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Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

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药学学报:英文版 2023年第7期13卷 3054-3066页

作者： Ya-Li Sang christophe Pannecouque erik De clercq Shuai Wang Fen-er.chen Department of chemistry Engineering Center of Catalysis and Synthesis for Chiral MoleculesFudan UniversityShanghai 200433China Shanghai Engineering center of Industrial Asymmetric catalysis for chiral Drugs Shanghai 200433China School of Science Harbin Institute of Technology(Shenzhen)Shenzhen 518055China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=96 min)in human liver microsomes,we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the c-5 position of *** strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 *** best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes(t1/2=2754 min),which was about 29-fold longer than that of 5(t1/2=96 min).This compound conferred picomolar inhibition of WT HIV-1(Ec50=0.9 nmol/L)and low nanomolar activity against five clinically drug-resistant mutant *** maintained particularly low cytotoxicity(cc50=264μmol/L)and good selectivity(SI=256,438).Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with ***,compound 9g was characterized by good safety *** displayed no apparent inhibition of cYP enzymes and h *** acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/*** findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

关键词： NNRTI HIV-1 DAPYs Picomolar Metabolic stability

基于机器学习的人工关节置换术后医院感染预测模型的构建与评价

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中华医院感染学杂志 2024年第12期34卷 1826-1830页

作者：甘文思干铁儿杨西帆余旭霞杨璐李文渊浙江大学公共卫生学院大数据健康科学系(浙江大学医学院附属第二医院临床大数据与统计中心) 浙江杭州310058 温州市中西医结合医院感染管理科浙江温州325000 浙江中医药大学附属第一医院(浙江省中医院)感染管理科浙江杭州310000

目的构建一种基于机器学习的预测模型,用于人工关节置换术后医院感染的预测.方法选择浙江省杭州市某三甲医院2017年1月-2022年11月进行人工关节置换手术的1800例住院患者作为研究对象,将数据集以3:1的比例随机分成训练集(1350例)和测试... 详细信息

目的构建一种基于机器学习的预测模型,用于人工关节置换术后医院感染的预测.方法选择浙江省杭州市某三甲医院2017年1月-2022年11月进行人工关节置换手术的1800例住院患者作为研究对象,将数据集以3:1的比例随机分成训练集(1350例)和测试集(450例).在训练集中应用递归特征消除方法进行自变量筛选,通过网格搜索方法确定逻辑回归、支持向量机(SVM)、决策树(DT)、极端梯度提升(XGBoost)和随机森林(RF)等五类模型的最佳参数.使用敏感度(TPR)、阳性预测值(PPV)、特异度(TNR)、阴性预测值(NPV)、F1分数、准确度和曲线下面积(AUc)等指标来评估模型性能,确定较优机器学习模型,并采用沙普利加性解释(SHAP)方法对较优模型中的变量重要性进行解释.结果1800例参与者中102例发生感染,发生率为5.67%;逻辑回归、DT、RF、SVM和XGBoost等五个模型在训练集中的AUc值达0.92、0.89、0.98、0.70、0.98;测试集中AUc值则分别为0.85、0.78、0.86、0.63、0.88;XGBoost、RF模型为较优的机器学习模型.SHAP结果显示围手术期抗菌药物使用天数、手术时间、年龄、国家医院感染监控系统(NNIS)评分、失血量是较为重要的预测因子.结论本研究建立了基于机器学习算法的人工关节置换术后医院感染风险预测模型,并比较了多种预测模型的效能,其中XGBoost、RF模型的总体性能较优,有利于及时准确地识别人工关节置换术后医院感染高危患者并实施有效的干预措施.

