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Acta Pharmaceutica Sinica B 2024年第4期14卷 1592-1604页

作者： Yuanjin Zhang Junze Huang Shengbo Huang Jie Liu Luyao Deng Chenmeizi Liang Yuanqing Guo Bingyi Yao Xin Wang Changning Maternity and Infant Health Hospital and School of Life Sciences Shanghai Key Laboratory of Regulatory BiologyEast China Normal UniversityShanghai 200241China

Organic anion-transporting polypeptides IB1(OATPIB1)plays a crucial role in the transport of ***,there are too few animal models related to OATPIB1,especially humanized animal *** this study,the human SLCOIB1 cDNA was inserted into the second exon of the rat Slcolb2 gene using CRISPR/Cas9 *** characteristics of statins were conducted in wild-type(WT),humanized OATPIB1(hOATPIB1),and OATPIB2 knockout(OATPIB2 KO)rats,*** results showed that human OATPIB1 was successfully expressed in rat liver and exhibited transport ***,the pharmacokinetic results revealed that OATPIB1 exhibited varying uptake levels of pivastatin,rosuvastatin,and fluvastatin,leading to different levels of exposure within the *** results were consistent with those obtained from in vitro experiments using overexpressed cell *** conclusion,we established a novel humanized SLCOIBI transgenic rat model to assess the role of human OATPIB1 in the uptake of different *** different uptake mediated by OATPIB1 may be an important reason for the different efficacy of *** hOATPIB1 rat is a promising model for improving the prediction of human drug transport.

关键词： CRISPR/Cas9 Drug transport Drug disposition Geneediting Humanized rat model OATP1B1 SLCO1B1 Statins

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4

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Genes & Diseases 2024年第4期11卷 411-425页

作者： Mengmeng Guo Pan Hu Jiayi Xie Kefu Tang Shixiu Hu Jialiang Sun Yundong He Jing Li Weiqiang Lu Huirong Liu Mingyao Liu Zhengfang Yi Shihong Peng Shanghai Key laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghai 200241China Prenatal Diagnosis Center Department of Clinical LaboratoryChangning Maternity and Infant Health HospitalEast China Normal UniversityShanghai 200051China Key laboratory of Acupuncture and Immunological Effects Shanghai University of Traditional Chinese MedicineShanghai 201203China Fengxian Hospital Affiliated to Southern Medical University Shanghai 201400China Shanghai Yuyao Biotech Co. Ltd.Shanghai 200241China

Gastric cancer is highly prevalent among digestive tract *** to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastric ***,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric *** our previous study,we identified a novel small molecule EP4 receptor antagonist called *** with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse ***,adminis-tration of YYo01 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 ***,our research revealed that YYo01 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than *** findings suggest that YYo01 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combination with other drugs.

关键词： EP4 Immunomodulation Synergy Tumor microenvironment YY001

An interpretable graph convolutional neural network based fault diagnosis method for building energy systems

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Building Simulation 2024年第7期17卷 1113-1136页

作者： Guannan Li Zhanpeng Yao Liang Chen Tao Li Chengliang Xu School of Urban construction Wuhan University of Science and TechnologyWuhan 430065China Anhui Province Key laboratory of Intelligent Building and Building Energy-saving Anhui Jianzhu UniversityHefei 230601China State Key laboratory of Green Building in Western China Xi'an University of Architecture&TechnologyXi'an 710055China Key laboratory of Low-grade Energy Utilization Technologies and Systems(Chongqing University) Ministry of Education of ChinaChongqing UniversityChongqing 400044China Hubei Provincial Engineering Research Centre of Urban Regeneration Wuhan University of Science and TechnologyWuhan 430081China

Due to the fast-modeling speed and high accuracy,deep learning has attracted great interest in the field of fault diagnosis in building energy systems in recent ***,the black-box nature makes deep learning models generally difficult to *** order to compensate for the poor interpretability of deep learning models,this study proposed a fault diagnosis method based on interpretable graph neural network(GNN)suitable for building energy *** method is developed by following three main steps:(1)selecting NC-GNN as a fault diagnosis model for building energy systems and proposing a graph generation method applicable to the model,(2)developing an interpretation method based on InputXGradient for the NC-GNN,which is capable of outputting the importance of the node features and automatically locating the fault related features,(3)visualizing the results of model interpretation and validating by matching with expert knowledge and maintenance *** was performed using the public ASHRAE RP-1043 chiller fault *** diagnosis results show that the proposed method has a diagnosis accuracy of over 96%.The interpretation results show that the method is capable of explaining the decision-making process of the model by identifying fault-discriminative *** almost all seven faults,their fault-discriminative features were correctly identified.

