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ABSTRACTHunting stability of high-speed train is an important objective for the optimization of bogie suspension parameters. An adequate hunting stability margin is required for the high-speed train. Besides, a remarkable ability to resist the influence caused by the disturbance of bogie suspension parameters and wheel-rail contact parameters on hunting stability is also required. In this paper, the concept of robustness of hunting stability is proposed, and the indexes for vehicle speed robustness, suspension parameter robustness, and wheel-rail contact equivalent conicity robustness are defined and chosen as the optimization objectives for the bogie suspension parameters. The multi-objective optimization method is used, which can optimize the key suspension parameters simultaneously to balance the multiple complicated and conflicting performance indexes, and six groups of typical suspension parameters are obtained by cluster analysis of Pareto frontier. The correlation between suspension parameters and each index is analysed by multivariate statistical analysis, and the optimization and matching rules for key suspension parameters of the high-speed train bogie based on hunting stability robustness are obtained. With the application of this method during the design process of suspension parameters, the hunting stability of high-speed trains in service can be greatly improved.

Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.