关键词：人工关节置换机器学习预测模型术后医院感染

炎症指标联合阴道分泌物预测宫颈环扎术后自发性早产的价值

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中国现代医生 2024年第7期62卷 5-8页

作者：史春波陈金亮陈安儿宁波市妇女儿童医院妇产科浙江宁波315010

目的探讨血清炎症指标联合阴道分泌物检查对宫颈环扎术后自发性早产(spontaneous premature birth,SPB)的预测价值。方法选取2018年1月至2022年12月于宁波市妇女儿童医院行孕期经阴道宫颈环扎的孕妇175例,根据其妊娠结局将其分为研究组(... 详细信息

目的探讨血清炎症指标联合阴道分泌物检查对宫颈环扎术后自发性早产(spontaneous premature birth,SPB)的预测价值。方法选取2018年1月至2022年12月于宁波市妇女儿童医院行孕期经阴道宫颈环扎的孕妇175例,根据其妊娠结局将其分为研究组(SPB,93例)和对照组(足月产,82例);比较两组孕妇的术后血常规、c反应蛋白(c-reaction protein,cRP)及阴道分泌物检查结果。采用多因素Logistic回归分析宫颈环扎术后SPB的独立危险因素,受试者操作特征曲线(receiver operating characteristic curve,ROc曲线)研究各指标单独或联合识别SPB的能力。结果研究组孕妇宫颈环扎术后的白细胞计数、cRP、支原体阳性率和细菌阳性率均显著高于对照组(Pc回归分析结果显示,宫颈环扎术后白细胞计数升高、cRP升高、阴道分泌物支原体培养阳性和细菌培养阳性均是SPB的独立危险因素(Pc曲线结果显示,上述指标单独及联合预测宫颈环扎术后SPB的曲线下面积分别为0.674、0.737、0.599、0.613、0.826,以四项指标联合的预测价值最大,敏感度79.6%,特异性79.3%。结论宫颈环扎术后白细胞计数、cRP检测联合阴道分泌物支原体、细菌培养对SPB有较好的预测价值。

关键词：宫颈环扎自发性早产预测价值

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出院后持续健康宣教对癫痫患者服药依从性及自测健康评分的影响

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黑龙江医学 2024年第4期48卷 466-468页

作者：李婷婷刘斯尔李莎莎刘艳德阳市人民医院神经内科四川德阳618000

目的:探讨出院后持续健康宣教对癫痫患者服药依从性及自测健康评分(SRHMS)的影响。方法:选取2017年1月—2018年12月德阳市人民医院神经内科收治的140例癫痫患者作为研究对象,按出院时间顺序将2017年1—12月出院患者为对照组(70例,行常... 详细信息

目的:探讨出院后持续健康宣教对癫痫患者服药依从性及自测健康评分(SRHMS)的影响。方法:选取2017年1月—2018年12月德阳市人民医院神经内科收治的140例癫痫患者作为研究对象,按出院时间顺序将2017年1—12月出院患者为对照组(70例,行常规出院指导),2018年1—12月出院患者作为观察组(70例,实施出院后持续健康宣教干预)。比较两组患者的临床疗效、用药依从率及不同时间点自测健康评定量表(SRHMS)评分情况。结果:干预后,观察组患者总有效率显著高于对照组,差异有统计学意义(χ^(2)=25.940,P0.05);出院后1个月、6个月、12个月,观察组患者SRHMS评分明显高于对照组,差异有统计学意义(t=7.507、27.570、8.199,P<0.05)。结论:出院后持续健康宣教用于癫痫患者,可有效提高其病情控制效果,改善其服药依从性和健康状态。

关键词：出院健康宣教癫痫依从性自测健康评分

Structure-based design of novel heter.cyclesubstituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4906-4917页

作者： Li-Min Zhao christophe Pannecouque erik De clerc Shuai Wang Fen-er.chen Key Laboratory of Natural Resources of changbai Mountain&Functional Molecules Ministry of EducationYanbian University College of PharmacyYanbian UniversityYanji 133002China Engineering center of catalysis and Synthesis for chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering center of Industrial Asymmetric catalysis for chiral Drugs Shanghai 200433China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66(SI=2019.80,S=1.9μg/mL),a series of novel heter.cycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heter.cyclic group with lower ***,the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility(SI=12,497.73,S=4472μg/mL)in comparison with ZLM-66(SI=2019.80,S=1.9μg/mL).This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains(K103N,L1001,Y181c,E138K,and K103N+Y181c).The analog also demonstrated favorable safety and pharmacokinetic profiles,as evidenced by its insensitivity to cYP and herG,lack of mortality and pathological damage,and good oral bioavailability in rats(F=27.1%).Further development of 7w for HIV therapy will be facilitated by this valuable information.

