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Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.

Most species of the genus Elizabethkingia are pathogenic to humans and animals, most commonly causing meningitis. However, our understanding of the pathogenic mechanisms involved is poor and there have been few pathological studies of Elizabethkingia spp. in animals. To understand the host injury induced by Elizabethkingia spp., we established a model of E. miricola infection in the black-spotted frog (Pelophylax nigromaculatus). The systematic pathology in and oxidative damage in the infection model were investigated. Our results show that recently isolated E. miricola is a bacterium that mainly parasitizes the host brain and that neurogenic organs are the predominant sites of damage. Infection mainly manifested as severe brain abscesses, meningoencephalitis, necrotic spondylitis, and necrotic retinitis. The liver, spleen, kidney, gastrointestinal tract, and lung were also affected to varying degrees, with bacterial necrotic inflammation. P. nigromaculatus also suffered enormous damage to its oxidative system during E. miricola infection, which may have further aggravated its disease state. Our results provide a preliminary reference for the study and treatment of Elizabethkingia spp.-induced neurological diseases in animals.

Precipitation and human activities are two essential forcing dynamics that influence hydrological processes. Previous research has paid more attention to either climate and streamflow or vegetation cover and streamflow, but rarely do studies focus on the impact of climate and human activities on streamflow and sediment. To investigate those impacts, the Zuli River Basin (ZRB), a typical tributary basin of the Yellow River in China, was chosen to identify the impact of precipitation and human activities on runoff and sediment discharge. A double mass curve (DMC) analysis and test methods, including accumulated variance analysis, sequential cluster, Lee-Heghnian, and moving t-test methods, were utilized to determine the abrupt change points based on data from 1956 to 2015. Correlation formulas and multiple regression methods were used to calculate the runoff and sediment discharge reduction effects of soil conservation measures and to estimate the contribution rate of precipitation and soil conservation measures to runoff and sediment discharge. Our results show that the runoff reduction effect of soil conservation measures (45%) is greater than the sediment discharge reduction effect (32%). Soil conservation measures were the main factor controlling the 74.5% and 75.0% decrease in runoff and sediment discharge, respectively. Additionally, the contribution rate of vegetation measures was higher than that of engineering measures. This study provides scientific strategies for water resource management and soil conservation planning at catchment scale to face future hydrological variability.