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| 1 | Major advances in studies of the physical geography and living environment of China during the past 70 years and future prospects显示文摘The natural environment provides material essentials for human survival and development. The characteristics,processes, regional differentiation and forcing mechanisms of the elements of the natural environment(e.g. geomorphology,climate, hydrology, soil, etc.) are the main objects of research in physical geography. China has a complex natural environment and huge regional differentiation and therefore it provides outstanding reserach opportunities in physical geography. This review summarizes the most important developments and the main contributions of research in the physical geography and human living environment in China during the past 70 years. The major topics addressed are the uplift of the Tibetan Plateau and the evolution of its cryosphere, the development of fluvial systems, the acidification of the vast arid region of the Asian interior, variations in the monsoon and westerly climate systems on multiple timescales, the development of lakes and wetlands, the watershed system model, soil erosion, past human-environment interactions, biogeography, and physical geographic zonality. After briefly introducing international research developments, we review the history of research in physical geography in China, focusing on the major achievements and major academic debates, and finally we summarize the status of current research and the future prospects. We propose that in the context of the national demand for the construction of an ecological civilization, we should make full use of the research findings of physical geography, and determine the patterns and mechanisms of natural environmental processes in order to continue to promote the continued contribution of physical geography to national development strategies, and to further contribute to the theory of physical geography from a global perspective. | Fahu CHEN Bojie FU Jun XIA Duo WU Shaohong WU Yili ZHANG Hang SUN Yu LIU Xiaomin FANG Boqiang QIN Xin LI Tingjun ZHANG Baoyuan LIU Zhibao DONG Shugui HOU Lide TIAN Baiqing XU Guanghui DONG Jingyun ZHENG Wei YANG Xin WANG Zaijun LI Fei Wang Zhenbo HU Jie WANG Jianbao LIU Jianhui CHEN Wei HUANG Juzhi HOU Qiufang CAI Hao LONG Ming JIANG Yaxian HU Xiaoming FENG Xingguo MO Xiaoyan YANG Dongju ZHANG Xiuhong WANG Yunhe YIN Xiaochen LIU | 2019 | Science China Earth Sciences2019，62，11： | 11 |
| 2 | Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model显示文摘Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial. | Xiaoyan Xu Yaqin Sun Xufeng Cen Bing Shan Qingwei Zhao Tingxue Xie Zhe Wang Tingjun Hou Yu Xue Mengmeng Zhang Di Peng Qiming Sun Cong Yi Ayaz Najafov Hongguang Xia | 2021 | Protein & Cell2021，12，10： | 5 |
| 3 | The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis显示文摘Dear Editor,Ferroptosis is an iron-dependent,non-apoptotic form of regulated cell death characterized by an accumulation of lipid.derived reactive oxygen species(ROS).The small-molecule compo und erastin in duces ferroptosis via in hibiti ng the cystineglutamate antiporter system x_(c).which consists of two subunits,namely the light chain xCT and the heavy chain 4F2hc(encoded by the SLC7A11 and SLC3A2 genes,respectively).^(1-4) | Renhong Yan Enjun Xie Yaning Li Jin Li Yuanyuan Zhang Ximin Chi Xueping Hu Lei xu Tingjun Hou Brent R.Stockwell Junxia Min Qiang Zhou Fudi Wang | 2022 | Cell Research2022，32，7： | 4 |
| 4 | Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays显示文摘Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases. | Wenfang Zhou Mojie Duan Weitao Fu Jinping Pang Qin Tang Huiyong Sun Lei Xu Shan Chang Dan Li Tingjun Hou | 2018 | Genomics, Proteomics & Bioinformatics2018，16，6： | 3 |
| 5 | Three-dimensional quantitantive structure-activity relationship study on paullones as CDK inhibitors using CoMSIA and CoMFA显示文摘 | Zhu Lili Hou Tingjun Xu Xiaojie | 2001 | J Mol Model2001，7，： | 2 |
| 6 | A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer显示文摘Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation. | Tiantian Xu Qisheng Ma Yanan Li Qing Yu Peichen Pan Yawen Zheng Zhijian Li Xiufang Xiong Tingjun Hou Bin Yu Hongmin Liu Yi Sun | 2022 | Signal Transduction and Targeted Therapy2022，7，11： | 2 |