关键词： HIV-1 RT NNRTIS ATDP Pyridone

A facile strategy for tuning the density of surface-grafted biomolecules for melt extrusion-based additive manufacturing applications

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Bio-Design and Manufacturing 2024年第3期7卷 277-291页

作者： I.A.O.Beeren G.Dos Santos P.J.Dijkstra c.Mota J.Bauer H.Ferreira Rui L.Reis N.Neves S.camarero-Espinosa M.B.Baker L.Moroni Department of complex Tissue Regeneration MERLN Institute for Technology-Inspired Regenerative MedicineMaastricht University6229 ER MaastrichtThe Netherlands 3B’s Research Group I3Bs–Research Institute on BiomaterialsBiodegradables and BiomimeticsHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineUniversity of MinhoAveParkZona Industrial da Gandra4805-017 BarcoGuimarãesPortugal IcVS/3B’s-PT Government Associate Laboratory 4806-909 Braga/GuimarãesPortugal POLYMAT University of the Basque Country UPV/EHU20018 Donostia/San SebastiánSpain IKerBASQUE Basque Foundation for Science48009 BilbaoSpain

Melt extrusion-based additive manufacturing(ME-AM)is a promising technique to fabricate porous scaffolds for tissue engi-neering ***,most synthetic semicrystalline polymers do not possess the intrinsic biological activity required to control cell *** of biomolecules on polymer.c surfaces of AM scaffolds enhances the bioactivity of a construct;however,there are limited strategies available to control the surface ***,we report a strategy to tune the surface density of bioactive groups by blending a low molecular weight poly(ε-caprolactone)5k(PcL5k)containing orthogonally reactive azide groups with an unfunctionalized high molecular weight PcL75k at different *** porous three-dimensional(3D)scaf-folds were then fabricated using a high weight percentage(75 wt.%)of the low molecular weight PcL *** a proof-of-concept test,we prepared films of three different mass ratios of low and high molecular weight polymers with a thermopress and reacted with an alkynated fluorescent model compound on the surface,yielding a density of 201-561 pmol/cm^(2).Subsequently,a bone morphogenetic protein 2(BMP-2)-derived peptide was grafted onto the films comprising different blend compositions,and the effect of peptide surface density on the osteogenic differentiation of human mesenchymal stromal cells(hMScs)was *** two weeks of culturing in a basic medium,cells expressed higher levels of BMP receptor II(BMPRII)on films with the conjugated *** addition,we found that alkaline phosphatase activity was only significantly enhanced on films contain-ing the highest peptide density(i.e.,561 pmol/cm^(2)),indicating the importance of the surface *** together,these results emphasize that the density of surface peptides on cell differentiation must be considered at the cell-material ***,we have presented a viable strategy for ME-AM community that desires to tune the bulk and surface functionality via blending of(m

关键词： Additive manufacturing Blending Surface functionalization Surface density click chemistry Human

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基于蒙古语情感分布学习的数据增强方法

计算机仿真 2024年第7期41卷 540-545页

作者：杨蕾苏依拉仁庆道尔吉吉亚图内蒙古工业大学信息工程学院内蒙古呼和浩特010080

现有的情感分布学习尚未应用于蒙古语中,并且暂无利用情感分布学习进行数据增强研究。基于此,将极坐标的思想融入普鲁契克情感轮中,提出一种极坐标情绪表示法,把情感分布转化为复合情绪向量并将情感轮注意力信息融入模型中进行蒙古语情... 详细信息

