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Background: Fenofibrate was reported to be beneficial for cholestasis in combination with ursodeoxycholic acid. However, its therapeutic action as single therapy for chronic cholestasis and the underlying mechanism are not known. Methods: In the present study, wild-type (WT) mice were administered a 0.05% ANIT diet to mimic chronic cholestatic liver injury. Mice were dosed fenofibrate 25 mg/kg twice every day for 10 days to investigate the therapeutic action of fenofibrate on chronic cholestatic liver injury. Ppara-null (KO) mice were used to explore PPARa’s role in the therapeutic outcome. Results: Fenofibrate, administered at 25 mg/kg twice daily, substantially reversed ANIT-induced chronic cholestatic liver injury shown by biochemical and pathological end points. The modifications of bile acid metabolism were found to be adaptive responses. The JNK–AP1–CCL2/CXCL2 axis was activated in all the mice administered ANIT which developed chronic cholestatic liver injury. But it was substantially decreased by fenofibrate in WT mice rather than that in KO mice. Conclusions: Low-dose fenofibrate reversed chronic cholestatic liver injury in mice. The therapeutic action was dependent on PPARa activation and occurred by inhibiting chemotaxis via the JNK–AP1–CCL2/CXCL2 signaling. These data provided an exciting basis for optimization of therapeutic fenofibrate regimen in the clinic. Additionally, they suggested anti-chemotaxis of low-dose fenofibrate in single therapy to treat cholestatic liver diseases.

Perfluoroalkoxy alkane (PFA) Teflon tubing has been widely used to draw air samples for analyzing atmospheric trace gases. However, impacts of long tubing on measurements of atmospheric trace gases have rarely been reported so far, especially for various organic trace gases. In this study, interactions between long tubing and various trace gases were assessed using a combination of laboratory tests, field experiments, and modeling techniques. A tower-based observation system of trace gases was also established using long tubes. The results show that measured concentrations of organic compounds required varying amounts of time (e.g., 10–474 s for a 400 m-long tubing at a flow rate of 13 standard liters per minute) to stabilize after traversing the tubing. Tubing delays of organic compounds were highly dependent on their saturation concentrations and the residence time in the tubing. In laboratory tests, there are no detectable losses of the targeted chemical species after traversing the 400 m-long tubing. In real applications, concentrations of nitric oxide (NO) cannot be well measured through long tubes in the daytime due to its low ambient concentrations and rapid consumption by ozone. Negligible losses were observed for most of the other targeted species when measured using long tubes. Measurements of various trace gases made by the vertical observation system can well characterize their concentrations and vertical distributions. However, the measurements of a trace gas made by the vertical observation system at each altitude cannot be used to interpret its temporal variability at time scales lower than its tubing delay. In addition to their usage on tall towers, long PFA Teflon tubes can be also used on mobile platforms (e.g., tethered balloons) for vertical measurements of atmospheric trace gases or to surveil emissions of targeted chemical species at multiple sites.

Cholestatic liver fibrosis occurs in liver injuries accompanied by inflammation, which develops into cirrhosis if not effectively treated in early stage. The aim of the study is to explore the effect of fenofibrate on liver fibrosis in chronic cholestatic mice. In this study, wild-type (WT) and Pparα-null (KO) mice were dosed alpha-naphthylisothiocyanate (ANIT) diet to induce chronic cholestasis. Induced liver fibrosis was determined by pathological biomarkers. Then fenofibrate 25 mg/kg was orally administrated to mice twice/day for 14 days. Serum and liver samples were collected for analysis of biochemistry and fibrosis. In WT mice, cholestatic biomarkers were increased by 5–8-fold and the expression of tissue inhibitors of metalloproteinases 1 (TIMP-1), Monocyte chemoattractant protein 1 (MCP-1), Collagen protein I (Collagen I) was increased by more than 10-fold. Fenofibrate significantly downgraded the biochemical and fibrotic biomarkers. In Western blot analysis, levels of collagenI and alpha-smooth muscle actin (α-SMA) were strongly inhibited by fenofibrate. In KO mice, liver fibrosis was induced successfully, but no improvement after fenofibrate treatment was observed. These data showed low-dose fenofibrate reverses cholestatic liver fibrosis in WT mice but not in KO mice, suggesting the dependence of therapeutic action on peroxisome proliferator-activated receptor alpha (PPARα). The study offers an additional therapeutic strategy for cholestatic liver fibrosis in practice.

This paper proposed a framework of a dual-arm-based robotic maintenance system, including visual recognition, trajectory planning, force feedback control and master–slave control. To meet the requirements of automated maintenance, we proposed an improved design for the structures of the first wall tiles and support boards, and established a complete communication structure for the maintenance system that can adapt to different hardware versions. Based on the proposed framework, an experimental platform with dual-arm manipulator was established to demonstrate the maintenance scenario of the FW of the blanket in Vacuum Vessel (VV). The experimental result verified the feasibility of automated robotic maintenance system applied to the future fusion reactor.

α-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPARα. However, little is known about how PPARα influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5genes and showed cross-talk between basal PPARα and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway (Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-κB and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPARα involves regulation of BA metabolism and inhibition of NF-κB/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPARα, caution should be exercised when one attempts to draw conclusions in which the PPARα is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.