| 7 | Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy显示文摘Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylation are the family members of cullin,the scaffold component of cullin RING ligases(CRLs).Currently,a potent E1 inhibitor,MLN4924,also known as pevonedistat,is in several clinical trials for anti-cancer therapy.Here we report the discovery,through virtual screening and structural modifications,of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1 e5.Surprisingly,unlike MLN4924,HA-1141 also triggers non-canonical endoplasmic reticulum(ER)stress and PKR-mediated terminal integrated stress response(ISR)to activate ATF4 at an early stage,and to inhibit protein synthesis and mTORC1 activity at a later stage,eventually leading to autophagy induction.Biologically,HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose.Taken together,our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress,leading to growth suppression of cancer cells. | Yanan Li Chaorong Wang Tiantian Xu Peichen Pan Qing Yu Lei Xu Xiufang Xiong Tingjun Hou Sunliang Cui Yi Sun | 2021 | Acta Pharmaceutica Sinica B2021，11，11： | 1 |
| 8 | Proteome-Wide Profiling of the Covalent-Druggable Cysteines with a Structure-Based Deep Graph Learning Network显示文摘Covalent ligands have attracted increasing attention due to their unique advantages,such as long residence time,high selectivity,and strong binding affinity.They also show promise for targets where previous efforts to identify noncovalent small molecule inhibitors have failed.However,our limited knowledge of covalent binding sites has hindered the discovery of novel ligands.Therefore,developing in silico methods to identify covalent binding sites is highly desirable.Here,we propose DeepCoSI,the first structure-based deep graph learning model to identify ligandable covalent sites in the protein.By integrating the characterization of the binding pocket and the interactions between each cysteine and the surrounding environment,DeepCoSI achieves state-of-the-art predictive performances.The validation on two external test sets which mimic the real application scenarios shows that DeepCosI has strong ability to distinguish ligandable sites from the others.Finally,we profiled the entire set of protein structures in the RCSB Protein Data Bank(PDB)with DeepCoSI to evaluate the ligandability of each cysteine for covalent ligand design,and made the predicted data publicly available on website. | Hongyan Du Dejun Jiang Junbo Gao Xujun Zhang Lingxiao Jiang Yundian Zeng Zhenxing Wu Chao Shen Lei Xu Dongsheng Cao Tingjun Hou Peichen Pan | 2022 | Research2022，，4： | 1 |
| 9 | Applications of genetic algorithms to the predication of blood-brain partitoning of a large set of drugs显示文摘 | Hou Tingjun Xu Xiaojie | 2002 | J Mol Model2002，8，： | 1 |
| 10 | Characterization of Domain–Peptide Interaction Interface: A Case Study on the Amphiphysin-1 SH3 Domain显示文摘 | Tingjun Hou Wei Zhang David A. Case Wei Wang | 2008 | Journal of Molecular Biology2008，，： | 1 |
| 11 | Adsorption and diffusion of benzene in ITQ-l type zeolite: Grand canonical Monte Carlo and molecular dynamics simulation study显示文摘 | HOU Tingjun ZHU Lili XU Xiaojie | 2000 | The Journal of Physical Chemistry B2000，104，39： | 1 |
| 12 | Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: mechanism for binding and drug resistance 显示文摘 | Hou Tingjun Yu Ron | 2007 | Journal of Medicinal Chemistry2007，50，： | 1 |
| 13 | Novel thieno[2,3-b]quinoline-procaine hybrid molecules:A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors显示文摘Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators against Src homology region 2 domain-containing phosphatase-1(SHP-1)to block STAT3 pathway represents a promising strategy for DLBCL therapy.Here we reported a new class of thieno[2,3-b]quinolineprocaine hybrid molecules as SHP-1 allosteric activators.The representative hybrid compound 3b displayed SHP-1 activating effect with EC50 of 5.48±0.28μmol/L.Further investigations confirmed that 3b allosterically interacted with SHP-1,switched it from close to open conformation,blocked SHP-1/p-STAT3 pathway,induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro,and delayed tumor growth in the xenograft model of SU-DHL-2.Overall,this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors,and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway. | Lei Xu Xuyang Mu Minmin Liu Zhijia Wang Chao Shen Qianwen Mu Bo Feng Yechun Xu Tingjun Hou Lixin Gao Haini Jiang Jia Li Yubo Zhou Wenlong Wang | 2023 | Chinese Chemical Letters2023，34，8： | 0 |