现有的情感分布学习尚未应用于蒙古语中,并且暂无利用情感分布学习进行数据增强研究。基于此,将极坐标的思想融入普鲁契克情感轮中,提出一种极坐标情绪表示法,把情感分布转化为复合情绪向量并将情感轮注意力信息融入模型中进行蒙古语情感分布学习。利用普鲁契克情感轮中任意两种基本情绪可以混合构成二元情绪的特性,为预测复合情绪向量扩展更为丰富的情绪标签,从而达到扩充数据集的目的。在蒙古语和中英文数据集上进行对比实验表明,基于极坐标情绪表示法的情感分布学习的性能优于传统方法。

关键词：情感分布学习蒙古语数据增强极坐标普鲁契克情感轮二元情绪

Synergistic Pd/cu catalysis enabled cross-coupling of glycosyl stannanes with sulfonium salts to access c-aryl/alkenyl glycals

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chinese chemical Letters 2023年第7期34卷 102-106页

作者： Weitao Yan Mingwen Zheng Peihsuan chuang Hao Sun Shiping Wang chunfa Xu Fen-er.chen Institute of Pharmaceutical Science and Technology College of ChemistryFuzhou UniversityFuzhou 350108China National Engineering Research center of chemical Fertilizer.catalyst College of Chemical EngineeringFuzhou UniversityFuzhou 350108China Engineering center of catalysis and Synthesis for chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering center of Industrial Asymmetric catalysis for chiral Drugs Fudan University.Shanghai 200433China

A highly efficient coupling of glycosyl stannanes and sulfonium salts enabled by synergistic Pd/cu catalysis is disclosed, facilitating the construction of c-aryl/alkenyl glycals under mild conditions in high *** protocol tolerates a wide scope of functional groups including ketone, cyano, ester, amide, nitro,halide. The one-pot formal c–H glycosylation starting from arene is demonstrated with a reaction sequence of dibenzothiophenylation/Stille coupling. Besides, a gram-scale reaction is performed successfully,showing the high applicability of this protocol.

关键词： c-glycals Sulfonium salts Synergistic catalysis carbohydrate Glycosyl stannanes Stille coupling

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莫西沙星治疗超早产儿人型支原体脑膜炎1例

中国当代儿科杂志 2024年第4期26卷 432-436页

作者：毛玮莹蓝江儿甘明宇张迅捷俞蕙胡黎园张蓉曹云肖蜜黎国家儿童医学中心/复旦大学附属儿科医院新生儿科上海201102 国家儿童医学中心/复旦大学附属儿科医院临床药学部上海201102 国家儿童医学中心/复旦大学附属儿科医院儿科研究院上海201102 国家儿童医学中心/复旦大学附属儿科医院感染科上海201102

患儿男,生后2 h,因早产(胎龄27+5周)、生后气促2 h入院。患儿入院后出现发热,血c反应蛋白升高,生后第4天脑脊液宏基因组二代测序示人型支原体阳性(序列数9898);生后第8天复查脑脊液宏基因组二代测序示人型支原体阳性(序列数56806)阳性... 详细信息

患儿男,生后2 h,因早产(胎龄27+5周)、生后气促2 h入院。患儿入院后出现发热,血c反应蛋白升高,生后第4天脑脊液宏基因组二代测序示人型支原体阳性(序列数9898);生后第8天复查脑脊液宏基因组二代测序示人型支原体阳性(序列数56806)阳性。患儿人型支原体化脓性脑膜炎诊断明确,抗生素调整为莫西沙星静脉滴注[5 mg/(kg·d)],总疗程4周。治疗后患儿脑脊液检查恢复正常,于生后第76天治愈出院。该文对新生儿人型支原体化脓性脑膜炎的诊断和治疗进行重点描述,介绍超早产儿人型支原体化脓性脑膜炎的多学科诊疗.

关键词：化脓性脑膜炎人型支原体莫西沙星超早产儿