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Aquaporin-9 (AQP9) is an aquaglyceroporin strongly expressed in the basolateral membrane of hepatocytes facing the sinusoids. AQP9 is permeable to hydrogen peroxide (H2O2) and glycerol as well as to water. Here, we report impaired liver regeneration in AQP9−/− mice which involves altered steady-state H2O2 concentration and glucose metabolism in hepatocytes. AQP9−/− mice showed remarkably delayed liver regeneration and increased mortality following 70% or 90% partial hepatectomy. Compared to AQP9+/+ littermates, AQP9−/− mice showed significantly greater hepatic H2O2 concentration and more severe liver injury. Fluorescence measurements indicated impaired H2O2 transport across plasma membrane of primary cultured hepatocytes from AQP9−/− mice, supporting the hypothesis that AQP9 deficiency results in H2O2 accumulation and oxidative injury in regenerating liver because of reduced export of intracellular H2O2 from hepatocytes. The H2O2 overload in AQP9−/− hepatocytes reduced PI3K-Akt and insulin signaling, inhibited autophagy and promoted apoptosis, resulting in impaired proliferation and increased cell death. In addition, hepatocytes from AQP9−/− mice had low liver glycerol and high blood glycerol levels, suggesting decreased glycerol uptake and gluconeogenesis in AQP9−/− hepatocytes. Adeno-associated virus (AAV)-mediated expression of hepatic expression of aquaglyceroporins AQP9 and AQP3 in AQP9−/− mice, but not water-selective channel AQP4, fully rescued the impaired liver regeneration phenotype as well as the oxidative injury and abnormal glucose metabolism. Our data revealed a pivotal role of AQP9 in liver regeneration by regulating hepatocyte H2O2 homeostasis and glucose metabolism, suggesting AQP9 as a novel target to enhance liver regeneration following injury, surgical resection or transplantation.

Objective To estimate the associations between long term exposure to air pollution and the first hospital admission related to kidney and total urinary system diseases.Design Nationwide longitudinal cohort study.Setting Data were collected from the Medicare fee-for-service for beneficiaries living in 34 849 zip codes across the continental United States from 2000 to 2016. Exposure variables were annual averages of traffic related pollutants (fine particles (PM2.5) and nitrogen dioxide (NO2)) that were assigned according to the zip code of residence of each beneficiary with the use of validated and published hybrid ensemble prediction models.Participants All beneficiaries aged 65 years or older who were enrolled in Medicare part A fee-for-service (n=61 097 767).Primary and secondary outcome measures First hospital admission with diagnosis codes for total kidney and urinary system disease or chronic kidney disease (CKD), analyzed separately.Results The average annual concentrations of air pollution were 9.8 µg/m3 for PM2.5 and 18.9 ppb for NO2. The total number of first admissions related to total kidney and urinary system disease and CKD were around 19.0 million and 5.9 million, respectively (2000-16). For total kidney and urinary system disease, hazard ratios were 1.076 (95% confidence interval 1.071 to 1.081) for a 5 µg/m3 increase in PM2.5 and 1.040 (1.036 to 1.043) for a 10 ppb increase in NO2. For CKD, hazard ratios were 1.106 (1.097 to 1.115) for a 5 µg/m3 increase in PM2.5 and 1.013 (1.008 to 1.019) for a 10 ppb increase in NO2. These positive associations between PM2.5 and kidney outcomes persisted at concentrations below national health based air quality standards.Conclusions The findings suggest that higher annual air pollution levels were associated with increased risk of first hospital admission related to diseases of the kidney and urinary system or CKD in the Medicare population.

