Simulation Study of Coal Failure Law under High-Pressure Water Jetting

High-pressure water jetting impinging on coal plays a relatively important role in improving pressure relief and permeability of the coal body, which can elevate the gas drainage effect and eliminate the outburst danger. But the slot formed by high-pressure water jetting impinging on the coal is affected by various factors in pressure relief and permeation of the surrounding coal. To explore how to improve the effect of pressure relief and permeability of the coal body in the process of high-pressure water jetting, the stress-strain and failure of the surrounding coal after the formation of slots were analyzed based on Fast Lagrangian Analysis of Continua 3D(FLAC3D) software, the influence and law exerted from each of the factors was screened out on pressure relief of the slot, and the mathematical model of the slot failure range was constructed. Results show that stress of slots impinged by high-pressure water jetting changes considerably in different directions. As vertical stress increases, the range of pressure relief and failure of the coal body gradually increase, and the pressure relief range enlarges exponentially with the increase of depth. The synergy pressure relief between slots can strengthen the pressure relief of the coal body. The findings obtained from this study can provide construction guidance and reference value for the onsite application of related hydraulic measures

STF-based diagnosis of AUV thruster faults

The diagnosis of thruster faults of autonomous underwater vehicles is studied in this paper. Based on the theory of strong tracking filter (STF), the AUV motion model and the thruster fault model are established. The STFs are designed for each thruster for the purpose of fault diagnosis. The AUV state and the fault deviation of the thruster are estimated online before the thruster faults are diagnosed based on residual analysis. The simulation experiments were conducted to verify the feasibility and effectiveness of the STF-based diagnosis of AUV thruster faults

SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1

BACKGROUND: Grb2 (Growth factor receptor-bound protein 2) is a key adaptor protein in maintaining the ERK activity via linking Sos1 (Son of sevenless homolog 1) or other proteins to activated RTKs, such as EGFR. Currently, little knowledge is available concerning the post-translational modification (PTM) of Grb2 except for its phosphorylation. Since emerging evidences have highlighted the importance of SUMOylation (Small ubiquitin-related modifier), a reversible PTM, in modulating protein functions, we wondered if Grb2 could be SUMOylated and thereby influences its functions especially involved in the Ras/MEK/ERK pathway. METHODS: SUMOylation of Grb2 was analyzed with the in vivo SUMOylation assay using the Ni(2+)-NTA affinity pulldown and the in vitro E.coli-based SUMOylation assay. To test the ERK activity and cell transformation, the murine fibroblast cell line NIH/3T3 and the murine colon cancer cell line CMT-93 were used for the experiments including Grb2 knockdown, ectopic re-expression, cell transformation and migration. Immunoprecipitation (IP) was employed for seeking proteins that interact with SUMO modified Grb2. Xenograft tumor model in mice was conducted to verify that Grb2 SUMOylation regulated tumorigenesis in vivo. RESULTS: Grb2 can be SUMOylated by SUMO1 at lysine 56 (K(56)), which is located in the linker region between the N-terminal SH3 domain and the SH2 domain. Knockdown of Grb2 reduced the ERK activity and suppressed cell motility and tumorigenesis in vitro and in vivo, which were all rescued by stable ectopic re-expression of wild-type Grb2 but not the mutant Grb2(K56R). Furthermore, Grb2 SUMOylation at K(56) increased the formation of Grb2-Sos1 complex, which sequentially leads to the activation of Ras/MEK/MAPK pathway. CONCLUSIONS: Our results provide evidences that Grb2 is SUMOylated in vivo and this modification enhances ERK activities via increasing the formation of Grb2-Sos1 complex, and may consequently promote cell motility, transformation and tumorigenesis

General machine learning model, review, and experimental-theoretic study of magnolol activity in enterotoxigenic induced oxidative stress

