Previous studies mainly focused on quantifying the contribution rate of different factors on annual runoff variation in the source region of the Yellow River (SRYR), while there are few studies on the seasonal runoff variation. In this study, the monthly water storage and monthly actual evaporation of SRYR were calculated by the monthly ABCD model, and then a seasonal Budyko frame was constructed. Finally, the contribution rate of climatic and anthropic factors on the seasonal runoff variation in Tangnaihai hydrological station were quantitatively calculated. It turned out that: (1) The changing point of runoff data at Tangnaihai hydrological station is 1989. (2) The ABCD monthly hydrological model could well simulate the monthly runoff variation of Tangnaihai hydrological station. (3) Anthropic factors play a major role in runoff change in spring, summer, and winter, while climatic factors play a major role in runoff change in autumn.

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Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.

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