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During the movement of Typhoon Hato (2017) over land, heavy rainfall occurred when the spiral rainband which was about 100 km distance away from the center of the typhoon passed the Dayao Mountain (with an elevation of 1.2 km). In this study, the structures and forming mechanism of the heavy rainband along the mountain range are investigated by using high-resolution model simulations. The results show the importance of topography in causing the heavy rainband. Upslope of the steep terrain lifts the cyclonic flow to produce strong upward motion when the rainband passes across with high wind speed. At the same time, the warm and humid air is lifted to the steep slope, causing unstable energy to accumulate over the windward slope, which is conducive to the occurrence of rainfall. In particular, the convective cells generated upstream of rainband will further strengthen and develop due to the uplift when they move close to the mountain foot. Some precipitation particles in the convective cells fall to the ground while others move downstream with the intense updrafts, forming heavy rainfall near the summit. As a result, the largest accumulative rainfall coincides well with the orientation of the mountain ridge. [ABSTRACT FROM AUTHOR]

Ibrutinib, orelabrutinib, and zanubrutinib are all Bruton's tyrosine kinase inhibitors, which have greatly improved the treatment of B-cell malignancies. In this study, an LC-MS/MS method was developed and validated for the determination of orelabrutinib, zanubrutinib, ibrutinib, and its active metabolite dihydrodiol ibrutinib in human plasma. The Ibrutinib-d5 was used as the internal standard. Pretreatment was performed using a simple protein precipitation step using acetonitrile. The ACQUITY UPLC HSS T3 column (2.1×50 mm, 1.8 μm) was used to separate the analytes, and the run time was 6.5 min. The mobile phase consisted of acetonitrile and 10 mM of ammonium formate, which contained 0.1% formic acid. The multiple reactions' monitoring transitions were selected at m/z 428.1→411.2, 472.2→455.2, 441.1→304.2, 475.2→304.2 and 446.2→309.2 respectively for orelabrutinib, zanubrutinib, ibrutinib, dihydrodiol ibrutinib and ibrutinib-d5 using positive ion electrospray ionization. The standard curves were linear, from 0.400 to 200 ng/mL for ibrutinib and dihydrodiol ibrutinib, 1.00–500 ng/mL for orelabrutinib, and 2.00–1000 ng/mL for zanubrutinib. Selectivity, the lower limit of quantitation, precision, accuracy, matrix effect, recovery, stability, and dilution integrity all met the acceptance criteria of FDA guidance. This method was used to quantify the plasma levels of orelabrutinib, zanubrutinib, ibrutinib, and dihydrodiol ibrutinib in clinical patients. [ABSTRACT FROM AUTHOR]

The feasibility of taking the ratio of 6β-hydroxycortisol (6β-OHCOR) to cortisol (COR) in plasma as a biomarker to reflect CYP3A4 activity needs to be verified, but the low concentration of 6β-OHCOR which is an endogenous substance in plasma presents a challenge for determination. In this study, a Liquid chromatography with tandem mass spectrometry (LC–MS/MS) method was established to simultaneously quantify the COR and 6β-OHCOR in plasma with COR-d4 and 6β-OHCOR-d4 as internal standards (ISs). Plasma samples were treated by protein precipitation using acetonitrile. Separation with a gradient elution within 5 min was achieved on C18+ column utilizing 5 mM ammonium formate and methanol. An API 4,000 MS in multiple reaction monitoring mode with transitions of 407.1 → 361.1 and 423.1 → 347.1 was utilized. Albumin solution was used as a surrogate matrix, with good linearities over the concentration of 1.20–300 ng/mL for COR and 0.0400–10.0 ng/mL for 6β-OHCOR. The precisions for intrarun and interrun were < 6.8%, and the accuracy was fell in the interval of −5.2 to 3.5%. Matrix effect was not found. Recovery was close to 100.0%. Stability was confirmed under the storage and processing conditions. The validated method was applied to evaluate the inhibitory effect of voriconazole to CYP3A by the ratio of 6β-OHCOR to COR. [ABSTRACT FROM AUTHOR]

A convenient and sensitive liquid chromatography–tandem mass spectrometry method was established to simultaneously quantify voriconazole (VRZ) and its metabolite, voriconazole N -oxide (VNO), in human urine. Voriconazole-d3 and voriconazole-d3 N -oxide were used as isotopic internal standards. Samples were processed by protein precipitation and separated using a ZORBAX SB-Aq column (1.8 μm, 2.1 × 50 mm). Mass spectrometry was performed using an API 4000 mass spectrometry by positive electrospray ionization. The flow rate was 0.6 mL/min. Gradient elution was performed with methanol and 0.1% formic acid as the organic and water phase, respectively. The VRZ and VNO calibration curves ranged from 20.0 to 7200 ng/mL in human urine. The specificity, matrix effect, extraction recovery, intra/inter-run precision, accuracy and stability were validated for both VRZ and VNO in human urine. The developed method was used to study urinary excretion after intravenous injection of 4 mg/kg VRZ in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

[Display omitted] Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins. [ABSTRACT FROM AUTHOR]

Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC‐MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Considering cephalexin as internal standard, analytes were separated on UltimateXB‐C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1, and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam, and the internal standard in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500–12.0 and 10.0–15,000 ng/mL, respectively. The intraday precisions were below 5.5%, the interday precisions were below 6.1%, and accuracies were within –8.1 to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

