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Through the geometric relationships and force analysis of the main components of pantographs on high-speed trains, the coefficients of aerodynamic forces and lift transmission between the pantograph and main components under crosswind conditions were derived. Based on the aerodynamic forces acting on the pantograph at different crosswind speeds, wind angles, and operating speeds, the aerodynamic lift of the pantograph and main components was ultimately determined. The results indicate that the aerodynamic lift of the pantograph is mainly distributed on the bow structure, with the aerodynamic lift of the upper frame all being negative values, while the absolute value of the aerodynamic lift of the lower arm rod is the smallest. The operating speed of the pantograph and the wind angle of the crosswind have a significant impact on the aerodynamic lift of the main components, while the impact of the crosswind speed is relatively small. At the same operating speed of the pantograph, the lower the corresponding crosswind speed, the smaller the aerodynamic lift of the pantograph. The aerodynamic lift of the pantograph tends to decrease gradually with the increase in crosswind speed, and the impact of crosswind speed decreases gradually with the increase in the pantograph operating speed. A comprehensive relationship formula between the aerodynamic lift of the pantograph and the operating speed, crosswind speed, and wind angle is obtained, and the empirical formula for the contact force of the bow net and train operating speed is modified. The research results are of great significance and value for the study and application of lift forces on pantographs under crosswind conditions. [ABSTRACT FROM AUTHOR]

The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.The histamine H4 receptor (H4R) plays key roles in immune cell function. Here, the authors report structures of H4R-Gi complex with various ligands bound, revealing distinct ligand binding modes and a basis for rational design of novel antihistamines targeting H4R. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid (LPA) exerts its physiological roles through the endothelialdifferentiation gene (EDG) family LPA receptors (LPAR1-3) or the non-EDG family LPA receptors (LPAR4-6). LPAR6 plays crucial roles in hair loss and cancer progression, yet its structural information is very limited. Here, we report the cryoelectron microscopy structure of LPA-bound human LPAR6 in complex with a mini G 13 or G q protein. These structures reveal a distinct ligand binding and recognition mode that differs significantly from that of LPAR1. Specifically, LPA uses its charged head to form an extensive polar interaction network with key polar residues on the extracellular side of transmembrane helix 5-6 and the extracellular loop 2. Structural comparisons and homology analysis suggest that the EDG and non-EDG families use two distinct modes for LPA binding. The structural observations are validated through functional mutagenesis studies. We further uncover the mechanisms of LPAR6 activation and principles of G-protein coupling. The structural information revealed by our study lays the groundwork for understanding LPAR6 signaling and provides a rational basis for designing compounds targeting LPAR6., Competing Interests: Competing interests statement:The authors declare no competing interest.