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Acta Pharmaceutica Sinica B 2024年第8期14卷 3624-3642页

作者： Kai Tang Shu Wang Siqi Feng Xinyu Yang Yueyang Guo Xiangli Ren Linyue Bai Bin Yu Hong-Min Liu yihui song School of Pharmaceutical Sciences&Key Laboratory of Advanced Drug Preparation Technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China College of Chemistry Pingyuan LaboratoryState Key Laboratory of Antiviral DrugsZhengzhou UniversityZhengzhou 450001China Tianjian Laboratory of Advanced Biomedical Sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450000China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Src homology-2-containing protein tyrosine phosphatase 2(SHP2)is a promising therapeutic target for cancer *** this work,we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors,leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent,selective,orally bioavailable allosteric SHP2 inhibitor(SHP2WT IC_(50)=2.7 nmol/L)with favorable pharmacokinetic profiles(F=42.5%;t_(1/2)=2.47 h).Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the“tunnel”allosteric site of ***-642 could effectively suppress cell proliferation(KYSE-520 cells IC_(50)=5.73μmol/L)and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling ***,oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model,with a T/C value of 83.69%.Collectively,TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

关键词： Protein tyrosine phosphatase Pyrazolopyrazine SHP2 inhibitor Esophageal cancer

服役温度影响的DD6单晶高温合金磨削/喷丸加工表面完整性演化规律研究

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机械工程学报 2024年第9期60卷 410-420页

作者：何喆黄新春宋艺辉史耀耀张兆顷史恺宁西北工业大学航空发动机高性能制造工业和信息化部重点实验室西安710072 西北工业大学航空发动机先进制造技术教育部工程研究中心西安710072 西北工业大学科学技术研究院西安710072

DD6单晶高温合金因具备优异的耐高温性和抗蠕变性,是航空发动机涡轮叶片的重要材料。喷丸是高温合金表面强化的重要工艺,可有效去除加工刀痕,提高材料表层组织硬度,改善材料疲劳性能。为改善DD6磨削、喷丸强化后的表面完整性状态,提高... 详细信息

DD6单晶高温合金因具备优异的耐高温性和抗蠕变性,是航空发动机涡轮叶片的重要材料。喷丸是高温合金表面强化的重要工艺,可有效去除加工刀痕,提高材料表层组织硬度,改善材料疲劳性能。为改善DD6磨削、喷丸强化后的表面完整性状态,提高工件服役性能,通过温度载荷影响实验研究,探究服役温度对DD6磨削、喷丸表面状态的影响规律。研究发现随温度升高,因表面材料产生重熔现象,导致表面形貌一致性下降,表面粗糙度增大,表层微观组织再结晶层变厚,其中表面形貌和微观组织变化受温度影响较为显著,且在喷丸强化后更为明显。采用SEM分析和EDS分析的方法对不同温度下的表面形貌和微观组织进行分析,确定影响表面形貌和粗糙度的因素主要为表面氧化现象和表层组织再结晶现象。通过分析发现表面氧化会造成表面元素流失,而表层微观组织再结晶会产生再结晶晶界,导致表层材料改性。故在加工时应考虑温度对材料表面完整性的影响合理控制磨削、喷丸工艺参数,降低微观组织损伤。研究成果为镍基单晶高温合金抗疲劳制造提供了理论依据。

关键词： DD6 服役温度表面完整性磨削-喷丸演化规律

GH4169G高温合金车削切削力与切削温度有限元仿真研究

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工具技术 2024年第1期58卷 95-100页

作者：牛湛皓史耀耀黄新春宋艺辉樊昱昌西北工业大学机电学院航空发动机高性能制造工业和信息化部重点实验室西北工业大学科学技术研究院

为研究GH4169G高温合金车削用量及刀具几何特性对切削力和切削温度的影响规律,基于ABAQUS有限元仿真软件,通过依次改变切削深度、切削速度和刀具几何角度,获得不同参数组合下切削力和切削温度的变化规律,进一步揭示车削参数和刀具几何... 详细信息

为研究GH4169G高温合金车削用量及刀具几何特性对切削力和切削温度的影响规律,基于ABAQUS有限元仿真软件,通过依次改变切削深度、切削速度和刀具几何角度,获得不同参数组合下切削力和切削温度的变化规律,进一步揭示车削参数和刀具几何角度对GH4169G高温合金切削过程中热—力耦合作用的影响机理,从而对切削工艺参数和刀具特性进行优选。

关键词： GH4169G高温合金车削有限元仿真切削力切削温度

病理组织切片制作中的免疫组化病理技术质控管理探讨

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中国卫生产业 2024年第3期21卷 63-66页

作者：宋宜慧王锐丁伟山曲阜市人民医院病理科山东曲阜273100

目的探讨病理组织切片制作中的免疫组化病理技术质控管理。方法选取2022年5月—2023年5月曲阜市人民医院病理科10名工作人员作为研究对象,根据时间不同分为两组,2022年5—11月为无质控组(n=10,常规免疫组化病理技术),2022年12月—2023年... 详细信息

