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Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin Chengwei Wu Li Feng Xiuyan Yang Mingzhu Zhao Yingyi Chen Shaoyong Lu Zhen zheng Xiaobing lan Yi Wang Yan zheng xuefeng Lu Qiufen Zhang Jian Zhang State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and BioinformaticsCenter Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China Department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China College of Pharmacy Ningxia Medical UniversityYinchuan 750004China Department of Pancreatic Surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour ***6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic ***,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be ***,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/***,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/*** allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural ***,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver *** our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic *** not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal Pancreatic cancer metastasis

Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

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Chinese Medical Journal 2024年第4期137卷 457-464页

作者： Mengqin Yuan Jian He xue Hu Lichao Yao Ping Chen zheng Wang Pingji Liu Zhiyu Xiong Yingan Jiang lanjuan Li Department of Infectious Diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430000China Department of Gastroenterology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong 510010China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Centre for Infectious DiseasesCollaborative Innovation Centre for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310000China

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains *** study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)***:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES ***,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and *** primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and *** analyses were adopted to confirm the robustness of the ***:A total of 3144 participants were enrolled for our observational study in *** multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with ***,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and *** results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and *** sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

关键词： Hypertension Non-alcoholic fatty liver disease National Health and Nutrition Examination Survey Mendelian randomization analysis Causality

Risk assessment of coastal flooding disaster by storm surge based on Elevation-Area method and hydrodynamic models:Taking Bohai Bay as an example

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China Geology 2024年第3期7卷 494-504页

作者： Fu Wang xue-zheng Liu Yong Li Heng Yu Ming-zheng Wen Yun-zhuang Hu Tianjin Center(North China Center of Geoscience Innovation) China Geological SurveyTianjin 300170China Key Laboratory of Coast Geo-Environment China Geological SurveyTianjin 300170China Tianjin Key Laboratory of Coast Geological Processes and Environmental Safety Tianjin 300170China Hebei University of Environmental Engineering Qinhuangdao 066102China Hebei Engineering Research Center for Ecological Restoration of seaward Rivers and Coastal Waters Qinhuangdao 066102China Department of Earth and Environment Boston UniversityBoston 02215USA

The future inundation by storm surge on coastal areas are currently *** increasing global sealevel due to climate change,the coastal flooding by storm surge is more and more frequently,especially in coastal lowland with land ***,the risk assessment of such inundation for these areas is of great significance for the sustainable socio-economic *** this paper,the authors use Elevation-Area method and Regional Ocean Model System(ROMS)model to assess the risk of the inundation of Bohai Bay by storm *** simulation results of Elevation-Area method show that either a 50-year or 100-year storm surge can inundate coastal areas exceeding 8000 km^(2);the numerical simulation results based on hydrodynamics,considering ground friction and duration of the storm surge high water,show that a 50-year or 100-year storm surge can only inundate an area of over 2000 km^(2),which is far less than 8000 km^(2);while,when taking into account the land subsidence and sea level rise,the very inundation range will rapidly increase by 2050 and *** storm surge will greatly impact the coastal area within about 10-30 km of the Bohai Bay,in where almost all major coastal projects are *** prompt response to flood disaster due to storm surge is urgently needed,for which five suggestions have been proposed based on the geological background of Bohai *** study may offer insight into the development of the response and adaptive plans for flooding disasters caused by storm surge.

关键词： Storm surge ROMS Elevation-Area method Numerical simulation land subsidence Flooding disaster Sea level rise Marine geological survey engineering Geological disaster survey engineering Bohai Bay

Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

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Science China(Life Sciences) 2024年第6期67卷 1119-1132页

作者： Qingqing Wei Changning xue Mengna Li Jianxia Wei Lemei zheng Shipeng Chen Yumei Duan Hongyu Deng Faqing Tang Wei Xiong Ming Zhou NHC Key Laboratory of Carcinogenesis Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Cancer Research Institute and School of Basic Medical Sciences Central South UniversityChangsha 410078China The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Central South UniversityChangsha 410078China Hunan Key Laboratory of Oncotarget Gene Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid *** occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal ***,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in *** m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic ***,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor *** this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis *** also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

关键词： ferroptosis m6A modification RNA methylation m^(6)A regulator tumor progression

In-situ Horizontal Extrusion Test of Herbaceous Root-Soil with Different Root Types

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Journal of Earth Science 2024年第3期35卷 918-928页

作者： Fangcui Liu Shengwen Qi Shenglin Qi Xiaokun Hou Yanrong Li Guangming Luo Lei xue xueliang Wang Juanjuan Sun Songfeng Guo Bowen zheng Key Laboratory of Shale Gas and Geoengineering Institute of Geology and GeophysicsChinese Academy of SciencesBeijing 100029China University of Chinese Academy of Sciences Beijing 100049China Innovation Academy for Earth Sciences Chinese Academy of SciencesBeijing 100029China China-Pakistan Joint Research Center on Earth Sciences CAS-HECIslamabad 45320Pakistan Government Affairs Service Center of Beijing Municipal Water Affairs Bureau Beijing 100073China Department of Earth Sciences and Engineering Taiyuan University of TechnologyTaiyuan 030024China

The influence of different types of roots on the soil is complex and still remains *** in-situ extrusion tests were conducted on two types of root systems,namely fibrous and tap root system,for three plants,Eleusine indica,Potentilla anserine,and Artemisia argyi,according to the classification in Botany,and the thrust-displacement curves and failure patterns of different samples were analysed by comparison to fill the aforementioned *** reveal that the roots can reduce the characteristics of soil brittleness and enhance its capability to resist large deformation,and different root types contribute different effects to the strain-hardening behavior of the root-soil *** contribution of the fibrous root system to strength is limited,whilst the tap root system substantially enhances strength and *** of failure patterns show that fibrous and tap root systems affect soil solidification and surface cracking ***,the effect of the tap root system depends on the composition of lateral and tap roots:long and rich lateral roots are effective for resisting the creation of cracks,but thick tap roots with few and thin lateral roots may lead to several surface cracks.

关键词： root types fibrous root tap root in-situ horizontal extrusion test root-soil cracks slope protection.

Underestimated benefits of NO_(x) control in reducing SNA and O_(3) based on missing heterogeneous HONO sources

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Frontiers of Environmental Science & Engineering 2024年第3期18卷 57-67页

作者： Shuping Zhang Haotian zheng Jun Liu Yao Shi Tianzeng Chen Chaoyang xue Fenfen Zhang Yueqi Jiang Xiangping Zhang Shovan Kumar Sahu Biwu Chu Jia Xing State Key Joint Laboratory of Environment Simulation and Pollution Control School of EnvironmentTsinghua UniversityBeijing 100084China China Academy of Civil Aviation Science and Technology Beijing 100028China State Key Joint Laboratory of Environment Simulation and Pollution Control Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China Yellow River Institute of Hydraulic Research Zhengzhou 450003China Centre for Climate Research Singapore Meteorological Service SingaporeSingapore 537054Singapore

Substantial NO_(x) emission mitigation is crucial for the synergistic reduction of particulate matter and ozone(O_(3))pollution in *** traditional air quality model does not consider heterogeneous HONO chemistry,leading to uncertainties in estimating the benefits of NO_(x) *** studies have shown that the parameterization of heterogeneous HONO formation increases both the simulated value of sulfate–nitrate–ammonium(SNA)and that of O_(3),thus adding the heterogeneous reactions of HONO into air quality models inevitably leads to changes in the estimated benefits of NO_(x) *** we investigated the changes in SNA and O_(3)concentrations from NO_(x) emission reduction before and after adding heterogeneous HONO reactions in the Community Multi-Scale Air Quality(CMAQ)*** heterogeneous HONO reactions in the simulation improved the benefits of NO_(x) reduction in terms of SNA control in *** 80%NO_(x) reduction,the reduction in SNA increased from 36.9%without considering heterogeneous HONO reactions to 42.8%with heterogeneous HONO *** reduction in the maximum daily 8h average(MDA8)O_(3)in summer caused by NO_(x) reduction increased slightly from 4.7%to 5.2%after adding heterogeneous HONO *** results in this study highlight the enhanced effectiveness of NO_(x) controls for the reduction of SNA and O_(3)after considering heterogeneous HONO formation in a complex chemical ambient,demonstrating the importance of NO_(x) controls in reducing PM2.5 and O_(3)pollution in China.

关键词： Heterogeneous HONO NO_(x) reduction PM_(2.5) O_(3)

Design and synthesis of polyoxovanadate-based framework for efficient dye degradation

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Tungsten 2024年第2期6卷 447-453页

作者： Qing lan Su-Juan Jin zheng Wang Xu-Yang Li Yan Xiong Zhuo-Cheng Wang Shan-Shan Liu Zhi-Ming Zhang Qiang Zhao Engineering Technology Research Center of Henan Province for Solar Catalysis School of Chemical and Pharmaceutical EngineeringNanyang Normal UniversityNanyang 473061China Institute of New Energy Materials&Low Carbon Technology Tianjin University of TechnologyTianjin 300384China

A new polyoxovanadate-based framework material[Cu(en)_(2)]_(4)V_(18)O_(42)(H_(2)O)·6H_(2)O(1)was designed and synthesized by hydrothermal reaction of NaVO_(3),Cu(NO_(3))_(2)·6H_(2)O and 1,2-diaminoethane(en)via carefully adjusting the pH value of the reaction *** structure of the title compound has been determined by single-crystal X-ray diff raction analysis,thermogravimetric analysis,infrared spectra and elemental *** structural analysis demonstrate the three-dimensional(3D)framework structure of compound 1,which was composed of the[V_(18)O_(42)(H_(2)O)]_(8)−({V_(18)O_(42)(H_(2)O)})anions linked by the Cu^(2+)*** 1 represents the fi rst 3D framework based on{V_(18)O_(42)(H_(2)O)}polyoxoanions and copper ***-driven degradation of residual organic pollutants in industrial wastewater is still a major problem for human *** experiments reveal that compound 1 possesses of excellent photocatalytic activity for the degradation of methylene blue and rhodamine B.

