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The coalbed methane resource under goaf is rich, but has not been effectively developed for a long time. Hydraulic fracturing technology stands as an effective means to augment coalbed methane recovery. The extraction and re-compaction of overlying coal seam will directly affect the expansion behavior of hydraulic fractures in the underlying coal seam. Though the large-scale (300 mm×300 mm×300 mm) true triaxial hydraulic fracturing experiments, the mechanical and acoustic emission response characteristics of coal were analyzed under different levels of loading and unloading stress perturbations. The damage variable T was proposed to characterize the degree of coal damage, and the relationship between damage and the initiation and expansion patterns of hydraulic fractures was elucidated. The results revealed that, the damage induced by vertical stress loading in the underlying coal significantly exceeded that in the unloading stage. When the vertical loading stress was below 11 MPa, the coal remained in an elastic stage with minimal damage. Loading between 11~15 MPa corresponded to the yielding stage, witnessing a substantial increase in damage. Loading between 15~18 MPa led to the strengthening stage, the pores and fractures of coal were gradually compacted. Damage variables T can effectively characterize the degree of internal damage of coal. When T=Tc, the internal damage of coal was comparable to that of a coal that has not disturbed by loading and unloading stress.Tc is the damage variable of coal without loading and unloading stress disturbance. When T＞Tc , the coal exhibited a stress-damaged state, with higher values of T corresponding to increasing damage levels. Conversely, when T＜Tc, the coal demonstrated a stress-compacted state, with smaller values of T indicating higher compaction degrees. The degree of stress damage in coal was negatively correlated with the fracture pressure, a high degree of damage made coal more prone to fracture, and it was favor to form the primary hydraulic fractures near the wellbore, which was conducive to hydraulic fracturing. The degree of compaction of coal was positively correlated with fracture pressure. The high degree of compaction weakened the effect of horizontal stress difference on hydraulic fracture expansion, and the hydraulic fracture near the wellbore was more developed, which hindered the formation of primary hydraulic fractures. Based on the research results, the principle of hydraulic fracturing construction scheme optimization for underlying coal seam in goaf was formulated and applied in the field. The hydraulic fracturing ability of the optimized scheme was significantly improved.

Abstract Background and purpose In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. Method C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. Results This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. Conclusion Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.

IntroductionGoose astrovirus (GAstV) is a newly emerging pathogen that is currently widespread among geese, causing visceral gout and leading to substantial gosling mortalities, posing a severe threat to the waterfowl industry. GAstV II is the predominant epidemic strain, characterized by its high morbidity and mortality rate. Consequently, there is an urgent necessity to develop an effective diagnostic approach to control the dissemination of GAstV II, particularly in clinical farms with limited laboratory resources.MethodsIn this study, a novel multi-enzyme isothermal rapid amplification (MIRA) and lateral flow dipstick (LFD) combined assay was developed. Different primers designed specific targeting a highly conserved region within the viral RdRp gene for the detection of GAstV II. Primers optimized and MIRA-LFD assay analyzed its performance regarding limits of detection, specificity, and efficiency of detection.ResultsThe developed MIRA amplification is conducted at a constant temperature and accomplished within 10 minutes. Subsequent naked-eye observation of the LFD strips merely takes 5 minutes. The established MIRA-LFD method exhibits high specificity, with no cross-reaction with other pathogens and attains a detection sensitivity of 1 copy/μl, which is consistent with the reverse transcription quantitative PCR (RT-qPCR) assay. Further evaluation with clinical samples indicates that the accuracy of this MIRA-LFD method correlates well with RT-qPCR for the detection of GAstV II. ConclusionIn summary, the convenience, sensitivity, and rapidity of this newly developed detection method offer a significant advantage for on-site diagnosis of GAstV II.

Abstract The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.

Abstract DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.