Background and AimsDespite the remarkable progress of metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD), the disease remains poorly improved. Since increased oxidative stress and inflammation contribute to the initiation and progression of fatty liver disorders, vitamin C (VC), an antioxidant agent, might be a suitable treatment option for MAFLD. However, the lack of clinically confirmed benefits makes clinicians challenging to recommend antioxidant supplements for MAFLD individuals.MethodsHerein, the nationally representative National Health and Nutrition Examination Survey 2017–2018 data were collected to evaluate the potential association between the serum VC levels with the risk of different categories of NALFD and the newly proposed MAFLD terminology. Hepatic steatosis was defined as controlled attenuated parameter scores ≥ 263 dB/m, whereas liver fibrosis (LF) status was defined as F0–F4, with the cutoff values of median liver stiffness being 6.3, 8.3, 10.5, and 12.5 (KPa), respectively. A cross-sectional analysis was performed to calculate the odds rate and determine the potential beneficial effects of VC.ResultsA total of 4,494 participants aged more than 18 years and conducted transient elastography examinations were included. Our findings demonstrated that participants with increased serum VC status were more likely to be female predominant, more educated, and moderate drinkers. Interestingly, female participants tended to have a lower prevalence of NAFLD, MAFLD, LF, and liver cirrhosis (LC) after stratification by gender. Moreover, our results revealed that participants from the quartile three group (quartile 3: 50.5–67.0 μmol/L) experienced a slightly lower risk of MAFLD than the risk of NAFLD. Of note, the serum concentration of VC (quartile 2: 30.9–50.5 μmol/L) inversely associated with LF and LC was lower than the serum VC level (quartile 3) associated with NAFLD and MAFLD. Notably, individuals from the quartile 3 group experienced a statistically significant 32.5, 42.0, 45.7, and 71% decrease in risk of NAFLD, MAFLD, LF, and LC, respectively.ConclusionIn summary, our findings suggested an inverse association between serum VC levels and NAFLD, MAFLD, LF, or LC. Additionally, adjustment of VC supplementation according to age, gender, and ethnicity may be a promising candidate for these diseases.

Neutrophil infiltration plays an important role in the initial phase of hepatic ischemia and reperfusion injury (HIRI). Despite many different key molecules that have been reported to meditate neutrophil trafficking in HIRI, the mechanism of this process has not been fully elucidated. In this study, we found that Carabin deficiency in myeloid cells (LysMCre : Carabinfl/fl) aggravated IRI-induced hepatic injury and apoptosis through increasing the infiltration of CD11b+Ly6G+ neutrophils. ImmGen Datasets further revealed that Carabin was expressed in bone marrow neutrophils (GM.BM) but was significantly downregulated in thio-induced peripheral neutrophils (GN.Thio.PC), which was consistently verified by comparing GM.BM and liver-infiltrating neutrophils induced by IRI. Mechanistically, up-regulation of Carabin in GM.BM in vitro reduced the expression levels of P-selectin, E-selectin, and αvβ3 integrin through inhibiting Ras-ERK and Calcineurin-NFAT signaling. Furthermore, blocking P-selectin, E-selectin, and αvβ3 integrin in LysMCre : Carabinfl/fl mice decreased the frequency and number of CD11b+Ly6G+ neutrophils and reversed hepatic ischemia−reperfusion damage. In conclusion, our results provide a new understanding of Carabin, such that it is expressed and functions not only in adaptive immune cells (T and B cells) but also in innate immune cells (neutrophils), contributing to the migration of neutrophils. These findings provide novel and promising therapeutic targets for the prevention of HIRI during liver transplantation or hepatic surgery.

Lithium disilicate (Li2Si2O5) glass-ceramics are an ideal material for dental restoration; however, their intrinsic brittleness and low defect tolerance limit the scope of their clinical applications. In this study, Li2Si2O5 whiskers were creatively synthesized via a mild-condition hydrothermal reaction. Self-reinforced Li2Si2O5 glass-ceramics were sintered by introducing the Li2Si2O5 whiskers, and their effects on phase, microstructure, and mechanical properties were systematically studied. The crystal-growth and toughening mechanisms were also discussed. The results showed that the Li2Si2O5 whiskers played an important role in inducing crystallization, and improving the microstructure and properties of the glass-ceramics. With increasing amounts of Li2Si2O5 whiskers, the crystallinities increased slightly, and the average crystal size also increased. The microstructure was composed of crystals of bimodal size distributions, in which some large, rod-like Li2Si2O5 crystals epitaxially grew along with the whiskers, and small crystals directly crystallized from the parent glass-ceramic powders. The Li2Si2O5 glass-ceramics exhibited high flexural strength (389.5 ± 11.77 MPa, LDW3), and fracture toughness (3.46 ± 0.10 MPa·m1/2, LDW5). The improved properties were attributed mainly to crack deflection and bridge-toughening mechanisms.

In order to solve the single machine scheduling problem, and improve the reliability and stability of the equipment, a single machine scheduling model considering piecewise linear deterioration and maintenance unavailability time was established according to the characteristics of continuous fault detection and discrete fault detection. Based on the system reliability theory, the single machine scheduling problem considering machine reliability was studied, and the advantages and disadvantages of maintenance strategy were compared by unified processing of decision conditions. The influence of related parameter changes on production scheduling optimization was determined by single factor and two factor adjustment analysis. The results show that the solution time of the model increases exponentially with the decreasing direction of unit delay cost, and the greater the unit delay cost, the faster the solution speed. The change of delay cost per unit time will not cause a significant change in maintenance cost, and the cost function does not have jumping nodes in flexible periodic maintenance, so it can not be adjusted adaptively. Ratio of preventive maintenance time to fault minor maintenance time has great influence on maintenance decision under discrete detection. The unified processing method of decision conditions can reduce the calculation time and detection cost, and better solve the problems of excessive maintenance or insufficient maintenance in discrete fault detection. These will help to reduce operating costs and improve economic benefits.