| 14 | MF-SuP-pK_(a): Multi-fidelity modeling with subgraph pooling mechanism for pK_(a) prediction显示文摘Acid-base dissociation constant(pK_(a)) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for pK_(a) prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-pK_(a)(multi-fidelity modeling with subgraph pooling for pK_(a) prediction), a novel pK_(a) prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledgeaware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-pK_(a) prediction. To overcome the scarcity of accurate pK_(a) data, lowfidelity data(computational pK_(a)) was used to fit the high-fidelity data(experimental pK_(a)) through transfer learning. The final MF-SuP-pK_(a) model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-pK_(a) achieves superior performances to the state-of-theart pK_(a) prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-pK_(a) achieves 23.83% and 20.12% improvement in terms of mean absolute error(MAE) on the acidic and basic sets, respectively. | Jialu Wu Yue Wan Zhenxing Wu Shengyu Zhang Dongsheng Cao Chang-Yu Hsieh Tingjun Hou | 2023 | Acta Pharmaceutica Sinica B2023，13，6： | 0 |
| 15 | Structural insights into ligand recognition and activation of the melanocortin-4 receptor显示文摘Melanocortin-4 receptor(MC4R)plays a central role in the regulation of energy homeostasis.Its high sequence similarity to other MC receptor family members,low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity.Here,we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric Gs protein stimulated by the endogenous peptide ligand a-MSH,FDA-approved drugs afamelanotide(Scenesse™)and bremelanotide(Vyleesi™),and a selective small-molecule ligand THIQ,respectively.Together with pharmacological studies,our results reveal the conserved binding mode of peptidic agonists,the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity,and a distinct activation mechanism for MC4R,thereby offering new insights into G protein coupling.Our work may facilitate the discovery of selective therapeutic agents targeting MC4R. | Huibing Zhang Li-Nan Chen Dehua Yang Chunyou Mao Qingya Shen Wenbo Feng Dan-Dan Shen Antao Dai Shanshan Xie Yan Zhou Jiao Qin Jin-Peng Sun Daniel H.Scharf Tingjun Hou Tianhua Zhou Ming-Wei Wang Yan Zhang | 2021 | Cell Research2021，31，11： | 0 |
| 16 | Correction to:Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model显示文摘CORRECTION TO:PROTEIN CELL http://gffzzd3cc09b8251d45dfo5pw6kf5x69b069xn.ffgz.tsg.suse.edu.cn/10.1007/S13238-021-00858-3 In legend of figure 1,this sentence“(C)293THK cells were treated as in a”should be corrected as“(C)293THK cells were treated as in(A)”.In legend of figure 2,“E-64D(10μmol/L)”in description of panel(B)should be removed.In section“Metformin activates chaperone-mediated autophagy”of RESULTS,E-64D in sentence“Metformininduced degradation of HK2 and PKM2 was blocked by lysosomal inhibitors(E-64D,Bafilomycin A1 and Leupeptin+NH4Cl)”should be removed. | Xiaoyan Xu Yaqin Sun Xufeng Cen Bing Shan Qingwei Zhao Tingxue Xie Zhe Wang Tingjun Hou Yu Xue Mengmeng Zhang Di Peng Qiming Sun Cong Yi Ayaz Najafov Hongguang Xia | 2022 | Protein & Cell2022，13，3： | 0 |
| 17 | Kinome-wide polypharmacology profiling of small molecules by multi-task graph isomorphism network approach显示文摘Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development,such as lead discovery,drug repurposing and elucidation of potential drug side effects.Therefore,a variety of machine learning-based models have been developed to predict these interactions.In this study,a model called auxiliary multi-task graph isomorphism network with uncertainty weighting(AMGU)was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network(MT-GIN)with the auxiliary learning and uncertainty weighting strategy.The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks(GNN)models on the internal test set.Furthermore,it also exhibited much better performance on two external test sets,suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity.Then,a naÏve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms,and the consistency of the interpretability results for 5typical epidermal growth factor receptor(EGFR)inhibitors with their structure-activity relationships could be observed.Finally,a free online web server called KIP was developed to predict the kinomewide polypharmacology effects of small molecules(http://gffzz8521fdf676b04592h5pw6kf5x69b069xn.ffgz.tsg.suse.edu.cn/kip). | Lingjie Bao Zhe Wang Zhenxing Wu Hao Luo Jiahui Yu Yu Kang Dongsheng Cao Tingjun Hou | 2023 | Acta Pharmaceutica Sinica B2023，13，1： | 0 |
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