BackgroundThe present study aimed to investigate the drug–drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.Research design and methodsA total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects.ResultsThe weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg−1 day−1 were recommended for patients with schizophrenia weighing 40–95 and 95–120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg−1 day−1 was recommended for those weighing 40–120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg−1 day−1 was recommended for patients with schizophrenia weighing 40–120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg−1 day−1 were recommended for those weighing 40–60 and 60–120 kg, respectively.ConclusionThis is the first investigation of the effects of fluoxetine on aripiprazole via drug–drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Broken coal and rock (BCR) are an important component medium of the caving zone in the goaf (or gob), as well as the main filling material of fault fracture zone and collapse column. The compaction seepage characteristics of BCR directly affect the safe and efficient mining of coal mines. Thus, numerous laboratory studies have focused on the compaction seepage characteristics of BCR. This paper first outlines the engineering problems involved in the BCR during coal mining including the air leakage, the spontaneous combustion, the gas drainage, and the underground reservoirs in the goaf. Water inrush related to tectonics such as faults and collapse columns and surface subsidence related to coal gangue filling and mining also involve the compaction seepage characteristics of BCR. Based on the field problems of BCR, many attempts have been made to mimic field environments in laboratory tests. The experimental equipment (cavity size and shape, acoustic emission, CT, etc.) and experimental design for the BCR were firstly reviewed. The main objects of laboratory analysis can be divided into compression tests and seepage test. During the compaction test, the main research focuses on the bearing deformation characteristics (stress-strain curve), pore evolution characteristics, and re-crushing characteristics of BCR. The seepage test mainly uses gas or water as the main medium to study the evolution characteristics of permeability under different compaction stress conditions. In the laboratory tests, factors such as the type of coal and rock mass, particle size, particle shape, water pressure, temperature, and stress path are usually considered. The lateral compression test of BCR can be divided into three stages, including the self-adjustment stage, the broken stage, and the elastic stage or stable stage. At each stage, stress, deformation, porosity, energy, particle size and breakage rate all have their own characteristics. Seepage test regarding the water permeability experiment of BCR is actually belong to variable mass seepage. While the experimental test still focuses on the influence of stress on the pore structure of BCR in terms of gas permeability. Finally, future laboratory tests focus on the BCR related coal mining including scaling up, long term loading and water immersion, mining stress path matching were discussed.

Layered composite roofs are characterized by developed bedding fissures, resulting in severe deformation and damage of rock bolts at the top of the roadway, as well as a poor roadway support effect. Increasing pretension force is an effective way to enhance the stiffness of the rock bolt support system. To clarify the influence and mechanism of the pretension force on the support effect of rock bolts in the layered roof, a roadway model of the layered roof was established using the interface unit of FLAC3D, and the simulation rock bolts were constructed using the pile unit, which can simulate the mechanical behaviors of rock bolts, such as tension, shear, bending, fracture, and anchor failure, and the pretension force was applied. On this basis, the deformation and failure characteristics and influencing factors of rock bolts in the layered roadway roof under different surrounding rock conditions were simulated and analyzed. The research shows the following: ① Field measurements showed minor shear deformation in the rock bolts at the center of the roadway roof, with lateral displacements of 5.7 cm and 5.3 cm. Significant shear deformation occurred in the rock bolts at the roof corners, with lateral displacements of 18.2 cm and 17.6 cm. ② Simulations of rock bolt deformation characteristics matched the field measurements closely, confirming the reliability of the simulation method, parameter selection, and calculation sequence. ③ The primary factors affecting rock bolt deformation are the structural plane strength and surrounding rock strength. Rock bolts are most susceptible to lateral displacement when the structural plane strength is low, the strength difference between rock layers is large, and the weaker layer is below the structural plane. The presented research can provide a reference for the instability mechanism and support treatment of the layered composite roof roadway.

BackgroundThe appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels.MethodsThe present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels.ResultsWithin normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02 mg/kg/day, divided into two doses, for children weighing 10–32 kg, and a dosage of 0.03 mg/kg/day, also divided into two doses, for children weighing 32–40 kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04 mg/kg/day split into two doses are recommended for children weighing 10–15, 15–32, and 32–40 kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02 mg/kg/day split into two doses are recommended for children weighing 10–17 and 17–40 kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02 mg/kg/day split into two doses is recommended for children weighing 10–40 kg.ConclusionsIt is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit.