RESUMEN
Short-wall block backfill mining can effectively control the movement of overlying strata, prevent water loss and utilize waste gangue materials. However, heavy metal ions (HMI) of gangue backfill materials in the mined-out area can be released and transported to the underlying aquifer, causing pollution of water resources in the mine. Accordingly, with short-wall block backfill mining technology, this study analyzed the sensitivity of gangue backfill materials to the environment. The pollution mechanism of gangue backfill materials to water resources was revealed, and the transport rules of HMI were explored. The regulation and control methods of water pollution in the mine were then concluded. The design method of backfill ratio for comprehensive protection of overlying and underlying aquifers was proposed. The results show that the release concentration of HMI, the gangue particle size, the floor lithology, the burial depth of the coal seam, and the depth of the floor fractures were the main factors that affected the transport behaviors of HMI. After long-term immersion, HMI of gangue backfill materials underwent hydrolysis and were released constantly. HMI were subjected to the coupled action of seepage, concentration, and stress and then driven by water head pressure and gravitational potential energy to transported downward along the pore and fracture channels in the floor with mine water as the carrier. Meanwhile, the transport distance of HMI increased with increasing release concentration of HMI, the permeability of the floor stratum, and the depth of floor fractures. Still, it decreased with increasing gangue particle size and the burial depth of the coal seam. On that basis, external-internal cooperative control methods were proposed to prevent the pollution of gangue backfill materials to mine water. Furthermore, the design method of the backfill ratio for comprehensive protection of overlying and underlying aquifers was proposed.
RESUMEN
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00464.].
RESUMEN
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 µM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a ß-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 µM and Bcl-xL at >99 µM, and induces cleaved caspase-3 in MV4-11 cells with an IC50 of 3 µM after 6 h.