目的探讨病理组织切片制作中的免疫组化病理技术质控管理。方法选取2022年5月—2023年5月曲阜市人民医院病理科10名工作人员作为研究对象,根据时间不同分为两组,2022年5—11月为无质控组(n=10,常规免疫组化病理技术),2022年12月—2023年5月为质控组(n=10,在无质控组基础上进行质控管理),对比两组的制片优良率、病理诊断结果、不良制片结果。结果质控组的制片耗费时间及出报告时间均显著短于无质控组,差异有统计学意义(P均<0.05)。质控组的制片质量、准确性、不良事件、制片过程各项得分均显著高于无质控组,差异有统计学意义(P均<0.05)。结论进行病理组织切片制作中运用免疫组化病理技术质控管理能有效缩短制片耗费时间及出报告时间,提升制片优良率及病理诊断结果,减少不良事件发生,具有临床应用意义。

关键词：病理组织切片制作免疫组化病理质控管理

Harnessing the cyclization strategy for new drug discovery

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4309-4326页

作者： Kai Tang Shu Wang Wenshuo Gao yihui song Bin Yu School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug *** one of the most commonly used methods in drug discovery,the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty,scaffold diversity and *** strategy could also be potentially used for the follow-on drug discovery without patent *** recent years,the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various ***,we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds,including the proteolysis targeting chimeras(PROTAC)***,we focus on four main strategies including fused ring cyclization,chain cyclization,spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead ***,the challenges including the synthetic intractability,relatively poor pharmacokinetics(PK)profiles and the absence of the structural information for rational structure-based cyclization are also briefly *** hope this review,not exhaustive,could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.

关键词： Ring cyclization Spirocyclization Macrocyclization Conformational constraint Lead generation New drug discovery

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

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Acta Pharmaceutica Sinica B 2021年第3期11卷 750-762页

作者： yihui song Min Zhao Yahong Wu Bin Yu Hong-Min Liu School of Pharmaceutical Sciences&Key Laboratory of Advanced Drug Preparation Technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China School of Life Sciences Zhengzhou UniversityZhengzhou 450001China

The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2(SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2(SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76 A. After initial screening of our in-house compound library(w2300 compounds), we identified 4 new SHP2-PTP inhibitors(0.17%hit rate) and 28 novel allosteric SHP2 inhibitors(1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP(SYK-85: IC_(50) Z 0.32 mmol/L;WS-635: IC_(50) Z 4.13 mmol/L) and thus represent novel scaffolds for designing new SHP2-PTP inhibitors. TK-147, an allosteric inhibitor, inhibited SHP2 potently(IC_(50) Z 0.25 mmol/L). In structure, TK-147 could be regarded as a bioisostere of the well characterized SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2. The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins.

关键词： SHP2 High-throughput screening Enzyme assay Thermal shift assay Allosteric inhibitors

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CO_(2)催化加氢合成甲醇研究进展

石油炼制与化工 2024年第2期55卷 75-83页

作者：王佳静王建文李茂帅宋奕慧王石维吕静鲍晓军马新宾福州大学石油化工学院福州350116 天津大学化工学院天津大学浙江研究院

热催化CO_(2)加氢制甲醇具有显著的减碳效应,能够有效储存可再生能源,具有广阔的工业应用前景。介绍了CO_(2)加氢制甲醇的反应网络及其热力学挑战,并概述了其工艺流程、国内外工业应用情况,系统综述了近年来不同活性组分催化剂的研究进... 详细信息

热催化CO_(2)加氢制甲醇具有显著的减碳效应,能够有效储存可再生能源,具有广阔的工业应用前景。介绍了CO_(2)加氢制甲醇的反应网络及其热力学挑战,并概述了其工艺流程、国内外工业应用情况,系统综述了近年来不同活性组分催化剂的研究进展,从催化剂的制备方式、活性位点、反应机理及动力学等方面阐述Cu基催化剂、贵金属催化剂、氧化物催化剂以及其他新型催化剂存在的问题和优势。重点阐述Cu基催化剂的构效关系,包括其活性组分结构、载体性质和助剂对催化活性和甲醇选择性的影响,并展望CO_(2)加氢制甲醇催化剂的未来发展方向。

关键词： CO_(2) 加氢甲醇催化剂反应机理反应动力学

智慧电梯数据服务平台对医院后勤管理的赋能研究

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中国医院建筑与装备 2024年第9期25卷 36-41页

作者：张晔杨晓东倪雨嘉方舒超宋逸恢狄斌蒋化冰上海市儿童医院上海200040 上海麦信数据科技有限公司上海201210 上海卫庆机电成套设备工程有限公司上海200232 上海诺亚木木机器人科技有限公司上海202150

基于儿童专科医院用梯特点,通过物联网手段将电梯管理数字化,利用大数据完成后勤管理部门对电梯系统智慧化管理的充分闭环,并有效实现维保、物业等相关部门在电梯高效使用和维护上的联动。

关键词：医院后勤管理智慧电梯数据服务平台物联网

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BrΦnsted acid-promoted ‘on-water’ C(sp^3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

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Chinese Chemical Letters 2020年第2期31卷 349-352页

作者： Shuo Yuan Sixi Wang Min Zhao Danqing Zhang Jinjie Chen Jian-Xin Li Jingya Zhang yihui song Jinyi Wang Bin Yu Hongmin Liu School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological *** efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry *** this communication,we report an efficient BrΦnsted acid-promoted C(sp^3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various *** title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the *** this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom *** this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal ***,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.

关键词： Isoindolinone Triazolo[1,5-a]pyrimidine Biaryl scaffold C(sp^3)-H activation Molecular hybridization SKP2-CKS1 interaction

Dietary sodium acetate and sodium butyrate attenuate intestinal damage and improve lipid metabolism in juvenile largemouth bass(Micropterus salmoides) fed a high carbohydrate diet by reducing endoplasmic reticulum stress

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