Hyperoside, as an active compound, widely exists in a large number of Chinese herbal medicines and has been reported to possess anti‐inflammatory and diuretic properties. However, the effects and underlying mechanisms of hyperoside on periodontitis have not been previously reported. In this study, we found that hyperoside ameliorates symptoms of periodontitis in a rat model, with improvements in alveolar bone resorption, relief of inflammatory infiltration, increase in orderly arrangement of collagen fibers and increase of osteogenic differentiation. In addition, hyperoside promoted proliferation, up‐regulated EdU‐positive cells, decreased cell‐cycle distribution and increased the protein expression of Ki67 and PCNA in rat bone mesenchymal stem cells (rBMSCs), as revealed by Cell Counting Kit‐8, EdU, flow cytometry and western blot analysis. Moreover, hyperoside significantly promoted osteogenic differentiation, as shown by quantitative RT‐PCR, western blot and alizarin red staining assays. Furthermore, hyperoside activated the nuclear factor‐κB (NF‐κB) signaling pathway in rBMSCs, similar to the results observed in vivo. Finally, BMS345541, an inhibitor of the NF‐κB signaling pathway, could reverse the effects of hyperoside on the biological functions in rBMSCs. In conclusion, our results suggest that hyperoside has potential therapeutic properties against periodontitis via promotion of proliferation and osteogenic differentiation of rBMSCs via activation of the NF‐κB signaling pathway.

Abstract Background Endobronchial ultrasound‐guided transbronchial lung biopsy (EBUS‐TBLB) and fluorodeoxyglucose positron emission tomography (FDG‐PET) have been widely used in the diagnosis of peripheral pulmonary lesions (PPLs). This study was conducted to determine the diagnostic value of EBUS‐TBLB combined with FDG‐PET in the assessment of PPLs. Methods The clinical data of 76 patients with PPLs who received both FDG‐PET and EBUS‐TBLB from January 2016 to February 2018 were retrospectively evaluated. Further subgroup analysis was performed according to lesion diameter (≤20 mm or >20 mm). Related diagnostic indices were calculated and compared between groups. Results When combining EBUS‐TBLB with FDG‐PET, the diagnostic accuracy rate, sensitivity, specificity, Youden's index, positive predictive value, and negative predictive value for PPLs were 86.8%, 90.2%, 73.3%, 63.5%, 93.2%, and 64.7%, respectively. In addition, the diagnostic accuracy rate of the combined approach was significantly higher than the single EBUS‐TBLB and FDG‐PET (P 20 mm than PPLs ≤20 mm. In addition, we found that positive bronchus sign and probe within the probe were two important factors conducing to enhancing the diagnostic accuracy rate for EBUS‐TBLB. Conclusions An integrated approach combining EBUS‐TBLB with FDG‐PET is particularly useful for diagnosing PPLs, and the improved diagnostic yields were especially evident for PPLs >20 mm.

Abstract Er3+-doped Ba0.85Ca0.15Ti0.9Zr0.1O3 (xEr-BCTZ, x = 0, 0.005, 0.01, 0.015) multifunctional thick films were prepared by the tape-casting method, using sol-gel-derived nano-sized powders as the matrix material. The surface morphologies, photoluminescence, and electrical properties were investigated. Dense microstructures with pure perovskite structure were obtained in the thick films. By doping an appropriate amount of Er3−, the samples exhibit superior up-conversion photoluminescence performance and simultaneously enhanced electrical performances. In addition, relatively higher texture fractions (with the largest value of 83.5%) were realized through introducing plate-like BaTiO3 templates to make the thick film grow by the [001]c orientation. And the ferro-/piezoelectric properties of the thick films were further improved, showing potential in the applications of micro-optoelectronic devices.

