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G protein-coupled receptors(GPCRs):advances in structures,mechanisms,and drug discovery

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1938-1980页

作者： Mingyang Zhang Ting Chen Xun lu Xiaobing lan Ziqiang Chen Shaoyong lu Key Laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Cardiology Changzheng HospitalAffiliated to Naval Medical UniversityShanghai 200003China Department of Orthopedics Changhai HospitalAffiliated to Naval Medical UniversityShanghai 200433China

G protein-coupled receptors(GPCRs),the largest family of human membrane proteins and an important class of drug targets,play a role in maintaining numerous physiological processes.Agonist or antagonist,orthosteric effects or allosteric effects,and biased signaling or balanced signaling,characterize the complexity of GPCR dynamic features.In this study,we first review the structural advancements,activation mechanisms,and functional diversity of GPCRs.We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years.Particularly,an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms.Finally,we highlight how the widespread GPCR-druggable allosteric sites can guide structure-or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

关键词： steric designing mechanisms

A CombustionModel for Explosive Charge Affected by a Bottom Gap in the Launch Environment

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Computer Modeling in Engineering & Sciences 2024年第2期138卷 1207-1236页

作者： ShiboWu Weidong Chen Jingxin Ma lan Liu Shengzhuo lu Honglin meng Xiquan Song College of Aerospace and Civil Engineering Harbin Engineering UniversityHarbin150001China General Department of Experimental Technology Beijing Institute of Structure and Environment EngineeringBeijing100076China Department of Economics Kunlun Energy Holding Company LimitedBeijing100101China

Launch safety of explosive charges has become an urgent problem to be solved by all countries in the world aslaunch situation of ammunition becomes consistentlyworse.However, the existing numericalmodels have differentdefects. This paper formulates an efficient computational model of the combustion of an explosive charge affectedby a bottom gap in the launch environment in the context of the material point method. The current temperatureis computed accurately from the heat balance equation, and different physical states of the explosive charges areconsidered through various equations of state. Microcracks in the explosive charges are described with respectto the viscoelastic statistical crackmechanics (Visco–SCRAM) model. Themethod for calculating the temperatureat the bottomof the explosive charge with respect to the bottomgap is described. Based on this combustionmodel,the temperature history of a Composition B (COMB) explosive charge in the presence of a bottom gap is obtainedduring the launch process of a 155-mm artillery. The simulation results show that the bottom gap thickness shouldbe no greater than 0.039 cm to ensure the safety of the COM B explosive charge in the launch environment. Thisconclusion is consistent with previous results and verifies the correctness of the proposed model. Ultimately, thispaper derives amathematical expression for themaximumtemperature of the COMB explosive chargewith respectto the bottomgap thickness (over the range of 0.00–0.039 cm), and establishes a quantitative evaluationmethod forthe launch safety of explosive charges.The research results provide some guidance for the assessment and detectionof explosive charge safety in complex launch environments.

关键词： Combustion model explosive charge safety launch environment bottom gap temperature

Research on virtual coupling technology in rail transit train collision protection

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Transportation Safety and Environment 2024年第1期6卷 40-46页

作者： Gaosong Li Jinbai Zou Weijie Ma meng lan School of Railway Transportation Shanghai Institute of TechnologyShanghai 201418China Shanghai Metro First Operation Co. LtdShanghai 201418China

In the research on the new generation of intelligent rail transit system,the prevention of train collision accidents is still a focus.Virtual coupling technology controls the running speed and interval distance of two or more trains cooperatively through Trainto-Train(T2T)direct communication technology.The aim is to form a coordinated logical system and jointly complete the train control and dispatching.In this paper,a virtual coupling train formation control method based on the model predictive control(MPC)framework is proposed.From the establishment of the virtual coupling system,the construction of an MPC model and decoupling method,how to integrate virtual coupling technology into the rail transit train collision protection is studied.The safety and reliability of the system are calculated through fault tree and the method of constructing reliability function.The research shows that if virtual coupling technology is used for train collision protection,the overall safety and reliability of the train control system is improved.

关键词： virtual coupling model predictive control collision protection

Wind disturbance compensated path-following control for fixed-wing UAVs in arbitrarily strong winds

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Chinese Journal of Aeronautics 2024年第2期37卷 431-445页

作者： Hao lu lan GAO Yunda YAN Mingzhe HOU Chenliang WANG Hangzhou Innovation Institute Beihang UniversityHangzhou 310051China School of Information Science and Technology Hangzhou Normal UniversityHangzhou 311121China Department of Computer Science University College LondonLondon WC1E 6BTUnited Kingdom Center for Control Theory and Guidance Technology Harbin Institute of TechnologyHarbin 150001China School of Automation Science and Electrical Engineering Beihang UniversityBeijing 100191China