Imatinib (IM), a milestone drug used in the field of molecular targeted therapy, has been reported to cause serious adverse liver effects, including liver failure and even death. Immune-mediated injury and mitochondrial dysfunction are involved in drug-induced liver injury. However, the mechanism of IM-induced hepatotoxicity remains unclear and warrants further study. In our study, Sprague Dawley rats were administered IM by gavage with 50 mg/kg body weight (BW) once daily for 10 days. Drug-induced liver injury accompanied by inflammatory infiltration was observed in rats following IM exposure, and the expression of NOD-like receptor protein 3 (NLRP3) inflammasome-related proteins was significantly increased compared with that of the control. HepG2 cells were exposed to 0–100 μM IM for 24 h. The results showed that IM decreased cell viability in a dose-dependent manner. Moreover, IM induced a state of obvious oxidative stress and activation of nuclear factor kappa B (NF-κB) in cells, which resulted in the activation of NLRP3 inflammasomes, including caspase 1 cleavage and IL-1β release. These results were significantly reduced after the use of the antioxidants N-acetyl-l-cysteine or the NF-κB inhibitor pyrrolidine di-thio-carbamate. Furthermore, NLRP3 knockdown significantly reduced the release of inflammatory cytokines and improved cell viability. In summary, our data demonstrated that oxidative stress and NLRP3 inflammasome activation are involved in the process of IM-induced hepatotoxicity. The results of this study provide a reference for the prevention and treatment of IM-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Regadenoson, the first selective adenosine A2A receptor agonist, is used to perform exercise stress test during radionuclide myocardial perfusion imaging. To detect the concentration of regadenoson in human plasma, a simple, fast, and sensitive tandem mass spectrometry method was established herein. Acetonitrile was used as a protein precipitation agent. Chromatographic separation was completed in 6.5 min using a BEH HILIC column (50 × 2.1 mm, 1.7 μm). The mobile phase consisted of 10 mmol/L ammonium acetate/acetonitrile (gradient elution). To quantify regadenoson and regadenoson‐d3, an API 4000 mass spectrometry in multiple reaction monitoring mode with transitions of 391.3→259.2 and 394.3→262.2, respectively, was utilized. The calibration curve was linear in the range of 0.100–50.0 μg/L, and the intrabatch and interbatch precisions were <9.7% and <13.0%, respectively, and the accuracy was 2.0–6.9%. There was no apparent matrix effect for regadenoson or regadenoson‐d3. The developed method was used to study the pharmacokinetic characteristics of regadenoson in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity. The aims of this study are to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with haematological malignancies. A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6β-hydroxycortisol and cortisol. During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately. [ABSTRACT FROM AUTHOR]

For optical measurement of high-temperature components, it is a challenge to analyze the measurement error caused by light refraction due to the inhomogeneous distribution of the air refractive index. Aiming at the problem of line laser measurement under the high-temperature environment, a method for analysis of line laser measurement error on high-temperature surfaces combined with backward ray tracing technology is proposed. The temperature field of the air is simulated based on the heat conduction theory, and the air refractive index is obtained according to the classical empirical formula. Combining with the refraction law of light and the laser triangulation method, the deviation of the spatial position corresponding to each point on the charged-coupled device is calculated. The imaging principle of backward ray tracing is applied to obtain the actual imaging point, and the measurement error of the sensor is calculated. The experiment results prove that the proposed method can effectively evaluate the line laser measurement error under the high-temperature environment. We analyze the system error of the laser sensor under high-temperature conditions and promote the development of high-temperature components on-machine measurement. [ABSTRACT FROM AUTHOR]

• 90 NAC transcription factors (TFs) were identified in the eggplant genome. • Conserved motifs, conserved domains and gene structure of SmNAC genes were resolved. • Chromosomal location, gene replication and synteny of SmNAC genes were investigated. • Expression patterns of SmNAC genes were analyzed in vegetative and reproductive organs, at different developmental stages. • qRT-PCR analyses of ATAF subfamily members, exhibited a large diversity in the regulation of different abiotic stresses. NAC proteins, as one of the largest plant-specific transcription factors, play key roles in plant growth, development process, and various abiotic/biotic stresses. In this study, 90 NAC transcription factors (TFs) were identified in the eggplant genome, among them, 80 NAC genes from eggplant (SmNAC) were anchored unevenly in 12 chromosomes, but 10 SmNAC genes were mapped on unanchored scaffolds. Phylogenetic analysis indicated that only fifty-nine SmNAC genes were divided into 14 different subfamilies. Gene structure analysis revealed that the number of exons ranged from 1 to 16. Motif analysis revealed that the identified SmNAC transcription factors included the conserved NAC domain and motif2 was the conserved motif. In aspects of gene duplication analysis, five pairs of tandem replications and three pairs of fragment replications were identified in eggplant genome. Subsequently, 49 SmNAC genes were collinear with NAC genes from Arabidopsis or tomato, moreover, seven SmNAC genes were collinear with NAC genes in other two species. In addition, expression patterns of SmNAC genes were analyzed in vegetative and reproductive organs, at different developmental stages. Nine genes were not expressed in all of the examined developmental stages, 36 SmNAC genes were ubiquitously expressed in all eggplant organs/tissues, but differentially expressed in different tissues, and other 45 SmNAC genes detected in some tissues declared their involvement in the growth and development of certain tissues. Following further qRT-PCR analysis of SmNAC19, SmNAC31 and SmNAC75 , belonging to ATAF subfamily, exhibited a large diversity in expression patterns, indicating their involvement in the regulation of different abiotic stresses. This study would help to further understand and enrich the physiological function of the SmNAC gene family in eggplant, and could provide high-quality genetic resources for eggplant genetics and breeding. [ABSTRACT FROM AUTHOR]