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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian chen Mingyue Zheng Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics.AOX-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor

A Novel Trajectory Tracking Control of AGV Based on Udwadia-Kalaba Approach

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IEEE/CAA Journal of Automatica Sinica 2024年第4期11卷 1069-1071页

作者： rongrong Yu Han Zhao Shengchao Zhen Kang Huang Xianmin chen Hao Sun Ke Shao the School of Mechanical Engineering Hefei University of TechnologyHefei 230009China the College of Mechanical and Electronic Engineering Shandong University of Science and TechnologyQingdao 266590China the University of Science and Technology of China Hefei 230026China

Dear Editor,This letter is about an automated guided vehicle(AGV)trajectory tracking control method based on Udwadia-Kalaba(U-K)approach.This method provides a novel,concise and explicit motion equation for constrained mechanical systems with holonomic and/or nonholonomic constraints as well as constraints that may be ideal or nonideal.In this letter.

关键词： letter constraints constrained

Regulation effects of water and nitrogen on yield,water,and nitrogen use efficiency of wolfberry

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Journal of Arid Land 2024年第1期16卷 29-45页

作者： GAO Yalin QI Guangping MA Yanlin YIN Minhua WANG Jinghai WANG chen TIAN rongrong XIAO Feng LU Qiang WANG Jianjun College of Water Conservancy and Hydropower Engineering Gansu Agricultural UniversityLanzhou 730070China Jingtaichuan Electric Power Irrigation Water Resource Utilization Center in Gansu Province Baiyin 730900China

Wolfberry(Lycium barbarum L.)is important for health care and ecological protection.However,it faces problems of low productivity and resource utilization during planting.Exploring reasonable models for water and nitrogen management is important for solving these problems.Based on field trials in 2021 and 2022,this study analyzed the effects of controlling soil water and nitrogen application levels on wolfberry height,stem diameter,crown width,yield,and water(WUE)and nitrogen use efficiency(NUE).The upper and lower limits of soil water were controlled by the percentage of soil water content to field water capacity(θ_(f)),and four water levels,i.e.,adequate irrigation(W0,75%-85%θ_(f)),mild water deficit(W1,65%-75%θ_(f)),moderate water deficit(W2,55%-65%θ_(f)),and severe water deficit(W3,45%-55%θ_(f))were used,and three nitrogen application levels,i.e.,no nitrogen(N0,0 kg/hm^(2)),low nitrogen(N1,150 kg/hm^(2)),medium nitrogen(N2,300 kg/hm^(2)),and high nitrogen(N3,450 kg/hm^(2))were implied.The results showed that irrigation and nitrogen application significantly affected plant height,stem diameter,and crown width of wolfberry at different growth stages(P<0.01),and their maximum values were observed in W1N2,W0N2,and W1N3 treatments.Dry weight per plant and yield of wolfberry first increased and then decreased with increasing nitrogen application under the same water treatment.Dry weight per hundred grains and dry weight percentage increased with increasing nitrogen application under W0 treatment.However,under other water treatments,the values first increased and then decreased with increasing nitrogen application.Yield and its component of wolfberry first increased and then decreased as water deficit increased under the same nitrogen treatment.Irrigation water use efficiency(IWUE,8.46 kg/(hm^(2)·mm)),WUE(6.83 kg/(hm^(2)·mm)),partial factor productivity of nitrogen(PFPN,2.56 kg/kg),and NUE(14.29 kg/kg)reached their highest values in W2N2,W1N2,W1N2,and W1N1 treatments.Results of principal component analysis(PCA)showe

关键词： water deficit growth characteristics yield water and nitrogen use efficiency principal component analysis

Reversing artemisinin resistance by leveraging thermo-responsive nanoplatform to downregulating GSH

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Chinese Chemical Letters 2024年第6期35卷 392-397页

作者： Yong-Dan Zhao Yidan Wang rongrong Wang Lina chen Hengtong Zuo Xi Wang Jihong Qiang Geng Wang Qingxia Li Canqi Ping Shuqiu Zhang Hao Wang School of Pharmacy Shanxi Medical UniversityTaiyuan 030001China National Center for Nanoscience and Technology Beijing 100190China Artemisinin Research Center Institute of Chinese Materia MedicaBeijing 100700China

Artemisinin(ART)resistance has been an emerging clinical problem,severely compromising antimalarial efficacy and threatening the global malaria elimination campaign.Albeit intensive studies about the molecular mechanism for ART resistance are under way,no effective therapeutic targets for reversing resistance have been applied.Here,we explore glutathione(GSH)as a therapeutic target to develop a thermo-responsive nanoplatform to specifically co-deliver ART and GSH synthesis inhibitor(L-buthionine sulfoximine,BSO)in a sustained manner,effectively reversing ART resistance in vivo.By combining with BSO,ART exerts increased antimalarial activity with reduced half-maximal inhibitory concentration(IC50)by 7.43-fold in ART-resistant strains.This work reveals that the GSH in ART-resistant parasites can be a promising therapeutic target for reversing ART resistance,paving the way for developing drug candidates and intelligent nanomedicines in malaria therapy.