Abstract Background Adipose-derived mesenchymal stem cells (AD-MSCs) are a type of stem cell that is abundant and widely used. The molecular characteristics of AD-MSCs from different passages from donors of different ages have not been well elucidated. Methods Six kinds of AD-MSCs ((E1, E2, E3, Y1, Y2, and Y3) with E denoting cells derived from an elderly patient, Y denoting cells derived from a young patient, and 1, 2, and 3 representing passages 3, 6, and 10) were obtained from human abdominal adipose tissue. We obtained the protein expression profile, the mRNA expression profile, the lncRNA expression profile, and the methylation profile of each kind of AD-MSC by sequencing. After calculating the stemness indices, genes related to stemness were extracted. The multiomics correlation analysis was performed in the stemness-related genes. In addition, short time-series expression miner (STEM) analysis was performed for all cell passages and donor ages. To further explore the biological functions of the stemness-related genes, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, the lncRNA-KEGG network and transcription factor (TF)-KEGG network were constructed based on the RNAInter database and TRRUST v2 database. Results The stemness of the Y1, E1, and Y2 cells was higher than that of the E2, Y3, and E3 cells. The stemness was the highest for Y1 cells and the lowest for E3 cells. STEM analysis showed that five stemness-related gene clusters were associated with the cell passages, and only one gene cluster was associated with age. The enrichment analysis results showed that the biological processes (BPs) and KEGG pathways were mainly involved in the proliferation, differentiation, and migration of cells. The global regulatory landscape of AD-MSCs was constructed: 25 TFs and 16 lncRNAs regulated 21 KEGG pathways through 27 mRNAs. Furthermore, we obtained a core stemness-related gene set consisting of ITGAV, MAD2L1, and PCNA. These genes were expressed at higher levels in Y1 cells than in E3 cells. Conclusion The multiomics global landscape of stemness-related gene clusters was determined for AD-MSCs, which may be helpful for selecting AD-MSCs with increased stemness.

Nowadays, the demand of “personalization” and “multiple varieties and small batch production” in machining is increasing dramatically. The great challenges of scheduling are brought about by the high flexibility of production and the necessity of equipment maintenance, and the scheduling problems are more complex due to the deteriorating effect of the production process. In order to solve the single machine scheduling problem with step-deteriorating jobs and fixed periodic maintenance strategy, the processing time was described by the piecewise linear function. Based on the properties of the periodic maintenance and the flexible periodic maintenance, two scheduling models were established respectively to minimize the tardiness penalties and maintenance cost. According to the numerical experiments and parameter analysis, the key factors and non-key factors of maintenance decision were determined. The result shows that flexible periodic maintenance has no idle time between adjacent batches. The objective function value increases step by step with the increase of ratio, which can realize “adaptive” adjustment of cost and has significant advantages over fixed cycle maintenance. The construction of a joint scheduling model of production and maintenance can realize the comparison of the advantages and disadvantages of maintenance strategies and the joint decision of production and maintenance, and reduce the operating cost of enterprise production and maintenance.

Abstract Background Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ASC patients, and construct a corresponding competing risk nomogram for LC-SM. Methods Data on 2705 patients with first primary lung ASC histologically diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) was utilized to calculate the 3-year and 5-year probabilities of LC-SM and OCSM, and a competing risk model was built. Based on the model, we developed a competing risk nomogram to predict the 3-year and 5-year cumulative probabilities of LC-SM and the corresponding concordance indexes (C-indexes) and calibration curves were derived to assess the model performance. To evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was conducted. Furthermore, patients were categorized into three groups according to the tertile values of the nomogram-based scores, and their survival differences were assessed using CIF curves. Results The 3-year and 5-year cumulative mortalities were 49.6 and 55.8% for LC-SM and 8.2 and 11.8% for OCSM, respectively. In multivariate analysis, increasing age, male sex, no surgery, and advanced T, N and M stages were related to a significantly higher likelihood of LC-SM. The nomogram showed good calibration, and the 3-year and 5-year C-indexes for predicting the probabilities of LC-SM in the validation cohort were both 0.79, which were almost equal to those of the ten-fold cross validation. DCA demonstrated that using the nomogram gained more benefit when the threshold probabilities were set within the ranges of 0.24–0.89 and 0.25–0.91 for 3-year and 5-year LCSM, respectively. In both the training and validation cohorts, the high-risk group had the highest probabilities of LC-SM, followed by the medium-risk and low-risk groups (both P

