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Late-stage modification of bioactive compounds:Improving druggability through efficient molecular editing

Acta Pharmaceutica Sinica B 2024年第3期14卷 1030-1076页

作者： Tongyu Huo xinyi zhao Zengrui Cheng Jialiang Wei Minghui Zhu Xiaodong Dou Ning Jiao State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Changping Laboratory Beijing 102206China Shanghai Key Laboratory of Green Chemistry and Chemical Processes East China Normal UniversityShanghai 200062China

Synthetic chemistry plays an indispensable role in drug discovery,contributing to hit compounds identification,lead compounds optimization,candidate drugs preparation,and so on.As Nobel Prize laureate James Black emphasized,“the most fruitful basis for the discovery of a new drug is to start with an old drug”1.Late-stage modification or functionalization of drugs,natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly.Such modifications alter the chemical space and physiochemical properties of these compounds,ultimately influencing their potency and druggability.To enrich a toolbox of chemical modification methods for drug discovery,this review focuses on the incorporation of halogen,oxygen,and nitrogen—the ubiquitous elements in pharmacophore components of the marketed drugs—through late-stage modification in recent two decades,and discusses the state and challenges faced in these fields.We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules.Ultimately,we hope this review would serve as a valuable resource,facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.

关键词： Late-stage modification Drug space Halogenation Oxygenation Nitrogenation Synthetic chemistry

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Catalytic conversion of mixed polyolefins under mild atmospheric pressure

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The Innovation 2024年第2期5卷 98-106页

作者： Binzhi zhao Hui Tan Jie Yang Xiaohui Zhang Zidi Yu Hanli Sun Jialiang Wei xinyi zhao Yufeng Zhang Lili Chen Dali Yang Jin Deng Yao Fu Zheng Huang Ning Jiao State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Beijing National Laboratory for Molecular Sciences College of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China The Institute for Advanced Studies Wuhan UniversityWuhan 430072China Hefei National Laboratory for Physical Sciences at the Microscale CAS Key Laboratory of Urban Pollutant ConversionAnhui Province Key Laboratory of Biomass Clean EnergyiChEMUniversity of Science and Technology of ChinaHefei 230026China State Key Laboratory of Organometallic Chemistry Chinese Academy of SciencesShanghai 200032China

The chemical recycling of polyolefin presents a considerable challenge,especially as upcycling methods struggle with the reality that plastic wastes typically consist of mixtures of polyethylene(PE),polystyrene(PS),and polypropylene(PP).We report a catalytic aerobic oxidative approach for polyolefins upcycling with the corresponding carboxylic acids as the product.This method encompasses three key innovations.First,it operates under atmospheric pressure and mild conditions,using O_(2) or air as the oxidant.Second,it is compatible with high-density polyethylene,low-density polyethylene,PS,PP,and their blends.Third,it uses an economical and recoverable metal catalyst.It has been demonstrated that this approach can efficiently degrade mixed wastes of plastic bags,bottles,masks,and foam boxes.

关键词： mixed Catalytic oxidative

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Uncertainty quantification of inverse analysis for geomaterials using probabilistic programming

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第3期16卷 895-908页

作者： Hongbo zhao Shaojun Li Xiaoyu Zang xinyi Liu Lin Zhang Jiaolong Ren School of Civil Engineering and Geomatics Shandong University of TechnologyZibo255000China State Key Laboratory of Geomechanics and Geotechnical Engineering Institute of Rock and Soil MechanicsChinese Academy of SciencesWuhan430071China

Uncertainty is an essentially challenging for safe construction and long-term stability of geotechnical engineering.The inverse analysis is commonly utilized to determine the physico-mechanical parameters.However,conventional inverse analysis cannot deal with uncertainty in geotechnical and geological systems.In this study,a framework was developed to evaluate and quantify uncertainty in inverse analysis based on the reduced-order model(ROM)and probabilistic programming.The ROM was utilized to capture the mechanical and deformation properties of surrounding rock mass in geomechanical problems.Probabilistic programming was employed to evaluate uncertainty during construction in geotechnical engineering.A circular tunnel was then used to illustrate the proposed framework using analytical and numerical solution.The results show that the geomechanical parameters and associated uncertainty can be properly obtained and the proposed framework can capture the mechanical behaviors under uncertainty.Then,a slope case was employed to demonstrate the performance of the developed framework.The results prove that the proposed framework provides a scientific,feasible,and effective tool to characterize the properties and physical mechanism of geomaterials under uncertainty in geotechnical engineering problems.

关键词： Geological engineering Geotechnical engineering Inverse analysis Uncertainty quantification Probabilistic programming

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Deep tectonics and seismogenic mechanisms of the seismic source zone of the Jishishan M_(s)6.2 earthquake on December 18,2023,at the northeast margin of the Tibetan Plateau

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Earth and Planetary Physics 2024年第3期8卷 514-521页

作者： Qiong Wang ShuYu Li xinyi Li Yue Wu PanPan zhao Yuan Gao Key Laboratory of Earthquake Prediction Institute of Earthquake ForecastingChina Earthquake AdministrationBeijing 100036China Institute of Geophysics China Earthquake AdministrationBeijing 100081China

On December 18,2023,an M_(s)6.2 earthquake occurred in Jishishan,Gansu Province,China.This earthquake happened in the eastern region of the Qilian Orogenic Belt,which is situated at the forefront of the NE margin of the Tibetan Plateau(i.e.,Qinghai-Tibet Plateau),encompassing a rhombic-shaped area that intersects the Qilian-Qaidam Basin,Alxa Block,Ordos Block,and South China Block.In this study,we analyzed the deep tectonic pattern of the Jishishan earthquake by incorporating data on the crustal thickness,velocity structure,global navigation satellite system(GNSS)strain field,and anisotropy.We discovered that the location of the earthquake was related to changes in the crustal structure.The results showed that the Jishishan M_(s)6.2 earthquake occurred in a unique position,with rapid changes in the crustal thickness,Vp/Vs,phase velocity,and S-wave velocity.The epicenter of the earthquake was situated at the transition zone between high and low velocities and was in proximity to a low-velocity region.Additionally,the source area is flanked by two high-velocity anomalies from the east and west.The principal compressive strain orientation near the Lajishan Fault is primarily in the NNE and NE directions,which align with the principal compressive stress direction in this region.In some areas of the Lajishan Fault,the principal compressive strain orientations show the NNW direction,consistent with the direction of the upper crustal fast-wave polarization from local earthquakes and the phase velocity azimuthal anisotropy.These features underscore the relationship between the occurrence of the Jishishan M_(s)6.2 earthquake and the deep inhomogeneous structure and deep tectonic characteristics.The NE margin of the Tibetan Plateau was thickened by crustal extension in the process of northeastward expansion,and the middle and lower crustal materials underwent structural deformation and may have been filled with salt-containing fluids during the extension process.The presence of this weak layer makes it easier for strong ea

关键词： Jishishan M_(s)6.2 earthquake crustal structure anisotropy stress and strain seismogenic mechanism northeast margin of the Tibetan Plateau

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The RNA m^(6)A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression

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Cellular & Molecular Immunology 2024年第1期21卷 6-18页

作者： Yang Liu Renjie Song Zhike Lu Lu zhao xinyi Zhan Yini Li Xuetao Cao Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Suzhou Institute of Systems Medicine Chinese Academy of Medical SciencesSuzhouChina Frontier Research Center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai UniversityTianjinChina School of Life Sciences Westlake UniversityHangzhouChina

Emergency granulopoiesis and neutrophil mobilization that can be triggered by granulocyte colony-stimulating factor(G-CSF)through its receptor G-CSFR are essential for antibacterial innate defense.However,the epigenetic modifiers crucial for intrinsically regulating G-CSFR expression and the antibacterial response of neutrophils remain largely unclear.N6-methyladenosine(m^(6)A)RNA modification and the related demethylase alkB homolog 5(ALKBH5)are key epigenetic regulators of immunity and inflammation,but their roles in neutrophil production and mobilization are still unknown.We used cecal ligation and puncture(CLP)-induced polymicrobial sepsis to model systemic bacterial infection,and we report that ALKBH5 is required for emergency granulopoiesis and neutrophil mobilization.ALKBH5 depletion significantly impaired the production of immature neutrophils in the bone marrow of septic mice.In addition,Alkbh5-deficient septic mice exhibited higher retention of mature neutrophils in the bone marrow and defective neutrophil release into the circulation,which led to fewer neutrophils at the infection site than in their wild-type littermates.During bacterial infection,ALKBH5 imprinted production-and mobilization-promoting transcriptome signatures in both mouse and human neutrophils.Mechanistically,ALKBH5 erased m^(6)A methylation on the CSF3R mRNA to increase the mRNA stability and protein expression of G-CSFR,consequently upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils.The RIP-qPCR results confirmed the direct binding of ALKBH5 to the CSF3R mRNA,and the binding strength declined upon bacterial infection,accounting for the decrease in G-CSFR expression on bacteria-infected neutrophils.Considering these results collectively,we define a new role of ALKBH5 in intrinsically driving neutrophil production and mobilization through m^(6)A demethylation-dependent posttranscriptional regulation,indicating that m^(6)A RNA modification in neutrophils is a potential target for treating bacteria

关键词： Emergency granulopoiesis Neutrophil mobilization ALKBH5 m^(6)A RNA modification G-CSF receptor

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Solid-state synthesis and ion transport characteristics of theβ-KSbF_(4)for all-solid-state fluoride-ion batteries

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Journal of Energy Chemistry 2024年第7期94卷 758-767页

作者： Jiali Liu Huahui zhao Jingcheng Xia Lingguang Yi Xiaoyi Chen Dongdu Li Shuhan Ni xinyi Su Yixuan Chen Min Liu Xianyou Wang National Base for International Science&Technology Cooperation National Local Joint Engineering Laboratory for Key Materials of New Energy Storage BatteryHunan Province Key Laboratory of Electrochemical Energy Storage&ConversionSchool of ChemistryXiangtan UniversityXiangtan 411105HunanChina College of New Energy Ningbo University of TechnologyNingbo 315336ZhejiangChina

All-solid-state fluoride ion batteries(FIBs)have been recently considered as a post-lithium-ion battery system due to their high safety and high energy density.Just like all solid-state lithium batteries,the key to the development of FIBs lies in room-temperature electrolytes with high ionic conductivity.β-KSbF_(4)is a kind of promising solid-state electrolyte for FIBs owing to its rational ionic conductivity and relatively wide electrochemical stability window at room temperature.However,the previous synthesis routes ofβ-KSbF_(4)required the use of highly toxic hydrofluoric acid and the ionic conductivity of as-prepared product needs to be further improved.Herein,the β-KSbF_(4)sample with an ionic conductivity of 1.04×10^(-4)s cm^(-1)(30°C)is synthesized through the simple solid-state route.In order to account for the high ionic conductivity of the as-synthesizedβ-KSbF_(4),X-ray diffraction(XRD),scanning electron microscopy(SEM),and energy dispersive X-ray spectroscopy(EDS)are used to characterize the physic-ochemical properties.The results show that the as-synthesizedβ-KSbF_(4)exhibits higher carrier concentra-tion of 1.0×10^(-6)S cm-Hz^(-1)K and hopping frequency of 1.31×10^(6)Hz at 30°C due to the formation of the fluorine vacancies.Meanwhile,the hopping frequency shows the same trend as the changes of ionic conductivity with the changes of temperature,while the carrier concentration is found to be almost con-stant.The two different trends indicate the hopping frequency is mainly responsible for the ionic conduc-tion behavior withinβ-KSbF_(4).Furthermore,the all-solid-state FIBs,in which Ag and Pb+PbF_(2)are adopted as cathode and anode,andβ-KSbF_(4)as fluoride ion conductor,are capable of reversible charge and discharge.The assembled FIBs show a discharge capacity of 108.4 mA h g^(-1)at 1st cycle and 74.2 mA h g^(-1)at 50th cycle.Based on an examination of the capacity decay mechanism,it has been found that deterioration of the electrolyte/electrode interface is an important reason for hindering the commer-c

关键词： Solid-state electrolyte Carrier concentration Hopping frequency β-KSbF_(4) All-solid-state fluoride ion batteries

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Rational design of a single-component mRNA vaccine against orthopoxvirus and SARS-CoV-2

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Science China(Life Sciences) 2024年第6期67卷 1311-1313页

作者： Yilong Yang Xiaofan zhao Yu Li Xiaodong Zai xinyi Wang Yue Zhang Xiaolin Wang Peng Lv Jun Zhang Lihua Hou Junjie Xu Wei Chen Laboratory of Advanced Biotechnology Beijing Institute of BiotechnologyAcademy of Military Medical SciencesBeijing 100071China

Dear Editor,In the era of COVID-19,the prevalence of viruses from other families poses new threats to humans.Despite the eradication of smallpox in 1980,the global outbreak of monkeypox in 2022(Lum et al.,2022;Nuzzo et al.,2022)alerted that the re-emerging orthopoxvirus(OPXV)remained a persistent threat to global health.OPXV includes a number of viruses with a broad host range,including variola virus(VARV),monkeypox virus(MPXV),vaccinia virus(VACV).