[Abstract] This study evaluated the antioxidative effects of magnolol based on the mouse model induced by Enterotoxigenic Escherichia coli (E. coli, ETEC). All experimental mice were equally treated with ETEC suspensions (3.45×109 CFU/ml) after oral administration of magnolol for 7 days at the dose of 0, 100, 300 and 500 mg/kg Body Weight (BW), respectively. The oxidative metabolites and antioxidases for each sample (organism of mouse) were determined: Malondialdehyde (MDA), Nitric Oxide (NO), Glutathione (GSH), Myeloperoxidase (MPO), Catalase (CAT), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx). In addition, we also determined the corresponding mRNA expressions of CAT, SOD and GPx as well as the Total Antioxidant Capacity (T-AOC). The experiment was completed with a theoretical study that predicts a series of 79 ChEMBL activities of magnolol with 47 proteins in 18 organisms using a Quantitative Structure- Activity Relationship (QSAR) classifier based on the Moving Averages (MAs) of Rcpi descriptors in three types of experimental conditions (biological activity with specific units, protein target and organisms). Six Machine Learning methods from Weka software were tested and the best QSAR classification model was provided by Random Forest with True Positive Rate (TPR) of 0.701 and Area under Receiver Operating Characteristic (AUROC) of 0.790 (test subset, 10-fold crossvalidation). The model is predicting if the new ChEMBL activities are greater or lower than the average values for the magnolol targets in different organisms.National Natural Science Foundation of China; 30972166Hunan Provincial Education Department; 08A031Hunan Provincial Innovation Foundation for Postgraduate; CX2011B304Hunan Provincial Innovation Foundation for Postgraduate; CX2014B300Xunta de Galicia; R2014/039Xunta de Galicia; GRC2014/049Ministerio de Economía y Competitividad; UNLC08-1E-002Ministerio de Economía y Competitividad; UNLC13-13-350

Positive Relationship between Total Antioxidant Status and Chemokines Observed in Adults

Objective. Human evidence is limited regarding the interaction between oxidative stress biomarkers and chemokines, especially in a population of adults without overt clinical disease. The current study aims to examine the possible relationships of antioxidant and lipid peroxidation markers with several chemokines in adults. Methods. We assessed cross-sectional associations of total antioxidant status (TAS) and two lipid peroxidation markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS) with a suite of serum chemokines, including CXCL-1 (GRO-α), CXCL-8 (IL-8), CXCL-10 (IP-10), CCL-2 (MCP-1), CCL-5 (RANTES), CCL-8 (MCP-2), CCL-11 (Eotaxin-1), and CCL-17 (TARC), among 104 Chinese adults without serious preexisting clinical conditions in Beijing before 2008 Olympics. Results. TAS showed significantly positive correlations with MCP-1 (r=0.15751, P=0.0014), MCP-2 (r=0.3721, P=0.0001), Eotaxin-1 (r=0.39598, P<0.0001), and TARC (r=0.27149, P=0.0053). The positive correlations remained unchanged after controlling for age, sex, body mass index, smoking, and alcohol drinking status. No associations were found between any of the chemokines measured in this study and MDA or TBARS. Similar patterns were observed when the analyses were limited to nonsmokers. Conclusion. Total antioxidant status is positively associated with several chemokines in this adult population

Pharmacokinetics and bioequivalence of sunitinib and Sutent® in Chinese healthy subjects: an open-label, randomized, crossover study

Purpose: The purpose of this study was to examine the pharmacokinetics (PK), bioequivalence and safety of generic sunitinib and its original product Sutent® in healthy Chinese subjects through a phase-I clinical trial.Methods: The study selected two groups of 24 healthy Chinese subjects in a 1:1 ratio through random allocation. Each participant received either 12.5 mg of sunitinib or Sutent® per cycle. A total of 15 different time points were employed for blood sample collection during each cycle. Furthermore, a comprehensive assessment of the drugs’ safety was consistently maintained throughout the trial.Results: The average adjusted geometric mean ratios (GMR) (90% CI) for the primary PK parameters Cmax, AUC0-t and AUC0-∞ were 97.04% (93.06%–101.19%), 98.45% (93.27%–103.91%) and 98.22% (93.15%–103.56%), respectively. The adjusted GMRs for essential pharmacokinetic (PK) parameters all met the requirements for bioequivalence, with values within the acceptable range of 80%–125%. In addition, the two drugs showed comparable results for the other PK parameters. These results indicate that the two drugs were bioequivalent. Furthermore, both drugs showed well safety.Conclusion: The research results proved that the PK and safety profiles of sunitinib in healthy Chinese subjects were comparable to those of Sutent®. These results advocate the clinical application of generic sunitinib as a potential alternative to original product Sutent® in the treatment of certain medical conditions