Abstract Background Exenatide, a glucagon like peptide 1 analog, has been suggested to reduce the cardiovascular disease risk factors, such as body weight, blood pressure and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This was the first randomized, open-label, controlled trial to compare the effects of exenatide versus insulin on subclinical atherosclerosis, as assessed by carotid-intima media thickness (CIMT), in patients with T2DM. Methods A total of 66 patients with T2DM admitted from March 10, 2015 to June 20, 2017 in the Department of Endocrinology, Beijing Hospital were randomized to receive twice-daily exenatide or aspartate 70/30 insulin for 52 weeks. The primary endpoint was change from baseline in CIMT, and secondary endpoints included changes at week 52 from baseline in body weight, glycemic markers, lipid metabolism markers, blood pressure, C-reactive protein, fibrinogen, 8-hydroxydeoxyguanosine, irisin, and brain natriuretic peptide. Results Exenatide more significantly reduced the CIMT from baseline compared with insulin after 52 weeks, with a mean difference of − 0.14 mm (95% interval confidence: − 0.25, − 0.02; P = 0.016). Weight and body mass index were both significantly reduced in the exenatide group over 52 weeks. Exenatide reduced total lipoprotein and low-density lipoprotein cholesterol levels more significantly than insulin at weeks 16 and 40. Correlation analyses showed that CIMT was positively correlated with low-density lipoprotein cholesterol. Conclusions Twice-daily exenatide could prevent atherosclerosis progression in patients with T2DM over a 52-week treatment period compared with insulin therapy. Trial registration Chinese Clinical Trial Registry ChiCTR-1800015658

Abstract Background Chronic cough is a common symptom in children and protracted bacterial bronchitis (PBB) is one of the causes of chronic cough. However, the understanding of this disease remains limited. The present study aims to update PBB in children. Methods The clinical data of children with PBB from 2014 to 2018 were retrospectively analyzed, and PBB clinical features of published studies were summarized. Electronic databases were searched in May 2019. Clinical studies were included in the present study. Reviews were undertaken in duplicate. Results Totally 712 cases were analyzed in this study, including 52 cases in our center and 660 cases from 14 studies. In the 52 cases, 88.5% of patients with PBB were less than 6 years old and all of them complained of wet cough. Three cases were confirmed with laryngomalacia, and microbiologically-based-PBB were identified in 13 cases (9 Streptococcus pneumonia, 3 Staphylococcus aureus, and 1 Pseudomonas aeruginosa). Twenty cases were completely remitted after treatment. In the 14 studies, the patients with PBB were typically younger than 3 years old, accompanying wheezing and airway malacia. Co-infection was common in most western cases, Streptococcus pneumonia, Haemophilus influenza and Moraxella catarrhalis were the top three pathogens. Symptoms were improved in most patients, whereas some cases with comorbidities required prolonged antibiotics treatment. Conclusions PBB is common in male infants with chronic wet cough and accompanied by wheezing and airway deformities. Most cases are clinically diagnosed PBB in China and microbiologically-based-PBB is common in western countries. Co-infection could be found, Streptococcus pneumoniae and Haemophilus influenza were the most frequent etiology in China and western countries, respectively. Patients with comorbidities may need extended antibiotics treatment for more than 2 weeks.

In vitro gynogenesis is an important tool used in haploid or homozygous double-haploid plant breeding. However, because of low repeatability, embryoid induction rate and quality, the molecular mechanisms remain poorly understood. Heat shock treatment can promote the transformation of the gametophytic pathway into the sporophyte pathway, which induces the occurrence of haploid. In this study, unfertilized ovaries were heat shocked for 0 h (A0) before flowering and for 0 h (A1), 4 h (A3), 8 h (A5), 12 h (A7), and 24 h (A8), respectively, at 37°C at the first day of the flowering stage. The ovule enlargement rate was increased from 0% at 25°C to 96.8% at 37°C (24 h treatment). Thus, we aimed to investigate the gene expression patterns in unfertilized ovules of watermelon after different periods of heat shock by using RNA-Seq technology. The results showed that compared with A3, A5, A7, and A8, the biosynthesis of amino acid, glycine, serine and threonine metabolic pathways in A1 has changed significantly. This indicated that heat shock treatment affected the synthesis and transformation of amino acids during ovule expansion. The transcriptome data suggested gene expressions of ovule growth were significantly changed by heat-specific influences. The results provide new information on the complex relationship between in vitro gynogenesis and temperature. This provides a basis for further study of the mechanism of heat shock affecting the expansion of watermelon ovule.

In this study, we aimed to study the effect of fluid shear stress on fibroblasts and BMSCs on plane and groove topographies. The results showed that 0.6-Hz stress had the greatest influence on the alignment, polarity, migration and adhesion of fibroblasts on plane by increasing the expression of reoriented actin and vinculin; whereas 1.0-Hz stress promoted differentiation of fibroblasts into myofibroblasts by increasing Col-I and α-SMA expression. Interestingly, under the given frequency stress, the groove structure strengthened the above characteristics of fibroblasts beyond adhesion, and promoted differentiation of BMSCs into myofibroblasts. The above results indicate that 0.6 Hz may improve the implant-tissue sealing, while 1.0-Hz stress probably causes the disordered fiber deposition around implants.