Wind is the primary challenge for low-speed fixed-wing unmanned aerial vehicles to follow a predefined flight path.To cope with various wind conditions,this paper proposes a wind disturbance compensated path following control strategy where the wind disturbance estimate is incorporated with the nominal guiding vector field to provide the desired airspeed direction for the inner-loop.Since the control input vector for the outer-loop kinematic subsystem needs to satisfy a magnitude constraint,a scaling mechanism is introduced to tune the proportions of the compensation and nominal components.Moreover,an optimization problem is formulated to pursue a maximum wind compensation in strong winds,which can be solved analytically to yield two scaling factors.A cascaded inner-loop tracking controller is also designed to fulfill the outer-loop wind disturbance compensated guiding vector field.High-fidelity simulation results under sensor noises and realistic winds demonstrate that the proposed path following algorithm is less sensitive to sensor noises,achieves promising accuracy in normal winds,and mitigates the deviation from a desired path in wild winds.

关键词： Path following Guiding vector field Wind disturbance Disturbance rejection Fixed wings

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

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International Journal of Oral Science 2024年第1期16卷 85-96页

作者： Qingling Huang Yi Xiao Ting lan Youguang lu Li Huang Dali Zheng Department of Biochemistry and Molecular Biology School of Basic Medical SciencesFujian Medical UniversityFuzhouChina Fujian Key Laboratory of Oral Diseases School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Preventive Dentistry School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Dentistry The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor progression.These findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

关键词： WNT squamous tumorigenesis

Gradient-induced long-range optical pulling force based on photonic band gap

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Light(Science & Applications) 2024年第5期13卷 865-874页

作者： Wenlong lu Alexey V.Krasavin Sheng lan Anatoly V.Zayats Qiaofeng Dai Guangdong Basic Research Center of Excellence for Structure and Fundamental Interactions of Matter Guangdong Provincial Key Laboratory of Nanophotonic Functional Materials and DevicesSchool of Information and Optoelectronic Science and EngineeringSouth China Normal UniversityGuangzhou 510006China Department of Physics and London Centre for Nanotechnology King’s College LondonLondon WC2R 2LSUK

Optical pulling provides a new degree of freedom in optical manipulation.It is generally believed that long-range optical pulling forces cannot be generated by the gradient of the incident field.Here,we theoretically propose and numerically demonstrate the realization of a long-range optical pulling force stemming from a self-induced gradient field in the manipulated object.In analogy to potential barriers in quantum tunnelling,we use a photonic band gap design in order to obtain the intensity gradients inside a manipulated object placed in a photonic crystal waveguide,thereby achieving a pulling force.Unlike the usual scattering-type optical pulling forces,the proposed gradient-field approach does not require precise elimination of the reflection from the manipulated objects.In particular,the Einstein-Laub formalism is applied to design this unconventional gradient force.The magnitude of the force can be enhanced by a factor of up to 50 at the optical resonance of the manipulated object in the waveguide,making it insensitive to absorption.The developed approach helps to break the limitation of scattering forces to obtain longrange optical pulling for manipulation and sorting of nanoparticles and other nano-objects.The developed principle of using the band gap to obtain a pulling force may also be applied to other types of waves,such as acoustic or water waves,which are important for numerous applications.

关键词： optical waveguide scattering

Modifications in aroma characteristics of'Merlot'dry red wines aged in American,French and Slovakian oak barrels with different toasting degrees

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Food Science and Human Wellness 2024年第1期13卷 381-391页

作者： Haocheng lu Binhao Cheng Yibin lan Changqing Duan Fei He Center for Viticulture and Enology College of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijing 100083China Key Laboratory of Viticulture and Enology Ministry of Agriculture and Rural AffairsBeijing 100083China

Aging in oak barrels is widely used in enology which could bring flavor changes and aromatic complexity to wines.In the present study,the aroma compounds were analyzed from the‘Merlot’dry red wines,which were fermented in two types of fermenters(stainless steel tank and rotated oak barrel)and aged in six types of oak barrels(three geographic origins×two toasting degrees)for different time(0,3,6 and 9 months,respectively).Results showed that 30 volatiles were associated with barrels and increased during oak aging.The fermenters could influence the intensities of the toast,leathery,smoky,fruity,floral and caramel aromas.The concentration of whisky lactone,eugenol,cis-isoeugenol,and the intensities of the toast and spicy aromas were highest in the wines aged in American oak and were lowest in the wines aged in French oak barrels.The concentrations of guaiacol,syringol,trans-isoeugenol,furfural alcohol,vanilla,cis-whisky lactone enabled the medium toasting barrels to be distinguished from the light toasting ones.The compounds originating from the barrels could be used to distinguish the types of different barrels,but the other general grape-derived and fermentation-derived volatiles could not.The fermenters,oak species and toasting degrees of the barrels all had significant effects on the aroma profiles of the aged‘Merlot’dry red wines,but the influence of the geographic origin was not obvious.

关键词： Wine Aroma Oak Barrel Oak species Toasting degrees Geographic origin Aging

Bioinspired Hemostatic Strategy via Pulse Ejections for Severe Bleeding Wounds

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Research 2024年第1期2023卷 281-299页

作者： Bitao lu Enling Hu Weiwei Ding Wenyi Wang Ruiqi Xie Kun Yu Fei lu Guangqian lan Fangyin Dai State Key Laboratory of Silkworm Genome Biology College of SericultureTextile and Biomass SciencesSouthwest UniversityChongqing 400715China Chongqing Engineering Research Center of Biomaterial Fiber and Modern Textile Chongqing 400715China Division of Trauma and Surgical Intensive Care Unit Research Institute of General SurgeryJinling HospitalMedical School of Nanjing UniversityNanjing210002 Jiangsu ProvinceChina Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic UniversityHong KongChina

Efficient hemostasis during emergency trauma with massive bleeding remains a critical challenge in prehospital settings.Thus,multiple hemostatic strategies are critical for treating large bleeding wounds.In this study,inspired by bombardier beetles to eject toxic spray for defense,a shape-memory aerogel with an aligned microchannel structure was proposed,employing thrombin-carrying microparticles loaded as a built-in engine to generate pulse ejections for enhanced drug permeation.Bioinspired aerogels,after contact with blood,can rapidly expand inside the wound,offering robust physical barrier blocking,sealing the bleeding wound,and generating a spontaneous local chemical reaction causing an explosivelike generation of CO_(2) microbubbles,which provide propulsion thrust to accelerate burst ejection from arrays of microchannels for deeper and faster drug diffusion.The ejection behavior,drug release kinetics,and permeation capacity were evaluated using a theoretical model and experimentally demonstrated.This novel aerogel showed remarkable hemostatic performance in severely bleeding wounds in a swine model and demonstrated good degradability and biocompatibility,displaying great potential for clinical application in humans.

关键词： wound sealing offering

Incidence and warning signs for complications of human brucellosis: a multi-center observational study from China

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Infectious Diseases of Poverty 2024年第1期13卷 53-62页

作者： Qing-Nan Shi Hui-Jie Qin Qiao-Shan lu hu Li Zhong-Fa Tao meng-Guang Fan Mu-Heta Aishan Zeng-Qiang Kou Qiu-lan Chen Wen-Wu Yin Yan-Ping Zhang National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases Chinese Center for Disease Control and PreventionChangbai RoadChangping DistrictBejing 102206China School of Public Health Guangxi Medical UniversityNanningChina Nanning Center for Disease Control and Prevention NanningChina Guizhou Center for Disease Control and Prevention GuiyangChina Inner Mongolia Center for Disease Control and Prevention HohhotChina Xinjiang Uighur Autonomous Region Center for Disease Control and Prevention UrumqiChina Shandong Center for Disease Control and Prevention JinanChina

Background Brucellosis is a severe zoonotic disease that is often overlooked,particularly in impoverished countries.Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes.However,there is currently a lack of established indicators or biomarkers for diagnosing these complications.Therefore,this study aimed to investigate potential warning signs of focal complications in human brucellosis,with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients.Methods A multi-center cross-sectional study was conducted in China from December 2019 to August 2021.The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a ques-tionnaire survey and medical record system.The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models.Receiver operating characteristic(ROC)curves and the area under the curve(AUC)were used for variable screening and model evaluation.Results A total of 880 participants diagnosed with human brucellosis were enrolled.The median age of the patients Was 50 years[interquartile range(IQR):41.5-58.0],and 54.8%had complications.The most common organ system affected by complications was the osteoarticular system(43.1%),with peripheral arthritis(30.0%),spondylitis(16.6%),paravertebral abscess(5.0%),and sacroilitis(2.7%)being the most prevalent.Complications in other organ systems included the genitourinary system(4.7%),respiratory system(4.7%),and hematologic system(4.6%).Several fac-tors were found to be associated with focal brucellosis.These factors included a long delay in diagnosis odds ratio(OR)=3.963,95%confidence interval(CI):1.906-8.238 for>90 daysl,the presence of underlying disease(OR=1.675,95%CI:1.176-2.384),arthralgia(OR=3.197,95%CI:1.986-5.148),eye bulging pain(OR=3.482,95%CI:1.349-8.988),C-reactive protein(CRP)>10 mg/L(OR=1.910,95%CI:1.310-2.784)and erythrocyte sedimentation rate(ESR)el

关键词： Brucellosis Complications Clinical spectrum Warning signs