Overburden failure and water-sand mixture outburst conditions of weakly consolidated overlying strata in Dananhu No.7 coal mine.

This study presents a case of weakly consolidated strata developed in Dananhu No.7 coal mine. Using a combination of numerical simulation, field measurement comparison, and the critical hydraulic gradient criterion, we investigate the overburden failure and the risk possibility of water-sand mixture inrush during excavation. The following are the principal findings: (1) Weakly consolidated rocks have poor physical characteristics, particularly when they are mudded and disintegrated after encountering water, which may become a favorable source of water-sand inrush; (2) The water-conducting zone develops to a height of 160.5 m with a crack-mining ratio of 15.29 times, extending upward to Toutunhe Formation aquifer. The predictions are consistent with measurements in adjacent mines with similar geological conditions; (3) Cracks without larger subsidence are developed at the front edge of the mining direction, and some parallel stepped cracks behind the goaf could be easily observed. Ground subsidence along the goaf center finally displays a symmetrically wide-gentle U shape; (4) The critical hydraulic gradient of Toutunhe Formation aquifer, aquifer above 3# coal seam, and aquifer of 3#-7# coal seam in Xishanyao Formation is 1.314, 1.351, and 1.380, the actual value is 0.692, 2.089, and 7.418 accordingly. It is inferred water-sand mixture outburst will not occur in Toutunhe Formation aquifer, while the potential risk exists in the aquifers of Xishanyao Formation. Through drainage and depressurization projects, a water-sand mixture outburst accident does not occur during excavation. This study reveals the overburden failure characteristics and the initiation mechanism of water-sand inrush in weakly cemented strata, as well as the internal relationship between them, which provides new research ideas for safe operation in other mining areas with similar geological conditions. The research work has certain practical guiding significance.

Groundwater chemical characteristic analysis and water source identification model study in Gubei coal mine, Northern Anhui Province, China.

This study aims to accurately identify mine water sources and reduce the hazards caused by water inrush accidents in coal mines. Taking the Gubei coal mine as an example, the water quality results of the water samples from the Cenozoic unconsolidated aquifer, Permian sandstone fracture aquifer, and Carboniferous Taiyuan Formation limestone karst fracture aquifer in the mine area were tested, and K++Na+, Ca2+, Mg2+, Cl-, SO42-, HCO3-, TDS (Total Dissolved Solids), and pH were selected as the main indicators to study the water chemistry characteristics of the aquifer through water chemistry component analysis, major ion content analysis, Piper trilinear analysis, and correlation analysis. Thirty-five groups of water samples were randomly selected and imported into SPSS software for factor analysis (FA) and downsized to three main factors as the input variables of the artificial neural network model. The particle swarm optimization (PSO) code was written based on the MATLAB platform to improve the self-adjustment weights and acceleration factors for optimizing the initial weights and thresholds of the Back-Propagation (BP) neural network. The training and prediction samples were learned in the ratio of 8:2, and the recognition results were compared with the traditional BP neural network model. Results showed that the groundwater of the Gubei coal mine demonstrated a water quality vertical zoning pattern, and the chemical composition was dominated by cation K++Na+ and anion Cl-. The FA-PSO-BP neural network model has a higher accuracy of water source discrimination compared with the cluster analysis and the FA-BP neural network model. The FA-PSO-BP neural network model is worthy of further application in the problem of water source identification in mine water inrush.

Improving Reporter Gene Assay Methodology for Evaluating the Ability of Compounds to Restore P53 Activity.

