A multibody dynamic model of the drilling system with drilling fluid

This article is intended to present a multibody dynamic model of the drilling system, consisting of drillstring and drilling fluid. The drillstring is a complex rigid–flexible coupling system, including rigid bodies, Euler–Bernoulli beam elements, constraints and dynamic loads, and its dynamic model is established using the absolute nodal coordinate formulation. The drilling fluid, composed of internal, annulus, and under-bit fluids, is modeled as one-dimensional compressible fluid; the relative flow of the drilling fluid is modeled using the Arbitrary Lagrangian–Eulerian description; the force of the drillstring acting on the drilling fluid is introduced through the drilling fluid transport motion; meanwhile, the reaction force acting on the drillstring is taken as an external load. The contact between the drillstring and drilling fluid is simulated based on Hertz contact theory, and the rock penetration model is built based on the rock-breaking velocity equation. Based on this model, the coupled vibration of the drillstring and the effects of the drilling fluid flow rate and density on the drilling process are investigated through several examples

Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitative Determination of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide in Dog Plasma

The PI3K/AKT/MTOR signalling pathway plays an important role in the growth and proliferation of tumour cells. N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691) is a new-generation selective AKT inhibitor developed at Zhejiang University. In this study, we developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the measurement of Hu7691 in dog plasma. Plasma was precipitated with acetonitrile and then separated on a trifunctionally bonded alkyl column. Excellent separation efficiency and selectivity were achieved by adjusting the mobile phase ratio, with a total running time of only 5 min. The linear dynamic range of the calibration curve was 5–1000 ng/mL. The method was fully validated, and all performance metrics met the criteria. The validated method was used for the pharmacokinetic monitoring and bioavailability assessment of Hu7691 in dogs. The results showed that the area under the curve and peak plasma concentration of Hu7691 increased with increasing dose (oral 5, 10, 20 mg/kg, intravenous 10 mg/kg), and oral bioavailabilities were 86.7%, 50.8%, and 50.5%, respectively, indicating a high bioavailability of Hu7691 in dogs. This provides a test basis for the clinical application of the compound

Simultaneous Quantification and Pharmacokinetic Study of Five Homologs of Dalbavancin in Rat Plasma Using UHPLC-MS/MS

Dalbavancin is a novel semisynthetic glycopeptide antibiotic that comprises multiple homologs and isomers of similar polarities. However, pharmacokinetic studies have only analyzed the primary components of dalbavancin, namely B0 and B1. In this study, an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to simultaneously determinate and investigate the five homologous components of dalbavancin, namely, A0, A1, B0, B1, and B2, in rat plasma. In this method, methanol was used to precipitate plasma, and a triple-bonded alkyl chromatographic column was used for molecule separation, using 0.1% formic acid-acetonitrile as the mobile phase for gradient elution. Targeted homologs were analyzed by a triple quadrupole mass spectrometer using positive electrospray ionization in multiple reaction monitoring mode. The linearity range was 50–2500 ng/mL with a high correlation coefficient (r2 > 0.998). This method was successfully applied in the pharmacokinetic analysis of dalbavancin hydrochloride to investigate dalbavancin components in rats

Comparative Pharmacokinetic Study of Forchlorfenuron in Adult and Juvenile Rats

Forchlorfenuron (CPPU) is a plant growth regulator extensively used in agriculture. However, studies on CPPU pharmacokinetics are lacking. We established and validated a rapid, sensitive, and accurate liquid chromatography–mass spectrometry method for CPPU detection in rat plasma. CPPU pharmacokinetics was evaluated in adult and juvenile rats orally treated with 10, 30, and 90 mg/kg of the compound. The area under the plasma drug concentration–time curve from 0 to 24 h (AUC), at the final time point sampled (AUC0–t), and the maximum drug concentration of CPPU increased in a dose-dependent manner. The pharmacokinetic parameters AUC0–t and absolute bioavailability were higher in the juvenile rats than in adult rats. The mean residence time and AUC0–t of juvenile rats in the gavage groups, except for the 10 mg/kg dose, were significantly higher in comparison to those observed for adult rats (p < 0.001). The plasma clearance of CPPU in juvenile rats was slightly lower than that in the adult rats. Taken together, juvenile rats were more sensitive to CPPU than adult rats, which indicates potential safety risks of CPPU in minors

Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells

Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response. [Display omitted] •Inducible high-density p300 enhancers form in proximity to highly dynamic genes•Strong transcriptional induction occurs with both primed and non-primed enhancers•De novo enhancers form in vivo during NK cell response to Toxoplasma gondii infection•STATs initiate chromatin opening with T-bet redeployment to non-canonical sites During development, innate lymphocytes acquire defined sets of primed enhancers facilitating the rapid immune response. In this issue of Immunity, Sciumè et al. delineate the epigenetic changes occurring during acute NK cell activation, revealing the formation of de novo enhancers and repurposing of both lineage-determining and signal-regulated transcription factors