关键词： Nanomedicines Drug delivery Artemisinins resistance Malaria Glutathione

The pentatricopeptide repeat protein EMP601 functions in maize seed development by affecting RNA editing of mitochondrial transcript ccmC

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作物学报:英文版 2023年第5期11卷 1368-1379页

作者： rongrong chen Qianhan Wei Yan Liu Jiankun Li Xuemei Du Yan chen Jianhua Wang Yunjun Liu The National Forestry and Grassland Administration Engineering Research Center for Germplasm Innovation and Utilization of Warm-Season Turfgrasses Jiangsu Key Laboratory for the Research and Utilization of Plant ResourcesInstitute of BotanyJiangsu Province and Chinese Academy of Sciences(Nanjing Botanical Garden Mem.Sun Yat-Sen)Nanjing 210008JiangsuChina Institute of Crop Sciences Chinese Academy of Agricultural SciencesBeijing 100081China College of Agronomy and Biotechnology China Agricultural UniversityBeijing 100094China College of Agronomy Henan Agricultural UniversityZhengzhou 450002HenanChina

Although several pentatricopeptide repeat(PPR) proteins are involved in post-transcriptional processing of mitochondrial RNA, it is unclear which specific protein is involved in the RNA editing of ccmC in maize(Zea mays). Here we report the identification of the maize empty pericarp 601(emp601) mutant and the map-based cloning of the Emp601 gene, which encodes an E2-type PPR protein that is targeted to mitochondria. A single-nucleotide deletion in the emp601 mutant caused a frameshift and introduced a premature stop codon into the predicted EMP601. This mutation was associated with reduced accumulation of mitochondrial complex Ⅲ as well as with inhibition of growth and differentiation of basal endosperm transfer layer cells, leading to final degeneration of the embryo and endosperm. We determine that loss of EMP601 function prevents the C-to-U RNA editing of the mitochondrial transcript ccmC at position 358.EMP601 binds to the ccmC transcript and directly interacts with Multiple organellar RNA editing factor 8and may be a component of the plant mitochondrial editosome. We conclude that EMP601 functions in RNA editing of mitochondrial ccmC transcripts and influences mitochondrial function and seed development.

关键词： Maize Empty pericarp 601 PPR Mitochondrial Ccmc Seed development

Phosphorylation regulation of nitrogen,phosphorus,and potassium uptake systems in plants

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The Crop Journal 2023年第4期11卷 1034-1047页

作者： Dongli Hao Xiaohui Li Weiyi Kong rongrong chen Jianxiu Liu Hailin Guo Jinyan Zhou The National Forestry and Grassland Administration Engineering Research Center for Germplasm Innovation and Utilization of Warm-Season Turfgrasses Jiangsu Key Laboratory for the Research and Utilization of Plant ResourcesInstitute of BotanyJiangsu Province and Chinese Academy of Sciences(Nanjing Botanical Garden Mem.Sun Yat-Sen)Nanjing 210014JiangsuChina Department of Agronomy and Horticulture Jiangsu Vocational College of Agriculture and ForestJurong 212400JiangsuChina

The uptake of ammonium,nitrate,phosphorus,and potassium ions by roots is mediated by specific ion transporter or channel proteins,and protein phosphorylation regulation events occurring on these proteins and their regulators determine their ultimate activity.Elucidating the mechanism by which protein phosphorylation modification regulates nutrient uptake will advance plant breeding for high nutrientuse efficiency.In this review,it is concluded that the root nutrient absorption system is composed of several,but not all,members of a specific ion transporter or channel family.Under nutrient-starvation conditions,protein phosphorylation-based regulation of these proteins and associated transcription factors increases ion transporter-or channel-mediated nutrient uptake capacity via direct function activity enhancement,allowing more protein trafficking to the plasma membrane,by strengthening the interaction of transporters and channels with partner proteins,by increasing their protein stability,and by transcriptional activation.Under excessive nutrient conditions,protein phosphorylation-based regulation suppresses nutrient uptake by reversing these processes.Strengthening phosphorylation regulation items that increase nutrient absorption and weakening phosphorylation modification items that are not conducive to nutrient absorption show potential as strategies for increasing nutrient use efficiency.

