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Abstract Dry–wet cycles can cause significant deterioration of compacted loess and thus affect the safety of fill slopes. The discrete element method (DEM) can take into account the non-homogeneous, discontinuous, and anisotropic nature of the geotechnical medium, which is more capable of reflecting the mechanism and process of instability in slope stability analysis. Therefore, this paper proposes to use the DEM to analyze the stability of compacted loess slopes under dry–wet cycles. Firstly, to solve the complex calibration problem between macro and mesoscopic parameters in DEM models, an efficient parameter optimization method was proposed by introducing the chaotic particle swarm optimization with sigmoid-based acceleration coefficients algorithm (CPSOS). Secondly, during the parameter calibration, a new indicator, the bonding ratio (BR), was proposed to characterize the development of pores and cracks in compacted loess during dry–wet cycles, to reflect the impact of dry–wet action on the degradation of bonding between loess aggregates. Finally, according to the results of parameter calibration, the stability analysis model of compacted loess slope under dry–wet cycling was established. The results show that the proposed optimization calibration method can accurately reflect the trend of the stress–strain curve and strength of the actual test results under dry–wet cycles, and the BR also reflects the degradation effect of dry–wet cycles on compacted loess. The slope stability analysis shows that the DEM reflects the negative effect of dry–wet cycles on the safety factor of compacted loess slopes, as well as the trend of gradual stabilization with dry–wet cycles. The comparison with the finite element analysis results verified the accuracy of the discrete element slope stability analysis.

Summary: The gene encoding the NUAK family kinase 1 (NUAK1) is frequently amplified and its expression is upregulated, activating oncogenic signaling in various cancers. However, little is known about its role in gastric cancer (GC). We investigate the mechanistic links among NUAK1, Hedgehog signaling, and tumorigenesis in GC. NUAK1 overexpression is validated in local and public GC cohorts. Patient-derived xenograft and transgenic mouse models demonstrate that NUAK1 depletion or inhibition dramatically ameliorates gastric tumorigenesis. NUAK1 upregulates GLI1 expression by activating STAT5-mediated transcription and stabilizing GLI1 protein. NUAK1 depletion or inhibition impairs cancer cell expansion, tumor formation, and chemotherapy resistance in in vitro and in vivo models. Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.