Endoscopic endonasal transsphenoidal surgery for unusual sellar lesions: eight cases and review of the literature

BackgroundPreoperative imaging for some unusual lesions in the sellar region can pose challenges in establishing a definitive diagnosis, impacting treatment strategies.MethodsThis study is a retrospective analysis of eight cases involving unusual sellar region lesions, all treated with endoscopic endonasal transsphenoidal surgery (EETS). We present the clinical, endocrine, and radiological characteristics, along with the outcomes of these cases.ResultsAmong the eight cases, the lesions were identified as follows: Solitary fibrous tumor (SFT) in one case, Lymphocytic hypophysitis (LYH) in one case, Cavernous sinus hemangiomas (CSH) in one case, Ossifying fibroma (OF) in two cases; Sphenoid sinus mucocele (SSM) in one case, Pituitary abscess (PA) in two cases. All patients underwent successful EETS, and their diagnoses were confirmed through pathological examination. Postoperatively, all patients had uneventful recoveries without occurrences of diabetes insipidus or visual impairment.ConclusionOur study retrospectively analyzed eight unusual lesions of the sellar region. Some lesions exhibit specific imaging characteristics and clinical details that can aid in preoperative diagnosis and inform treatment strategies for these unusual sellar diseases

The research on FBW7 gene enhances antitumor effect of paclitaxel on pancreatic cancer through GSDME-mediated pyroptosis

Background and purpose: Pancreatic cancer is a highly malignant disease. Most patients are in advanced stage upon diagnosis. Systemic chemotherapy is an important treatment method, but the chemotherapy drug resistance to tumors brings many problems to clinical treatment. As a commonly used chemotherapy drug, paclitaxel can induce apoptosis in tumor cells. The FBW7 gene is a tumor suppressor gene, and the loss of its function can lead to tumor occurrence and progression. Research has shown that it has the effect of promoting tumor cell apoptosis and inhibiting tumor proliferation. In addition, this gene has been proven to promote apoptosis and ferroptosis, which increase the effect of chemotherapy drugs. Pyroptosis is a programmed cell death mode mediated by gasdermin (GSDM) protein, and this cell death is often accompanied by inflammatory reactions. This study aimed to investigate whether FBW7 gene can promote the anti-tumor effect of paclitaxel by increasing pyroptosis. Methods: A PANC-1 cell line overexpressing FBW7 was constructed using lentivirus transfection. The correlation between FBW7 and GSDME gene expressions was detected by immunohistochemistry in clinical samples, and the expression levels of mRNA and protein were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot. We observed the morphological changes of cells treated with paclitaxel under light microscopy. Cell counting kit-8 (CCK-8) was used to detect the effect of paclitaxel on cell viability, and flow cytometry and lactate dehydrogenase (LDH) release assay were performed to detect the effect of paclitaxel on cell death. Western blot was used to detect caspase-3 and GSDME activation after paclitaxel treatment. Results: RTFQ-PCR and Western blot experiments showed that overexpression of FBW7 gene increased the expression of GSDME. Immunohistochemical staining of pathological sections of clinical patients also showed that the expressions of FBW7 and GSDME genes was positively correlated in vivo. Flow cytometry and LDH release experiments showed that the level of cell death in pancreatic cancer cell line PANC-1 overexpressing FBW7 was significantly increased compared with its empty vector (EV) cells after being treated with paclitaxel. Under light microscopy, it was observed that the number of cells with pyroptosis was significantly higher in PANC-1 cell lines overexpressing FBW7 than in EV cells. The CCK-8 experiment results showed that the cell viability was significantly lower in FBW7 overexpressed cell lines than in EV cells after paclitaxel treatment. Western blot experiment results showed that after pancreatic cancer cell line PANC-1 was treated with paclitaxel, the protein expressions of active-caspase-3 and GSDME-NT in FBW7 overexpression cell lines increased, which proved that they had more obvious activation, indicating that the FBW7 gene can increase the sensitivity of PANC-1 cells to paclitaxel through caspase-3/GSDME signaling pathway induced cell pyroptosis. Conclusion: FBW7 can increase the sensitivity of pancreatic cancer cells to paclitaxel by increasing the expression of GSDME, which is realized through caspase-3/GSDME pathway