关键词： Ammonium uptake machinery Nitrate uptake machinery Phosphate uptake machinery Potassium uptake machinery Transcription factors Protein phosphorylation

First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1760-1767页

作者： Xiaofeng chen Hao Xu Xiaobing chen Tongpeng Xu Yitong Tian Deqiang Wang Fen Guo Kangxin Wang Guangfu Jin Xiao Li Rong Wang Fengyuan Li Yongbin Ding Jie Tang Yueyu Fang Jing Zhao Liang Liu Ling Ma Lijuan Meng Zhiguo Hou rongrong Zheng Yang Liu Ni Guan Bei Zhang Shuang Tong Shiqing chen Xing Li Yongqian Shu Department of Oncology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Gusu School Nanjing medical UniversitySuzhouChina Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingChina Department of General surgery The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of Oncology Henan Cancer Hospital Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer&Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer ZhengzhouChina Department of Oncology Digestive Disease Institute&Cancer Institute of Jiangsu UniversityAffiliated Hospital of Jiangsu UniversityZhenjiangChina Department of Oncology Suzhou Hospital of Nanjing Medical UniversitySuzhouChina Department of Oncology Nanjing PuKou People’s HospitalNanjingChina Department of Epidemiology School of Public HealthNanjing Medical UniversityNanjingChina Department of Pathology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of general surgery Jurong Branch hospital of Jiangsu Province People HospitalJurongChina Department of Medical Oncology Liyang People’s HospitalLiyangChina Department of radiology Nanjing PuKou People’s HospitalNanjingChina Jiangsu Hengrui Pharmaceuticals ShanghaiChina Department of Medical Affairs 3D Medicines Inc.ShanghaiChina Shanghai OrigiMed Co. Ltd.ShanghaiChina

Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

关键词： regimen cancer doses

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

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Neural Regeneration Research 2025年第2期20卷 518-532页

作者： Conglin Wang Fangyuan cheng Zhaoli Han Bo Yan Pan Liao Zhenyu Yin Xintong Ge Dai Li rongrong Zhong Qiang Liu Fanglian chen Ping Lei Department of Geriatrics Tianjin Medical University General HospitalTianjinChina School of Medicine Nankai UniversityTianjinChina Tianjin Neurological Institute TianjinChina

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

关键词： AKT astrocyte blood-brain barrier cerebral edema exosomes human-induced pluripotent stem cells intracerebral hemorrhage neural stem cells neuroinflammation PI3K

Arecoline causes cognitive impairment and potential addiction via disturbing Kenyon cells in bumblebee brain

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Food Science and Human Wellness 2024年

作者： Huiling Liu Xiaohuan Mu rongrong Fan Jieteng chen Jie Ma Liang Meng Xiaosong Hu Hao Zheng Shanshan Liu Xiaofei Wang College of Food Science and Nutritional Engineering National Engineering Research Center for Fruit and Vegetable Processing Key Laboratory of Fruits and Vegetables Processing Ministry of Agriculture Engineering Research Centre for Fruits and Vegetables Processing Ministry of Education China Agricultural University BGI-Qingdao

Areca nut is the basic ingredient of betel quid， which is chewed by hundreds of millions of people in south-eastern Asia. Chewing of areca nut has been associated with oral cancers potentially due to its specific alkaloids， among which arecoline constitutes about 90% of total fraction. Being the world’s fourth most commonly used psychoactive substance， arecoline evokes stimulation， addiction， and other direct neurological effects， while its misuse correlates to neurotoxic effects. However， what might underlie its neurotoxic mechanisms has been poorly documented. The brain is encoded by a complex network of neuronal and glial cell types， and neurotoxicity of hazardous compounds present transcriptional heterogeneity. Recently， the eusocial bumblebee has been used as a model for studying brain effects， with sophisticated cognitive capability and precisely measured brain architecture. Here， we decipher cell-type-specific mental risks to arecoline using bumblebees. Arecoline induced locomotor hyperactivity and cognitive impairment. Single nucleus RNA sequencing (snRNA-seq) unearthed arecoline-induced cell-specific responses， primarily targeted on Kenyon cells (KC). Moreover， high-dose arecoline induced distinctive cell responses among KC subtypes， particularly class I large Kenyon cell (lKC)， leading to DNA damage， excitatory/inhibitory (E/I) imbalance， and calcium dyshomeostasis， which potentially resulted in cognitive impairment. Given arecoline’s popularity and growing exposure risks to humans， neurological health risks of areca nut warrant serious consideration.

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