Tumor suppressor protein P53 induces cycle arrest and apoptosis by mediating the transcriptional expression of its target genes. Mutations causing conformational abnormalities and post-translational modifications that promote degradation are the main reasons for the loss of P53 function in tumor cells. Reporter gene assays that can scientifically reflect the biological function can help discover the mechanism and therapeutic strategies that restore P53 function. In the reporter gene system of this work, tetracycline-inducible expression of wild-type P53 was used to provide a fully activated state as a 100% activity reference for the objective measurement of biological function. It was confirmed by RT-qPCR, cell viability assay, immunofluorescence, and Western blot analysis that the above-mentioned reporter gene system could correctly reflect the differences in biological activity between the wild-type and mutants. After that, the system was tentatively used for related mechanism research and compound activity evaluation. Through the tetracycline-induced co-expression of wild-type P53 and mutant P53 in exact proportion, it was observed that the response modes of typical transcriptional response elements (TREs) to dominant negative P53 mutation effect were not exactly the same. Compared to the relative multiple-to-solvent control, the activity percentage relative to the 100% activity reference of wild-type P53 can better reflect the actual influence of the so-called P53 mutant reactivator. Similarly, relative to the 100% activity reference, it can objectively reflect the biological effects caused by the inhibitor of P53 negative factors, such as MDM2. In conclusion, this study provides a 100% activity reference and a reliable calculation model for relevant basic research and drug development.

Therapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biological inhibitors such as TNF-α and IL-6 antibodies have achieved success in clinical therapy, small molecule inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacological effects on the experimental arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body weight loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.

Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ.

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Spectroscopic insights on imidazole substituted phthalocyanine photosensitizers: fluorescence properties, triplet state and singlet oxygen generation.

Imidazole substituted metal phthalocyanine (Pc) complexes were synthesized. UV-vis absorption, steady state and time-resolved fluorescence, as well as laser flash photolysis were used to measure the photophysical and photosensitizing properties. All the imidazole-phthalocyanine conjugates show high ΦT (quantum yield of excited triplet formation), high ΦΔ (singlet oxygen formation yield, >0.50) and good fluorescence properties (quantum yield Φf>0.20 and lifetime τf>3.0 ns). Compared to the unsubstituted Pc, both α- and ß-imidazole substitutions result in the remarkable decrease in Φf and τf, but the α-substitution is stronger. The imidazole substitution, on the other hand, causes the increase of ΦT, τT, and ΦΔ values. Magnesium phthalocyanine (MgPc) is more susceptible to the substitution than zinc phthalocyanine (ZnPc). The mechanism responsible for the result is suggested based on the involvement of intramolecular photoinduced electron transfer. The high ΦΔ and appropriate fluorescence properties make the Pcs good candidate for PDT photosensitizers.

Non-toxic dose chidamide synergistically enhances platinum-induced DNA damage responses and apoptosis in Non-Small-Cell lung cancer cells.

Combination of low doses of histone deacetylases inhibitors and chemotherapy drugs is considered as one of the most promising strategies to increase the anticancer efficacy. Chidamide is a novel benzamide chemical class of HDAC inhibitor that selectively inhibited HDAC1, 2, 3 and 10. We sought to determine whether chidamide may enhance platinum-induced cytotoxicity in NSCLC cells. In this study, the combination of chidamide with carboplatin showed a good synergism on growth inhibition with the mean combination index value as 0.712 and 0.639 in A549 and NCI-H157 cells, respectively. The used concentration of chidamide was non-toxic on cells by itself as low as 0.3µM. All of our experiments were comparisons between combination regimen and single carboplatin regimen in A549 and NCI-H157 cell lines. Phosphorylated histone H2A.X (γH2A.X), a hall marker of DNA damage response, was dramatically increased by the combination treatment. Cell cycle analysis by flow cytometry and phosphorylation level analysis of histone H3 (Ser10) by western blotting showed that combination treatment significantly increased the percentage of G2/M phase of cells. Mitochondrial membrane potential and cleaved-PARP1 level analysis indicate that chidamide synergistically enhances carboplatin-induced apoptosis. Additionally, synergistic effects of chidamide were found when it was combined with two other platinum drugs (cisplatin and oxaliplatin). The results suggest that Chidamide in combination with platinum drugs may be a novel therapeutic option for NSCLC.