrosis factor(P<0.001),erythrocyte sedimentation rate(P=0.001),and ferritin(P=0.001).During the 30-day observation period,23 patients died.Mortality was significantly higher in high-PCT-level patients than in patients with low PCT levels(43.1%vs.1.3%;P<0.001).The risks of death(P<0.0001)and ventilator use(P<0.0001)were increased in patients with PCT levels of 0.085 ng/mL or greater.Conclusions:A PCT level of 0.085 ng/mL or greater on admission could effectively predict death and ventilator use in severe and critical COVID-19 patients.
基金Hebei Natural Science Fund for Distinguished Young Scholar,Grant/Award Number:E2019209433Natural Science Foundation of Hebei Province,Grant/Award Number:E2022209158+2 种基金National Natural Science Foundation of China,Grant/Award Number:52302223National Research Foundation of Korea,Grant/Award Number:NRF-2019R1A2C2090443Technology Innovation Program(Ministry of Trade,Industry&Energy,Korea),Grant/Award Number:20013621。
文摘Rechargeable aqueous zinc-ion batteries(AZIBs)offer high energy density,low cost,and are environmentally friendly,rendering them potential energy storage devices.However,dendrite growth on the zinc anode and numerous side reac-tions during operation challenge their commercialization.Recent advancements have introduced various materials for the functionalization of zinc anodes.These developments effectively mitigate the performance degradation of zinc anode,enhancing both its cycle stability and the overall performance of AZIBs.Herein,the construction of functionalized zinc anodes is discussed,current materials(including organic,inorganic and their composites)for modified zinc anodes are categorized,and the protective mechanism behind functionalized zinc anodes is analyzed.The study concludes by outlining the characteristics of materials suitable for dendritic-free zinc anode construction and the prospects for future development directions of functionalized zinc anodes in AZIBs.
文摘Over the last 30 years,the number of people with cardiovascular disease(CVD)has continued to increase globally,with hypertension being the leading risk factor for CVD.The burden of hypertension is especially large in countries and regions undergoing economic development and lifestyle transition.The latest survey data from China show that from 2012 to 2015,the prevalence of hypertension among residents aged18 years was as high as 27.9%;that is,one in four adults suffer from hypertension[1].It follows that the current prevention and control of hypertension is poor.Therefore,how best to improve hypertension management to reduce the CVD burden is a major global consideration.Here we depict the challenges that cardiologists and neurologist face in the present era of CVD.
