Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-de...Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.展开更多
In electrocatalysis,two-dimensional(2D)materials have attracted extensive interests due to their unique electronic structure and physical properties.In recent years,many efforts have been devoted to improving the cata...In electrocatalysis,two-dimensional(2D)materials have attracted extensive interests due to their unique electronic structure and physical properties.In recent years,many efforts have been devoted to improving the catalytic activity of 2D materials.However,the stability of 2D materials under catalytic conditions,as a critical issue,requires better understanding for any practical applications.This review summarizes recent progress in electrocatalytic stability of 2D materials,including four intrinsic factors that affect the stability of 2D materials:1.Weak interactions between 2D catalyst and substrate;2,delamination of 2D catalyst layers;3.metastable phase of 2D materials;4.chemistry and environmental instability of 2D materials.Meanwhile,some corresponding solutions are summarized for each factor.In addition,this review proposes potential routes for developing 2D catalytic materials with both high activity and stability.展开更多
In this paper, the evolution of the microphysical characteristics in different regions(eyewall, inner core, and outer rainbands) and different quadrants [downshear left(DL), downshear right(DR), upshear left(UL), and ...In this paper, the evolution of the microphysical characteristics in different regions(eyewall, inner core, and outer rainbands) and different quadrants [downshear left(DL), downshear right(DR), upshear left(UL), and upshear right(UR)]during the final landfall of Typhoon Ewiniar(2018) is analyzed using two-dimensional video disdrometer and S-band polarimetric radar data collected in Guangdong, China. Due to the different types of underlying surfaces, the periods before landfall(mainly dominated by underlying sea surface) and after landfall(mainly dominated by underlying land surface) are also analyzed. Both before landfall and after landfall, the downshear quadrants had the dominate typhoon precipitation. The outer rainbands had more graupel than the inner core, resulting in a larger radar reflectivity, differential reflectivity, specific differential phase shift, and mass-weighted mean diameter below the melting layer. Compared with other regions, the eyewall region had the smallest mean logarithmic normalized intercept parameter before landfall and the smallest mean mass-weighted mean diameter and the largest mean logarithmic normalized intercept parameter after landfall. The hydrometeor size sorting was obvious in the eyewall and inner core(especially in the eyewall) after landfall. A high concentration of large raindrops fell in the DL quadrant, and more small raindrops fell in the UR quadrant. Although the icephase process and warm rain process were both important in the formation of tropical cyclone precipitation, the warm rain process(ice-phase process) contributed more liquid water before landfall(after landfall). This investigation provides a reference for improving the microphysical parameterization scheme in numerical models.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
最佳线性无偏估计(BLUE,Best Linear Unbiased Estimation)滤波用于雷达目标跟踪时,有计算量小,置信度高等优点.但是当互斜距测量误差较大时,BLUE滤波会产生非高斯转换量测,导致跟踪精度降低.为解决此问题,对其量测转换模型进行修正:通...最佳线性无偏估计(BLUE,Best Linear Unbiased Estimation)滤波用于雷达目标跟踪时,有计算量小,置信度高等优点.但是当互斜距测量误差较大时,BLUE滤波会产生非高斯转换量测,导致跟踪精度降低.为解决此问题,对其量测转换模型进行修正:通过引入方位预测,减小方位误差三角函数的非线性影响,得到准高斯分布的转换量测.分析视线坐标系下BLUE滤波的性能,推导引入方位预测的条件,给出改进算法工作流程.推导三坐标雷达下的滤波模型参数,提出转换量测高斯化水平的评估指标并仿真证明:改进算法的转换量测更逼近高斯分布,因此跟踪性能更好,而计算量只有轻微增加.本算法思想同样适用于其他非线性误差较大的场合,对解决类似问题有借鉴意义.展开更多
基金sponsored by BeiGene.Third-party medical writing assistance was provided by Ghina Yaacoub,MSc,of Ashfield MedComms,an Inizio Company,and funded by BeiGene.
文摘Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.
基金support from the National Key R&D Program of China,China (Nos.2022YFA1505200)the National Natural Science Foundation of China,China (Nos.21872114,92163103,and 21972121)the Fundamental Research Funds for the Central Universities,China (Nos.20720210017 and 20720210009)。
文摘In electrocatalysis,two-dimensional(2D)materials have attracted extensive interests due to their unique electronic structure and physical properties.In recent years,many efforts have been devoted to improving the catalytic activity of 2D materials.However,the stability of 2D materials under catalytic conditions,as a critical issue,requires better understanding for any practical applications.This review summarizes recent progress in electrocatalytic stability of 2D materials,including four intrinsic factors that affect the stability of 2D materials:1.Weak interactions between 2D catalyst and substrate;2,delamination of 2D catalyst layers;3.metastable phase of 2D materials;4.chemistry and environmental instability of 2D materials.Meanwhile,some corresponding solutions are summarized for each factor.In addition,this review proposes potential routes for developing 2D catalytic materials with both high activity and stability.
基金jointly supported by Guangdong Basic and Applied Basic Research Foundation (2021A1515011415)the National Natural Science Foundation of China (Grant Nos. 42075086, 41975138, and 42005062)the Natural Science Foundation of Guangdong Province, China (2019A1515010814)。
文摘In this paper, the evolution of the microphysical characteristics in different regions(eyewall, inner core, and outer rainbands) and different quadrants [downshear left(DL), downshear right(DR), upshear left(UL), and upshear right(UR)]during the final landfall of Typhoon Ewiniar(2018) is analyzed using two-dimensional video disdrometer and S-band polarimetric radar data collected in Guangdong, China. Due to the different types of underlying surfaces, the periods before landfall(mainly dominated by underlying sea surface) and after landfall(mainly dominated by underlying land surface) are also analyzed. Both before landfall and after landfall, the downshear quadrants had the dominate typhoon precipitation. The outer rainbands had more graupel than the inner core, resulting in a larger radar reflectivity, differential reflectivity, specific differential phase shift, and mass-weighted mean diameter below the melting layer. Compared with other regions, the eyewall region had the smallest mean logarithmic normalized intercept parameter before landfall and the smallest mean mass-weighted mean diameter and the largest mean logarithmic normalized intercept parameter after landfall. The hydrometeor size sorting was obvious in the eyewall and inner core(especially in the eyewall) after landfall. A high concentration of large raindrops fell in the DL quadrant, and more small raindrops fell in the UR quadrant. Although the icephase process and warm rain process were both important in the formation of tropical cyclone precipitation, the warm rain process(ice-phase process) contributed more liquid water before landfall(after landfall). This investigation provides a reference for improving the microphysical parameterization scheme in numerical models.
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.
文摘最佳线性无偏估计(BLUE,Best Linear Unbiased Estimation)滤波用于雷达目标跟踪时,有计算量小,置信度高等优点.但是当互斜距测量误差较大时,BLUE滤波会产生非高斯转换量测,导致跟踪精度降低.为解决此问题,对其量测转换模型进行修正:通过引入方位预测,减小方位误差三角函数的非线性影响,得到准高斯分布的转换量测.分析视线坐标系下BLUE滤波的性能,推导引入方位预测的条件,给出改进算法工作流程.推导三坐标雷达下的滤波模型参数,提出转换量测高斯化水平的评估指标并仿真证明:改进算法的转换量测更逼近高斯分布,因此跟踪性能更好,而计算量只有轻微增加.本算法思想同样适用于其他非线性误差较大的场合,对解决类似问题有借鉴意义.