Vicariance and dispersal events inferred from mitochondrial genomes and nuclear genes (18S, 28S) shaped global Cryptocercus distributions

Cryptocercus Scudder, a genus of wingless, subsocial cockroaches, has low vagility but exhibits a disjunct distribution in eastern and western North America, and in China, South Korea and the Russian Far East. This distribution provides an ideal model for testing hypotheses of vicariance through plate tectonics or other natural barriers versus dispersal across oceans or other natural barriers. We sequenced 45 samples of Cryptocercus to resolve phylogenetic relationships among members of the genus worldwide. We identified four types of tRNA rearrangements among samples from the Qin-Daba Mountains. Our maximum-likelihood and Bayesian phylogenetic trees, based on mitochondrial genomes and nuclear genes (18S, 28S), strongly supported six major lineages of Cryptocercus, which displayed a clear geographical distribution pattern. We used Bayesian molecular dating to estimate the evolutionary timescale of the genus, and reconstructed Cryptocercus ancestral ranges using statistical dispersal-vicariance analysis (S-DIVA) in RASP. Two dispersal events and six vicariance events for Cryptocercus were inferred with high support. The initial vicariance event occurred between American and Asian lineages at 80.5 Ma (95% credibility interval: 60.0–104.7 Ma), followed by one vicariance event within the American lineage 43.8 Ma (95% CI: 32.0–57.5 Ma), and two dispersal 31.9 Ma (95% CI: 25.8–39.5 Ma), 21.7 Ma (95% CI: 17.3–27.1 Ma) plus four vicariance events c. 29.3 Ma, 27.2 Ma, 24.8 Ma and 16.7 Ma within the Asian lineage. Our analyses provide evidence that both vicariance and dispersal have played important roles in shaping the distribution and diversity of these woodroaches

Exploring the clinical efficacy and mechanism of high-position colon dialysis combined with Traditional Chinese Medicine retention enema in real-world patients with stage 3–5 chronic kidney disease (non-dialysis) based on the theory of the Gut–Kidney axis

Background: With societal and economic development, the annual incidence of chronic kidney disease (CKD) is increasing. Current treatments for CKD are limited, and once patients progress to the uraemic stage, it places a significant economic burden on families and society. Based on the “gut–kidney axis” theory and real-world research, this study aims to evaluate the clinical efficacy, safety, and potential mechanism of high-position colon dialysis combined with traditional Chinese medicine (TCM) retention enema in treating stage 3–5 chronic kidney disease (non-dialysis). Additionally, it seeks to identify new therapeutic targets and approaches for CKD treatment.Methods: The TCM decoction was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Orbitrap-High Resolution Mass Spectrometry (UPLC-Q-Orbitrap-HRMS). Participants meeting the inclusion criteria were divided into a control group (n = 153) and a treatment group (n = 159) based on their preferences and physicians’ recommendations. Both groups adhered to a high-quality low-protein, low-salt, low-phosphorus, and low-fat diet supplemented with essential amino acids, and were monitored for blood pressure, blood glucose, and blood lipids. The treatment group received high-position colon dialysis combined with TCM retention enemas (administered at least 12 times every other day).Results: Thirteen compounds were identified from the herbs by UPLC-Q-Orbitrap-HRMS. The CKD3–5 treatment group exhibited improvements in blood biochemistry and other laboratory indices, with significant enhancements in renal function-related indices for CKD4 and CKD5 stages (p &lt; 0.05). Following treatment, indoxyl sulfate (IS), endotoxin, and D-lactic acid levels decreased to a certain extent in both groups, with a statistically significant difference observed within the treatment group (p &lt; 0.05). The treatment group displayed a significant reduction in aerobic bacterial colonies, an increase in anaerobic bacterial colonies, a decrease in Escherichia coli colonies, and an increase in Bifidobacterium and Lactobacillus colonies (p &lt; 0.05). No significant changes in colony numbers were observed in the control group.Conclusion: High-position colon dialysis combined with TCM retention enema may serve as an adjuvant treatment for CKD4-5 (non-dialysis), and its mechanism may be related to the reduction of uraemic toxins, improvement of intestinal mucosal barrier function, and regulation of intestinal microecology.Clinical Trial Registration:https://www.chictr.org.cn/, identifier ChiCTR2200062852