关键词： al. vaccine Rational

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Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1199-1208页

作者： xinyi Yang Xu Zheng Yuqi Zhu Xiaying zhao Jun Liu Jiangna Xun Songhua Yuan Jun Chen Hanyu Pan Jinlong Yang Jing Wang Zhimin Liang Xiaoting Shen Yue Liang Qinru Lin Huitong Liang Min Li Fei Peng Daru Lu Jianqing Xu Hongzhou Lu Shibo Jiang Ping zhao Huanzhang Zhu State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology Ministry of EducationInstitute of GeneticsSchool of Life SciencesYiwu Research InstituteFudan UniversityShanghaiChina Department of Microbiology Faculty of Naval MedicineNaval Medical UniversityShanghai 200433China Scientific Research Center Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina Department of Infectious Diseases and Immunology Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina Changzheng Hospital Naval Medical UniversityShanghaiChina Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Shanghai Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghaiChina Department of Infectious Diseases and Nursing Research Institution National Clinical Research Center for Infectious DiseasesThe Third People’s Hospital of ShenzhenShenzhenGuangdongChina

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes multi-organ damage,which includes hepatic dysfunction,as observed in over 50%of COVID-19 patients.Angiotensin I converting enzyme(peptidyl-dipeptidase A)2(ACE2)is the primary receptor for SARS-CoV-2 entry into host cells,and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2,but at extremely low levels.Consequently,we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells.To address this question,we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1(ASGR1)promoted SARS-CoV-2 pseudovirus infection of HeLa cells.In Huh-7 cells,simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection.In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells,both of which barely expressed ACE2,SARSCoV-2 pseudovirus could successfully establish an infection.However,after treatment with ASGR1 antibody or siRNA targeting ASGR1,the infection rate significantly dropped,suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism.We confirmed that ASGR1 could interact with Spike protein,which depends on receptor binding domain(RBD)and N-terminal domain(NTD).Finally,we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells.After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA,the infection efficiency of the live virus decreased significantly.Collectively,these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

关键词： ACE2 infection glycoprotein

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Maternal Preconception Serum Alanine Aminotransferase Levels and Risk of Preterm Birth among Reproductive-Aged Women—China,2013-2017

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China CDC weekly 2024年第10期6卷 181-188,I0001页

作者： Chuanyu zhao Jiajing Jia Hanbin Wu Qin Xu xinyi Lyu Meiya Liu Xuan Hu Jueming Lei Yuzhi Deng Yuan He Yuanyuan Wang Zuoqi Peng Ya Zhang Hongguang Zhang Qiaomei Wang Haiping Shen Yiping Zhang Donghai Yan Ying Yang Xu Ma National Research Institute for Family Planning BeijingChina National Human Genetic Resources Center BeijingChina Graduate School of Peking Union Medical College BeijingChina Department of Epidemiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Summary What is already known about this topic?The significance of maternal liver health concerning preterm birth(PTB)is well recognized;however,there is a gap in understanding the precise influence of preconception s... 详细信息

关键词： Serum precise concerning

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基于危险天气不确定性的最小风险路径规划方法

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工程科学学报 2024年第5期46卷 887-896页

作者：王岩韬赵昕颐中国民航大学国家空管运行安全技术重点实验室天津300300

为降低飞行过程中遭遇危险天气的概率,同时避免大范围绕飞导致的路径与耗油增加,针对航路中的雷暴、积冰和颠簸天气,使用数值预报和概率预报,面向航前飞行计划,提出一种基于危险天气不确定性的最小风险路径规划方法.首先,基于概率预报... 详细信息

为降低飞行过程中遭遇危险天气的概率,同时避免大范围绕飞导致的路径与耗油增加,针对航路中的雷暴、积冰和颠簸天气,使用数值预报和概率预报,面向航前飞行计划,提出一种基于危险天气不确定性的最小风险路径规划方法.首先,基于概率预报数据使用配料法和C-F模型计算雷暴发生概率,基于数值预报数据计算积冰预测指数和颠簸预测指数;然后,融合多类型危险天气,提出一种具备风险标识的栅格化地图;在此基础上,改进传统路径最短的规划算法,构建以风险最小化为目标的Dijkstra和A^(*)算法;最后,使用2023年4月3日华中地区强对流天气预测数据建立风险地图,使用上述改进算法与传统Dijkstra、A^(*)和RRT算法进行路径规划并对比分析.结果表明,传统Dijkstra和A^(*)算法可计算得到最短飞行路径,而改进的A^(*)算法可计算得到总风险最小路径;若综合考虑飞行风险与路径长度,改进的Dijkstra算法最为适合.

关键词：危险天气概率预报不确定性推理飞行路径规划风险最小化

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