RESUMEN
We employ a combination of accelerated molecular dynamics and machine learning to unravel how the dynamic characteristics of CBL-B and C-CBL confer their binding affinity and selectivity for ligands from subtle structural disparities within their binding pockets and dissociation pathways. Our predictive model of dissociation rate constants (k off) demonstrates a moderate correlation between predicted k off and experimental IC50 values, which is consistent with experimental k off and τ-random accelerated molecular dynamics (τRAMD) results. By employing a linear regression of dissociation trajectories, we identified key amino acids in binding pockets and along the dissociation paths responsible for activity and selectivity. These amino acids are statistically significant in achieving activity and selectivity and contribute to the primary structural discrepancies between CBL-B and C-CBL. Moreover, the binding free energies calculated from molecular mechanics with generalized Born and surface area solvation (MM/GBSA) highlight the ΔG difference between CBL-B and C-CBL. The k off prediction, together with the key amino acids, provides important guides for designing drugs with high selectivity.
RESUMEN
Metastasis and recurrence are major causes of colorectal cancer (CRC) death, but their molecular mechanisms are unclear. In this study, genes associated with CRC metastasis and recurrence were identified by weighted gene coexpression network analysis, selecting the top 25% most variant genes in the dataset GSE33113. By average linkage hierarchical clustering, a total of 21 modules were generated. One key module was identified as the most relevant to the prognosis of CRC. Gene Ontology analysis indicated that genes associated with tumor metastasis and recurrence in this module were significantly enriched in inflammatory biological functions. Functional analysis was performed on the key module, and candidate hub genes (ADAM8, LYN, and S100A9) were screened out by expression and survival analysis. In summary, the three core genes identified in this study could greatly improve our understanding of CRC metastasis and recurrence. The results also provide a theoretical basis for the use of three core genes (ADAM8, LYN, and S100A9) as a combined marker for early diagnosis, which could benefit CRC patients.
Asunto(s)
Proteínas ADAM/genética , Biomarcadores de Tumor/genética , Calgranulina B/genética , Neoplasias Colorrectales/genética , Proteínas de la Membrana/genética , Familia-src Quinasas/genética , Neoplasias Colorrectales/patología , Biología Computacional , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Metástasis de la Neoplasia/genética , Recurrencia Local de Neoplasia/genética , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
The Qinghai-Tibet Plateau is an extremely vulnerable area that is sensitive to human activities. In recent years, more and more human disturbances have been detected in this area. This study analyzed the spatial distribution and ecological risks of 7 heavy metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) in two regions, namely the Bailong River and Yellow River and their two tributaries (BY region) in Gannan and the Yarlung Zangbo River and its two tributaries (YZ region) in Tibet. In terms of spatial distribution, concentrations of the seven heavy metals were higher in the east and lower in the west of the BY region. The average concentrations all exceeded the background value of the Qinghai-Tibet Plateau, especially for Cd (4.50 times) and As (2.83 times). High Pb concentrations were mainly found in water, urban and rural residential land, and industrial and construction land. In the YZ region, heavy metal concentrations were lower along the river, while high-altitude areas exhibited higher heavy metal concentrations. The average concentrations of Ni, Zn, As, and Cd exceeded the background values of the Qinghai-Tibet Plateau, especially that of Cd (3.13 times), which mostly exhibited high values in water coverage areas. The geo-accumulation index method and the potential ecological risk index method show that the degree of As and Cd pollution was relatively high in the BY region in Gannan, with the greatest potential ecological risk occurring in the water coverage area. In the YZ region in Tibet, the degree of Cd pollution was high, with the highest potential ecological risk also occurring in the water coverage area. This study provides significant guidance for the environmental protection, sustainable development, and utilization of soil under different types of land use in the Qinghai-Tibet Plateau.