Objective To evaluate the therapeutic effects of high-flow nasal cannula (HFNC) oxygen therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and type II respiratory failure.Methods Seventy-two patients with AECOPD and type II respiratory failure were randomly allocated to an HFNC oxygen therapy trial group or a non-invasive positive-pressure ventilator therapy (NIPPV) control group. Their arterial blood gas parameters and comfort, evaluated using a questionnaire, were compared before and after the therapeutic interventions.Results The PaCO2and blood HCO3−concentration of both groups were significantly reduced by the treatments, whereas the pH, PaO2and PaO2/FiO2were increased. The PaCO2of the experimental group was significantly lower than that of the control group following treatment. The PaO2of the experimental group was significantly higher than that of the control group. The tracheal intubation rates of the two groups did not significantly differ. After treatment, all the indices of comfort were rated higher in the HFNC group than in the NIPPV group.Conclusions HFNC has a good therapeutic effect in patients with AECOPD and type II respiratory failure. It improves patient comfort and has clinical value.

Sustainability has become an important factor from which we can judge the performance of modern manufacturing systems. The condition perception of sustainable manufacturing capability (SMC) can provide reliable manufacturing information and data support for manufacturing systems. This paper proposes an intelligent condition perception network (ICPN) for SMC of manufacturing systems, which focuses on the production condition monitoring, the energy consumption metering, and the perception data transfer. The proposed hybrid wireless perception network consists of the embedded Radio Frequency Identification (RFID) perception modules, embedded energy consumption perception modules and environment perception modules. In view of the several heterogeneous networks might coexist in the manufacturing environment, the heterogeneous networks adaptation device is designed to figure out the problem of differences of data transmission in heterogeneous networks. Finally, a prototype system is deployed in a laboratory environment. The experimental results demonstrate that the system can satisfy the requirements of condition perception for SMC.

Background: The antiepileptic drug carbamazepine (CBZ) is a typical inducer of cytochrome P450 (CYP) 3A and 2C in the clinic. It is considered a strong constitutive androstane receptor activator, however both CBZ and its main metabolite CBZ 10, 11-epoxide have been reported to be pregnane X receptor (PXR) activators whose maximal efficacy and potency are comparable with the human PXR ligand rifampicin. It is unknown whether or not PXR plays a substantially important role in in vivoinduction of CYP by CBZ administration. Methods: In this study, wild type and Pxr-/- mice were administered with CBZ for 5 days. Serum and liver samples were collected and subjected to hepatotoxicity assessment and CYP induction analysis. Results: CYP2b, 2c and 3a were induced similarly in terms of transcription level, enzyme activity and protein abundance in both wild type and Pxr-/- mice. Inductive profile of CYPs in mice by CBZ administration accorded with those reported in rats, but differed from clinically reported data. Conclusions: These data suggest that in vivoinduction of CYP in mice by multiple administration of CBZ is independent of PXR. Knowledge of the featured CYP induction profile in mice helps us understand species related CYP induction profiles among rodents and humans resulting from administration of CBZ.

Recent advances in analytical methodologies have made it possible to bring metabolomic profiling into quantitative metabolomics that permits precise measurements of comprehensive small-molecule profiles. Modern liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM) mode serves as the foundation for accurate simultaneous multi-analyte quantitation across large sample sets to provide high-quality information on target molecular profiles in complex systems. Despite the intrinsic multiplexing potential of the LC-MRM-MS technique, the key bottleneck in current LC-MRM-based assays is generally the limited analyte coverage and throughput capacity. Nowadays, the MRM-based approach has emerged as an attractive strategy for quantitative proteomic analysis and high-throughput biomarker discovery. So far, the full potential of the contemporary LCMRM methodology unleashed for quantitative metabolite profiling and metabolomic measurements of non-peptidic small molecules is rarely discussed. In this review we attempt to provide an overview on the major recent developments in LC-MRM-based strategies for quantitative profiling of multi- and non-target small molecules in biological samples. This article highlights the utility and power of the LC-MRM-based targeted approaches as valuable bioanalytical tools for low-cost, multiplexed quantitation on a large scale, with special emphasis on the promise of combining various strategies for expanding coverage and throughput of the LC-MRM-based assays to cover the gap between a widely targeted profiling and large-scale unknown screening towards comparative or quantitative metabolomics. General issues raised in metabolite profiling, such as basic aspects of bioanalysis, methodological dilemmas and challenges in quantitative metabolomics are addressed, and different strategies to circumvent the existing bottleneck and potential pitfalls of the current LC-MRM-MS techniques are outlined. In addition, the rudiments of LC-MRM-MS and its recent applications in combination with such strategies for biomarker quantitation and verification is also described.

Fibrates are a group of peroxisome proliferator-activated receptor a agonists used in the treatment of dyslipidemia; however, they have been reported to cause species-related hepatocarcinogenesis and clinical myotoxicity. Gemfibrozil is one of the most commonly used fibrates, and it shows the highest risk for myotoxicity among the fibrates. The inhibitory drug-drug interaction mechanism associated with gemfibrozil has been explored recently, and the induction of human P450 3A4 and 2C8 has been reported. In this study, in vivoinduction of rat P450 by gemfibrozil was studied in Sprague-Dawley rats. After the rats were dosed with gemfibrozil by oral gavage, microsomes were prepared. The metabolic activities of P450 3A1/2, 2C6, and 2D2 were assayed using probe substrates, and the systemic concentration of gemfibrozil during its administration was determined. P450 3A1/2 and 2C6 activities were induced 32-77% in the rats by gemfibrozil when the exposure concentration was in the clinical range. These data indicate that the inducibility of homologous P450 isoforms by gemfibrozil is similar in Sprague-Dawley rats and in humans. Inductive drug-drug interactions and inhibitory actions are involved in the co-administration of gemfibrozil with other drugs, which suggests the relevance for a fibrate-toxicology investigation.

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor α. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.