关键词： fault diagnosis graph neural network building energy system InputXGradient feature interpretation

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1145-1163页

作者： Juanjuan Feng Zhengke Lian Xinting Xia Yue Lu Kewen Hu Yunpeng Zhang Yanan Liu Longmiao Hu Kun Yuan Zhenliang Sun Xiufeng Pang Shanghai Key laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghai 200241China Joint Center for Translational Medicine Southern Medical University Affiliated Fengxian HospitalShanghai 201499China Cancer Institute Fudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai 200032China

MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant ***,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor *** flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from *** molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional ***,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse ***,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

关键词： KRAS-mutant lung cancer MEK inhibitors Drug resistance Metabolic rewiring Mitochondrial oxidative phosphorylation Pyruvate dehydrogenase complex Carnitine palmitoyl transferase IA

The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia

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Acta Pharmaceutica Sinica B 2023年第2期13卷 648-661页

作者： Jian Lu Xuyang Shang Bingyi Yao Dongyi Sun Jie Liu Yuanjin Zhang He Wang Jingru Shi Huaqing Chen Tieliu Shi Mingyao Liu Xin Wang Changning Maternity and Infant Health Hospital and School of Life Sciences Shanghai Key Laboratory of Regulatory BiologyEast China Normal UniversityShanghai 200241China

Cholesterol is an important precursor of many endogenous *** of cholesterol homeostasis can cause many pathological changes,leading to liver and cardiovascular ***1A is widely involved in cholesterol metabolic network,but its exact function has not been fully ***,we aim to explore how CYP1A regulates cholesterol *** data showed that CYP1A1/2 knockout(KO)rats presented cholesterol deposition in blood and *** serum levels of low-density lipoprotein cholesterol,high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO *** studies found that the lipogenesis pathway(LXRa-SREBP1-SCD1)of KO rats was activated,and the key protein of cholesterol ester hydrolysis(CES1)was ***,lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing *** findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.

关键词： Hyperlipidemia Hypercholesteremia Cholesterol CYP1A Lipidosis LXR CES1 Lansoprazole

Gains from no real PAINS:Where‘Fair Trial Strategy’stands in the development of multitarget ligands

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3417-3432页

作者： Jianbo Sun Hui Zhong Kun Wang Na Li Li Chen State Key laboratory of Natural Medicines Department of Natural Medicinal ChemistrySchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China Department of Pharmacology of Traditional Chinese Medicine School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China

Compounds that selectively modulate multiple targets can provide clinical benefits and are an alternative to traditional highly selective agents for unique ***-throughput screening(HTS)for multitarget-directed ligands(MTDLs)using approved drugs,and fragment-based drug design has become a regular strategy to achieve an ideal multitarget ***,the unexpected presence of panassay interference compounds(PAINS)suspects in the development of MTDLs frequently results in nonspecific interactions or other undesirable effects leading to artefacts or false-positive data of biological *** available filters can help to identify PAINS suspects;however,these filters cannot comprehensively conclude whether these suspects are"bad"or ***,these in silico approaches may inappropriately label a ligand as *** than 80% of the initial hits can be identified as PAINS by the filters if appropriate biochemical tests are not used resulting in false positive data that are unacceptable for medicinal chemists in manuscript peer review and future ***,extensive offline experiments should be used after online filtering to discriminate"bad"PAINS and avoid incorrect evaluation of good *** suggest that the use of"Fair Trial Strategy"to identify interesting molecules in PAINS suspects to provide certain structure-function insight in MTDL development.

关键词： Multitarget-directed ligands PAINS suspects In silico filtering Biochemical experiment Fair trial strategy

construction method of quantitative evaluation model for the maturity of Korla fragrant pear

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International Journal of Agricultural and Biological Engineering 2022年第4期15卷 243-250页

作者： Shihui Yu Yurong Tang Haipeng Lan Xiaolong Li Hong Zhang Yong Zeng Hao Niu Xiaozhen Jin Yang Liu College of Mechanical and Electrical Engineering Tarim UniversityAlaer 843300XinjiangChina College of Mechanical and Electronic Engineering Shandong Agricultural UniversityTai’an271018ShandongChina Zibo Agricultural Machinery Service Center Zibo 255000ShandongChina

The maturity variation laws of Korla fragrant pears were explored for a quantitative evaluation of harvest maturity to solve the reasonable matching between harvest maturity of Korla fragrant pears and market quality *** fragrant pears from different harvesting periods were chosen as the research *** quality indexes were chosen as the evaluation indexes per industry standards,including hardness,soluble solid content(SSC),single-fruit weight,fruit longitudinal diameter,fruit equatorial diameter,pericarp color parameters(L*,a*,and b*),and titratable *** data of these quality indexes with accumulated temperature were *** of several quality indexes were gained through principal component analysis.A mathematical model of scores and accumulated temperatures was *** this basis,a quantitative maturity model of Korla fragrant pears was *** demonstrate that SSC,single-fruit weight,fruit longitudinal diameter,fruit equatorial diameter,L*,a*,and b*are significantly and positively correlated with the accumulated ***,hardness and titratable acid showed significant negative correlations with the accumulated *** between scores of principal components and accumulated temperature conform to the Sigmoidal *** constructed quantitative maturity model of Korla fragrant pears can quantify the maturity of *** conclusions can provide insight into the harvest periods,evaluate Korla fragrant pears’maturity,and lay a theoretical foundation for quantitative research on fruit maturity.

关键词： Korla fragrant pear quantitative evaluation maturity principal component analysis accumulated temperature

Prediction method for nutritional quality of Korla pear during storage

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International Journal of Agricultural and Biological Engineering 2021年第3期14卷 247-254页

作者： Yang Liu Qiang Zhang Hao Niu Hong Zhang Haipeng Lan Yong Zeng Fuguo Jia College of Engineering Northeast Agricultural UniversityHarbin 150030China College of Mechanical and Electrical Engineering Tarim UniversityAlarXinjiang 843300China College of Engineering Huazhong Agricultural UniversityWuhan 430070China

It is difficult to control the quality of Korla pear with different degrees of maturity during ***,a method was proposed for predicting the effects of harvest maturity and cold storage time on the quality indices(soluble solid content(SSC)and Vitamin C(Vc)content)of Korla *** generalized regression neural network(GRNN)and adaptive neuro-fuzzy inference system(ANFIS)were employed to predict the quality changes of Korla fragrant pear fruit during *** results demonstrated that during cold storage the SSC in pears with 10%-70%harvest maturity showed continuous increases in the first 90 d of storage and then a slight decline thereafter,while that in pears with 80%and 90%harvest maturity exhibited slow decreases throughout the storage *** the extension of storage time,the Vc content of pears with 10%-90%harvest maturity showed continuous *** harvest maturity of Korla pear was extremely positively correlated with SSC and Vc content(p<0.01)in a given storage *** time showed an extremely significant negative correlation with the Vc content(p<0.01)at the 40%-90%harvest maturity and an significant negative correlation with the Vc content(p<0.05)at the 10%-30%harvest *** the 10%-70%harvest maturity,storage time showed a significant positive correlation with the SSC(p<0.05).The trained model could well predict the variation trend of quality indices of pear fruit during *** ANFIS with the input membership function of gbellmf had the best performance in predicting the SSC(RMSE=0.175;R2=0.98),and that with the input membership function of trimf exhibited the best performance in predicting Vc content(RMSE=0.075;R2=0.99).The research findings can provide reference for predicting the fruit nutritional quality at delivery and decision-making on the storage time of Korla fragrant pear.

关键词： Korla fragrant pear harvest maturity storage time nutritional quality prediction method

Structure, function, and mechanism of the TNFAIP8 (TIPE) family of proteins in cancer and inflammation

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BIOCELL 2023年第10期47卷 2217-2232页

作者： ZIPENG LIN CHUXI TANG LE KANG GUANXI LAI SHIWEN LIU YIXIANG WU HUIQUN TIAN SONG LIU School of Pharmacy&Clinical Pharmacy School of Integrative PharmacyGuangdong Pharmaceutical UniversityGuangzhou510006China Department of Biomedical Sciences laboratory Affiliated Dongyang Hospital of Wenzhou Medical UniversityDongyang322100China The Second People’s Hospital of China Three Gorges University Yichang443000China Guangdong Province Key laboratory for Biotechnology Drug Candidates Guangdong Pharmaceutical UniversityGuangzhou510006China Key Specialty of Clinical Pharmacy The First Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhou510080China

The multiple roles of the tumor necrosis factor(TNF)-α-inducible protein 8(TNFAIP8),also named TIPE family of proteins have been shown in tumor and inflammation progression and regulation of cellular autophagy and *** this review,we found that the TIPE family showed highly homologous sequences and conserved functional domains,such as the death effector domain(DED)-like domain but displayed different roles and mechanisms in different biological *** example,while TIPE is primarily associated with tumor progression and antitumor drug resistance,TIPE1 suppresses tumor progression in most ***2 has multiple roles in tumor progression regulation,and antitumor drug ***,TIPE2 was also involved in inflammatory response regulation,tumor typing,and staging.A few studies reported that TIPE3 was engaged in tumor development by activating the phosphatidylinositol-3-kinase(PI3K)/protein kinase B(AKT)signaling *** structure,function,and mechanism of the TIPE family in cancer and inflammation have been summarized in this *** might serve as a reference for further research on the TIPE family and shed new light on the crosstalk among antitumor responses,inflammation,and immunology.

关键词： TIPE TIPE1 TIPE2 TIPE3 DED-like domain

Comprehensive evaluation of Korla fragrant pears and optimization of plucking time during the harvest period

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International Journal of Agricultural and Biological Engineering 2022年第3期15卷 242-250页

作者： Zhentao Wang Yurong Tang Xiaozhen Jin Yang Liu Hong Zhang Hao Niu Haipeng Lan College of Mechanical and Electrical Engineering Tarim UniversityAlar 843300XinjiangChina Zibo Agricultural Machinery Service Center Zibo 255000ShandongChina

To optimize the harvest of Korla fragrant pears and to provide a theoretical basis for post-harvest processing,a total of 26 basic indices of Korla fragrant pears,including their morphology,quality,and softening age,were *** harvest period ranged from August 22nd to October 6th,samples were collected every 5 d(totally 10 plucking days,indicated as H1-H10).The results indicated that changes in pectin content were the main causes of softening in fragrant *** scavenging of free radicals mainly occurred because of the collaborative effects of superoxide dismutase(SOD)and catalase(CAT).In the harvest periods H1-H3,the hardness,titratable acid(TA),chlorophyll content,density,and diameter of the stone cells,as well as the cellulose and hemicellulose content of the Korla fragrant pears were at their *** the periods H7-H10,the single-fruit weight,fruit horizontal and vertical diameter,color coordinates L,a*,b*,soluble-solids content(SSC),SOD activity,CAT activity,and water-soluble pectin were higher than in the other plucking *** highest vitamin C(VC)content and moderate values for a variety of indicators were observed during *** in the Korla fragrant pears during H1-H3 mainly manifested through changes in softening-related *** H3-H10,changes in the softening-related,aging-related,color-related,and quality indices had a dominant *** this basis,some suggestions for the post-harvest processing of fragrant pears have been ***,during H1-H3,are suitable for transportation and storage;during H7-H10 are suitable for fresh-eating and further processing;and during H3-H7,exhibited moderate values for a variety of indicators and had the highest commercial *** research provides a systematic evaluation of the characteristics of mature Korla fragrant pears during the harvest period and can form the basis for fruit quality control and processing of Korla fragrant pears.

关键词： Korla fragrant pear harvest period plucking time quality fruit maturity evaluation optimization