关键词： Polyoxovanadate Framework Polyoxovanadate-based framework Photocatalytic Organic pollutants

Plate tectonics in the Archean:Observations versus interpretations

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Science China Earth Sciences 2024年第1期67卷 1-30页

作者： YongFei zheng School of Earth and Space Sciences University of Science and Technology of ChinaHefei 230026China Key Laboratory of Crust-Mantle Materials and Environment Chinese Academy of SciencesHefei 230026China Center of Excellence for Comparative Planetology Chinese Academy of SciencesHefei 230026China

Plate tectonics theory,established in the 1960s,has been successful in explaining many geological phenomena,processes and events that occurred in the ***,the theory has often struggled to provide a coherent framework in interpreting geological records in continental interior and Precambrian *** dealing with the relationship between plate tectonics and continental geology,continental interior tectonics was often separated from continental margin tectonics in the inheritance and development of their structure and *** separation led to the illusion that the plate tectonics theory is not applicable to Precambrian geology,particularly in explaining the fundamental geological characteristics of Archean *** this illusion does not mean that the Archean continental crust did not originate from a regime of plate tectonics,it led to the development of alternative tectonic models,often involving vertical movements under a regime of stagnant lid tectonics,including not only endogenous processes such as gravitational sagduction,mantle plumes and heat pipes but also exogenous processes such as bolide *** vertical processes were not unique to the Archean but persisted into the *** result from mantle poloidal convection at different depths,not specific to any particular *** the plate tectonics theory from the traditional kinematic model in the 20th century to a holistic kinematic-dynamic model in the 21st century and systematically examining the vertical transport of matter and energy at plate margins,it is evident that plate tectonics can explain the common geological characteristics of Archean cratons,such as lithological associations,structural patterns and metamorphic *** deciphering the structure and composition of convergent plate margins as well as their dynamics,the formation and evolution of continental crust since the Archean can be divided into ancient plate tectonics in the Preca

关键词： Plate tectonics Archean geology Continental origin Crustal reworking Plate interior Plate margin

Glaucoma drainage device implantation and cyclophotocoagulation in the management of refractory glaucoma after Descemet-stripping automated endothelial keratoplasty

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International Journal of Ophthalmology(English edition) 2024年第2期17卷 257-264页

作者： Min-Shu Wang xue-Chuan Dong Mi-Yun zheng Xiang Fan Ge-Ge Xiao Jing Hong Ling-Ling Wu Department of Ophthalmology Peking University Third HospitalBeijing 100191China Key Laboratory of Restoration of Damaged Ocular Nerve Beijing 100191China NIMO Ophthalmology Research Institute Beijing 100176China Department of Ophthalmology the First Hospital of PutianTeaching HospitalFujian Medical UniversityPutian 351100Fujian ProvinceChina

AIM:To compare the surgical outcomes of glaucoma drainage device implantation(GDI)and trans-scleral neodymium:YAG cyclophotocoagulation(CPC)in the management of refractory glaucoma after Descemetstripping automated endothelial keratoplasty(DSAEK).METHODS:This retrospective study on observational case series enrolled 29 patients who underwent DSAEK and posterior anti-glaucoma surgery(15 with GDI and 14 with CPC).The main outcome measures were intraocular pressure(IOP),glaucoma surgery success rate(defined as IOP of 6–21 mm Hg without additional anti-glaucoma operation),number of glaucoma medications,endothelial graft status,and best-corrected visual acuity(BCVA).RESULTS:The mean follow-up time was 34.1 and 21.0mo for DSAEK or glaucoma surgeries,both for the GDI and CPC *** groups showed significant IOP reduction after glaucoma *** GDI group presented a significantly higher success rate in IOP control than the CPC group(60%vs 21.4%,P=0.03).Both procedures significantly decreased the number of glaucoma medications(P=0.03).Forty percent and 57%of cases in the GDI and the CPC group,respectively,experienced endothelial graft failure during follow-up(P=0.36).Significantly worse BCVA after surgery was observed in the CPC group but not in the GDI ***:Both GDI and CPC significantly decrease IOP in eyes with glaucoma after *** is preferable to CPC in refractory glaucoma cases after DSAEK,as it manifests a significantly higher success rate for IOP control,similar endothelial graft failure rate,and relatively preserves BCVA than CPC.

关键词： glaucoma drainage device implantation cyclophotocoagulation refractory glaucoma Descemetstripping automated endothelial keratoplasty